U.S. patent application number 17/381140 was filed with the patent office on 2022-06-09 for treatment of hepatocellular carcinoma characterized by hepatitis b virus infection.
The applicant listed for this patent is Celgene Corporation. Invention is credited to Ellen FILVAROFF, Kristen M. HEGE, Shaoyi LI.
Application Number | 20220175770 17/381140 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-09 |
United States Patent
Application |
20220175770 |
Kind Code |
A1 |
FILVAROFF; Ellen ; et
al. |
June 9, 2022 |
TREATMENT OF HEPATOCELLULAR CARCINOMA CHARACTERIZED BY HEPATITIS B
VIRUS INFECTION
Abstract
Provided herein are methods for treating and/or preventing
hepatocellular carcinoma (HCC) characterized by hepatitis B virus
(HBV) infection in a patient, comprising administering an effective
amount of
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically
acceptable salt or tautomer thereof (collectively referred to
herein as "Compound 1") to the patient having HCC characterized by
HBV infection.
Inventors: |
FILVAROFF; Ellen; (San
Francisco, CA) ; HEGE; Kristen M.; (Burlingame,
CA) ; LI; Shaoyi; (Warren, NJ) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Corporation |
Summit |
NJ |
US |
|
|
Appl. No.: |
17/381140 |
Filed: |
July 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16624301 |
Dec 19, 2019 |
11096940 |
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PCT/US2018/038697 |
Jun 21, 2018 |
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17381140 |
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62523688 |
Jun 22, 2017 |
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International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61P 35/00 20060101 A61P035/00; A61K 31/44 20060101
A61K031/44; A61K 31/517 20060101 A61K031/517; A61K 39/395 20060101
A61K039/395; A61K 45/06 20060101 A61K045/06 |
Claims
1-45. (canceled)
46. A method for treating hepatocellular carcinoma (HCC)
characterized by hepatitis B virus (HBV) infection in a patient,
comprising administering an effective amount of
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically
acceptable salt or tautomer thereof to the patient having HCC
characterized by HBV infection; wherein
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically
acceptable salt or tautomer thereof is administered in combination
with a second therapeutic agent; and wherein the second therapeutic
agent is an anti-CTLA-4 antibody.
47. The method of claim 46, wherein the anti-CTLA-4 antibody is
ipilimumab.
48. The method of claim 46, wherein HBV infection is determined by
at least one of the variables selected from the group consisting
of: patient history of HBV, prior or current treatment for HBV,
cirrhosis attributed to HBV, the presence of HBV proteins or
antigens, the presence of antibodies to HBV proteins or antigens,
HBV viral load, and the presence of HBV DNA.
49. The method of claim 46, wherein HBV infection is determined by
patient history of HBV.
50. The method of claim 46, wherein HBV infection is determined by
prior treatment for HBV.
51. The method of claim 46, wherein HBV infection is determined by
current treatment for HBV.
52. The method of claim 46, wherein HBV infection is determined by
cirrhosis attributed to HBV.
53. The method of claim 46, wherein HBV infection is determined by
the presence of HBV proteins or antigens.
54. The method of claim 46, wherein HBV infection is determined by
the presence of antibodies to HBV proteins or antigens.
55. The method of claim 46, wherein HBV infection is determined by
HBV viral load.
56. The method of claim 46, wherein HBV infection is determined by
the presence of HBV DNA.
57. The method of claim 46, wherein HBV infection is determined by
at least one of the variables selected from the group consisting of
the presence of HBV surface antigen (HBsAG), the presence of HBV
core antigen (HBcAG), the presence of HBV envelope antigen (HBeAg),
the presence of HBV x antigen (HBxAg), the presence of HBV
core-related antigen (HBcrAg), the presence of antibody to HBV
surface antigen (anti-HBsAg), the presence of antibody to HBV core
antigen (anti-HBcAg), the presence of antibody to HBV envelope
antigen (anti-HBeAg), the presence of antibody to HBV x antigen
(anti-HBxAg), the presence of antibody to HBV core-related antigen
(anti-HBcrAg), the use of HBV medications, HBV viral load, the
presence of HBV DNA, the presence of HBV mRNA, and the presence of
HBV protein.
58. The method of claim 46, wherein the HCC is unresectable
HCC.
59. The method of claim 46, wherein the HCC is previously untreated
HCC.
60. The method of claim 46, wherein the HCC is previously treated
HCC, wherein the previous treatment comprises sorafenib.
61. The method of claim 46, wherein the HCC is previously treated
HCC, wherein the previous treatment comprises chemotherapy.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 16/624,301, filed Dec. 19, 2019 which is a U.S. National Stage
filing under 35 U.S.C. .sctn. 371 of International Application No.
PCT/US2018/038697, filed Jun. 21, 2018, which claims the benefit of
and priority to U.S. Provisional Application No. 62/523,688, filed
Jun. 22, 2017, the entire contents of each of which are
incorporated herein by reference.
1. FIELD
[0002] Provided herein are methods for treating and/or preventing
hepatocellular carcinoma (HCC) characterized by hepatitis B virus
(HBV) infection in a patient, comprising administering an effective
amount of
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically
acceptable salt or tautomer thereof (collectively referred to
herein as "Compound 1") to the patient having HCC characterized by
HBV infection. Further provided herein are compounds for use in
such methods. Particularly provided herein is
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically
acceptable salt or tautomer thereof for use in such methods.
2. BACKGROUND
[0003] The connection between abnormal protein phosphorylation and
the cause or consequence of diseases has been known for over 20
years. Accordingly, protein kinases have become a very important
group of drug targets. See Cohen, Nat. Rev. Drug Disc., 2002,
1:309-315, Grimmiger et al., Nat. Rev. Drug Disc., 2010,
9(12):956-970. Various protein kinase inhibitors have been used
clinically in the treatment of a wide variety of diseases, such as
cancer and chronic inflammatory diseases, including diabetes and
stroke. See Cohen, Eur. J. Biochem., 2001, 268:5001-5010, Protein
Kinase Inhibitors for the Treatment of Disease: The Promise and the
Problems, Handbook of Experimental Pharmacology, Springer Berlin
Heidelberg, 2005, 167.
[0004] The protein kinases belong to a large and diverse family of
enzymes that catalyze protein phosphorylation and play a critical
role in cellular signaling. Protein kinases may exert positive or
negative regulatory effects, depending upon their target protein.
Protein kinases are involved in specific signaling pathways which
regulate cell functions such as, but not limited to, metabolism,
cell cycle progression, cell adhesion, vascular function,
apoptosis, and angiogenesis. Malfunctions of cellular signaling
have been associated with many diseases, the most characterized of
which include cancer and diabetes. The regulation of signal
transduction by cytokines and the association of signal molecules
with protooncogenes and tumor suppressor genes have been well
documented. Similarly, the connection between diabetes and related
conditions, and deregulated levels of protein kinases, has been
demonstrated. See e.g., Sridhar et al., Pharm. Res., 2000,
17(11):1345-1353. Viral infections and the conditions related
thereto have also been associated with the regulation of protein
kinases. Park et al., Cell, 2000, 101(7):777-787.
[0005] The protein named mTOR (mammalian target of rapamycin), also
called FRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr protein
kinase, that has been shown to be one of the most critical proteins
in the mTOR/PI3K/Akt pathway that regulates cell growth and
proliferation. Georgakis and Younes, Expert Rev. Anticancer Ther.,
2006, 6(1):131-140. mTOR exists within two complexes, mTORC1 and
mTORC2. While mTORC1 is sensitive to rapamycin analogs (such as
temsirolimus or everolimus), mTORC2 is largely
rapamycin-insensitive. Notably, rapamycin is not a TOR kinase
inhibitor. Several mTOR inhibitors have been or are being evaluated
in clinical trials for the treatment of cancer. Temsirolimus was
approved for use in renal cell carcinoma in 2007 and everolimus was
approved in 2009 for renal cell carcinoma patients that have
progressed on vascular endothelial growth factor receptor
inhibitors. In addition, sirolimus was approved in 1999 for the
prophylaxis of renal transplant rejection. The interesting but
limited clinical success of these mTORC1 inhibitory compounds
demonstrates the usefulness of mTOR inhibitors in the treatment of
cancer and transplant rejection, and the increased potential for
compounds with both mTORC1 and mTORC2 inhibitory activity.
[0006] HCC, also known as malignant hepatoma, is the most common
primary malignancy of the liver and accounts for 80-90% of primary
liver tumors. HCC is one of the most common and devastating
malignant diseases worldwide, responsible for more than 1 million
deaths annually in the world (Parkin et al., CA Cancer J. Clin.
1999, 49:33-64; Bruix et al., Cancer Cell, 2004, 5:215-219).
[0007] The major risk factors for the development of HCC include
hepatitis B or C viral infection, and alcoholic liver disease
(Rustgi, Gastroenterol. Clin. North Am., 1987, 16:545-551; Bosch et
al., Semin. Liver Dis., 1999, 19:271-285; Bosch et al.,
Gastroenterology, 2004, 127:S5-S16; Moradpour et al., Eur. J.
Gastro & Hepatol., 2005, 17:477-483; Koike et al., J.
Gastroenterol. Hepatol., 2008, 23:S87-S91; de Oliveria Andrade, J.
Glob. Infect. Dis., 2009, 1:33-37). HCC arises most commonly in
cirrhotic livers following infection with HBV or hepatitis C virus
(HCV) (Liaw, Semin. Liver Dis., 2005, 25:40-47; Koike, Clin.
Gastroenterol. Hepatol., 2005, 3:132-135). HCC is associated with
HBV infection in about 50% of cases (Liaw, Semin. Liver Dis., 2005,
25:40-47). HCV infection is the cause of 70% of the cases of HCC in
Japan (Hasan et al., Hepatology, 1990, 12:589-591; El-Serag et al.,
N. Engl. J. Med., 1999, 340:745-750). The HCC incidence has been
increasing in Western countries in recent years due to the spread
of HCV infection (El-Serag, Hepatology, 2002, 36:S74-83; Trevisani
et al., Carcinogenesis, 2008, 29:1299-1305) and increasing
incidence of non-alcoholic steatosis (Torres et al., Semin. Liver.
Dis., 2012, 32(1):30-38).
[0008] HCC has poor prognosis with median survival less than 2
years from the date of prognosis. HCC survival rates vary across
studies but generally are 10-20% for 5 year survival. HBV-related
HCC has extremely poor prognosis with median survival less than 16
months. Survival rates of HBV-related HCC ranged from 36% to 67%
after 1 year and from 15% to 26% after 5 year of diagnosis. (Nguyen
et al., J. Viral. Hepat., 2009, 16(7):453-463).
[0009] Although various chemotherapy regimens are available,
traditionally, chemotherapy is not considered an effective
treatment option for HCC. Systemic chemotherapy response rates of
10% can be seen, with response rates up to 20% using intra-arterial
chemotherapy. Treatment options for subjects with unresectable HCC
are severely limited and there remains a high unmet medical need
for effective therapies in this disease.
[0010] Citation or identification of any reference in Section 2 of
this application is not to be construed as an admission that the
reference is prior art to the present application.
3. SUMMARY
[0011] In one aspect, provided herein is a method for treating
and/or preventing HCC characterized by HBV infection in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such a method for treating and/or
preventing HCC characterized by HBV infection in a patient. In
certain embodiments, provided herein is a method for treating HCC
characterized by HBV infection in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for treating HCC characterized
by HBV infection in a patient. In other embodiments, provided
herein is a method for preventing HCC characterized by HBV
infection in a patient, comprising administering an effective
amount of Compound 1 to the patient having HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such a method
for preventing HCC characterized by HBV infection in a patient.
[0012] In certain embodiments, the HCC characterized by HBV
infection is unresectable HCC characterized by HBV infection. Thus,
in some embodiments, provided herein is a method for treating
unresectable HCC characterized by HBV infection in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such a method for treating unresectable
HCC characterized by HBV infection in a patient. In other
embodiments, provided herein is a method for preventing
unresectable HCC characterized by HBV infection in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such a method for preventing unresectable
HCC characterized by HBV infection in a patient.
[0013] In another aspect, provided herein is a method for treating
and/or preventing HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating and/or
preventing HCC characterized by HBV infection in a patient, wherein
the method comprises screening a biological test sample from the
patient for HBV infection, and administering an effective amount of
Compound 1 to the patient having HCC characterized by HBV
infection. In certain embodiments, provided herein is a method for
treating HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating HCC
characterized by HBV infection in a patient, wherein the method
comprises screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. In other
embodiments, provided herein is a method for preventing HCC
characterized by HBV infection in a patient, comprising screening a
biological test sample from the patient for HBV infection, and
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for preventing HCC
characterized by HBV infection in a patient, wherein the method
comprises screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection.
[0014] In certain embodiments, the HCC characterized by HBV
infection is unresectable HCC characterized by HBV infection. Thus,
in some embodiments, provided herein is a method for treating
unresectable HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having unresectable HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such a method
for treating unresectable HCC characterized by HBV infection in a
patient, wherein the method comprises screening a biological test
sample from the patient for HBV infection, and administering an
effective amount of Compound 1 to the patient having unresectable
HCC characterized by HBV infection. In yet other embodiments,
provided herein is a method for preventing unresectable HCC
characterized by HBV infection in a patient, comprising screening a
biological test sample from the patient for HBV infection, and
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for preventing unresectable HCC
characterized by HBV infection in a patient, wherein the method
comprises screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection.
[0015] In yet another aspect, provided herein is a method for
selecting a patient having HCC for Compound 1 treatment, comprising
a) obtaining a biological test sample from the patient; b)
analyzing the sample for HBV infection; c) selecting the patient
having HCC for Compound 1 treatment if HBV infection is determined
in the sample. In certain embodiments, the method further comprises
a step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for selecting a patient
having HCC for Compound 1 treatment, comprising a) obtaining a
biological test sample from the patient; b) analyzing the sample
for HBV infection; c) selecting the patient having HCC for Compound
1 treatment if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, also provided
herein is Compound 1 for use in a method for selecting a patient
having HCC for Compound 1 treatment, wherein the method comprises
a) obtaining a biological test sample from the patient; b)
analyzing the sample for HBV infection; c) selecting the patient
having HCC for Compound 1 treatment if HBV infection is determined
in the sample; and d) administering an effective amount of Compound
1 to the patient having HCC characterized by HBV infection.
[0016] In certain embodiments, the HCC is unresectable HCC. Thus,
in some embodiments, provided herein is a method for selecting a
patient having unresectable HCC for Compound 1 treatment,
comprising a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) selecting the patient
having unresectable HCC for Compound 1 treatment if HBV infection
is determined in the sample. In other embodiments, provided herein
is a method for selecting a patient having unresectable HCC for
Compound 1 treatment, comprising a) obtaining a biological test
sample from the patient; b) analyzing the sample for HBV infection;
c) selecting the patient having unresectable HCC for Compound 1
treatment if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Thus, also
provided herein is Compound 1 for use in a method for selecting a
patient having unresectable HCC for Compound 1 treatment, wherein
the method comprises a) obtaining a biological test sample from the
patient; b) analyzing the sample for HBV infection; c) selecting
the patient having unresectable HCC for Compound 1 treatment if HBV
infection is determined in the sample; and d) administering an
effective amount of Compound 1 to the patient having unresectable
HCC characterized by HBV infection.
[0017] In still another aspect, provided herein is a method for
predicting response to treatment with Compound 1 in a patient
having HCC, the method comprising: a) obtaining a biological test
sample from the patient; b) analyzing the sample for HBV infection;
c) predicting an increased likelihood of response to the Compound 1
treatment of the patient's HCC if HBV infection is determined in
the sample. In certain embodiments, the method further comprises a
step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for predicting response to
treatment with Compound 1 in a patient having HCC, the method
comprising: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of response to the Compound 1 treatment of the
patient's HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, also provided
herein is Compound 1 for use in a method for predicting response to
treatment with Compound 1 in a patient having HCC, wherein the
method comprises: a) obtaining a biological test sample from the
patient; b) analyzing the sample for HBV infection; c) predicting
an increased likelihood of response to the Compound 1 treatment of
the patient's HCC if HBV infection is determined in the sample; and
d) administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection.
[0018] In certain embodiments, the HCC is unresectable HCC. Thus,
in some embodiments, provided herein is a method for predicting
response to treatment with Compound 1 in a patient having
unresectable HCC, the method comprising: a) obtaining a biological
test sample from the patient; b) analyzing the sample for HBV
infection; c) predicting an increased likelihood of response to the
Compound 1 treatment of the patient's unresectable HCC if HBV
infection is determined in the sample. In other embodiments,
provided herein is a method for predicting response to treatment
with Compound 1 in a patient having unresectable HCC, the method
comprising: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of response to the Compound 1 treatment of the
patient's unresectable HCC if HBV infection is determined in the
sample; and d) administering an effective amount of Compound 1 to
the patient having unresectable HCC characterized by HBV infection.
Thus, also provided herein is Compound 1 for use in a method for
predicting response to treatment with Compound 1 in a patient
having unresectable HCC, wherein the method comprises: a) obtaining
a biological test sample from the patient; b) analyzing the sample
for HBV infection; c) predicting an increased likelihood of
response to the Compound 1 treatment of the patient's unresectable
HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection.
[0019] In another aspect, provided herein is a method for
predicting therapeutic efficacy of Compound 1 in a patient having
HCC, the method comprising: a) obtaining a biological test sample
from the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's HCC if HBV infection is determined in
the sample. In certain embodiments, the method further comprises a
step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for predicting therapeutic
efficacy of Compound 1 in a patient having HCC, the method
comprising: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of therapeutic efficacy of Compound 1 in the
patient's HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, also provided
herein is Compound 1 for use in a method for predicting therapeutic
efficacy of Compound 1 in a patient having HCC, wherein the method
comprises: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of therapeutic efficacy of Compound 1 in the
patient's HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection.
[0020] In certain embodiments, the HCC is unresectable HCC. Thus,
in some embodiments, provided herein is a method for predicting
therapeutic efficacy of Compound 1 in a patient having unresectable
HCC, the method comprising: a) obtaining a biological test sample
from the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's unresectable HCC if HBV infection is
determined in the sample. In other embodiments, provided herein is
a method for predicting therapeutic efficacy of Compound 1 in a
patient having unresectable HCC, the method comprising: a)
obtaining a biological test sample from the patient; b) analyzing
the sample for HBV infection; c) predicting an increased likelihood
of therapeutic efficacy of Compound 1 in the patient's unresectable
HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Thus, also
provided herein is Compound 1 for use in a method for predicting
therapeutic efficacy of Compound 1 in a patient having unresectable
HCC, wherein the method comprises: a) obtaining a biological test
sample from the patient; b) analyzing the sample for HBV infection;
c) predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's unresectable HCC if HBV infection is
determined in the sample; and d) administering an effective amount
of Compound 1 to the patient having unresectable HCC characterized
by HBV infection.
[0021] The present embodiments can be understood more fully by
reference to the detailed description and examples, which are
intended to exemplify non-limiting embodiments.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 depicts study design for Part B of the clinical study
of Example 6.1.
[0023] FIG. 2. shows patient characteristics for the Part B HCC
cohort.
[0024] FIGS. 3A and 3B show pharmacokinetics (PK) data of Compound
1 (FIG. 3A) and its metabolite M1 (FIG. 3B) in HCC-HBV positive
patients (n=12) and HCC-HBV negative patients (n=39).
[0025] FIG. 4 shows disposition of HCC treated population (TP) by
HBV status.
[0026] FIGS. 5A and 5B show Kaplan-Meier curve for overall survival
(OS) for HCC cohort. FIG. 5A shows OS for all HCC patients without
differentiating HBV infected and non-HBV infected patients. FIG. 5B
shows OS by HBV status for HCC cohort (p=0.19).
[0027] FIGS. 6A and 6B show Kaplan-Meier curve for progression free
survival (PFS) for HCC cohort. FIG. 6A shows PFS for all HCC
patients without differentiating HBV infected and non-HBV infected
patients. FIG. 6B shows PFS by HBV status for HCC cohort.
[0028] FIG. 7 shows best percentage change from baseline in total
length of target lesions in efficacy-evaluable HBV infected versus
non-HBV infected patients receiving Compound 1.
[0029] FIG. 8 summarizes survival and response data for HBV
infected versus non-HBV infected patients receiving Compound 1.
[0030] FIG. 9 shows an exemplary radiographic response from two HBV
infected HCC patients treated with Compound 1. Patient A shows
regression of intrathoracic metastases at the first on-treatment
restaging compared to baseline. Patient B shows intrahepatic tumor
regression at the first on-treatment restaging compared to
baseline.
[0031] FIG. 10 shows exemplary alpha-fetoprotein (AFP) response in
two HCC patients with partial response (PR) receiving Compound 1
treatment. Both patients show early clinically significant, marked
reduction of AFP on treatment compared to baseline elevated
levels.
5. DETAILED DESCRIPTION
5.1 Definitions
[0032] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
can mean "one", but it is also consistent with the meaning of "one
or more", "at least one" and "one or more than one."
[0033] As used herein, the terms "comprising" and "including" can
be used interchangeably. The terms "comprising" and "including" are
to be interpreted as specifying the presence of the stated features
or components as referred to, but does not preclude the presence or
addition of one or more features, or components, or groups thereof.
Additionally, the terms "comprising" and "including" are intended
to include examples encompassed by the term "consisting of".
Consequently, the term "consisting of" can be used in place of the
terms "comprising" and "including" to provide for more specific
embodiments of the invention.
[0034] The term "consisting of" means that a subject-matter has at
least 90%, 95%, 97%, 98% or 99% of the stated features or
components of which it consists. In another embodiment the term
"consisting of" excludes from the scope of any succeeding
recitation any other features or components, excepting those that
are not essential to the technical effect to be achieved.
[0035] As used herein, the term "or" is to be interpreted as an
inclusive "or" meaning any one or any combination. Therefore, "A, B
or C" means any of the following: "A; B; C; A and B; A and C; B and
C; A, B and C". An exception to this definition will occur only
when a combination of elements, functions, steps or acts are in
some way inherently mutually exclusive.
[0036] As used herein, the term "pharmaceutically acceptable
salt(s)" refers to a salt prepared from a pharmaceutically
acceptable non-toxic acid or base including an inorganic acid and
base and an organic acid and base. Suitable pharmaceutically
acceptable base addition salts of Compound 1 include, but are not
limited to, metallic salts made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc or organic salts made from
lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. Suitable non-toxic acids include, but are not limited to,
inorganic and organic acids such as acetic, alginic, anthranilic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
formic, fumaric, furoic, galacturonic, gluconic, glucuronic,
glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phenylacetic, phosphoric, propionic, salicylic,
stearic, succinic, sulfanilic, sulfuric, tartaric acid, and
p-toluenesulfonic acid. Specific non-toxic acids include
hydrochloric, hydrobromic, phosphoric, sulfuric, and
methanesulfonic acids. Examples of specific salts thus include
hydrochloride and mesylate salts. Others are well-known in the art,
see for example, Remington's Pharmaceutical Sciences, 18.sup.th
eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science
and Practice of Pharmacy, 19.sup.th eds., Mack Publishing, Easton
Pa. (1995).
[0037] "Tautomer" refers to isomeric forms of a compound that are
in equilibrium with each other. The concentrations of the isomeric
forms will depend on the environment the compound is found in and
may be different depending upon, for example, whether the compound
is a solid or is in an organic or aqueous solution. For example, in
aqueous solution, pyrazoles may exhibit the following isomeric
forms, which are referred to as tautomers of each other:
##STR00001##
[0038] As readily understood by one skilled in the art, a wide
variety of functional groups and other structures may exhibit
tautomerism and all tautomers of Compound 1 are within the scope of
the present invention.
[0039] "Treating" as used herein, means an alleviation, in whole or
in part, of symptoms associated with a disorder or disease (e.g.,
HCC characterized by HBV infection), or slowing, or halting of
further progression or worsening of those symptoms.
[0040] "Preventing" as used herein, means the prevention of the
onset, recurrence or spread, in whole or in part, of the disease or
disorder (e.g., HCC characterized by HBV infection), or a symptom
thereof.
[0041] As used herein, "administer" or "administration" refers to
the act of physically delivering a substance as it exists outside
the body into a patient, such as by oral, mucosal, intradermal,
intravenous, intramuscular delivery and/or any other method of
physical delivery described herein or known in the art. When a
disease, disorder or condition, or a symptom thereof, is being
treated, administration of the substance typically occurs after the
onset, recurrence or spread of disease, disorder or condition or
symptoms thereof. When a disease, disorder or condition, or
symptoms thereof, are being prevented, administration of the
substance typically occurs before the onset, recurrence or spread
of the disease, disorder or condition or symptoms thereof.
[0042] The term "effective amount" in connection with Compound 1
means an amount alone or in combination capable of alleviating, in
whole or in part, a symptom associated with HCC, or slowing or
halting further progression or worsening of those symptoms, or
treating or preventing HCC in a subject having or at risk for
having HCC. The effective amount of Compound 1, for example in a
pharmaceutical composition, may be at a level that will exercise
the desired effect; for example, about 0.005 mg/kg of a subject's
body weight to about 10 mg/kg of a patient's body weight in unit
dosage for both oral and parenteral administration.
[0043] As used herein, the term "combination" or administration "in
combination" includes administration as a mixture, simultaneous
administration using separate formulations, and consecutive
administration in any order.
[0044] "Consecutive" means that a specific time has passed between
the administration of the active agents. For example, "consecutive"
may be that more than 10 minutes have passed between the
administration of the separate active agents. The time period can
then be more than 10 min, more than 30 minutes, more than 1 hour,
more than 3 hours, more than 6 hours or more than 12 hours.
[0045] As used herein, the term "immune checkpoint inhibitor" or
"checkpoint inhibitor" refers to molecules that totally or
partially reduce, inhibit, interfere with or modulate one or more
checkpoint proteins. Without being limited by a particular theory,
checkpoint proteins regulate T-cell activation or function.
Non-limiting examples of checkpoint inhibitors include CTLA-4,
CD80, CD86, PD-1, PD-L1, and PD-L2 (Pardoll, Nature Rev. Cancer,
2012, 12:252-264).
[0046] The terms "patient" and "subject" as used herein include an
animal, including, but not limited to, an animal such as a cow,
monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse,
rat, rabbit or guinea pig, in one embodiment a mammal, in another
embodiment a human.
[0047] As used herein, the term "treated population" or "TP" refers
to all enrolled subjects who took at least 1 dose of Compound 1.
Drug exposure and all safety analyses are based on the treated
population.
[0048] As used herein, the term "efficacy evaluable population" or
"EE population" refers to all subjects who met eligibility
criteria, completed at least 1 cycle of Compound 1 treatment, and
had baseline and at least 1 postbaseline efficacy assessment.
Efficacy assessment means radiological or clinical assessment of
given type of tumor, or tumor assessment by other appropriate means
described by relevant tumor response criteria. Specifically,
efficacy assessment may include valid radiologic tumor assessment
for subjects with HCC. In addition, subjects are to take at least
70% of assigned days of Compound 1 during Cycle 1 or have Cycle 2
dosing records to be defined as having completed at least 1
treatment cycle.
[0049] As used herein, the term "biological test sample" refers to
a sample taken from serum, plasma, blood, dried blood/plasma spots,
hepatocytes, primary tumor, or sites of metastasis of HCC,
including but not limited to, lungs, lymph nodes, adrenal glands,
bones, peritoneum, portal vein, brain, saliva, parotid tissue,
etc.
[0050] The term "HBV positive" or "HBV infected," used
interchangeably herein, refers to the HBV status of HCC patients,
which is determined by an algorithm to identify subjects with HCC
considered to have been infected with HBV. Variables useable for
the algorithm include but are not limited to the following: medical
history of HBV, immunization history, prior or current treatment
for HBV, cirrhosis attributed to HBV, serological testing for HBV
antigens and/or antibodies, HBV load, and the presence of HBV DNA.
Non-limiting examples of such variables are the presence of HBV
surface antigen (HBsAg), the presence of antibody to HBV surface
antigen (anti-HBsAg), the presence of HBV core antigen (HBcAg), the
presence of antibody to HBV core antigen (anti-HBcAg), the presence
of HBV envelope protein antigen (HBeAg), the presence of antibody
to HBV envelope protein antigen (anti-HBeAg), the presence of HBV
x-protein antigen (HBxAg), the presence of antibody to HBV
x-protein antigen (HBxAg), the presence of HBV core-related antigen
(HBcrAg), the presence of antibody to HBV core-related antigen
(anti-HBcrAg), HBV viral load, use of anti HBV medications, the
presence of HBV DNA, the presence of HBV mRNA, and the presence of
HBV protein. Similarly, the term "HBV negative" or "non-HBV
infected," used interchangeably herein, refers to the HBV status of
HCC patients, who are considered to have neither HBV infection nor
a history of it.
[0051] As used herein, the term "hepatocellular carcinoma (HCC)
characterized by hepatitis B virus (HBV) infection" is defined to
be interchangeable with the terms "HCC associated with HBV
infection," "HCC related to HBV infection," "HCC with a history of
HBV infection," "HBV positive HCC," "HBV associated HCC," "HBV
related HCC," or "HBV infected HCC."
[0052] The term "likelihood" generally refers to an increase in the
probability of an event. The term "likelihood" when used in
reference to the effectiveness of a cancer patient response
generally contemplates an increased probability that a cancer or
tumor syndrome, or symptom thereof, will be lessened or
decreased.
[0053] The term "predict" generally means to determine or tell in
advance. When used to "predict" the effectiveness of a cancer
treatment, for example, the term "predict" can mean that the
likelihood of the outcome of the treatment can be determined at the
outset, before the treatment has begun, or before the treatment
period has progressed substantially.
[0054] The terms "determining", "measuring", "evaluating",
"assessing," and "assaying" as used herein generally refer to any
form of measurement, and include determining whether an element is
present or not. These terms include both quantitative and/or
qualitative determinations.
[0055] In the context of HCC, inhibition may be assessed by
inhibition of disease progression, inhibition of tumor growth,
reduction of primary tumor, relief of tumor-related symptoms,
inhibition of tumor secreted factors (such as, for example, AFP),
delayed appearance of primary or secondary tumors, slowed
development of primary or secondary tumors, decreased occurrence of
primary or secondary tumors, slowed or decreased severity of
secondary effects of disease, arrested tumor growth and regression
of tumors, increased Time To Progression (TTP), increased
Progression Free Survival (PFS), increased Overall Survival (OS),
among others. OS as used herein means the time from randomization
(for example, first dose date) until death from any cause, and is
measured in the intent-to-treat population. TTP as used herein
means the time from randomization (for example, first dose date)
until objective tumor progression; TTP does not include deaths. As
used herein, PFS means the time from randomization (for example,
first dose date) until objective tumor progression or death. In one
embodiment, PFS rates are computed using the Kaplan-Meier
estimates. In one embodiment, the survival rate is defined as the
Kaplan-Meier estimated proportion of subjects surviving at 6, 9, 12
months. As used herein, Disease control rate (DCR) means the
percentage of subjects with complete (CR), or partial response (PR)
or stable disease (SD). As used herein, Time To Response (TTR)
means the time from randomization (for example, first dose date) to
the first documentation of response of PR or better. As used
herein, Duration of response (DOR) means the time from the time
when criteria are first met for CR/PR (whichever is first recorded)
until the first date that recurrent or progressive disease is
objectively documented.
[0056] In certain embodiments, the treatment of HCC may be assessed
by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see
Thereasse et al., J. National Cancer Institute, 2000, 92:205-216
and Eisenhauer et al., European J. Cancer, 2009, 45:228-247).
Overall responses for all possible combinations of tumor responses
in target and non-target lesions with or without the appearance of
new lesions are as follows:
TABLE-US-00001 Target Non-target New Overall lesions lesions
lesions response CR CR No CR CR Incomplete No PR response/SD PR
Non-PD No PR SD Non-PD No SD PD Any Yes or no PD Any PD Yes or no
PD Any Any Yes PD CR = complete response; PR = partial response; SD
= stable disease; and PD = progressive disease.
[0057] With respect to the evaluation of target lesions, complete
response (CR) is the disappearance of all target lesions, partial
response (PR) is at least a 30% decrease in the sum of the longest
diameter of target lesions, taking as reference the baseline sum
longest diameter, progressive disease (PD) is at least a 20%
increase in the sum of the longest diameter of target lesions,
taking as reference the smallest sum longest diameter recorded
since the treatment started or the appearance of one or more new
lesions, and stable disease (SD) is neither sufficient shrinkage to
qualify for partial response nor sufficient increase to qualify for
progressive disease, taking as reference the smallest sum longest
diameter since the treatment started.
[0058] With respect to the evaluation of non-target lesions, CR is
the disappearance of all non-target lesions and normalization of
tumor marker level, incomplete response/SD is the persistence of
one or more non-target lesion(s) and/or the maintenance of tumor
marker level above the normal limits, and PD is the appearance of
one or more new lesions and/or unequivocal progression of existing
non-target lesions.
[0059] In some embodiments, the treatment of HCC may also be
assessed by modified Response Evaluation Criteria in Solid Tumors
(mRECIST for HCC) (see Lencioni et al. Semin Liver Dis. 2010
February; 30(1):52-60.
5.2 Compound 1
[0060] Provided herein are uses for the compound having the
structure:
##STR00002##
and having the name
7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)--
3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, including
pharmaceutically acceptable salts or tautomers thereof
(collectively referred to herein as "Compound 1").
[0061] Compound 1 can be prepared using reagents and methods known
in the art, including the methods provided in U.S. Pat. No.
8,110,578, issued on Feb. 7, 2012; U.S. Pat. No. 8,569,494, issued
on Oct. 29, 2013; and U.S. Pat. No. 9,359,364, issued on Jun. 7,
2016, the entire contents of each of which are incorporated herein
by reference.
[0062] As used herein "metabolite M1" refers to the compound having
the structure
##STR00003##
and having the name
1-((trans)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)--
3,4-dihydropyrazino[2,3-b]-pyrazin-2(1 H)-one, or tautomers
thereof.
[0063] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
5.3 Methods of Use and Compound 1 for Use in Such Methods
[0064] Compound 1 as provided herein can be used in all methods
provided herein. In one aspect, provided herein is a method for
treating and/or preventing HCC characterized by HBV infection in a
patient, comprising administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating and/or
preventing HCC characterized by HBV infection in a patient. In
certain embodiments, provided herein is a method for treating HCC
characterized by HBV infection in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for treating HCC characterized
by HBV infection in a patient. In other embodiments, provided
herein is a method for preventing HCC characterized by HBV
infection in a patient, comprising administering an effective
amount of Compound 1 to the patient having HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such a method
for preventing HCC characterized by HBV infection in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. In certain
embodiments, the HCC characterized by HBV infection is unresectable
HCC characterized by HBV infection. Thus, in some embodiments,
provided herein is a method for treating unresectable HCC
characterized by HBV infection in a patient, comprising
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating
unresectable HCC characterized by HBV infection in a patient. In
other embodiments, provided herein is a method for preventing
unresectable HCC characterized by HBV infection in a patient,
comprising administering an effective amount of Compound 1 to the
patient having unresectable HCC characterized by HBV infection.
Provided herein is Compound 1 for use in such a method for
preventing unresectable HCC characterized by HBV infection in a
patient.
[0065] In some embodiments, provided herein is a method for
treating and/or preventing HCC associated with HBV infection in a
patient, comprising administering an effective amount of Compound 1
to the patient having HCC associated with HBV infection. Provided
herein is Compound 1 for use in such a method for treating and/or
preventing HCC associated with HBV infection in a patient. In
certain embodiments, provided herein is a method for treating HCC
associated with HBV infection in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HCC associated with HBV infection. Provided herein is
Compound 1 for use in such a method for treating HCC associated
with HBV infection in a patient. In other embodiments, provided
herein is a method for preventing HCC associated with HBV infection
in a patient, comprising administering an effective amount of
Compound 1 to the patient having HCC associated with HBV infection.
Provided herein is Compound 1 for use in such a method for
preventing HCC associated with HBV infection in a patient. In one
embodiment, the HCC associated with HBV infection is unresectable
HCC associated with HBV infection.
[0066] In some embodiments, provided herein is a method for
treating and/or preventing HCC related to HBV infection in a
patient, comprising administering an effective amount of Compound 1
to the patient having HCC related to HBV infection. Provided herein
is Compound 1 for use in such a method for treating and/or
preventing HCC related to HBV infection in a patient. In certain
embodiments, provided herein is a method for treating HCC related
to HBV infection in a patient, comprising administering an
effective amount of Compound 1 to the patient having HCC related to
HBV infection. Provided herein is Compound 1 for use in such a
method for treating HCC related to HBV infection in a patient. In
other embodiments, provided herein is a method for preventing HCC
related to HBV infection in a patient, comprising administering an
effective amount of Compound 1 to the patient having HCC related to
HBV infection. Provided herein is Compound 1 for use in such a
method for preventing HCC related to HBV infection in a patient. In
one embodiment, the HCC related to HBV infection is unresectable
HCC related to HBV infection.
[0067] In some embodiments, provided herein is a method for
treating and/or preventing HCC with a history of HBV infection in a
patient, comprising administering an effective amount of Compound 1
to the patient having HCC with a history of HBV infection. Provided
herein is Compound 1 for use in such a method for treating and/or
preventing HCC with a history of HBV infection in a patient. In
certain embodiments, provided herein is a method for treating HCC
with a history of HBV infection in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HCC with a history of HBV infection. Provided herein is
Compound 1 for use in such a method for treating HCC with a history
of HBV infection in a patient. In other embodiments, provided
herein is a method for preventing HCC with a history of HBV
infection in a patient, comprising administering an effective
amount of Compound 1 to the patient having HCC with a history of
HBV infection. Provided herein is Compound 1 for use in such a
method for preventing HCC with a history of HBV infection in a
patient. In one embodiment, the HCC with a history of HBV infection
is unresectable HCC with a history of HBV infection.
[0068] In some embodiments, provided herein is a method for
treating and/or preventing HBV positive HCC in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HBV positive HCC. Provided herein is Compound 1 for
use in such a method for treating and/or preventing HBV positive
HCC in a patient. In certain embodiments, provided herein is a
method for treating HBV positive HCC in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HBV positive HCC. Provided herein is Compound 1 for use in
such a method for treating HBV positive HCC in a patient. In other
embodiments, provided herein is a method for preventing HBV
positive HCC in a patient, comprising administering an effective
amount of Compound 1 to the patient having HBV positive HCC.
Provided herein is Compound 1 for use in such a method for
preventing HBV positive HCC in a patient. In one embodiment, the
HBV positive HCC is unresectable HBV positive HCC.
[0069] In some embodiments, provided herein is a method for
treating and/or preventing HBV associated HCC in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HBV associated HCC. Provided herein is Compound 1
for use in such a method for treating and/or preventing HBV
associated HCC in a patient. In certain embodiments, provided
herein is a method for treating HBV associated HCC in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HBV associated HCC. Provided herein is Compound 1
for use in such a method for treating HBV associated HCC in a
patient. In other embodiments, provided herein is a method for
preventing HBV associated HCC in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HBV associated HCC. Provided herein is Compound 1 for use in
such a method for reventing HBV associated HCC in a patient. In one
embodiment, the HBV associated HCC is unresectable HBV associated
HCC.
[0070] In some embodiments, provided herein is a method for
treating and/or preventing HBV related HCC in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HBV related HCC. Provided herein is Compound 1 for use in
such a method for treating and/or preventing HBV related HCC in a
patient. In certain embodiments, provided herein is a method for
treating HBV related HCC in a patient, comprising administering an
effective amount of Compound 1 to the patient having HBV related
HCC. Provided herein is Compound 1 for use in such a method for
treating HBV related HCC in a patient. In other embodiments,
provided herein is a method for preventing HBV related HCC in a
patient, comprising administering an effective amount of Compound 1
to the patient having HBV related HCC. Provided herein is Compound
1 for use in such a method for preventing HBV related HCC in a
patient. In one embodiment, the HBV related HCC is unresectable HBV
related HCC.
[0071] In some embodiments, provided herein is a method for
treating and/or preventing HBV infected HCC in a patient,
comprising administering an effective amount of Compound 1 to the
patient having HBV infected HCC. Provided herein is Compound 1 for
use in such a method for treating and/or preventing HBV infected
HCC in a patient. In certain embodiments, provided herein is a
method for treating HBV infected HCC in a patient, comprising
administering an effective amount of Compound 1 to the patient
having HBV infected HCC. Provided herein is Compound 1 for use in
such a method for treating HBV infected HCC in a patient In other
embodiments, provided herein is a method for preventing HBV
infected HCC in a patient, comprising administering an effective
amount of Compound 1 to the patient having HBV infected HCC.
Provided herein is Compound 1 for use in such a method for
preventing HBV infected HCC in a patient. In one embodiment, the
HBV infected HCC is unresectable HBV infected HCC.
[0072] In another aspect, provided herein is a method for treating
and/or preventing HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating and/or
preventing HCC characterized by HBV infection in a patient, wherein
the method comprises screening a biological test sample from the
patient for HBV infection, and administering an effective amount of
Compound 1 to the patient having HCC characterized by HBV
infection. In certain embodiments, provided herein is a method for
treating HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for treating HCC
characterized by HBV infection in a patient, wherein the method
comprises screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection. In other
embodiments, provided herein is a method for preventing HCC
characterized by HBV infection in a patient, comprising screening a
biological test sample from the patient for HBV infection, and
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for preventing HCC
characterized by HBV infection in a patient, wherein the method
comprises screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection.
[0073] In certain embodiments, the HCC characterized by HBV
infection is unresectable HCC characterized by HBV infection. Thus,
in some embodiments, provided herein is a method for treating
unresectable HCC characterized by HBV infection in a patient,
comprising screening a biological test sample from the patient for
HBV infection, and administering an effective amount of Compound 1
to the patient having unresectable HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such a method
for treating unresectable HCC characterized by HBV infection in a
patient, wherein the method comprises screening a biological test
sample from the patient for HBV infection, and administering an
effective amount of Compound 1 to the patient having unresectable
HCC characterized by HBV infection. In yet other embodiments,
provided herein is a method for preventing unresectable HCC
characterized by HBV infection in a patient, comprising screening a
biological test sample from the patient for HBV infection, and
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Provided
herein is Compound 1 for use in such a method for preventing
unresectable HCC characterized by HBV infection in a patient,
wherein the method comprises screening a biological test sample
from the patient for HBV infection, and administering an effective
amount of Compound 1 to the patient having unresectable HCC
characterized by HBV infection.
[0074] In certain embodiments, the HCC characterized by HBV
infection is previously untreated HCC characterized by HBV
infection. Thus, in some embodiments, provided herein is a method
for treating previously untreated HCC characterized by HBV
infection in a patient, comprising screening a biological test
sample from the patient for HBV infection, and administering an
effective amount of Compound 1 to the patient having previously
untreated HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such a method for treating previously
untreated HCC characterized by HBV infection in a patient, wherein
the method comprises screening a biological test sample from the
patient for HBV infection, and administering an effective amount of
Compound 1 to the patient having previously untreated HCC
characterized by HBV infection. In other embodiments, the HCC
characterized by HBV infection is previously treated HCC
characterized by HBV infection. Thus, in some embodiments, provided
herein is a method for treating previously treated HCC
characterized by HBV infection in a patient, comprising screening a
biological test sample from the patient for HBV infection, and
administering an effective amount of Compound 1 to the patient
having previously treated HCC characterized by HBV infection.
Provided herein is Compound 1 for use in such a method for treating
previously treated HCC characterized by HBV infection in a patient,
wherein the method comprises screening a biological test sample
from the patient for HBV infection, and administering an effective
amount of Compound 1 to the patient having previously treated HCC
characterized by HBV infection. In some embodiments, the HCC
characterized by HBV infection is previously treated with at least
one therapy. In some such embodiments, the HCC characterized by HBV
infection was previously treated at least with sorafenib and/or
chemotherapy. In one embodiment, the HCC characterized by HBV
infection is previously treated with one therapy. In another
embodiment, the HCC characterized by HBV infection is previously
treated with two therapies. In still another embodiment, the HCC
characterized by HBV infection is previously treated with three
therapies. In still other embodiments, the HCC characterized by HBV
infection is previously treated with four therapies. In some such
embodiments, the HCC characterized by HBV infection is previously
treated HCC, wherein the previous treatment comprises sorafenib
and/or chemotherapy. In some such embodiments, the HCC
characterized by HBV infection is previously treated HCC, wherein
the previous treatment comprises at least sorafenib and/or
chemotherapy. In some such embodiments, the HCC characterized by
HBV infection is previously treated HCC, wherein the previous
treatment comprises sorafenib. In some other such embodiments, the
HCC characterized by HBV infection is previously treated HCC,
wherein the previous treatment comprises at least chemotherapy.
[0075] In yet another aspect, provided herein is a method for
selecting a patient having HCC for Compound 1 treatment, comprising
a) obtaining a biological test sample from the patient; b)
analyzing the sample for HBV infection; c) selecting the patient
having HCC for Compound 1 treatment if HBV infection is determined
in the sample. In certain embodiments, the method further comprises
a step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for selecting a patient
having HCC for Compound 1 treatment, comprising a) obtaining a
biological test sample from the patient; b) analyzing the sample
for HBV infection; c) selecting the patient having HCC for Compound
1 treatment if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, further provided
herein is Compound 1 for use in such a method for selecting a
patient having HCC for Compound 1 treatment, wherein the method
comprises a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) selecting the patient
having HCC for Compound 1 treatment if HBV infection is determined
in the sample; and d) administering an effective amount of Compound
1 to the patient having HCC characterized by HBV infection.
[0076] In certain embodiments, the HCC is unresectable HCC. In some
embodiments, provided herein is a method for selecting a patient
having unresectable HCC for Compound 1 treatment, comprising a)
obtaining a biological test sample from the patient; b) analyzing
the sample for HBV infection; c) selecting the patient having
unresectable HCC for Compound 1 treatment if HBV infection is
determined in the sample. In other embodiments, provided herein is
a method for selecting a patient having unresectable HCC for
Compound 1 treatment, comprising a) obtaining a biological test
sample from the patient; b) analyzing the sample for HBV infection;
c) selecting the patient having unresectable HCC for Compound 1
treatment if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Thus,
further provided herein is Compound 1 for use in such a method for
selecting a patient having unresectable HCC for Compound 1
treatment, wherein the method comprises a) obtaining a biological
test sample from the patient; b) analyzing the sample for HBV
infection; c) selecting the patient having unresectable HCC for
Compound 1 treatment if HBV infection is determined in the sample;
and d) administering an effective amount of Compound 1 to the
patient having unresectable HCC characterized by HBV infection.
[0077] In still another aspect, provided herein is a method for
predicting response to treatment with Compound 1 in a patient
having HCC, the method comprising: a) obtaining a biological test
sample from the patient; b) analyzing the sample for HBV infection;
c) predicting an increased likelihood of response to the Compound 1
treatment of the patient's HCC if HBV infection is determined in
the sample. In certain embodiments, the method further comprises a
step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for predicting response to
treatment with Compound 1 in a patient having HCC, the method
comprising: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of response to the Compound 1 treatment of the
patient's HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, further provided
herein is Compound 1 for use in such a method for predicting
response to treatment with Compound 1 in a patient having HCC,
wherein the method comprises: a) obtaining a biological test sample
from the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of response to the Compound 1
treatment of the patient's HCC if HBV infection is determined in
the sample; and d) administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection.
[0078] In certain embodiments, the HCC is unresectable HCC. In some
embodiments, provided herein is a method for predicting response to
treatment with Compound 1 in a patient having unresectable HCC, the
method comprising: a) obtaining a biological test sample from the
patient; b) analyzing the sample for HBV infection; c) predicting
an increased likelihood of response to the Compound 1 treatment of
the patient's unresectable HCC if HBV infection is determined in
the sample. In other embodiments, provided herein is a method for
predicting response to treatment with Compound 1 in a patient
having unresectable HCC, the method comprising: a) obtaining a
biological test sample from the patient; b) analyzing the sample
for HBV infection; c) predicting an increased likelihood of
response to the Compound 1 treatment of the patient's unresectable
HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection. Thus,
further provided herein is Compound 1 for use in such a method for
predicting response to treatment with Compound 1 in a patient
having unresectable HCC, wherein the method comprises: a) obtaining
a biological test sample from the patient; b) analyzing the sample
for HBV infection; c) predicting an increased likelihood of
response to the Compound 1 treatment of the patient's unresectable
HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having unresectable HCC characterized by HBV infection.
[0079] In another aspect, provided herein is a method for
predicting therapeutic efficacy of Compound 1 in a patient having
HCC, the method comprising: a) obtaining a biological test sample
from the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's HCC if HBV infection is determined in
the sample. In certain embodiments, the method further comprises a
step d) administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Thus, in some
embodiments, provided herein is a method for predicting therapeutic
efficacy of Compound 1 in a patient having HCC, the method
comprising: a) obtaining a biological test sample from the patient;
b) analyzing the sample for HBV infection; c) predicting an
increased likelihood of therapeutic efficacy of Compound 1 in the
patient's HCC if HBV infection is determined in the sample; and d)
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Thus, further provided
herein is Compound 1 for use in such a method for predicting
therapeutic efficacy of Compound 1 in a patient having HCC, wherein
the method comprises: a) obtaining a biological test sample from
the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's HCC if HBV infection is determined in
the sample; and d) administering an effective amount of Compound 1
to the patient having HCC characterized by HBV infection.
[0080] In certain embodiments, the HCC is unresectable HCC. In some
embodiments, provided herein is a method for predicting therapeutic
efficacy of Compound 1 in a patient having unresectable HCC, the
method comprising: a) obtaining a biological test sample from the
patient; b) analyzing the sample for HBV infection; c) predicting
an increased likelihood of therapeutic efficacy of Compound 1 in
the patient's unresectable HCC if HBV infection is determined in
the sample. In other embodiments, provided herein is a method for
predicting therapeutic efficacy of Compound 1 in a patient having
unresectable HCC, the method comprising: a) obtaining a biological
test sample from the patient; b) analyzing the sample for HBV
infection; c) predicting an increased likelihood of therapeutic
efficacy of Compound 1 in the patient's unresectable HCC if HBV
infection is determined in the sample; and d) administering an
effective amount of Compound 1 to the patient having unresectable
HCC characterized by HBV infection. Thus, further provided herein
is Compound 1 for use in such a method for predicting therapeutic
efficacy of Compound 1 in a patient having unresectable HCC,
wherein the method comprises: a) obtaining a biological test sample
from the patient; b) analyzing the sample for HBV infection; c)
predicting an increased likelihood of therapeutic efficacy of
Compound 1 in the patient's unresectable HCC if HBV infection is
determined in the sample; and d) administering an effective amount
of Compound 1 to the patient having unresectable HCC characterized
by HBV infection.
[0081] In various methods provided herein, HBV infection is
determined by at least one of the variables selected from the group
consisting of: patient history of HBV, prior or current treatment
for HBV, cirrhosis attributed to HBV, the presence of HBV proteins
or antigens, the presence of antibodies to HBV proteins or
antigens, HBV viral load, and the presence of HBV DNA. In one
embodiment, HBV infection is determined by patient history of HBV.
In another embodiment, HBV infection is determined by prior
treatment for HBV. In yet another embodiment, HBV infection is
determined by current treatment for HBV. In still another
embodiment, HBV infection is determined by cirrhosis attributed to
HBV. In another embodiment, HBV infection is determined by the
presence of HBV proteins or antigens. In another embodiment, HBV
infection is determined by the presence of antibodies to HBV
proteins or antigens. In yet another embodiment, HBV infection is
determined by HBV viral load. In yet another embodiment, HBV
infection is determined by the presence of HBV DNA. In certain
embodiments, HBV infection is determined by two, three, four, five,
six, seven, or all of the variables selected from the group
consisting of: patient history of HBV, prior treatment for HBV,
current treatment for HBV, cirrhosis attributed to HBV, the
presence of HBV proteins, the presence of HBV antigens, the
presence of antibodies to HBV proteins, the presence of antibodies
to HBV antigens, HBV viral load, and the presence of HBV DNA.
[0082] In another embodiment, in various methods provided herein,
HBV infection is determined by at least one of the variables
selected from the group consisting of: the presence of HBsAg, the
presence of HBcAg, the presence of HBeAg, the presence of HBxAg,
the presence of HBcrAg, the presence of anti-HBsAg, the presence of
anti-HBcAg, the presence of anti-HBeAg, the presence of anti-HBxAg,
the presence of anti-HBcrAg, HBV viral load, the use of HBV
medications, the presence of HBV DNA, the presence of HBV mRNA, and
the presence of HBV protein. In one embodiment, HBV infection is
determined by the presence of HBsAg. In another embodiment, HBV
infection is determined by the presence of HBcAg. In another
embodiment, HBV infection is determined by the presence of HBeAg.
In another embodiment, HBV infection is determined by the presence
of HBxAg. In another embodiment, HBV infection is determined by the
presence of HBcrAg. In yet another embodiment, HBV infection is
determined by the presence of anti-HBsAg. In yet another
embodiment, HBV infection is determined by the presence of
anti-HBcAg. In yet another embodiment, HBV infection is determined
by the presence of anti-HBeAg. In yet another embodiment, HBV
infection is determined by the presence of anti-HBxAg. In yet
another embodiment, HBV infection is determined by the presence of
anti-HBcrAg. In still another embodiment, HBV infection is
determined by HBV viral load. In one embodiment, HBV infection is
determined by the use of HBV medications. In one embodiment, HBV
infection is determined by the presence of HBV DNA. In another
embodiment, HBV infection is determined by the presence of HBV
mRNA. In yet another embodiment, HBV infection is determined by the
presence of HBV protein. In another embodiment, HBV infection is
related to the lack of immunization. In some embodiments, HBV
infection is determined by two, three, four, five, six, seven,
eight, nine, ten, or all of the variables selected from the group
consisting of: the presence of HBsAg, the presence of HBcAg, the
presence of HBeAg, the presence of HBxAg, the presence of HBcrAg,
the presence of anti-HBsAg, the presence of anti-HBcAg, the
presence of anti-HBeAg, the presence of anti-HBxAg, the presence of
anti-HBcrAg, HBV viral load, the use of HBV medications, the
presence of HBV DNA, the presence of HBV mRNA, and the presence of
HBV protein.
[0083] The HBV DNA detected can be any fragment of the HBV genome,
whether encoding an HBV protein or not. The HBV mRNA detected can
be any fragment of the HBV mRNA pool. The HBV protein detected can
be any HBV protein or fragments thereof.
[0084] In some embodiments, the HBV DNA is the DNA encoding HBxAg
or fragments thereof. In certain embodiments, the HBV mRNA is the
mRNA of HBxAg or fragments thereof. In other embodiments, the HBV
protein is HBxAg or fragments thereof.
[0085] In some embodiments, the HBV DNA is the DNA encoding HBsAg
or fragments thereof. In certain embodiments, the HBV mRNA is the
mRNA of HBsAg or fragments thereof. In other embodiments, the HBV
protein is HBsAg or fragments thereof.
[0086] In some embodiments, the HBV DNA is the DNA encoding HBcAg
or fragments thereof. In certain embodiments, the HBV mRNA is the
mRNA of HBcAg or fragments thereof. In other embodiments, the HBV
protein is HBcAg or fragments thereof.
[0087] In some embodiments, the HBV DNA is the DNA encoding HBeAg
or fragments thereof. In certain embodiments, the HBV mRNA is the
mRNA of HBeAg or fragments thereof. In other embodiments, the HBV
protein is HBeAg or fragments thereof.
[0088] In some embodiments, the HBV DNA is the DNA encoding HBerAg
or fragments thereof. In certain embodiments, the HBV mRNA is the
mRNA of HBcrAg or fragments thereof. In other embodiments, the HBV
protein is HBcrAg or fragments thereof.
[0089] In various methods provided herein, HBV infection can be
detected in a biological sample from a patient. In some
embodiments, the biological sample is a sample from serum, plasma,
blood, dried blood/plasma spots, hepatocytes, primary tumor, or
sites of metastasis of HCC, including but not limited to, lungs,
lymph nodes, adrenal glands, bones, peritoneum, portal vein, brain,
saliva, parotid tissue, etc. In some embodiments, HBV infection is
detected by serological methods. In other embodiments, HBV
infection is detected by molecular methods. Serological methods
include but are not limited to enzyme linked immunosorbent assay
(ELISA), chemiluminescent enzyme immunoassay or chemiluminescent
immunoassay (CLEIA or CLIA), time resolved fluroimmunoassay
(TRFIA), chemiluminescent microparticle immunoassay (CMIA),
electro-chemiluminescent immunoassay (ECLIA), and golden
immunochromatographic assay (GICA). Molecular methods include but
are not limited to nucleic acid hybridization, nucleic acid
amplification (e.g., PCR, real time PCR, multiplex PCR, and
branched DNA assay), sequencing, and enzymatic digestion of nucleic
acids. Both serological and molecular methods can be conducted on
automated systems (such as Abbott AxSYM, Roche Elecsys, Abbott
Architect, version 2.0 of CobasAmpliPrep/CobasTaqMan
(CAP/CTM)).
[0090] In certain embodiments, the various assays detect at least
one biomarker of HBV selected from the group consisting of HBsAg,
anti-HBsAg, HBcAg, anti-HBcAg, HBeAg, anti-HBeAg, HBxAg,
anti-HBxAg, HBcrAg, and anti-HBcrAg. In one embodiment, the
biomarker is HBsAg. In another embodiment, the biomarker is
anti-HBsAg. In yet another embodiment, the biomarker is HBcAg. In
still another embodiment, the biomarker is anti-HBcAg. In one
embodiment, the biomarker is HBeAg. In another embodiment, the
biomarker is anti-HBeAg. In one embodiment, the biomarker is HBxAg.
In still another embodiment, the biomarker is anti-HBxAg. In still
another embodiment, the biomarker is HBerAg. In another embodiment,
the biomarker is anti-HBcrAg. In yet another embodiment, the
various assays detect two, three, four, five, six, seven, eight,
nine or all biomarkers of HBV selected from the group consisting of
HBsAg, anti-HBsAg, HBcAg, anti-HBcAg, HBeAg, anti-HBeAg, HBxAg,
anti-HBxAg, HBcrAg, and anti-HBcrAg.
[0091] In various methods provided herein, Compound 1 is
administered in combination with a second therapeutic agent to the
HCC patient characterized by HBV infection. In one embodiment, the
second therapeutic agent is sorafenib. In another embodiment, the
second therapeutic agent is
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
(Compound 2). In yet another embodiment, the second therapeutic
agent is an immune check point inhibitor (e.g., CTLA-4 inhibitor,
PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, LAG-3 inhibitor,
TIM3 inhibitor, IDO inhibitor, OX40 agonist, GITR agonist, CD137
agonist, CD40 agonist, recombinant human interleukin-15). In still
another embodiment, Compound 1 is administered in combination with
a second and a third therapeutic agents to the HCC patient
characterized by HBV infection. In some embodiment, the second and
the third therapeutic agents are selected from the group consisting
of sorafenib, Compound 2, and an immune check point inhibitor
(e.g., PD-1 inhibitor). In one embodiment, the second and the third
therapeutic agents are sorafenib and Compound 2. In another
embodiment, the second and the third therapeutic agents are
sorafenib and an immune check point inhibitor (e.g., PD-1
inhibitor). In yet another embodiment, the second and the third
therapeutic agents are Compound 2 and an immune check point
inhibitor (e.g., PD-1 inhibitor). In still another embodiment, the
second and the third therapeutic agents are two different immune
check point inhibitors (e.g., PD-1 inhibitor and CTLA-4
inhibitor).
[0092] In one embodiment, the checkpoint inhibitor is a CTLA-4
inhibitor. In one embodiment, the CTLA-4 inhibitor is an
anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include,
but are not limited to, those described in U.S. Pat. Nos.
5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736;
6,984,720; and 7,605,238, all of which are incorporated herein in
their entireties. In one embodiment, the anti-CTLA-4 antibody is
tremelimumab (also known as ticilimumab or CP-675,206). In another
embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as
MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG
antibody that binds to CTLA-4. Ipilimumab is marketed under the
trade name Yervoy.TM..
[0093] In one embodiment, the checkpoint inhibitor is a PD-1/PD-L1
inhibitor. Examples of PD-1/PD-L1 inhibitors include, but are not
limited to, those described in U.S. Pat. Nos. 7,488,802; 7,943,743;
8,008,449; 8,168,757; 8,217,149, and PCT Patent Application
Publication Nos. WO2003042402, WO2008156712, WO2010089411,
WO2010036959, WO2011066342, WO2011159877, WO2011082400, and
WO2011161699, all of which are incorporated herein in their
entireties.
[0094] In one embodiment, the checkpoint inhibitor is a PD-1
inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1
antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317,
nivolumab (also known as ONO-4538, BMS-936558, or MDX1106) or
pembrolizumab (also known as MK-3475, SCH 900475, or
lambrolizumab). In one embodiment, the anti-PD-1 antibody is
nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody,
and is marketed under the trade name Opdivo.TM.. In a specific
embodiment, Compound 1 is administered in combination with
nivolumab to the patient having HCC characterized by HBV infection.
Thus, provided is a method of treating HCC characterized by HBV
infection, wherein the method comprises administering an effective
amount of Compound 1 in combination with nivolumab to said patient.
Provided herein is Compound 1 for use in a method of treating HCC
characterized by HBV infection, wherein the method comprises
administering an effective amount of Compound 1 in combination with
nivolumab to said patient. In a specific embodiment, Compound 1 is
administered in combination with nivolumab to the patient having
HCC characterized by HBV infection, wherein the HCC is previously
treated with at least one therapy. Thus, provided is a method of
treating HCC characterized by HBV infection previously treated with
at least one therapy, wherein the method comprises administering an
effective amount of Compound 1 in combination with nivolumab to
said patient. In one such embodiment, the previous therapy
comprises sorafenib or chemotherapy. In one such embodiment, the
previous therapy comprises sorafenib and chemotherapy. Provided
herein is Compound 1 for use in a method of treating HCC
characterized by HBV infection previously treated with at least one
therapy, wherein the method comprises administering an effective
amount of Compound 1 in combination with nivolumab to said patient.
In a specific embodiment, Compound 1 is administered in combination
with nivolumab to the patient having HCC characterized by HBV
infection, wherein the HCC is previously treated with sorafenib.
Thus, provided is a method of treating HCC characterized by HBV
infection previously treated with sorafenib, wherein the method
comprises administering an effective amount of Compound 1 in
combination with nivolumab to said patient. Provided herein is
Compound 1 for use in a method of treating HCC characterized by HBV
infection previously treated with sorafenib, wherein the method
comprises administering an effective amount of Compound 1 in
combination with nivolumab to said patient. In a specific
embodiment, Compound 1 is administered in combination with
nivolumab to the patient having HCC characterized by HBV infection,
wherein the HCC is previously treated with chemotherapy. Thus,
provided is a method of treating HCC characterized by HBV infection
previously treated with chemotherapy, wherein the method comprises
administering an effective amount of Compound 1 in combination with
nivolumab to said patient. Provided herein is Compound 1 for use in
a method of treating HCC characterized by HBV infection previously
treated with chemotherapy, wherein the method comprises
administering an effective amount of Compound 1 in combination with
nivolumab to said patient.
[0095] In another embodiment, the anti-PD-1 antibody is
pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4
antibody and is marketed under the trade name Keytruda.TM.. In yet
another embodiment, the anti-PD-1 antibody is CT-011, a humanized
antibody. In yet another embodiment, the anti-PD-1 antibody is
AMP-224, a fusion protein. In another embodiment, the PD-1 antibody
is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability
to bind Fc gamma receptor I is specifically engineered out, and
which has a unique binding signature to PD-1 with high affinity and
superior target specificity.
[0096] In one embodiment, the checkpoint inhibitor is a PD-L1
inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1
antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736
(durvalumab). In another embodiment, the anti-PD-L1 antibody is
BMS-936559 (also known as MDX-1105-01). In yet another embodiment,
the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A, and
Tecentriq.RTM.).
[0097] In one embodiment, the checkpoint inhibitor is a PD-L2
inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2
antibody. In one embodiment, the anti-PD-L2 antibody is
rHIgM12B7A.
[0098] In one embodiment, the checkpoint inhibitor is a lymphocyte
activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3
inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al.,
J. Immunol., 2007, 179, 4202-4211). In another embodiment, the
LAG-3 inhibitor is BMS-986016.
[0099] In one embodiment, the checkpoint inhibitor is a B7
inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor
or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is
MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res.,
2012, 3834).
[0100] In one embodiment, the checkpoint inhibitor is a TIM3
(T-cell immunoglobulin domain and mucin domain 3) inhibitor
(Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et
al., J. Exp. Med., 2010, 207, 2187-94).
[0101] In one embodiment, the checkpoint inhibitor is an OX40
(CD134) agonist. In one embodiment, the checkpoint inhibitor is an
anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is
anti-OX-40. In another embodiment, the anti-OX40 antibody is
MEDI6469.
[0102] In one embodiment, the checkpoint inhibitor is a GITR
agonist. In one embodiment, the checkpoint inhibitor is an
anti-GITR antibody. In one embodiment, the anti-GITR antibody is
TRX518.
[0103] In one embodiment, the checkpoint inhibitor is a CD137
agonist. In one embodiment, the checkpoint inhibitor is an
anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is
urelumab. In another embodiment, the anti-CD137 antibody is
PF-05082566.
[0104] In one embodiment, the checkpoint inhibitor is a CD40
agonist. In one embodiment, the checkpoint inhibitor is an
anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is
CF-870,893.
[0105] In one embodiment, the checkpoint inhibitor is recombinant
human interleukin-15 (rhIL-15).
[0106] In one embodiment, the checkpoint inhibitor is an IDO
inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In
another embodiment, the IDO inhibitor is indoximod.
[0107] Examples of such additional agents include, but are not
limited to: Abraxane.RTM. (paclitaxel protein-bound particles for
injectable suspension (albuin-bound)); ace-11; acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin;
aldesleukin; altretamine; ambomycin; ametantrone acetate;
amrubicin; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;
cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride;
ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan
hydrochloride; lanreotide acetate; lapatinib; letrozole; leuprolide
acetate; liarozole hydrochloride; lometrexol sodium; lomustine;
losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; romidepsin; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; stem cell treatments such
as PDA-001; streptonigrin; streptozocin; sulofenur; talisomycin;
tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride;
temoporfin; teniposide; teroxirone; testolactone; thiamiprine;
thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene
citrate; trestolone acetate; triciribine phosphate; trimetrexate;
trimetrexate glucuronate; triptorelin; tubulozole hydrochloride;
uracil mustard; uredepa; vapreotide; verteporfin; vinblastine
sulfate; vincristine sulfate; vindesine; vindesine sulfate;
vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;
vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;
vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
[0108] Other examples include, but are not limited to: 20-epi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorlns;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (e.g., GLEEVEC.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (GENASENSE.RTM.); O.sup.6-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0109] In one embodiment, the patient has received at least one
prior therapy for HCC. In another embodiment, the patient has
received one prior therapy for HCC. In yet another embodiment, the
patient has received two prior therapies for HCC. In still another
embodiment, the patient has received three prior therapies for HCC.
In another embodiment, the patient has received no prior therapy
for HCC. In some embodiments, the prior therapy is a systemic
therapy (e.g., drug treatment). In other embodiments, the prior
therapy is a locoregional therapy (e.g., radiotherapy).
[0110] In one embodiment, provided herein are methods for
preventing or delaying a RECIST (for example, RECIST 1.1) of PD in
a patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such methods for preventing or delaying a
RECIST (for example, RECIST 1.1) of PD in a patient having HCC
characterized by HBV infection. In one embodiment, provided herein
are methods for preventing or delaying a mRECIST for HCC of PD in a
patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such methods for preventing or delaying a
mRECIST for HCC of PD in a patient having HCC characterized by HBV
infection. In one embodiment, the prevention or delaying of PD is
characterized or achieved by a change in overall size of the target
lesions, for example, between -30% and -20% compared to
pre-treatment. In another embodiment, the change in size of the
target lesions is a reduction in overall size of more than 30%, for
example, more than 50% reduction in target lesion size compared to
pre-treatment. In another, the prevention is characterized or
achieved by a reduction in size or a delay in progression of
non-target lesions compared to pre-treatment. In one embodiment,
the prevention is achieved or characterized by a reduction in the
number of target lesions compared to pre-treatment. In another, the
prevention is achieved or characterized by a reduction in the
number or quality of non-target lesions compared to pre-treatment.
In one embodiment, the prevention is achieved or characterized by
the absence or the disappearance of target lesions compared to
pre-treatment. In another, the prevention is achieved or
characterized by the absence or the disappearance of non-target
lesions compared to pre-treatment. In another embodiment, the
prevention is achieved or characterized by the prevention of new
lesions compared to pre-treatment. In yet another embodiment, the
prevention is achieved or characterized by the prevention of
clinical signs or symptoms of disease progression compared to
pre-treatment, such as HCC-related cachexia or increased pain.
[0111] In certain embodiments, provided herein are methods for
decreasing the size of a target lesion in a patient having HCC
characterized by HBV infection compared to pre-treatment,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such methods for decreasing the size of a
target lesion in a patient having HCC characterized by HBV
infection compared to pre-treatment.
[0112] In certain embodiments, provided herein are methods for
decreasing the size of a non-target lesion in a patient having HCC
characterized by HBV infection compared to pre-treatment,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such methods for decreasing the size of a
non-target lesion in a patient having HCC characterized by HBV
infection compared to pre-treatment.
[0113] In certain embodiments, provided herein are methods for
achieving a reduction in the number of target lesions in a patient
having HCC characterized by HBV infection compared to
pre-treatment, comprising administering an effective amount of
Compound 1 to the patient having HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such methods
for achieving a reduction in the number of target lesions in a
patient having HCC characterized by HBV infection compared to
pre-treatment.
[0114] In certain embodiments, provided herein are methods for
achieving a reduction in the number of non-target lesions in a
patient having HCC characterized by HBV infection compared to
pre-treatment, comprising administering an effective amount
Compound 1 to the patient having HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such methods
for achieving a reduction in the number of non-target lesions in a
patient having HCC characterized by HBV infection compared to
pre-treatment.
[0115] In certain embodiments, provided herein are methods for
achieving an absence of all target lesions in a patient having HCC
characterized by HBV infection, comprising administering an
effective amount of Compound 1 to the patient having HCC
characterized by HBV infection. Provided herein is Compound 1 for
use in such methods for achieving an absence of all target lesions
in a patient having HCC characterized by HBV infection.
[0116] In certain embodiments, provided herein are methods for
achieving an absence of all non-target lesions in a patient having
HCC characterized by HBV infection, comprising administering an
effective amount of Compound 1 to the patient having HCC
characterized by HBV infection. Provided herein is Compound 1 for
use in such methods for achieving an absence of all non-target
lesions in a patient having HCC characterized by HBV infection.
[0117] In certain embodiments, provided herein are methods for
treating HCC characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a CR, PR or SD, as determined by RECIST (for example, RECIST 1.1
or mRECIST for HCC). Provided herein is Compound 1 for use in such
methods for treating HCC characterized by HBV infection, wherein
the methods comprise administering an effective amount of Compound
1 to a patient having HCC characterized by HBV infection, wherein
the treatment results in a CR, PR or SD, as determined by RECIST
(for example, RECIST 1.1 or mRECIST for HCC).
[0118] In certain embodiments, provided herein are methods for
treating HCC characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a reduction in target lesion size, a reduction in non-target
lesion size, a reduction in target lesion number, a reduction in
non-target lesion number, and/or the absence of all target and/or
non-target lesions, compared to pre-treatment. Provided herein is
Compound 1 for use in such methods treating HCC characterized by
HBV infection, wherein the methods comprise administering an
effective amount of Compound 1 to a patient having HCC
characterized by HBV infection, wherein the treatment results in a
reduction in target lesion size, a reduction in non-target lesion
size, a reduction in target lesion number, a reduction in
non-target lesion number, and/or the absence of all target and/or
non-target lesions, compared to pre-treatment.
[0119] In certain embodiments, provided herein are methods for
treating HCC characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in prevention or retarding of clinical progression, such as
HCC-related cachexia or increased pain. Provided herein is Compound
1 for use in such methods for treating HCC characterized by HBV
infection, wherein the methods comprise administering an effective
amount of Compound 1 to a patient having HCC characterized by HBV
infection, wherein the treatment results in prevention or retarding
of clinical progression, such as HCC-related cachexia or increased
pain.
[0120] In one embodiment, provided herein are methods for improving
the Eastern Cooperative Oncology Group Performance Status (ECOG) of
a patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection. Provided herein is Compound 1
for use in such methods for improving the Eastern Cooperative
Oncology Group Performance Status (ECOG) of a patient having HCC
characterized by HBV infection.
[0121] In another embodiment, provided herein are methods for
inducing a therapeutic response assessed by Positron Emission
Tomography (PET) outcome of a patient having HCC characterized by
HBV infection, comprising administering an effective amount of
Compound 1 to the patient having HCC characterized by HBV
infection. Provided herein is Compound 1 for use in such methods
for inducing a therapeutic response assessed by Positron Emission
Tomography (PET) outcome of a patient having HCC characterized by
HBV infection. In certain embodiments, provided herein are methods
for treating HCC characterized by HBV infection, the methods
comprising administering an effective amount of Compound 1 to a
patient having HCC characterized by HBV infection, wherein the
treatment results in a reduction in tumor metabolic activity, for
example, as measured by fluorodeoxyglucose (FDG)-PET imaging.
Provided herein is Compound 1 for use in such methods for treating
HCC characterized by HBV infection, wherein the methods comprises
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a reduction in tumor metabolic activity, for example, as
measured by fluorodeoxyglucose (FDG)-PET imaging. Other molecular
imaging agents for PET, such as choline, fluorocholine (FCH), or
fluorothylcholine (FEC), are also contemplated.
[0122] In yet another embodiment, provided herein are methods for
inducing a therapeutic response assessed by angiography outcome of
a patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such methods for inducing a therapeutic
response assessed by angiography outcome of a patient having HCC
characterized by HBV infection. In certain embodiments, provided
herein are methods for treating HCC characterized by HBV infection,
the methods comprising administering an effective amount of
Compound 1 to a patient having HCC characterized by HBV infection,
wherein the treatment results in a reduction in tumor vessels as
assessed by angiography. Provided herein is Compound 1 for use in
such methods for treating HCC characterized by HBV infection,
wherein the methods comprise administering an effective amount of
Compound 1 to a patient having HCC characterized by HBV infection,
wherein the treatment results in a reduction in tumor vessels as
assessed by angiography.
[0123] In still another embodiment, provided herein are methods for
inducing a therapeutic response assessed by ultrasonography outcome
of a patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection. Provided herein is
Compound 1 for use in such methods for inducing a therapeutic
response assessed by ultrasonography outcome of a patient having
HCC characterized by HBV infection. In certain embodiments,
provided herein are methods for treating HCC characterized by HBV
infection, the methods comprising administering an effective amount
of Compound 1 to a patient having HCC characterized by HBV
infection, wherein the treatment results in a reduction in tumor
mass as assessed by ultrasonography. Provided herein is Compound 1
for use in such methods for treating HCC characterized by HBV
infection, the methods comprising administering an effective amount
of Compound 1 to a patient having HCC characterized by HBV
infection, wherein the treatment results in a reduction in tumor
mass as assessed by ultrasonography.
[0124] In another embodiment, provided herein are methods for
inducing a therapeutic response assessed by diffusion-weighted MRI
outcome of a patient having HCC characterized by HBV infection,
comprising administering an effective amount of Compound 1 to the
patient having HCC characterized by HBV infection. Provided herein
is Compound 1 for use in such methods for inducing a therapeutic
response assessed by diffusion-weighted MRI outcome of a patient
having HCC characterized by HBV infection. In certain embodiments,
provided herein are methods for treating HCC characterized by HBV
infection, the methods comprising administering an effective amount
of Compound 1 to a patient having HCC characterized by HBV
infection, wherein the treatment results in a reduction in tumor
lesions as assessed by diffusion-weighted MRI. Provided herein is
Compound 1 for use in such methods for treating HCC characterized
by HBV infection, wherein the methods comprise administering an
effective amount of Compound 1 to a patient having HCC
characterized by HBV infection, wherein the treatment results in a
reduction in tumor lesions as assessed by diffusion-weighted
MRI.
[0125] In yet another embodiment, provided herein are methods for
inducing a therapeutic response assessed by acoustic radiation
force impulse (ARFI) imaging outcome of a patient having HCC
characterized by HBV infection, comprising administering an
effective amount of Compound 1 to the patient having HCC
characterized by HBV infection. Provided herein is Compound 1 for
use in such methods for inducing a therapeutic response assessed by
acoustic radiation force impulse (ARFI) imaging outcome of a
patient having HCC characterized by HBV infection. In certain
embodiments, provided herein are methods for treating HCC
characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a reduction in tumor stiffness as assessed by ARFI imaging.
Provided herein is Compound 1 for use in such methods for treating
HCC characterized by HBV infection, wherein the methods comprise
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a reduction in tumor stiffness as assessed by ARFI imaging.
[0126] In certain embodiments, provided herein are methods for
treating HCC characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in a reduction in level of AFP. Provided herein is Compound 1 for
use in such methods for treating HCC characterized by HBV
infection, the methods comprising administering an effective amount
of Compound 1 to a patient having HCC characterized by HBV
infection, wherein the treatment results in a reduction in level of
AFP. In some embodiments, provided herein are methods for reducing
level of AFP in a patient having HCC characterized by HBV
infection, comprising administering an effective amount of Compound
1 to the patient having HCC characterized by HBV infection.
Provided herein is Compound 1 for use in such methods for reducing
level of AFP in a patient having HCC characterized by HBV
infection. In some such embodiments, the level of AFP is assessed
in a biological sample of the patient, such as in circulating blood
cells and/or tumor biopsies. In such embodiments, the level of AFP
is assessed by comparison of the level of AFP before and after
administration of Compound 1. In certain embodiments, provided
herein are methods for measuring reduction of AFP level in a
patient having HCC characterized by HBV infection, comprising
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection, measuring the level of
AFP in the patient, and comparing the level of AFP after and before
administration of Compound 1. Provided herein is Compound 1 for use
in such methods for measuring reduction of AFP level in a patient
having HCC characterized by HBV infection, comprising administering
an effective amount of Compound 1 to the patient having HCC
characterized by HBV infection, measuring the level of AFP in the
patient, and comparing the level of AFP after and before
administration of Compound 1. In some embodiments, the reduction of
AFP level is assessed in circulating blood cells. In some
embodiments, the reduction of AFP level is assessed in tumor
biopsies. In certain embodiments, the AFP level is the mRNA level
of AFP. In other embodiments, the AFP level is the protein level of
AFP.
[0127] In one embodiment, provided herein are methods for
inhibiting phosphorylation of S6RP, 4E-BP1 and/or AKT in a patient
having HCC characterized by HBV infection, comprising administering
an effective amount of Compound 1 to the patient having HCC
characterized by HBV infection. Provided herein is Compound 1 for
use in such methods for inhibiting phosphorylation of S6RP, 4E-BP1
and/or AKT in a patient having HCC characterized by HBV infection.
In some such embodiments, the inhibition of phosphorylation is
assessed in a biological sample of the patient, such as in
circulating blood cells and/or tumor biopsies. In such embodiments,
the amount of inhibition of phosphorylation is assessed by
comparison of the amount of phospho-S6RP, 4E-BP1 and/or AKT before
and after administration of Compound 1. In certain embodiments,
provided herein are methods for measuring inhibition of
phosphorylation of S6RP, 4E-BP1 or AKT in a patient having HCC
characterized by HBV infection, comprising administering an
effective amount of Compound 1 to the patient having HCC
characterized by HBV infection, measuring the amount of
phosphorylated S6RP, 4E-BP1 and/or AKT in the patient, and
comparing the amount of phosphorylated S6RP, 4E-BP1 and/or AKT
after and before administration of Compound 1. Provided herein is
Compound 1 for use in such methods for measuring inhibition of
phosphorylation of S6RP, 4E-BP1 or AKT in a patient having HCC
characterized by HBV infection, wherein the method comprises
administering an effective amount of Compound 1 to the patient
having HCC characterized by HBV infection, measuring the amount of
phosphorylated S6RP, 4E-BP1 and/or AKT in the patient, and
comparing the amount of phosphorylated S6RP, 4E-BP1 and/or AKT
after and before administration of Compound 1. In some embodiments,
the inhibition of phosphorylation of S6RP, 4E-BP1 and/or AKT is
assessed in circulating blood cells. In some embodiments, the
inhibition of phosphorylation of S6RP, 4E-BP1 and/or AKT is
assessed in tumor biopsies.
[0128] In certain embodiments, provided herein are methods for
inhibiting phosphorylation of S6RP, 4E-BP1 and/or AKT in a
biological sample of a patient having HCC characterized by HBV
infection, comprising administering an effective amount of Compound
1 to the patient having HCC characterized by HBV infection and
comparing the amount of phosphorylated S6RP, 4E-BP1 and/or AKT in a
biological sample of the patient obtained prior to and after
administration of Compound 1, wherein less phosphorylated S6RP,
4E-BP1 and/or AKT in the biological sample obtained after
administration of Compound 1 relative to the amount of
phosphorylated S6RP, 4E-BP1 and/or AKT in the biological sample
obtained prior to administration of Compound 1 indicates
inhibition. Provided herein is Compound 1 for use in such methods
for inhibiting phosphorylation of S6RP, 4E-BP1 and/or AKT in a
biological sample of a patient having HCC characterized by HBV
infection, wherein the method comprises administering an effective
amount of Compound 1 to the patient having HCC characterized by HBV
infection and comparing the amount of phosphorylated S6RP, 4E-BP1
and/or AKT in a biological sample of the patient obtained prior to
and after administration of Compound 1, wherein less phosphorylated
S6RP, 4E-BP1 and/or AKT in the biological sample obtained after
administration of Compound 1 relative to the amount of
phosphorylated S6RP, 4E-BP1 and/or AKT in the biological sample
obtained prior to administration of Compound 1 indicates
inhibition. In some embodiments, the inhibition of phosphorylation
of S6RP, 4E-BP1 and/or AKT is assessed in circulating blood cells.
In some embodiments, the inhibition of phosphorylation of S6RP,
4E-BP1 and/or AKT is assessed in tumor biopsies. Inhibition of
phosphorylation of S6RP (Ser235/236 and/or Ser240/244), 4E-BP1
(Thr37/46), and/or AKT (Ser473) can be measured by various
methodology including flow cytometry, ELISA, immunohistochemistry
(IHC), immunofluorescence (IF) using phosphorylation-specific
antibodies.
[0129] In some embodiments, provided herein are methods for
treating HCC characterized by HBV infection, the methods comprising
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in one or more of inhibition of disease progression, inhibition of
tumor growth, reduction of primary tumor, relief of tumor-related
symptoms, inhibition of tumor secreted factors (e.g., AFP), delayed
appearance of primary or secondary tumors, slowed development of
primary or secondary tumors, decreased occurrence of primary or
secondary tumors, slowed or decreased severity of secondary effects
of disease, arrested tumor growth and regression of tumors,
increased TTP, increased PFS, and/or increased OS, among others.
Provided herein is Compound 1 for use in such methods for treating
HCC characterized by HBV infection, wherein the methods comprise
administering an effective amount of Compound 1 to a patient having
HCC characterized by HBV infection, wherein the treatment results
in one or more of inhibition of disease progression, inhibition of
tumor growth, reduction of primary tumor, relief of tumor-related
symptoms, inhibition of tumor secreted factors (e.g., AFP), delayed
appearance of primary or secondary tumors, slowed development of
primary or secondary tumors, decreased occurrence of primary or
secondary tumors, slowed or decreased severity of secondary effects
of disease, arrested tumor growth and regression of tumors,
increased TTP, increased PFS, and/or increased OS, among
others.
[0130] Further provided herein are methods for treating patients
who have been previously treated for HCC, as well as those who have
not previously been treated. Provided herein is Compound 1 for use
in such methods for treating patients who have been previously
treated for HCC, as well as those who have not previously been
treated. Further provided herein are methods for treating patients
who have undergone surgery in an attempt to treat HCC, as well as
those who have not. Provided herein is Compound 1 for use in such
methods for treating patients who have undergone surgery in an
attempt to treat HCC, as well as those who have not. Because
patients with HCC have heterogeneous clinical manifestations and
varying clinical outcomes, the treatment given to a patient may
vary, depending on his/her prognosis. The skilled clinician will be
able to readily determine without undue experimentation specific
secondary agents (see for example U.S. Provisional Application Nos.
61/980,124 and 61/980,125 and U.S. Patent Publication Nos.
2015/0297590 and 2015/0297605, each incorporated by reference
herein in their entirety), types of surgery, and types of non-drug
based standard therapy that can be effectively used to treat an
individual patient with HCC.
[0131] Compound 1 can be combined with radiation therapy,
chemoembolization, radio frequency ablation, thermal techniques
(e.g., microwave ablation, laser ablation, and cryoablation),
non-thermal techniques (e.g., reversible electroporation,
irreversible electroporation, and light-activated drug therapy), or
surgery. In certain embodiments, Compound 1 is administered to
patient who is undergoing radiation therapy, has previously
undergone radiation therapy or will be undergoing radiation
therapy. In some embodiments, Compound 1 is administered to patient
who is undergoing chemoembolization, has previously undergone
chemoembolization or will be undergoing chemoembolization. In other
embodiments, Compound 1 is administered to patient who is
undergoing radio frequency ablation, has previously undergone radio
frequency ablation or will be undergoing radio frequency ablation.
In yet other embodiments, Compound 1 is administered to patient who
is undergoing microwave ablation, has previously undergone
microwave ablation or will be undergoing microwave ablation. In
still other embodiments, Compound 1 is administered to patient who
is undergoing laser ablation, has previously undergone laser
ablation or will be undergoing laser ablation. In certain
embodiments, Compound 1 is administered to patient who is
undergoing cryoablation, has previously undergone cryoablation or
will be undergoing cryoablation. In some embodiments, Compound 1 is
administered to patient who is undergoing reversible
electroporation, has previously undergone reversible
electroporation or will be undergoing reversible electroporation.
In other embodiments, Compound 1 is administered to patient who is
undergoing irreversible electroporation, has previously undergone
irreversible electroporation or will be undergoing irreversible
electroporation. In yet other embodiments, Compound 1 is
administered to patient who is undergoing light-activated drug
therapy, has previously undergone light-activated drug therapy or
will be undergoing light-activated drug therapy. In yet other
embodiments, Compound 1 is administered to a patient who is
undergoing tumor removal surgery, has previously undergone tumor
removal surgery or will be undergoing tumor removal surgery.
[0132] Further provided herein are methods of reducing, treating
and/or preventing adverse or undesired effects associated with
conventional therapy including, but not limited to, surgery,
chemotherapy, radiation therapy, hormonal therapy, biological
therapy and immunotherapy. Provided herein is Compound 1 for use in
such methods of reducing, treating and/or preventing adverse or
undesired effects associated with conventional therapy including,
but not limited to, surgery, chemotherapy, radiation therapy,
hormonal therapy, biological therapy and immunotherapy. Compound 1
and other active ingredients can be administered to a patient prior
to, during, or after the occurrence of the adverse effect
associated with conventional therapy.
[0133] In some embodiments, the HCC is unresectable HCC. In certain
embodiments, the HCC is resistant to at least one anticancer
therapy. In other embodiments, the HCC is relapsed or refractory to
at least one anticancer therapy. In yet other embodiments, the HCC
is metastatic.
[0134] In each of the embodiments provided herein, the term "HCC
characterized by HBV infection" is interchangeable with the terms
"HCC associated with HBV infection," "HCC related to HBV
infection," "HCC with a history of HBV infection," "HBV positive
HCC," "HBV associated HCC," "HBV related HCC," or "HBV infected
HCC."
5.4 Pharmaceutical Compositions and Routes of Administration
[0135] Compositions as provided herein can be used in all methods
provided herein.
[0136] Provided herein are compositions comprising an effective
amount of Compound 1 and compositions comprising an effective
amount of Compound 1 and pharmaceutically acceptable carriers or
vehicles. In some embodiments, the pharmaceutical composition
described herein is suitable for oral, parenteral, mucosal,
transdermal or topical administration.
[0137] Compositions of Compound 1 include the pharmaceutical
compositions provided in U.S. Pat. No. 9,403,829, issued on Aug. 2,
2016; and U.S. Pat. No. 9,604,939, issued on Mar. 28, 2017, the
entire contents of each of which are incorporated herein by
reference.
[0138] Compound 1 can be administered to a patient orally or
parenterally in the conventional form of preparations, such as
capsules, microcapsules, tablets, granules, powder, troches, pills,
suppositories, injections, suspensions and syrups. Suitable
formulations can be prepared by methods commonly employed using
conventional, organic or inorganic additives, such as an excipient
(e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose,
cellulose, talc, calcium phosphate or calcium carbonate), a binder
(e.g., cellulose, methylcellulose, hydroxymethylcellulose,
polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic,
polyethyleneglycol, sucrose or starch), a disintegrator (e.g.,
starch, carboxymethylcellulose, hydroxypropylstarch, low
substituted hydroxypropylcellulose, sodium bicarbonate, calcium
phosphate or calcium citrate), a lubricant (e.g., magnesium
stearate, light anhydrous silicic acid, talc or sodium lauryl
sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or
orange powder), a preservative (e.g, sodium benzoate, sodium
bisulfite, methylparaben or propylparaben), a stabilizer (e.g.,
citric acid, sodium citrate or acetic acid), a suspending agent
(e.g., methylcellulose, polyvinyl pyrroliclone or aluminum
stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose),
a diluent (e.g., water), and base wax (e.g., cocoa butter, white
petrolatum or polyethylene glycol). The effective amount of
Compound 1 in the pharmaceutical composition may be at a level that
will exercise the desired effect; for example, about 0.005 mg/kg of
a patient's body weight to about 10 mg/kg of a patient's body
weight in unit dosage for both oral and parenteral administration.
In certain embodiments, the pharmaceutical composition comprises
Compound 1 and suitable additives. In other embodiments, the
pharmaceutical composition comprises Compound 1 only. In yet other
embodiments, the pharmaceutical composition comprises Compound 1
and suitable additives in capsules. In still other embodiments, the
pharmaceutical composition comprises Compound 1 only in
capsules.
[0139] The dose of Compound 1 to be administered to a patient is
rather widely variable and can be patient-dependent to the judgment
of a health-care practitioner. In general, Compound 1 can be
administered one to four times a day in a dose of about 0.005 mg/kg
of a patient's body weight to about 10 mg/kg of a patient's body
weight in a patient, but the above dosage may be properly varied
depending on the age, body weight and medical condition of the
patient and the type of administration. In one embodiment, the dose
is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of
a patient's body weight, about 0.05 mg/kg of a patient's body
weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg
of a patient's body weight to about 0.75 mg/kg of a patient's body
weight or about 0.25 mg/kg of a patient's body weight to about 0.5
mg/kg of a patient's body weight. In one embodiment, one dose is
given per day. In another embodiment, two doses are given per day.
In any given case, the amount of Compound 1 administered will
depend on such factors as the solubility of the active component,
the formulation used and the route of administration. In some
embodiments, the effective amount of Compound 1 in the
pharmaceutical composition is about 0.01, 0.25, 0.05, 0.75, 0.1,
0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0
mg/kg of a patient's body weight in unit dosage for oral
administration. In one embodiment, the effective amount of Compound
1 in the pharmaceutical composition is about 0.21 mg/kg of a
patient's body weight in unit dosage for oral administration. In
another embodiment, the effective amount of Compound 1 in the
pharmaceutical composition is about 0.43 mg/kg of a patient's body
weight in unit dosage for oral administration. In yet another
embodiment, the effective amount of Compound 1 in the
pharmaceutical composition is about 0.64 mg/kg of a patient's body
weight in unit dosage for oral administration.
[0140] In another embodiment, provided herein are methods for the
treatment or prevention of HCC characterized by HBV infection
comprising administration of about 0.375 mg/day to about 750
mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to
about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18
mg/day to about 37 mg/day of Compound 1 to a patient in need
thereof. Provided herein is Compound 1 for use in such methods for
the treatment or prevention of HCC characterized by HBV infection,
wherein the method comprises administration of about 0.375 mg/day
to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about
3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day
or about 18 mg/day to about 37 mg/day of Compound 1 to a patient in
need thereof. In a particular embodiment, the methods disclosed
herein comprise administration of 15 mg/day, 30 mg/day, 45 mg/day
or 60 mg/day of Compound 1 to a patient in need thereof. In another
embodiment, the methods disclosed herein comprise administration of
0.5 mg/day, 1 mg/day, 2 mg/day, 4 mg/day, 8 mg/day, 16 mg/day, 20
mg/day, 25 mg/day, 30 mg/day or 40 mg/day of Compound 1 to a
patient in need thereof. In a particular embodiment, the methods
disclosed herein comprise administration of 15 mg/day, 20 mg/day,
or 30 mg/day of Compound 1 to a patient in need thereof. In some
such embodiments, the methods additionally comprise administration
of 240 mg nivolumab every 2 weeks. In some such embodiments, the
methods additionally comprise administration of 480 mg nivolumab
every 4 weeks.
[0141] In another embodiment, provided herein are methods for the
treatment or prevention of HCC characterized by HBV infection
comprising administration of about 0.1 mg/day to about 1200 mg/day,
about 1 mg/day to about 100 mg/day, about 10 mg/day to about 1200
mg/day, about 10 mg/day to about 100 mg/day, about 100 mg/day to
about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600
mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day
or about 600 mg/day to about 800 mg/day of Compound 1 to a patient
in need thereof. Provided herein is Compound 1 for use in such
methods for the treatment or prevention of HCC characterized by HBV
infection, wherein the method comprises administration of about 0.1
mg/day to about 1200 mg/day, about 1 mg/day to about 100 mg/day,
about 10 mg/day to about 1200 mg/day, about 10 mg/day to about 100
mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to
about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400
mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day
of Compound 1 to a patient in need thereof. In a particular
embodiment, the methods disclosed herein comprise administration of
0.1 mg/day, 0.5 mg/day, 1 mg/day, 10 mg/day, 15 mg/day, 20 mg/day,
30 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 60 mg/day, 75 mg/day,
100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300
mg/day, 400 mg/day, 600 mg/day or 800 mg/day of Compound 1 to a
patient in need thereof. In a specific embodiment, the methods
disclosed herein comprise administration of 0.1 mg/day of Compound
1 to a patient in need thereof. In a specific embodiment, the
methods disclosed herein comprise administration of 0.5 mg/day of
Compound 1 to a patient in need thereof. In a specific embodiment,
the methods disclosed herein comprise administration of 1 mg/day of
Compound 1 to a patient in need thereof. In a specific embodiment,
the methods disclosed herein comprise administration of 10 mg/day
of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
15 mg/day of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
20 mg/day of Compound 1 to a patient in need thereof. In a specific
embodiment, provided herein are methods for the treatment or
prevention of HCC characterized by HBV infection comprising
administration of 30 mg/day of Compound 1 to a patient in need
thereof. Provided herein is Compound 1 for use in such methods for
the treatment or prevention of HCC characterized by HBV infection,
wherein the method comprises administration of 30 mg/day of
Compound 1 to a patient in need thereof. In a specific embodiment,
the methods disclosed herein comprise administration of 40 mg/day
of Compound 1 to a patient in need thereof. In another specific
embodiment, provided herein are methods for the treatment or
prevention of HCC characterized by HBV infection comprising
administration of 45 mg/day of Compound 1 to a patient in need
thereof. Provided herein is Compound 1 for use in such methods for
the treatment or prevention of HCC characterized by HBV infection,
wherein the method comprises administration of 45 mg/day of
Compound 1 to a patient in need thereof. In a specific embodiment,
the methods disclosed herein comprise administration of 50 mg/day
of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
60 mg/day of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
75 mg/day of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
100 mg/day of Compound 1 to a patient in need thereof. In a
specific embodiment, the methods disclosed herein comprise
administration of 125 mg/day of Compound 1 to a patient in need
thereof. In a specific embodiment, the methods disclosed herein
comprise administration of 150 mg/day of Compound 1 to a patient in
need thereof. In a specific embodiment, the methods disclosed
herein comprise administration of 200 mg/day of Compound 1 to a
patient in need thereof. In a specific embodiment, the methods
disclosed herein comprise administration of 250 mg/day of Compound
1 to a patient in need thereof. In a specific embodiment, the
methods disclosed herein comprise administration of 300 mg/day of
Compound 1 to a patient in need thereof. In a specific embodiment,
the methods disclosed herein comprise administration of 400 mg/day
of Compound 1 to a patient in need thereof. In a specific
embodiment, the methods disclosed herein comprise administration of
600 mg/day of Compound 1 to a patient in need thereof. In a
specific embodiment, the methods disclosed herein comprise
administration of 800 mg/day of Compound 1 to a patient in need
thereof. In some such embodiments, the methods additionally
comprise administration of 240 mg nivolumab every 2 weeks. In some
such embodiments, the methods additionally comprise administration
of 480 mg nivolumab every 4 weeks.
[0142] In another embodiment, provided herein are unit dosage
formulations that comprise between about 0.1 mg and about 2000 mg,
about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg
and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg
and about 1000 mg of Compound 1. In one embodiment, provided herein
are unit dosage formulations that comprise between about 0.1 mg and
about 2000 mg of Compound 1. In one embodiment, provided herein are
unit dosage formulations that comprise between about 1 mg and 200
mg of Compound 1. In one embodiment, provided herein are unit
dosage formulations that comprise between about 35 mg and about
1400 mg of Compound 1. In one embodiment, provided herein are unit
dosage formulations that comprise between about 125 mg and about
1000 mg of Compound 1. In one embodiment, provided herein are unit
dosage formulations that comprise between about 250 mg and about
1000 mg of Compound 1. In one embodiment, provided herein are unit
dosage formulations that comprise between about 500 mg and about
1000 mg of Compound 1.
[0143] In a particular embodiment, provided herein are unit dosage
formulation comprising about 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 5 mg,
10 mg, 15 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125
mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg of
Compound 1.
[0144] In another embodiment, provided herein are unit dosage
formulations that comprise 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5
mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125
mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg,
700 mg, 750 mg, 1000 mg or 1400 mg of Compound 1. In a particular
embodiment, provided herein are unit dosage formulations that
comprise about 5 mg, about 15 mg, about 20 mg, about 30 mg, about
45 mg, and about 50 mg of Compound 1. In one embodiment, provided
herein are unit dosage formulations that comprise 0.1 mg of
Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 0.25 mg of Compound 1. In one
embodiment, provided herein are unit dosage formulations that
comprise 0.5 mg of Compound 1. In one embodiment, provided herein
are unit dosage formulations that comprise 1 mg of Compound 1. In
one embodiment, provided herein are unit dosage formulations that
comprise 2.5 mg of Compound 1. In another embodiment, provided
herein are unit dosage formulations that comprise 5 mg of Compound
1. In yet another embodiment, provided herein are unit dosage
formulations that comprise 10 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 15 mg of
Compound 1. In still another embodiment, provided herein are unit
dosage formulations that comprise 20 mg of Compound 1. In one
embodiment, provided herein are unit dosage formulations that
comprise 30 mg of Compound 1. In one embodiment, provided herein
are unit dosage formulations that comprise 35 mg of Compound 1. In
another embodiment, provided herein are unit dosage formulations
that comprise 45 mg of Compound 1. In one embodiment, provided
herein are unit dosage formulations that comprise 50 mg of Compound
1. In one embodiment, provided herein are unit dosage formulations
that comprise 60 mg of Compound 1. In one embodiment, provided
herein are unit dosage formulations that comprise 70 mg of Compound
1. In one embodiment, provided herein are unit dosage formulations
that comprise 100 mg of Compound 1. In one embodiment, provided
herein are unit dosage formulations that comprise 125 mg of
Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 140 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 175 mg
of Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 200 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 250 mg
of Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 280 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 350 mg
of Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 500 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 560 mg
of Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 700 mg of Compound 1. In one embodiment,
provided herein are unit dosage formulations that comprise 750 mg
of Compound 1. In one embodiment, provided herein are unit dosage
formulations that comprise 1000 mg of Compound 1. In one
embodiment, provided herein are unit dosage formulations that
comprise 1400 mg of Compound 1.
[0145] Compound 1 can be administered once daily (QD), or divided
into multiple daily doses such as twice daily (BID), three times
daily (TID), and four times daily (QID). In a specific embodiment,
Compound 1 is administered QD. In another embodiment, Compound 1 is
administered BID. In yet another embodiment, Compound 1 is
administered TID. In still another embodiment, Compound 1 is
administered QID. In addition, the administration can be continuous
(i.e., daily for consecutive days or every day), intermittent,
e.g., in cycles (i.e., including days, weeks, or months of rest
without drug). In a preferred embodiment, the administration is
continuous. In another preferred embodiment, Compound 1 is
administered in 28-day cycles. In a preferred embodiment, Compound
1 is administered continuously in a daily dosing in 28-day cycles.
In a preferred embodiment, Compound 1 is administered continuously
in a daily dosing in 28-day cycles at a dose of 30 mg/day. In a
preferred embodiment, Compound 1 is administered continuously in a
daily dosing in 28-day cycles at a dose of 45 mg/day. In a
preferred embodiment, Compound 1 is administered continuously in a
daily dosing in 28-day cycles at a dose of 30 mg/day with no rest
period between each 28-day cycle. In a preferred embodiment,
Compound 1 is administered continuously in a daily dosing in 28-day
cycles at a dose of 45 mg/day with no rest period between each
28-day cycle.
[0146] Compound 1 can be administered orally for reasons of
convenience. In one embodiment, when administered orally, Compound
1 is administered with a meal and water. In another embodiment,
Compound 1 is dispersed in water or juice (e.g., apple juice or
orange juice) and administered orally as a suspension. In another
embodiment, when administered orally, Compound 1 is administered in
a fasted state. Preferably, Compound 1 is administered orally. In
one preferred embodiment, Compound 1 is administered orally at a
dose of 30 mg/day. In another preferred embodiment, Compound 1 is
administered orally at a dose of 45 mg/day. In a preferred
embodiment, Compound 1 is administered continuously in a daily oral
dosing in 28-day cycles at a dose of 30 mg/day. In another
preferred embodiment, Compound 1 is administered continuously in a
daily oral dosing in 28-day cycles at a dose of 45 mg/day. In a
preferred embodiment, Compound 1 is administered continuously in a
daily oral dosing in 28-day cycles at a dose of 30 mg/day with no
rest period between each 28-day cycle. In another preferred
embodiment, Compound 1 is administered continuously in a daily oral
dosing in 28-day cycles at a dose of 45 mg/day with no rest period
between each 28-day cycle.
[0147] Compound 1 can also be administered intradermally,
intramuscularly, intraperitoneally, percutaneously, intravenously,
subcutaneously, intranasally, epidurally, sublingually,
intracerebrally, intravaginally, transdermally, rectally,
mucosally, by inhalation, or topically to the ears, nose, eyes, or
skin. The mode of administration is left to the discretion of the
health-care practitioner and can depend in-part upon the site of
the medical condition.
[0148] In one embodiment, provided herein are capsules containing
Compound 1 without an additional carrier, excipient or vehicle.
[0149] In another embodiment, provided herein are compositions
comprising an effective amount of Compound 1 and a pharmaceutically
acceptable carrier or vehicle, wherein a pharmaceutically
acceptable carrier or vehicle can comprise an excipient, diluent,
or a mixture thereof. In one embodiment, the composition is a
pharmaceutical composition.
[0150] The compositions can be in the form of tablets, chewable
tablets, capsules, solutions, parenteral solutions, troches,
suppositories and suspensions and the like. Compositions can be
formulated to contain a daily dose, or a convenient fraction of a
daily dose, in a dosage unit, which may be a single tablet or
capsule or convenient volume of a liquid. In one embodiment, the
solutions are prepared from water-soluble salts, such as the
hydrochloride salt. In general, all of the compositions are
prepared according to known methods in pharmaceutical chemistry.
Capsules can be prepared by mixing Compound 1 with a suitable
carrier or diluent and filling the proper amount of the mixture in
capsules. The usual carriers and diluents include, but are not
limited to, inert powdered substances such as starch of many
different kinds, powdered cellulose, especially crystalline and
microcrystalline cellulose, sugars such as fructose, mannitol and
sucrose, grain flours and similar edible powders.
[0151] Tablets can be prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful. In
one embodiment, the pharmaceutical composition is lactose-free.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders.
[0152] A lubricant might be necessary in a tablet formulation to
prevent the tablet and punches from sticking in the die. The
lubricant can be chosen from such slippery solids as talc,
magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils. Tablet disintegrators are substances that swell
when wetted to break up the tablet and release the compound. They
include starches, clays, celluloses, algins and gums. More
particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood cellulose, powdered natural sponge, cation-exchange
resins, alginic acid, guar gum, citrus pulp and carboxymethyl
cellulose, for example, can be used as well as sodium lauryl
sulfate. Tablets can be coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compositions can also be formulated
as chewable tablets, for example, by using substances such as
mannitol in the formulation.
[0153] When it is desired to administer Compound 1 as a
suppository, typical bases can be used. Cocoa butter is a
traditional suppository base, which can be modified by addition of
waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of
various molecular weights are in wide use.
[0154] The effect of Compound 1 can be delayed or prolonged by
proper formulation. For example, a slowly soluble pellet of
Compound 1 can be prepared and incorporated in a tablet or capsule,
or as a slow-release implantable device. The technique also
includes making pellets of several different dissolution rates and
filling capsules with a mixture of the pellets. Tablets or capsules
can be coated with a film that resists dissolution for a
predictable period of time. Even the parenteral preparations can be
made long-acting, by dissolving or suspending Compound 1 in oily or
emulsified vehicles that allow it to disperse slowly in the
serum.
5.5 Kits
[0155] In certain embodiments, provided herein are kits comprising
Compound 1. In particular embodiments, provided herein are kits
comprising a unit dosage form comprising Compound 1 in a sealed
container, wherein the unit dosage form comprises about 1 mg to
about 100 mg of Compound 1. In particular embodiments, provided
herein are kits comprising a unit dosage form comprising Compound 1
in a sealed container, wherein the unit dosage form comprises about
5 mg, about 20 mg or about 50 mg of Compound 1.
[0156] In other embodiments, provide herein are kits comprising
Compound 1 and means for monitoring patient response to
administration of Compound 1. In certain embodiments, the patient
has HCC characterized by HBV infection. In particular embodiments,
the patient response measured is inhibition of disease progression,
inhibition of tumor growth, reduction of primary and/or secondary
tumor(s), relief of tumor-related symptoms, improvement in quality
of life, inhibition of tumor secreted factors (e.g., AFP), delayed
appearance of primary and/or secondary tumor(s), slowed development
of primary and/or secondary tumor(s), decreased occurrence of
primary and/or secondary tumor(s), slowed or decreased severity of
secondary effects of disease, arrested tumor growth and/or
regression of tumors.
[0157] In other embodiments, provide herein are kits comprising
Compound 1 and means for monitoring patient response to
administration of Compound 1, wherein said response is RECIST (for
example, RECIST 1.1 or mRECIST for HCC) or ECOG.
[0158] In other embodiments, provided herein are kits comprising
Compound 1 and means for measuring the amount of inhibition of
phosphorylation of S6RP, 4E-BP1 and/or AKT in a patient. In certain
embodiments, the kits comprise means for measuring inhibition of
phosphorylation of S6RP, 4E-BP1 and/or AKT in circulating blood
cells and/or tumor biopsies of a patient. In certain embodiments,
provided herein are kits comprising Compound 1 and means for
measuring the amount of inhibition of phosphorylation as assessed
by comparison of the amount of phospho-S6RP, 4E-BP1 and/or AKT
before, during and/or after administration of Compound 1. In
certain embodiments, the patient has HCC characterized by HBV
infection.
[0159] Inhibition of phosphorylation of S6RP, 4E-BP1, and/or AKT
can be measured in blood, skin, tumor, and/or circulating tumor
cells (CTCs) in blood by various methodology including flow
cytometry, ELISA, IHC using phosphorylation-specific
antibodies.
[0160] In certain embodiments, the kits provided herein comprise an
amount of Compound 1 effective for treating or preventing HCC
characterized by HBV infection.
[0161] In certain embodiments, the kits provided herein further
comprise instructions for use, such as for administering Compound 1
and/or monitoring patient response to administration of Compound
1.
6. EXAMPLES
6.1 Clinical Study 1
[0162] A Phase 1/2 Multi-Center, Open-Label, Dose Finding Study to
Assess the Safety, Tolerability, PK and Preliminary Efficacy of
Compound 1 Administered Orally to Subjects with Phase 1/2,
Multi-Center, Open-Label, Dose Finding Study to Assess the Safety,
Tolerability, PK and Preliminary Efficacy of Compound 1
Administered Orally to Subjects with Phase 1/2, Multi-Center, Open
Label, Dose Finding Study to Assess the Safety, Tolerability, PK
and Preliminary Efficacy of Compound 1 Administered Orally to
Subjects with Phase 1/2, Multi-Center, Open-Label, Dose Finding
Study to Assess the Safety, Tolerability, PK and Preliminary
Efficacy of Compound 1 Administered Orally to Subjects with
HCC.
[0163] The study was designed as a Phase 1/2 trial consisting of
two parts: dose escalation (Part A) and dose expansion (Part
B).
[0164] Part A was an open-label, dose-escalating study of subjects
with various hematologic or solid malignancies. The primary
objectives were to determine the maximum tolerated dose (MTD) and
the preliminary PK of Compound 1. The MTD of Compound 1 was
determined to be 45 mg/day, and the nontolerated dose (NTD) was
determined to be 60 mg/day. The PK and PD data supported once daily
dosing with Compound 1.
[0165] Part B, the preliminary efficacy-seeking phase, was an
open-label, dose-expansion study, which involved subjects with
HCC.
[0166] The primary objectives for Part B were (a) to determine the
safety and tolerability of Compound 1 when administered orally and
(b) to determine the preliminary PK of Compound 1 following both
single and multiple oral dosing of Compound 1.
[0167] The secondary objectives of Part B were: (a) to provide
information on the preliminary efficacy of Compound 1; (b) to
characterize the PK of M1 (the metabolite of Compound 1) following
oral dosing of Compound 1; (c) to characterize the PK of Compound 1
and M1 in subjects with HCC; and (d) to evaluate the extent of
inhibition of phosphorylation of S6RP and/or 4E-BP1 for mTORC1
activity and AKT and/or other relevant biomarkers for mTORC2
activity in peripheral blood samples and tumor biopsies following
treatment with Compound 1.
[0168] Subjects received continuous daily dosing of Compound 1 in
28-day cycles (FIG. 1). Therapy was discontinued if there was
evidence of disease progression, but subjects continued to receive
Compound 1 as long as the investigator considered that the subjects
derived benefit from treatment. Therapy was discontinued if there
was unacceptable toxicity or if the subject decided to withdraw
from the study. Subjects were contacted 28 days after the last dose
of study drug to assess the status of adverse events (AEs) and to
determine whether any new events or death had occurred. In addition
to those subjects who had died on study, approximately 28 subjects
were consented for follow-up every 2 months (.+-.1 week) after
completing the treatment phase in order to determine their date of
death and complete an overall survival analysis.
[0169] The inclusion criteria for selection of study population
include: (1) understand and voluntarily sign an informed consent
document prior to any study-related assessments/procedures were
conducted; (2) men and women, .gtoreq.18 years old, with
histologically or cytologically-confirmed, advanced unresectable
HCC including subjects who had progressed on (or not been able to
tolerate) standard anticancer therapy or for whom no standard
anticancer therapy exists; (3) ECOG performance status of 0 or 1;
(4) subjects must have had the following laboratory values:
absolute neutrophil count.gtoreq.1.5.times.109/L,
hemoglobin.gtoreq.9 g/dL, platelets.gtoreq.100.times.109/L,
potassium within normal limits or correctable with supplements,
aspartate aminotransferase (AST) and alanine aminotransferase
(ALT).ltoreq.2.5.times. upper limit of normal (ULN) or
.ltoreq.5.0.times.ULN, serum bilirubin.ltoreq.1.5.times.ULN or
.ltoreq.2.times.ULN, serum creatinine.ltoreq.1.5.times.ULN or
24-hour clearance.gtoreq.50 mL/min, negative serum or urine
pregnancy test within 48 hours before starting study treatment in
females of childbearing potential; (5) able to adhere to the study
visit schedule and other protocol requirements; (6) retrieval of
formalin-fixed, paraffin embedded archival tumor tissue, either in
tumor blocks or sectioned/mounted specimens for gene mutation
and/or IHC biomarker assay. Only in exceptional circumstances was
an exemption waiver granted by the sponsor. (7) satisfactory
screening biopsy for gene mutation and/or IHC biomarker assay for
accessible tumors; (8) histologically-confirmed HCC with measurable
disease. The following criteria are in addition to, or supersede,
above criteria where applicable: platelet
count.gtoreq.60.times.109/L if portal hypertension was present,
Child-Pugh score of <7 (i.e., Class A liver function or better),
at least 4 weeks from last dose of .alpha.-interferon and/or
ribavirin, at least 4 weeks from prior percutaneous ethanol
injection, radiofrequency ablation, transarterial embolization, or
cryotherapy with documentation of progressive or recurrent
disease.
[0170] The exclusion criteria for selection of study population
include: (1) symptomatic central nervous system metastases.
Subjects with brain metastases that had been previously treated and
were stable for 6 weeks were allowed. (2) known acute or chronic
pancreatitis; (3) subjects with any peripheral
neuropathy.gtoreq.National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) Grade 2; (4) subjects with
persistent diarrhea or malabsorption Grade.gtoreq.2, despite
medical management; (5) impaired cardiac function or clinically
significant cardiac diseases, including any of the following: left
ventricular ejection fraction (LVEF)<45% as determined by
multiple gated acquisition (MUGA) scan or echocardiogram, complete
left bundle branch, or bifascicular, block, congenital long QT
syndrome, persistent or clinically meaningful ventricular
arrhythmias or atrial fibrillation, QT interval with Fridericia
correction (QTcF)>460 msec on screening ECG (mean of triplicate
recordings), unstable angina pectoris or myocardial
infarction.ltoreq.3 months prior to starting Compound 1, other
clinically significant heart disease such as congestive heart
failure requiring treatment or uncontrolled hypertension (blood
pressure.gtoreq.160/95 mmHg); (6) subjects with diabetes on active
treatment or subjects with either of the following: fasting blood
glucose.gtoreq.126 mg/dL (7.0 mmol/L), or glycosylated hemoglobin
(HbAlc).gtoreq.6.5%; (7) other concurrent severe and/or
uncontrolled concomitant medical conditions (e.g., active or
uncontrolled infection) that could have caused unacceptable safety
risks or compromised compliance with the protocol; (8) prior
systemic cancer-directed treatments or investigational
modalities.ltoreq.5 half lives or 4 weeks, whichever was shorter,
prior to starting study drug or who had not recovered from side
effects of such therapy. Subjects must have recovered from any
effects of recent radiotherapy that might have confounded the
safety evaluation of study drug. (9) subjects who had undergone
major surgery.ltoreq.2 weeks prior to starting study drug or who
had not recovered from side effects of such therapy; (10) women who
were pregnant or breast feeding. Adults of reproductive potential
not employing 2 forms of birth control: (a) female subjects of
childbearing potential must have agreed to use 2 adequate forms of
contraception methods simultaneously (one must have been
non-hormonal) from the time of giving informed consent until 28
days after the last dose of Compound 1. Female subjects of
child-bearing potential, defined as sexually mature women who had
not undergone a hysterectomy or bilateral oophorectomy, or who had
not been naturally postmenopausal (i.e., who had not menstruated at
all) for at least 24 consecutive months. (b) male subjects with
partners who were female with child-bearing potential must have
agreed that they or their partners would use at least 2 effective
contraceptive methods (including 1 barrier method) when engaging in
reproductive sexual activity throughout the study, and would avoid
conceiving for 28 days after the last dose of Compound 1. (11)
subjects with known human immunodeficiency virus infection; (12)
any significant medical condition, laboratory abnormality, or
psychiatric illness that would have prevented the subject from
participating in the study; (13) any condition including the
presence of laboratory abnormalities, which placed the subject at
unacceptable risk if he/she were to participate in the study; (14)
any condition that confounded the ability to interpret data from
the study; (15) concurrent active second malignancy for which the
subject was receiving therapy, excluding nonmelanomatous skin
cancer or carcinoma in situ of the cervix.
[0171] Compound 1 was supplied in three strengths, 2.5 mg, 10 mg,
and 20 mg, containing only the active pharmaceutical ingredient in
reddish brown size Number 1 gelatin capsules for oral
administration. No other excipients were used.
[0172] HBV Status of HCC Patients
[0173] An algorithm was developed to identify study subjects with
HCC considered to have either a chronic HBV or a history of it.
Variables in the clinical trial database used for the algorithm
included the following: history of HBV, prior or current treatment
for HBV, cirrhosis attributed to HBV, and hepatitis serology (Table
1). A review using the algorithm identified 12 subjects as HBV
positive.
TABLE-US-00002 TABLE 1 Determination of HBV Status of Subjects
Using Algorithm Serology.sup.a Final HBV Anti- Anti- HBV Status
HBsAg HBsAg HBcAg HBV load medications Determination + Positive
>20 IU/mL Positive + + + Positive + + Positive + + Positive +
Positive + + + + Positive + + + Positive + + Positive + Negative +
Negative Anti-HBc = antibody to hepatitis B core antigen; Anti-HBs
= antibody to hepatitis B surface antigen; HBsAG = hepatitis B
surface antigen; HBV = hepatitis B virus. .sup.a"+" = Positive
serology for HBsAG, antiHBs, antiHBc, or HBV viral load at
screening or Cycle 1 Day 1.
[0174] Accordingly to the original protocol of Part B, 25 HCC
patients started treatment of Compound 1 at 45 mg/day. After the
protocol Amendment 9, 28 new HCC subjects in an additional cohort
were started at 30 mg/day. The appropriateness of the 30 mg/day
dose was supported by the PK and PD data from Part A. Compound 1
was administered orally, in an uninterrupted once daily schedule
with no rest period between each 28-day cycle. Subjects continued
to receive Compound 1 for as long as they derived benefit from
treatment as judged by the investigator. Patient characteristics of
the HCC patients are shown in FIG. 2.
[0175] PK Analysis
[0176] The PK profiles of Compound 1 and its metabolite M1 were
determined from serial blood and urine collections during the first
treatment cycle. Plasma and urine Compound 1 and M1 were measured
using validated chiral liquid chromatography-mass spectrometry
methods. The lower limit of quantification (LLOQ) in plasma was
1.00 or 2.00 ng/mL for Compound 1 and 10.0 ng/mL for M1. The LLOQ
in urine was 5.00 ng/mL for Compound 1 and 20 ng/mL for M1.
[0177] The following general PK parameters were assessed: [0178]
AUC.sub..infin.: area under the plasma concentration-time curve
after a dose of Compound 1 [0179] AUC.sub.1: area under the plasma
concentration-time curve from time 0 to the last measurable
concentration at time t [0180] AUC.sub.t: area under the plasma
concentration-time curve from time 0 to .tau., where .tau. is the
dosing interval [0181] AUC.sub.% extrap: percentage of
AUC.sub..infin. due to extrapolation from the last quantifiable
time to infinity [0182] C.sub.max: peak (maximum) plasma
concentration [0183] T.sub.max: time to peak (maximum) plasma
concentration [0184] CL/F: total body clearance [0185] CL.sub.ss/F:
total body clearance at steady state [0186] Vz/F: apparent volume
of distribution [0187] Rac (AUC.sub.t): accumulation ratio based on
AUC.sub.t [0188] T.sub.last: time of last measurable concentration
[0189] C.sub.last: last measurable concentration [0190]
.lamda..sub.z: terminal elimination rate constant (first-order)
[0191] .lamda..sub.z lower: lower limit of time (h) included in the
calculation of .lamda..sub.z [0192] .lamda..sub.z N: number of data
points used in the calculation of .lamda..sub.z [0193]
.lamda..sub.z upper: upper limit of time (h) included in the
calculation of .lamda..sub.z [0194] HL .lamda..sub.z: terminal
half-life
[0195] FIGS. 3A and 3B show plasma concentration of Compound 1
(FIG. 3A) and its metabolite M1 (FIG. 3B) in HBV infected HCC
patients (n=12) and non-HBV infected HCC patients (n=39). In FIG.
3A, overlap of the exposure data for HBV infected HCC patients and
non-HBV infected HCC patients indicates that the Compound 1
exposure in HBV infected HCC patients is comparable to the exposure
observed in non-HBV infected HCC patients. Similar results for the
M1 exposure were shown in FIG. 3B.
[0196] Subject Disposition for the HCC Patients
[0197] All subjects enrolled in Part B were included in the
analysis of subject disposition. Reasons for study discontinuation
include the following categories: adverse effect, disease
progression, withdrew consent, death, lost to follow-up, protocol
violation, and other.
[0198] Information on HCC patient disposition by HBV status in the
TP is shown in FIG. 4. Of the 25 HCC patients enrolled for 45
mg/day Compound 1 treatment, 17 were determined to be EE. Of the 28
HCC patients enrolled for 30 mg/day Compound 1 treatment, 24 were
determined to be EE. Thus, of the total 53 HCC patients, 41
patients were evaluable for efficacy after 13 withdrew prior to
first valid restaging. Of the total 53 HCC patients, 12 were
determined to be HBV infected, and 41 were non-HBV infected.
[0199] Efficacy Analysis
[0200] All efficacy analyses were based on both the TP and EE
Population. Subjects were evaluated for efficacy during Cycles 2,
4, 6, and every 3 months after Cycle 6. The primary efficacy
variable was response rate. Efficacy endpoints for HCC matured once
all enrolled subjects had withdrawn from the study.
[0201] Tumor response for HCC was based on investigator's overall
evaluation with RECIST. Response rate was determined by a best
overall response of either CR or PR. Disease control rate (DCR)
included CR, PR, and SD.
[0202] OS was defined as the time from first dose to death. All
deaths, regardless of the cause of death, were included. Subjects
who had not died were censored at the last contact date when the
subject was known to be alive or the clinical cut-off date,
whichever was earlier.
[0203] Median of OS times were calculated using the Kaplan-Meier
method and the corresponding 95% CIs were presented. The
Kaplan-Meier survival curves are presented in FIGS. 5A and 5B.
[0204] Median OS for the HCC cohort was 6.9 months (FIG. 5A), and
median PFS was 16 weeks (FIG. 6A). Although it was not
statistically significant, a trend towards increased OS in HBV
infected HCC patients versus non-HBV infected HCC patients was
observed. For example, the median OS for HBV infected HCC patients
was 12.07 months, whereas the median OS for non-HBV infected HCC
patients was 5.16 months (p=0.19) (FIGS. 5B and 8). Radiographic
responses of target lesions are summarized in a waterfall plot
(FIG. 7). Five subjects had >30% regression of target tumor
lesion with best overall responses by RECIST 1.1 of 3 PR, 1 SD and
1 PD. Of these 5 subjects, the 3 subjects with PR were HBV
positive, the subject with SD was HBV negative, and the subject
with PD was HBV negative. In addition, the disease control rate
(DCR) for all subjects was 54.7% (95% CI: 40.4%, 68.4%). By HBV
status, the DCR was 91.7% (95% CI: 61.5%, 99.8%) for subjects who
were HBV positive and 43.9% (95% CI: 28.5%, 60.3%) for those who
were HBV negative (p=0.0066) (FIG. 8).
[0205] The rate of target tumor shrinkage (i.e., lesions reducing
in size relative to screening) for all subjects was 45.3% (95% CI:
31.6%, 59.6%). By HBV status, the target tumor shrinkage rate was
66.7% (95% CI: 34.9, 90.1%) for subjects who were HBV positive was
and 39.0% (95% CI: 24.2%, 55.5%) for those who were HBV negative
(data not shown).
[0206] Illustrative examples of radiographic improvement in two
patients treated with Compound 1 are shown in FIG. 9. Patient A
shows regression of intrathoracic metastases at the first
on-treatment restaging compared to baseline. Patient B shows
intrahepatic tumor regression at the first on-treatment restaging
compared to baseline.
[0207] Assessment of AFP and HBV Viral Load for the HCC
Patients
[0208] For the HCC subjects, baseline and change from baseline in
AFP and HBV viral load (HBsAg positive subjects only) were
summarized with descriptive statistics. In addition, a Wilcoxon's
signed rank test was conducted to analyze change from baseline in
AFP at selected scheduled visits. The p-values of such tests were
provided. Change from baseline in HBV viral load was analyzed
similarly. The percentage of subjects with a >50% decline from
baseline in AFP was summarized for the TP.
[0209] Examples of AFP reduction in two HBV positive patients who
were treated with Compound 1 and showed PR are shown in FIG. 10.
Both patients show early clinically significant, marked reduction
of AFP on treatment compared to baseline elevated levels.
[0210] Discussion.
[0211] For the HCC TP, the overall response rate (ORR) was 5.7%. No
subject experienced a CR. While modest, the objective response rate
is comparable to that reported for sorafenib, a compound approved
for the treatment of advanced HCC (Llovet et al, N Engl J Med,
2008, 359:78-90). A total of 49.1% of subjects showed a best
response of SD, yielding a DCR of 54.7%. Relative to pretreatment,
45.3% of subjects showed target lesion regression. For the EE
Population, also considered an important subgroup to evaluate for
tumor response in early phase studies, the ORR was 7.3%, the DCR
was 68.3%, and rate of tumor regression relative to pretreatment
was 56.1%. For the 3 subjects who reached PR, the median duration
of response (DOR) was 124.0 days. For the 26 subjects with a best
response of SD, the median duration of SD was 112.0 days. For the
TP, median PFS was 3.7 months and median OS was 30.0 weeks; the EE
population outcomes were very similar.
[0212] Although not always statistically significant, all response
outcomes were numerically more favorable in the subset of HCC
subjects who were HBV positive compared with those with other risk
factors (hepatitis C virus or non-infectious). All 3 subjects
achieving PR were HBV positive, yielding an ORR of 25% compared
with 0% in the HBV negative subgroups. The DCR was 91.7% versus
43.9%, the tumor regression rate relative to baseline was 66.7%
versus 39.0%, median PFS was 14.8 versus 14.4 weeks, and median OS
was 52.4 versus 22.4 weeks. These differences could not be
completely explained by imbalances for baseline disease
characteristics although HBV positive subjects were younger, male,
and primarily Asian.
[0213] Conclusion.
[0214] Treatment with Compound 1 showed encouraging preliminary
evidence of antitumor activity in subjects with HCC. This was
especially true for the subset of HCC subjects considered HBV
positive. Compound 1 was well tolerated in these subjects, with a
side effect profile comparable with other drugs targeting the mTOR
pathway. Based on safety, PD, and efficacy data in this study, a
starting dose of 30 mg daily is proposed.
6.2 Clinical Study 2
[0215] An Open-Label Phase 2 Trial of Dual TORC1/TORC2 Inhibitor
Compound 1 in HBV+ Advanced Hepatocellular Carcinoma (HCC) Subjects
Who have Received at Least One Prior Line of Systemic Therapy.
[0216] Indication.
[0217] Hepatitis B virus (HBV) positive, unresectable HCC subjects
who have received at least one prior line of systemic therapy.
[0218] Objectives.
[0219] The primary objectives of the trial are: To evaluate
pharmacokinetics (PK), safety, tolerability and overall response
rate (ORR) of Compound 1 in HBV+HCC subjects who have received at
least one prior line of systemic therapy.
[0220] The secondary objectives of the trial are: To evaluate
overall survival (OS), time to progression (TTP), progression-free
survival (PFS), disease control rate (DCR), duration of response
(DOR), time to response (TTR), and survival rate.
[0221] Trial Design.
[0222] This trial is an Asian multi-regional clinical trial (MRCT)
in which Compound 1 will be administered orally to hepatitis B
positive (HBV+) HCC subjects who have received at least one prior
line of systemic therapy. It is designed as an open-label phase 2
trial evaluating the pharmacokinetics (PK), safety, tolerability
and efficacy of oral Compound 1 administered daily until the
radiologic disease progression (according to RECIST 1.1) or
intolerable toxicity.
[0223] Study Population.
[0224] Number and Population of Subjects: Approximately 30 HBV+,
unresectable HCC subjects who have received at least one prior line
of systemic therapy will be enrolled in this trial, including 6 at
the dose of 15 mg and 24 at the dose of 30 mg. If the ORR in
subjects with starting dose of 30 mg is greater than 15%, then this
study may be expanded to enroll additional approximately 96
subjects (approximately 120 subjects receiving the 30 mg starting
dose level in total) using ORR as the primary endpoint, to further
evaluate the efficacy and safety.
[0225] Inclusion Criteria:
[0226] Male or female, .gtoreq.18 years of age at the time the ICF
is signed; Confirmed pathologic or radiologic diagnosis of HCC
according to the American Association for the Study of Liver
Disease (AASLD) guidelines; Unresectable stage B (intermediate) or
C (advanced) HCC according to the Barcelona Clinic Liver Cancer
(BCLC) staging. If stage B, the subject must have progressed after,
or not be eligible for, surgical or locoregional therapy; HBV+ is
defined as chronic HBV infection or a history of HBV infection,
based on any of the following serologic results: HBcAb+, HBsAg+,
HBV-DNA+; Received at least one prior line of systemic therapy
(with radiologic disease progression during or following sorafenib
and/or chemotherapy). Subjects with alternative treatments such as
regorafenib and/or anti PD-1 antibodies etc. approved by local
health authorities are allowed to enter study if they meet all
other inclusion/exclusion criteria; Chemotherapy includes FOLFOX
(fluorouracil, leucovorin and oxaliplatin) or any other
platinum-containing regimen; Chemotherapy.gtoreq.two cycles; ECOG
performance status score of 0 or 1; Satisfactory serum chemistry
results, evidenced by the following: AST (SGOT) and ALT
(SGPT).ltoreq.5.times. upper limit of normal (ULN); Total
bilirubin.ltoreq.2.times.ULN; Creatinine.ltoreq.1.5.times.ULN or
24-hour clearance.gtoreq.50 mL/min; Adequate bone marrow function,
evidenced by the following: Absolute neutrophil count
(ANC).gtoreq.1.5.times.10.sup.9 cells/L,
Platelets.gtoreq.75.times.10.sup.9 cells/L, Hemoglobin.gtoreq.9
g/dL, Child-Pugh A (score 5 or 6 only) without encephalopathy; Male
subjects (including those who have had a vasectomy) must agree to
use a condom during sexual intercourse with females of
child-bearing potential, and shall not conceive a child starting
from the time of ICF signature, while on study medication, and for
3 months after the last dose of study drug; Female subjects of
child-bearing potential must have both of the following: Agree to
the use of two study physician-approved contraceptive methods
simultaneously, or practice complete abstinence starting at the
time of ICF signature, while on study medication, and for 28 days
following the last dose of study drug. True abstinence: When this
is in line with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods
of contraception. Acceptable contraceptive methods include: Oral,
injectable, or implantable hormonal contraceptive; intra-uterine
device; barrier contraceptive with spermicide; or vasectomized
partner, together with at least one barrier method. Have negative
serum pregnancy test result at screening, confirmed by negative
urine pregnancy test within 72 hours prior to first dose of study
drug (if serum test occurred >72 hours from first dose);
pregnancy test must have a sensitivity of at least 25 mIU/mL.
[0227] Exclusion Criteria:
[0228] The presence of any of the following will exclude a subject
from enrollment: Intolerant to sorafenib/regorafenib, e.g., the
subject must have discontinued either drug due to toxicity;
Symptomatic central nervous system metastases. Brain metastases
that have previously been treated and are stable for 4 weeks before
the first dose date are allowed; Received sorafenib/regorafenib
within 14 days prior to Screening; Locoregional HCC therapy (e.g.,
TACE, RFA), systemic chemotherapy, hormonal therapy (e.g.,
tamoxifen) or investigational therapy within 4 weeks (or 5
half-lives, whichever is shorter) prior to Screening; Tested
positive for both HBV and hepatitis C virus (HCV). (HCV positive is
defined as anti-HCV or HCV-RNA positive); Life expectancy of less
than 3 months; Prior therapy with mTOR (TORC1 and/or TORC2)
inhibitors including sirolimus, temsirolimus, everolimus, and other
investigational or approved mTOR/PI3K/AKT inhibitors; Major surgery
or significant trauma within 28 days prior to Screening; Not
recovered from the acute toxic effects of prior anticancer therapy,
radiation or major surgery/significant trauma at Screening; Minor
surgery within 7 days prior to Screening (excluding the placement
of central/peripheral lines or skin biopsy); Receiving active,
ongoing treatment with systemic corticosteroids at a prednisone
equivalent dose of .gtoreq.10 mg daily or other systemic immune
system modulators; Uncontrolled diabetes, defined as HbAlc>8%;
Prior organ transplant; Persistent diarrhea or
malabsorption.gtoreq.National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE, Version 4.03) grade
2, despite medical management, or any significant gastrointestinal
disorder that could affect the absorption of study drug; Clinically
significant bleeding, especially from esophageal varices, requiring
medical intervention within 28 days prior to Screening; Known
history or current diagnosis of human immunodeficiency virus (HIV)
infection, regardless of treatment status; Concurrent active second
malignancy for which the subject is receiving therapy, excluding
non-melanomatous skin cancer, non-progressive prostate cancer
treated with hormonal therapy, or carcinoma in situ of the cervix.
Any cancer curatively treated >5 years prior to entry is
permitted; Uncontrolled intercurrent illness including, but not
limited to ongoing or active infection (e.g., tuberculosis)
requiring antibiotic, antifungal, or antiviral therapy (other than
anti-HBV therapy), symptomatic heart failure, cardiac arrhythmia,
acute or chronic pancreatitis or psychiatric illness/social
situations that would limit compliance with study requirements;
Significant medical conditions, laboratory abnormalities, or
psychiatric illnesses that would prevent the subject from complying
fully with this protocol; Any condition including the presence of
laboratory abnormalities, which places subjects at unacceptable
risk should they participate in the trial; Any condition that
confounds the ability to interpret data from the trial.
[0229] Length of Trial.
[0230] Enrollment of the estimated 30 subjects is expected to take
approximately 4 months. Completing PK, safety and preliminary
efficacy evaluations is expected to take approximately 4 months.
The end of Study is defined as either the date of the last visit of
the last subject to complete the trial, or the date of receipt of
the last data point (e.g., date of death) from the last subject
that is required for primary analysis, whichever is the earlier
date.
[0231] Study Treatments.
[0232] The starting dose of Compound 1 will be 15 mg daily for 28
days each cycle for the first 6 fully evaluable (including PK
outcomes) subjects. Providing dose-limiting toxicity (DLT) occurs
in less than 2 of 6 subjects who complete Cycle 1, additional 24
subjects will be enrolled at the starting dose of 30 mg daily.
Subjects who tolerated the 15 mg dose level may then dose-escalate
to 30 mg at the Investigator's discretion until enrollment of 30 mg
group starts. If the ORR in subjects with starting dose of 30 mg is
greater than 15%, then this study may be expanded to enroll
additional approximately 96 subjects (approximately 120 subjects in
total) using ORR as the primary end point, to further evaluate the
efficacy and safety.
[0233] All subjects will receive Compound 1 once daily in
continuous 28-day cycles (except cycle 1) until the appearance of
radiologic disease progression, toxicity, subject or physician
decision or death. At the discretion of the Investigator, treatment
may continue beyond radiologic progression until clear symptomatic
deterioration if no other treatment options are available. Dose
interruptions of up to 3 weeks, and up to two dose reductions (to
20 mg and 15 mg) will be allowed to mitigate toxicity. Dose
reescalation will be allowed only one time if the same toxicity
does not recur at the reduced dose for least one cycle (4
weeks).
[0234] Antiviral therapy is required, and HBV-DNA viral load will
be monitored in all subjects with chronic HBV infection. Serum
AST/ALT is also monitored.
[0235] After cessation of study drug treatment, subsequent
anti-cancer therapy and survival status will be followed in all
subjects until death.
[0236] Overview of Efficacy Assessments.
[0237] Subjects will be evaluated for tumor response and
progression according to RECIST 1.1 guidelines every 8 weeks (.+-.5
days) until radiologic disease progression, death or withdrawal of
consent. mRECIST may be also used when the trial is expanded, if
necessary.
[0238] All anticancer treatments administered, especially for HCC,
following the last dose of study drugs will be captured until death
or withdrawal of consent. Disease progression and date of
progression on each subsequent therapy will be documented.
Following disease progression, survival will be followed every 8
weeks (.+-.1 week) until death or withdrawal of consent.
[0239] Overview of Safety Assessments.
[0240] All subjects will be monitored for adverse events, starting
from the time the subject signs the informed consent form (ICF)
until 28 days after the last dose of study drug. A thorough
evaluation of medical conditions will be conducted during screening
for eligibility. Vital signs, laboratory assessments (e.g. serum
chemistry, hematology, fasting plasma glucose, glycated hemoglobin
[HbAlc]), 12-lead electrocardiogram (ECGs), and ECOG performance
status will be monitored. Contraception must be practised during
the trial to avoid pregnancy in trial subjects and their partners,
and females of child-bearing potential will have regular pregnancy
testing.
[0241] Overview of Pharmacokinetic Assessments.
[0242] Blood samples will be collected for intensive sampling in
all 30 subjects in order to estimate the PK of Compound 1 and
metabolites in Asian subjects.
[0243] Overview of Exposure-Response Analyses.
[0244] Exposure-response analyses will be performed to evaluate
relationships between Compound 1 and/or M1 exposure and clinical
outcomes of efficacy and safety.
[0245] Overview of Biomarker Assessments.
[0246] Biomarkers will be evaluated. Inhibition of pAKT, pS6RP,
p4EB-P1, and/or other relevant biomarkers will be assayed in
peripheral blood and tumor. Correlative analyses will be completed
for drug exposure, adverse events and clinical outcomes as
appropriate.
6.3 Clinical Study 3
[0247] A Phase 2 Open-Label Trial of Dual TORC1/TORC2 Inhibitor
Compound 1 Combined with Nivolumab in HBV+ Advanced Hepatocellular
Carcinoma (HCC) Subjects Previously Treated with Sorafenib
[0248] Indication.
[0249] Hepatitis B virus (HBV) positive, unresectable HCC subjects
previously treated with sorafenib.
[0250] Objectives.
[0251] The primary objectives of the trial are: To evaluate safety,
tolerability and overall response rate (ORR) of Compound 1 combined
with nivolumab in HBV+HCC subjects previously treated with
sorafenib.
[0252] The secondary objectives of the trial are: To evaluate
duration of response (DOR), survival rate, disease control rate
(DCR), time to response (TTR), time to progression (TTP),
progression-free survival (PFS), and overall survival (OS).
[0253] Trial Design.
[0254] This trial is an Asian multi-regional clinical trial (MRCT)
in which Compound 1 in low dose and following high dose will be
administered orally in combination with standard dose nivolumab in
HBV+ advanced HCC subjects previously treated with sorafenib. This
is an open-label phase 2 trial to evaluate the tolerability, safety
and efficacy of Compound 1 in combination with nivolumab.
[0255] Study Population.
[0256] Number and Population of Subjects: Approximately 30-42 HBV+,
unresectable HCC subjects previously treated with sorafenib will be
enrolled first. If the observed ORR of the combination therapy
reaches approximately 20%, then this trial may be expanded to
approximately 126 subjects in total using ORR as the primary end
point, to further evaluate the efficacy and safety.
[0257] Inclusion Criteria:
[0258] Male or female, .gtoreq.18 years of age at the time the ICF
is signed; Confirmed pathologic or radiologic diagnosis of HCC
according to the American Association for the Study of Liver
Disease (AASLD) guidelines; Unresectable stage B (intermediate) or
C (advanced) HCC according to the Barcelona Clinic Liver Cancer
(BCLC) staging. If stage B, the subject must have progressed after,
or not be eligible for, surgical or locoregional therapy;
Measurable disease as defined by RECIST 1.1; Radiologic disease
progression following sorafenib treatment. Subjects with
alternative treatments such as regorafenib approved by local health
authorities are allowed to enter study if they meet all other
inclusion/exclusion criteria; HBV+ is defined as chronic HBV
infection or a history of HBV infection, based on any of the
following serologic results: HBcAb+, HBsAg+, HBV-DNA+; Patients
with active HBV infection are required to be receiving effective
antiviral therapy and their viral load should be <500 IU/mL
before first study dose; ECOG performance status score of 0 or 1;
Satisfactory serum chemistry results, evidenced by the following:
AST (SGOT) and ALT (SGPT).ltoreq.5.times. upper limit of normal
(ULN), Total bilirubin .ltoreq.2.times.ULN, Creatinine
.ltoreq.1.5.times.ULN or 24-hour clearance.gtoreq.50 mL/min;
Adequate bone marrow function, evidenced by the following: Absolute
neutrophil count (ANC).gtoreq.1.5.times.10.sup.9 cells/L,
Platelets.gtoreq.75.times.10.sup.9 cells/L, Hemoglobin .gtoreq.9
g/dL, Child-Pugh A (score 5 or 6 only) with no encephalopathy; Male
subjects (including those who have had a vasectomy) must agree to
use a condom during sexual intercourse with females of
child-bearing potential, and shall not conceive a child starting
from the time of ICF signature, while on study medication, and for
5 months after the last dose of study drug; Female subjects of
child-bearing potential must have both of the following: Agree to
the use of two study physician-approved contraceptive methods
simultaneously, or practice complete abstinence starting at the
time of ICF signature, while on study medication, and for 5 months
following the last dose of study drug. True abstinence: When this
is in line with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods
of contraception. Acceptable contraceptive methods include: Oral,
injectable, or implantable hormonal contraceptive; intra-uterine
device; barrier contraceptive with spermicide; or vasectomized
partner, together with at least one barrier method. Have negative
serum pregnancy test result at screening, confirmed by negative
urine pregnancy test within 72 hours prior to first dose of study
drug (if serum test occurred >72 hours from first dose);
pregnancy test must have a sensitivity of at least 25 mIU/mL.
[0259] Exclusion Criteria:
[0260] The presence of any of the following will exclude a subject
from enrollment: Intolerant to sorafenib, i.e., the subject must
have discontinued drug due to toxicity; Symptomatic central nervous
system metastases. Metastases previously treated and stable for
.gtoreq.4 weeks before the first dose date are allowed; History of
hepatic encephalopathy; Received sorafenib within 14 days prior to
first dose of study drug; Locoregional HCC therapy (e.g., TACE,
RFA), systemic chemotherapy, hormonal therapy (e.g., tamoxifen) or
investigational therapy within 4 weeks (or 5 half-lives, whichever
is shorter) prior to first dose of study drug; Plan to receive
locoregional HCC therapy (e.g., TACE, RFA) during the trial;
Co-infection with HBV and HCV/HDV hepatitis virus infection; Life
expectancy of less than 3 months; Prior therapy with mTOR (TORC1
and/or TORC2) inhibitors including sirolimus, temsirolimus,
everolimus, and other investigational or approved mTOR/PI3K/AKT
inhibitors; Prior therapy with any medication targeting T-cell
activation or checkpoint pathways (including those targeting PD-1,
PD-L1 or PD-L2, CD137, or cytotoxic T-lymphocyte antigen [CTLA-4]);
History of autoimmune disease; Prior or current clinically
significant ascites; Major surgery or significant trauma within 28
days prior to Screening; Not recovered from the acute toxic effects
of prior anticancer therapy, radiation or major surgery/significant
trauma at Screening; Minor surgery within 7 days prior to Screening
(excluding the placement of central/peripheral lines or skin
biopsy); Receiving active, ongoing treatment with systemic
corticosteroids at a prednisone equivalent dose of .gtoreq.10 mg
daily or other systemic immune system modulators; Uncontrolled
diabetes, defined as HbAlc>8%; Prior organ transplant;
Persistent diarrhea or malabsorption.gtoreq.National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE, Version 4.03) grade 2, despite medical management, or any
significant gastrointestinal disorder that could affect the
absorption of study drug; Clinically significant bleeding,
especially from esophageal varices, requiring medical intervention
within 28 days prior to Screening; Known history or current
diagnosis of human immunodeficiency virus (HIV) infection,
regardless of treatment status; Concurrent active second malignancy
for which the subject is receiving therapy, excluding
non-melanomatous skin cancer, non-progressive prostate cancer
treated with hormonal therapy, or carcinoma in situ of the cervix.
Any cancer curatively treated >5 years prior to entry is
permitted; Uncontrolled intercurrent illness including, but not
limited to ongoing or active infection (e.g., tuberculosis)
requiring antibiotic, antifungal, or antiviral therapy (other than
anti-HBV therapy), symptomatic heart failure, cardiac arrhythmia,
acute or chronic pancreatitis or psychiatric illness/social
situations that would limit compliance with study requirements;
Significant medical conditions, laboratory abnormalities, or
psychiatric illnesses that would prevent the subject from complying
fully with this protocol; Any condition including the presence of
laboratory abnormalities, which places subjects at unacceptable
risk should they participate in the trial; Any condition that
confounds the ability to interpret data from the trial.
[0261] Length of Trial.
[0262] Enrollment of the estimated 30-42 subjects is expected to
take approximately 5 months. Completing tolerability, safety and
preliminary efficacy evaluations is expected to take approximately
8 months. The end of study is defined as either the date of the
last visit of the last subject to complete the trial, or the date
of receipt of the last data point (e.g., date of death) from the
last subject that is required for primary analysis, whichever is
the earlier date.
[0263] Study Treatments.
[0264] Compound 1 will be administrated at different daily dose
level (15 mg, 30 mg or 20 mg) orally at the following schedule in
combination with nivolumab given in a standard schedule (240 mg
every 2 weeks, intravenous infusion). The dose escalation scheme
will be based on a modified 3+3 design.
[0265] Initially 3 subjects will be enrolled in the cohort of
Compound 1 15 mg combination therapy: If no dose-limiting toxicity
(DLT) occurs, 3 new subjects will be enrolled in the cohort of
Compound 1 30 mg combination therapy. If 1 DLT occurs, additional 3
subjects will be enrolled in the Compound 1 15 mg combination
cohort. Providing no further DLTs occur, 3 new subjects will be
evaluated in the cohort of Compound 1 30 mg combination. If 2 or
more DLTs occur, it will be discussed with Safety Review Committee
and Principle Investigator(s) to discontinue trial or explore other
appropriate trial design.
[0266] For the initial 3 subjects in the cohort of Compound 1 30 mg
combination: If no DLT occurs, 24 new subjects will be enrolled at
the dose level of Compound 1 30 mg combination. If 1 DLT occurs,
additional 3 subjects will be enrolled in the Compound 1 30 mg
combination cohort. Providing no more than 1 DLT occurs in 6
subjects in the cohort of Compound 1 30 mg combination, additional
24 subjects will be enrolled in the cohort of Compound 1 30 mg
combination. If 2 of 3 or 6 subjects at the dose level of Compound
1 30 mg combination therapy experience DLTs, 3 new subjects will be
enrolled in a cohort of Compound 1 20 mg combination. If no DLT
occurs in the 3 subjects at the dose level of Compound 1 20 mg
combination, the study will proceed to enroll additional 24
subjects at the dose level of Compound 1 20 mg combination therapy.
If 1 DLT occurs, additional 3 subjects will be enrolled at the same
dose level of Compound 1 20 mg combination. Providing DLTs occur in
less than 2 of 6 subjects in the cohort of Compound 1 20 mg
combination, the study will proceed to enroll additional 24
subjects in the cohort of Compound 1 20 mg combination. If 2 of 3
or 6 subjects at the dose level of Compound 1 20 mg combination
therapy experienced DLTs, the study will proceed to enroll
additional 24 subjects in the cohort of Compound 1 15 mg
combination.
[0267] If the ORR of the combination therapy at optimal dose level
reaches about 20%, then this study will be expanded to a total of
about 126 subjects using ORR as the primary endpoint, in order to
further evaluate the efficacy and safety.
[0268] DLTs include early hyperglycemia, rash, fatigue, and
mucositis, any of which .gtoreq.grade 3, and hepatic impairment
according to study CheckMate 040 results, which commences within 6
weeks of first dose.
[0269] All subjects will receive Compound 1 orally once daily in
continuous 28-day cycles in combination with nivolumab intravenous
infusion every 2 weeks until the appearance of radiologic disease
progression (according to RECIST 1.1), unacceptable toxicity,
subject or physician decision, withdrawal of consent, or death. At
the discretion of the Investigator, treatment may continue beyond
radiologic progression until clear symptomatic deterioration if no
other treatment options are available.
[0270] Antiviral therapy is required, and HBV-DNA viral load will
be monitored in all subjects with chronic HBV infection. Serum
AST/ALT is also monitored.
[0271] After cessation of study drug treatment, subsequent
anti-cancer therapy and survival status will be followed in all
subjects until death.
[0272] Overview of Efficacy Assessments.
[0273] Subjects will be evaluated for tumor response and
progression according to RECIST 1.1 guidelines until radiologic
disease progression, death or withdrawal of consent. mRECIST may be
also used when the trial is expanded, if necessary. The tumor
response assessments will be performed every 6 weeks (.+-.5 days)
for first 24 weeks, and every 12 weeks (.+-.1 week) thereafter.
[0274] All anticancer treatments administered, especially for HCC,
following the last dose of combination treatment will be captured
until death or withdrawal of consent. Disease progression and date
of progression on each subsequent therapy will be documented.
Following disease progression, survival will be followed every 12
weeks (.+-.1 week) until death or withdrawal of consent.
[0275] Overview of Safety Assessments.
[0276] All subjects will be monitored for adverse events, starting
from the time the subject signs the informed consent form (ICF)
until 28 days after the last dose of combination treatment. A
thorough evaluation of medical conditions will be conducted during
screening for eligibility. Vital signs, laboratory assessments
(e.g. serum chemistry, hematology, fasting plasma glucose, glycated
hemoglobin [HbAlc]), 12-lead electrocardiogram (ECGs), and ECOG
performance status will be monitored. Contraception must be
practiced during the trial to avoid pregnancy in trial subjects and
their partners, and females of child-bearing potential will have
regular pregnancy testing.
[0277] Overview of Biomarker Assessments.
[0278] Biomarkers will be evaluated. Inhibition of pAKT, pS6RP,
p4EB-P1, and/or other relevant biomarkers will be assayed in
peripheral blood and tumor tissue. Correlative analyses will be
completed for drug exposure, adverse events and clinical outcomes
as appropriate.
[0279] From the foregoing, it will be appreciated that, although
specific embodiments have been described herein for the purpose of
illustration, various modifications may be made without deviating
from the spirit and scope of what is provided herein. All of the
references referred to above are incorporated herein by reference
in their entireties.
* * * * *