U.S. patent application number 15/664930 was filed with the patent office on 2018-01-11 for methods for treating pancreatic cancer using combination therapies.
The applicant listed for this patent is Ipsen Biopharm Ltd.. Invention is credited to Eliel Bayever, Navreet Dhindsa, Jonathan Basil Fitzgerald, Jaeyeon Kim, Peter Laivins, Victor Moyo, Clet Niyikiza.
Application Number | 20180008591 15/664930 |
Document ID | / |
Family ID | 57601636 |
Filed Date | 2018-01-11 |
United States Patent
Application |
20180008591 |
Kind Code |
A1 |
Bayever; Eliel ; et
al. |
January 11, 2018 |
Methods for Treating Pancreatic Cancer Using Combination
Therapies
Abstract
Provided are methods for treating pancreatic cancer in a patient
by administering liposomal irinotecan (MM-398) alone or in
combination with additional therapeutic agents. In one embodiment,
the liposomal irinotecan (MM-398) is co-administered with
5-fluorouracil and leucovorin.
Inventors: |
Bayever; Eliel; (New York,
NY) ; Dhindsa; Navreet; (Boston, MA) ;
Fitzgerald; Jonathan Basil; (Arlington, MA) ;
Laivins; Peter; (Rowayton, CT) ; Moyo; Victor;
(Ringoes, NJ) ; Niyikiza; Clet; (Gulph Mills,
PA) ; Kim; Jaeyeon; (Lexington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ipsen Biopharm Ltd. |
Wrexham |
|
GB |
|
|
Family ID: |
57601636 |
Appl. No.: |
15/664930 |
Filed: |
July 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15241128 |
Aug 19, 2016 |
9717724 |
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15664930 |
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14406776 |
Dec 10, 2014 |
9452162 |
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PCT/US2013/045495 |
Jun 12, 2013 |
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15241128 |
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61784382 |
Mar 14, 2013 |
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61659211 |
Jun 13, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 9/0019 20130101;
A61K 9/1271 20130101; A61K 47/24 20130101; A61K 31/513 20130101;
A61K 47/26 20130101; A61P 35/00 20180101; A61K 31/519 20130101;
A61K 9/127 20130101; A61K 47/28 20130101; A61K 31/4745 20130101;
A61K 31/4745 20130101; A61K 31/519 20130101; A61K 31/513
20130101 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61K 47/26 20060101 A61K047/26; A61K 31/519 20060101
A61K031/519; A61K 9/00 20060101 A61K009/00; A61K 31/513 20060101
A61K031/513; A61K 9/127 20060101 A61K009/127; A61K 47/28 20060101
A61K047/28; A61K 47/24 20060101 A61K047/24 |
Claims
1. A method of treating patients with metastatic adenocarcinoma of
the pancreas after disease progression following gemcitabine-based
therapy who are not homozygous for the UTG1A1*28 allele, the method
comprising intravenously administering to the patient in need
thereof an antineoplastic therapy once every two weeks, the
antineoplastic therapy consisting of: a. administering liposomal
irinotecan as an intravenous infusion in an amount providing 70
mg/m.sup.2 of irinotecan free base, the liposomal irinotecan
composition comprising irinotecan encapsulated in irinotecan
liposomes having a diameter of approximately 110 nm and an
irinotecan terminal elimination half-life in the patient of 25.8
hours; b. 200 mg/m.sup.2 of the (l) form of leucovorin; and c.
2,400 mg/m.sup.2 of 5-fluorouracil.
2. The method of claim 1, wherein liposomal irinotecan has an area
under the plasma concentration curve extrapolated to time infinity
(AUC.sub.0-.infin.) of 1091-1705 [h.mu.g/mL].
3. The method of claim 1, wherein liposomal irinotecan has an area
under the plasma concentration curve extrapolated to time infinity
(AUC.sub.0-.infin.) of 1364 [h.mu.g/mL].
4. The method of claim 1, wherein liposomal irinotecan has a
maximum plasma concentration of 29-47 micrograms/mL.
5. The method of claim 1, wherein liposomal irinotecan has a
maximum plasma concentration of 37 micrograms/mL.
6. The method of claim 1, wherein the irinotecan liposomes are
unilamellar lipid bilayer vesicles comprising phosphatidylcholine,
cholesterol, and a polyethyleneglycol-derivatized
phosphatidyl-ethanolamine.
7. The method of claim 1, wherein the irinotecan liposomes are
approximately 110 nm in diameter.
8. The method of claim 1, wherein the irinotecan liposomes
encapsulate an aqueous space containing irinotecan in a gelated or
precipitated state as the sucrose octasulfate salt.
9. The method of claim 1, wherein the liposomal irinotecan
comprises mg/mL 1,2-di stearoyl-sn-glycero-3-phosphocholine (DSPC),
cholesterol, and mg/mL methoxy-terminated olyethylene glycol (MW
2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE).
10. The method of claim 1, wherein the 200 mg/m.sup.2 of the (l)
form of leucovorin is provided by administering 400 mg/m.sup.2 of
the (l+d) form of leucovorin.
11. A method of treating patients with metastatic adenocarcinoma of
the pancreas after disease progression following gemcitabine-based
therapy who are not homozygous for the UTG1A1*28 allele, the method
comprising intravenously administering to the patient in need
thereof an antineoplastic therapy once every two weeks, the
antineoplastic therapy consisting of: a. administering liposomal
irinotecan as an intravenous infusion over 90 minutes in an amount
providing 70 mg/m.sup.2 of irinotecan free base, the liposomal
irinotecan composition comprising irinotecan encapsulated in
irinotecan liposomes having an area under the plasma concentration
curve extrapolated to time infinity (AUC.sub.0-.infin.) of about
1091-1705 [h.mu.g/mL]; followed by b. 200 mg/m.sup.2 of the (l)
form of leucovorin; and c. 2,400 mg/m.sup.2 of 5-fluorouracil.
12. The method of claim 11, wherein the irinotecan liposomes have a
diameter of approximately 110 nm and comprise phosphatidylcholine,
cholesterol, and a polyethyleneglycol-derivatized
phosphatidyl-ethanolamine
13. The method of claim 11, wherein the 200 mg/m.sup.2 of the (l)
form of leucovorin is provided by administering 400 mg/m.sup.2 of
the (l+d) form of leucovorin.
14. The method of claim 11, wherein liposomal irinotecan has a
maximum plasma concentration of about 29-47 micrograms/mL.
15. The method of claim 11, wherein the irinotecan liposomes
encapsulate an aqueous space containing irinotecan in a gelated or
precipitated state as the sucrose octasulfate salt.
16. A method of treating pancreatic cancer in a human patient who
has previously been treated with gemcitabine, the method comprising
intravenously administering to the patient in need thereof an
antineoplastic therapy once every two weeks, the antineoplastic
therapy consisting of: a single dose of 70 mg/m.sup.2 of irinotecan
free base in an irinotecan nanoparticle composition comprising
irinotecan nanoparticles having a diameter of 80-140 nm,
administered in combination with 200 mg/m.sup.2 of the (l) form of
leucovorin and 2,400 mg/m.sup.2 of 5-fluorouracil, to treat the
pancreatic cancer in the human patient, wherein the irinotecan
nanoparticle composition has one or more characteristics selected
from the group consisting of: a. an area under the plasma
concentration curve extrapolated to time infinity
(AUC.sub.0-.infin.) of about 1091-1705 [h.mu.g/mL]; and b. a
maximum plasma concentration of about 29-47 micrograms/mL.
17. The method of claim 16, wherein the irinotecan liposome has an
irinotecan terminal elimination half-life in the patient of at
least about 2-fold higher than that of 125 mg/m.sup.2 free
irinotecan as CPT-11 irinotecan hydrochloride injection.
18. The method of claim 16, wherein the irinotecan nanoparticles
comprise irinotecan encapsulated in a unilamellar lipid bilayer
vesicle composed of phosphatidylcholine, cholesterol, and a
polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and the
200 mg/m.sup.2 of the (l) form of leucovorin is provided by
administering 400 mg/m.sup.2 of the (l+d) form of leucovorin.
19. The method of claim 16, wherein the irinotecan nanoparticle
composition has an irinotecan terminal elimination half-life in the
patient of about 25.8 hours.
20. The method of claim 16, wherein the irinotecan is converted to
SN-38 within the human patient and the AUC of the SN-38 increases
less than proportionally with the dose of the liposomal irinotecan.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/241,128 (filed Aug. 19, 2016) now U.S. Pat.
No. 9,717,724, issued Aug. 1, 2017, which is a continuation-in-part
of U.S. patent application Ser. No. 14/406,776 (filed Dec. 10,
2014), now U.S. Pat. No. 9,452,162, issued Sep. 27, 2016, which are
incorporated by reference herein their entirety, and which in turn
is a 371 of international application number PCT/US2013/045495
which claims the benefit of priority of U.S. Provisional
Application No. 61/659,211 (filed Jun. 13, 2012) and U.S.
Provisional Application No. 61/784,382 (filed Mar. 14, 2013), all
of which are incorporated herein by reference.
BACKGROUND
[0002] Despite improvements in cancer treatments, there remains a
critical need to further improve therapies so as to prolong
patients' lives while maintaining quality of life, particularly in
the case of advanced cancers such as pancreatic cancers that often
are, or become, resistant to current therapeutic modalities.
[0003] Incidence of pancreatic cancer has markedly increased during
the past several decades. It now ranks as the fourth leading cause
of cancer death in the United States. Pancreatic cancer's high
mortality rate is due to a dearth of effective therapies and a
complete absence of reliably durable therapies. Because of the
location of the pancreas, pancreatic cancer is typically not
diagnosed until a tumor has become large enough to produce systemic
symptoms. This, coupled with the absence of good screening tools
and a limited understanding of risk factors, results in patients
usually having advanced disease, often advanced metastatic disease,
at the time of diagnosis. Metastatic pancreatic cancer has a dismal
prognosis and is almost uniformly fatal, with an overall survival
rate of less than 4% at 5 years.
[0004] Chemotherapy with one or more of 5-fluorouracil (5-FU) and
gemcitabine has been shown to prolong survival in pancreatic
cancer. Combination therapies including folinic acid (leucovorin or
levoleucovorin (LV)), 5-fluorouracil, and irinotecan (FOLFIRI),
folinic acid, 5-fluorouracil, irinotecan and oxaliplatin
(FOLFIRINOX), or, less commonly, a combination of folinic acid,
5-fluorouracil, and oxaliplatin (FOLFOX) are also used to treat
some pancreatic cancers. Irinotecan is
7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycampothecin,
IUPAC name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxolH-pyrano[-
3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylat-
e. Irinotecan is a member of the topoisomerase I inhibitor class of
drugs and is a semi-synthetic and water soluble analog of the
naturally-occurring alkaloid, camptothecin. Also known as CPT-11,
irinotecan is currently marketed formulated as an aqueous solution
as Camptosar.RTM. (irinotecan hydrochloride injection).
Topoisomerase I inhibitors such as irinotecan work to arrest
uncontrolled cell growth by inhibiting the unwinding of DNA and
thereby preventing DNA replication.
[0005] The pharmacology of irinotecan is complex, with extensive
metabolic conversions involved in the activation, inactivation, and
elimination of the drug. Irinotecan is a prodrug that is converted
by nonspecific carboxylesterases into a 100-1000 fold more active
metabolite, SN-38. SN-38 is not recognized by P-glycoprotein, a
drug transporter that plays an important role in acquired drug
resistance by pumping certain drugs out of cells, so irinotecan is
likely to be active in tumors resistant to other standard
chemotherapies. In the body, SN-38 is cleared via glucuronidation,
for which major pharmacogenetic variability has been described, and
biliary excretion. These drug properties contribute to the marked
heterogeneities in efficacy and toxicity observed clinically with
irinotecan. Irinotecan hydrochloride injection is approved in the
United States for treatment of metastatic colon or renal cancer and
is also used to treat colorectal, gastric, lung, uterine cervical
and ovarian cancers.
[0006] There are few approved treatment options for advanced or
metastatic pancreatic cancers, particularly for those of exocrine
origin. Single-agent gemcitabine is the current standard of care in
first-line treatment of advanced and metastatic pancreatic
adenocarcinoma. In clinical trials, single-agent gemcitabine has
consistently demonstrated a median prolongation of survival of 5 to
6 months and a 1-year survival rate of about 20%. Single agent
gemcitabine was also approved as second line treatment for patients
previously treated with but no longer responsive to 5-fluorouracil,
with a median overall prolongation of survival of 3.9 months.
[0007] Based upon what is known of the biology of pancreatic
cancer, a variety of targeted agents have been evaluated, but only
erlotinib, a protein tyrosine kinase inhibitor targeted to EGFR,
has been approved for first-line use in advanced pancreatic cancer,
and the approval is only for use in combination with gemcitabine.
The co-administration of erlotinib with gemcitabine resulted in a
statistically significant benefit in survival, and improvements in
median survival (6.4 months vs. 5.9 months), and 1-year survival
rate (24% vs. 17%) compared to gemcitabine alone. Clinical trials
evaluating other targeted agents, including studies testing the
antibodies bevacizumab and cetuximab, have been disappointingly
negative. Thus, there is an urgent need for improvements in, and
effective alternatives to, current therapies for pancreatic cancer.
The disclosed invention addresses this need and provides other
benefits.
SUMMARY
[0008] Provided are methods for treating pancreatic cancer in a
patient (i.e., a human patient) comprising administering to the
patient liposomal irinotecan (e.g., irinotecan sucrose octasulfate
salt liposome injection, also referred to as MM-398) alone or in
combination with 5-fluorouracil (5-FU) and leucovorin (together,
5-FU/LV), according to a particular clinical dosage regimen.
Compositions adapted for use in such methods are also provided.
[0009] Preferably, the liposomal irinotecan is irinotecan sucrose
octasulfate salt liposome injection. MM-398 irinotecan liposome
injection contains the topoisomerase 1 inhibitor irinotecan
encapsulated with sucrose octasulfate in a lipid bilayer vesicle or
liposome and formulated for intravenous administration. MM-398 is
indicated in combination with 5-fluorouracil and leucovorin for the
treatment of patients with metastatic adenocarcinoma of the
pancreas whose disease has progressed following gemcitabine-based
therapy.
[0010] In one aspect, a method for treatment (e.g., effective
treatment) of pancreatic cancer in a patient is provided, the
method comprising: administering to the patient, and affective
amount of liposomal irinotecan, wherein the method comprises at
least one cycle, wherein the cycle is a period of 3 weeks, and
wherein for each cycle the liposomal irinotecan is administered on
day 1 of the cycle at a dose of 120 mg/m.sup.2, except if the
patient is homozygous for the UGT1A1*28 allele, wherein liposomal
irinotecan is administered on day 1 of cycle 1 at a dose of 80
mg/m.sup.2. In one embodiment, the dose of liposomal irinotecan
administered to the patient homozygous for the UGT1A1*28 allele is
increased after one cycle in increments of 20 mg/m.sup.2, up to a
maximum of 120 mg/m.sup.2.
[0011] In another aspect, a method for treatment of pancreatic
cancer in a patient is provided, the method comprising
co-administering to the patient an effective amount each of
liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin,
wherein the method comprises at least one cycle of administration,
wherein the cycle is a period of 2 weeks, and wherein for each
cycle:
[0012] (a) liposomal irinotecan is administered to patients not
homozygous for the UGT1A1*28 allele on day 1 of each cycle at a
dose of 80 mg/m.sup.2, and to patients homozygous for the UGT1A1*28
allele on day 1 of cycle 1 at a dose of 60 mg/m.sup.2 and on day 1
of each subsequent cycle at a dose of ranging from 60 mg/m.sup.2 to
80 mg/m.sup.2 (e.g., 60 mg/m.sup.2 or 70 mg/m.sup.2 or 80
mg/m.sup.2);
[0013] (b) 5-FU is administered at a dose of 2400 mg/m.sup.2;
and
[0014] (c) leucovorin is administered at a dose of 200 mg/m.sup.2
(l form, or levoleucovorin) or 400 mg/m.sup.2 (l+d racemic
form).
[0015] In one embodiment, the dose of liposomal irinotecan
administered to the patient homozygous for the UGT1A1*28 allele is
increased after one cycle to 80 mg/m.sup.2. In one embodiment, in
each cycle, the liposomal irinotecan is administered prior to the
leucovorin and the leucovorin is administered prior to the
5-FU.
[0016] In another embodiment, the liposomal irinotecan is
administered intravenously over 90 minutes.
[0017] In another embodiment, the 5-FU is administered
intravenously over 46 hours.
[0018] In another embodiment, leucovorin is administered
intravenously over 30 minutes.
[0019] In another embodiment, prior to each administration of
liposomal irinotecan, the patient is pre-medicated with
dexamethasone and/or a 5-HT3 antagonist or another anti-emetic.
[0020] In another embodiment, the pancreatic cancer is an exocrine
pancreatic cancer selected from the group consisting of acinar cell
carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell
tumor, intraductal papillary-mucinous neoplasm (IPMN), mucinous
cystadenocarcinoma, pancreatoblastoma, serous cystadenocarcinoma,
and solid and pseudopapillary tumors. Metastatic Pancreatic Cancer
(mPAC) represents a significant unmet need, with approximately 80%
of patients with mPAC succumbing to disease within 12 months.
[0021] In one embodiment, treating the patient results in a
positive outcome, wherein the positive outcome is pathologic
complete response (pCR), complete response (CR), partial response
(PR) or stable disease (SD). In another embodiment, the combination
therapy with liposomal irinotecan, 5-FU and leucovorin results in
therapeutic synergy.
[0022] In another embodiment, the liposomal irinotecan is
formulated as irinotecan sucrose octasulfate salt liposome
injection (MM-398). Irinotecan sucrose octasulfate salt liposome
injection may also be referred to as irinotecan HCl liposome
injection because irinotecan HCl is the active pharmaceutical
ingredient that is used to load irinotecan into liposomes
containing triethylammonium sucrose octasulfate to prepare MM-398
liposomes. This nomenclature may be used even though the
hydrochloride ion of the irinotecan HCl reacts with the
triethylammonium ion of the triethylammonium sucrose octasulfate to
yield triethylammonium chloride (triethylamine hydrochloride),
leaving irinotecan sucrose octasulfate salt as the entrapped
pharmaceutical agent within the MM-398 liposomes. In another
aspect, kits for treating pancreatic cancer in a patient are
provided, the kit comprising a dose of liposomal irinotecan and
instructions for using liposomal irinotecan as described
herein.
[0023] In another aspect, kits for treating pancreatic cancer in a
patient are provided, the kit comprising a dose of each liposomal
irinotecan, 5-fluorouracil (5-FU), and leucovorin, and instructions
for using liposomal irinotecan, 5-FU, and leucovorin as described
herein.
[0024] In one embodiment, the kit encompasses treating an exocrine
pancreatic cancer selected from the group consisting of acinar cell
carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell
tumor, intraductal papillary-mucinous neoplasm (IPMN), mucinous
cystadenocarcinoma, pancreatoblastoma, serous cystadenocarcinoma,
and solid and pseudopapillary tumors.
[0025] In one embodiment, the liposomal irinotecan is liposomal
irinotecan sucrose octasulfate salt injection (MM-398).
[0026] In another aspect, a formulation of liposomal irinotecan for
co-administration with 5-fluorouracil (5-FU) and leucovorin in at
least one cycle is provided, wherein the cycle is a period of 2
weeks, the formulation of irinotecan is a liposomal formulation of
irinotecan, and wherein:
[0027] (a) liposomal irinotecan is administered to patients not
homozygous for the UGT1A1*28 allele on day 1 of each cycle at a
dose of 80 mg/m.sup.2 and to patients homozygous for the UGT1A1*28
allele on day 1 of cycle 1 at a dose of 60 mg/m.sup.2 and on day 1
of each subsequent cycle at a dose of 60 mg/m.sup.2 or 80
mg/m.sup.2;
[0028] (b) 5-FU is administered at a dose of 2400 mg/m.sup.2;
and
[0029] (c) leucovorin is administered at a dose of 200 mg/m.sup.2
(l form, or levoleucovorin) or 400 mg/m.sup.2 (l+d racemic
form).
[0030] In one embodiment, after cycle 1 the dose of liposomal
irinotecan administered to the patient homozygous for the UGT1A1*28
allele is increased to 80 mg/m.sup.2. In another embodiment, the
liposomal irinotecan is administered intravenously over 90
minutes.
[0031] In another embodiment, the 5-FU is administered
intravenously over 46 hours.
[0032] In another embodiment, leucovorin is administered
intravenously over 30 minutes.
[0033] In another embodiment, prior to each administration of
liposomal irinotecan, the patient is pre-medicated with
dexamethasone and/or a 5-HT3 antagonist or another anti-emetic.
[0034] In another embodiment, the pancreatic cancer is an exocrine
pancreatic cancer selected from the group consisting of acinar cell
carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell
tumor, intraductal papillary-mucinous neoplasm (IPMN), mucinous
cystadenocarcinoma, pancreatoblastoma, serous cystadenocarcinoma,
and solid and pseudopapillary tumors.
[0035] In another embodiment, the liposomal formulation of
irinotecan is irinotecan sucrose octasulfate salt liposome
injection.
[0036] In another aspect is provided a method of improving
chemotherapy outcomes by increasing tumor vascularity, the method
comprising administering to a patient having a tumor an amount of
irinotecan sucrose octasulfate salt liposome injection effective to
increase tumor vascularity and concomitantly administering an
effective amount of a chemotherapy agent other than irinotecan to
the patient.
[0037] In another aspect is provided irinotecan sucrose octasulfate
salt liposome injection for concomitant administration to a patient
having a tumor of 1) an amount of irinotecan sucrose octasulfate
salt liposome injection effective to increase tumor vascularity and
2) an effective amount of a chemotherapy agent other than
irinotecan.
[0038] The therapy can be safely and effectively administered to
patients diagnosed with metastatic adenocarcinoma of the pancreas
after disease progression following gemcitabine-based therapy. The
amount of leucovorin administered can be selected to provide a
desired effect of the 5-fluorouracil (e.g., an amount of leucovorin
comprising 200 mg/m.sup.2 of levoleucovorin, such as 400 mg/m.sup.2
of the (l+d) racemic form of leucovorin). For example, the patient
can be treated with an antineoplastic therapy (referred to herein
as "MM-398+5-FU/LV (MM-398 80 mg/m.sup.2 q2w regimen)") comprising:
80 mg/m.sup.2 of irinotecan encapsulated in a MM-398 irinotecan
liposome (e.g., as a 90 minute intravenous infusion) followed by
400 mg/m.sup.2 of the antineoplastic agent (l+d) racemic leucovorin
(e.g., as a 30 minute intravenous infusion) followed by 2,400
mg/m.sup.2 of the antineoplastic agent 5-fluorouracil (e.g., as an
intravenous infusion over 46 hours), without administering any
other antineoplastic agents for the treatment of the pancreatic
cancer (e.g., without administering gemcitabine).
[0039] Unless otherwise indicated, recitation of the amount of the
irinotecan in liposomal irinotecan is expressed herein as the
amount of irinotecan hydrochloride trihydrate (molecular weight of
about 677 g/mol) providing a given amount of irinotecan free base:
for example, 80 mg/m.sup.2 of irinotecan hydrochloride trihydrate
(e.g., as approved under the non-liposomal irinotecan product
CAMPTOSAR.RTM.) contains about the equivalent amount of irinotecan
free base as a dose of 70 mg/m.sup.2 of irinotecan in the MM-398
liposome formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 is a graph showing the anti-tumor activity of MM-398
in an orthotopic pancreatic tumor model expressing luciferase
(L3.6pl).
[0041] FIG. 2 is a graph showing accumulation of SN-38 in tumors
following treatment with free irinotecan or liposomal irinotecan
(MM-398).
[0042] FIG. 3 is a graph showing the effect of MM-398 on Carbonic
Anhydrase IX Staining in a HT29 Xenograft Model.
[0043] FIG. 4 shows the effect of MM-398 on perfusion of small
molecule Hoechst stain.
[0044] FIG. 5 summarizes the pharmacokinetics of MM-398 in q3w
(irinotecan, liposome+free drug).
[0045] FIG. 6 summarizes the pharmacokinetics of MM-398 in q3w.
[0046] FIG. 7 is a schematic illustration of a Phase 3 study
design. Patients who are homozygous for UGT1A1*28 allele and are
randomized to Arm A, will receive the first cycle of therapy at a
reduced dose of 80 mg/m.sup.2. If the patient does not experience
any drug related toxicity after the first administration of MM-398,
from cycle 2 onwards, the dose may be increased in increments of 20
mg/m.sup.2, up to a maximum of 120 mg/m.sup.2. Patients who are
homozygous for UGT1A1*28 allele and are randomized to Arm C, will
receive the first cycle therapy at a reduced dose of 60 mg/m.sup.2.
If the patient does not experience any drug related toxicity after
the first administration of MM-398, from cycle 2 onwards, the dose
may be increased to 80 mg/m.sup.2.
[0047] FIG. 8 is a graph providing the overall survival of patients
in an assessment of the clinical efficacy and safety of the
irinotecan liposome injection monotherapy or the irinotecan
liposome injection in combination with 5-fluorouracil and
leucovorin (the irinotecan liposome injection+5-FU/LV), compared to
an active control arm of 5-FU/LV.
[0048] FIG. 9 is a flow-chart representation of the NAPOLI-1 study
design.
[0049] FIG. 10 is a table providing the baseline characteristics of
the Intent to Treat (ITT) (all randomized patients) population. In
the table, CA19-9 at baseline was unknown in 3% of the
patients.
[0050] FIGS. 11A and 11B are graphical representations of overall
survival (ITT population) in MM-398+5-FU/LV vs. MM-398 or 5-FU/LV
alone. The data presented is the protocol-defined primary analysis
data cut after 305 events. "**" denotes un-stratified HR: 0.67
(0.49-0.92), p=0.0122; "***" denotes un-stratified HR: 0.99
(0.77-1.28), p=0.9416.
[0051] FIG. 12 is a flow chart explaining the ITT (all randomized
patients) and PP (Per Protocol) populations. The Per Protocol
population comprises eligible patients who received .gtoreq.80%
dose density of the protocol defined treatment during the first 6
weeks of treatment.
[0052] FIGS. 13 and 14 are graphical representations of overall
survival (OS) for the Per Protocol (PP) patient population vs. the
Non-Per Protocol (Non-PP) patient population. The results presented
in the figures are a data cut from a protocol-defined primary
analysis. Per protocol population was defined as patients who
received at least 80% of the protocol defined treatment during the
first 6 weeks of treatment and did not have protocol deviations
related to inclusion/exclusion criteria, receiving prohibited
therapies or not receiving treatment as randomized. FIG. 13
represents the PP population and FIG. 14 represents the Non-PP
population.
[0053] FIG. 15 is a table providing the demographic characteristics
for the Per Protocol (PP) patient population vs. the Non-Per
Protocol (Non-PP) patient population. CA19-9 includes only patients
who had a measured CA19-9 prior to treatment. "**" denotes results
that showed a statistically significant difference (p
value.ltoreq.0.01). "***" denotes the median (1st quartile, 3rd
quartile).
[0054] FIG. 16 is a table providing the dose modifications and
treatment exposure. Duration of exposure is the time from (the date
of the last administration of the study drug+the projected days to
the next dose of the study drug administration-the date of the
first study drug administration).
[0055] FIG. 17 is a table providing the safety data (adverse
events) for the study. In the table, (1) the safety population
refers to those patients receiving at least one dose of the study
drug; (2) percentages of the populations having adverse events
(AE's) were provided per CTCAE Version 4; and (3) hematologic
adverse events include only those patients who had at least one
post-baseline assessment.
[0056] FIG. 18 is a pictorial representation of nanoliposomal
irinotecan (MM-398).
[0057] FIG. 19 provides a pharmacokinetic analysis of the extended
circulation of irinotecan and the SN38 metabolite after
administration of irinotecan within the liposome vs. irinotecan
HCl, in patients with gastric cancer. Nal-IRI is nanoliposomal
Irinotecan; AUC is area under the curve; C.sub.max is maximal
concentration. Comparing nal-IRI with irinotecan HCl, total
irinotecan AUC was 46 times greater and total irinotecan C.sub.max
was 13.4 times greater, SN-38 AUC was 1.4 times greater, and SN-38
C.sub.max was 0.19 times greater. The peak of SN-38 metabolite was
lower with nal-IRI versus irinotecan HCl, without an increase in
SN-38 plasma AUC.
[0058] FIG. 20 provides irinotecan and SN38 levels in tumor tissue
and plasma 72 hours after treatment with MM-398. Nal-IRI is
nanoliposomal irinotecan; LLoQ is the lower limit of quantitation.
Drug metabolite quantitation in tumor biopsies and plasma from
patients in a study of patients (N=14) with advanced solid tumors.
Tumor biopsy material averaged 10.5 mg (range, 3.3-21.9 mg);
metabolite detection was in an LC/MS/MS TSQ Vantage instrument,
with LLoQ of 50 pg/mL for irinotecan and 100 pg/mL for SN-38.
Plasma analysis was performed at QPS according to validated
procedures, with LLoQ of 140 ng/mL for irinotecan and 600 pg/mL for
SN-38.
[0059] FIG. 21A is a graphical representation of the Overall
Survival Rate (OS) corresponding to treatment with MM-398+5-FU/LV
vs. 5-FU/LV alone.
[0060] FIG. 21B is a graphical representation of the Overall
Survival Rate (OS) corresponding to treatment with MM-398 vs.
5-FU/LV alone.
[0061] FIG. 22A is a graphical representation of the Progression
Free Survival Rate (PFS) corresponding to treatment with
MM-398+5-FU/LV vs. 5-FU/LV alone.
[0062] FIG. 22B is a graphical representation of the Progression
Free Survival Rate (PFS) corresponding to treatment with MM-398 vs.
5-FU/LV alone.
[0063] FIG. 23 is a Kaplan-Meier graph of Overall Survival (OS) in
the NAPOLI-1 trial. OS, overall survival; CI, confidence interval;
nal-IRI, nanoliposomal irinotecan; 5-FU, 5-fluorouracil; LV,
leucovorin. OS analysis includes all patients randomized after
implementation of a protocol amendment that added the
nal-IRI+5-FU/LV combination arm.
[0064] FIG. 24 is a trial profile.
[0065] FIG. 25 is a table providing demographics and baseline
characteristics (PRO Population).
[0066] FIG. 26 is a graphical representation of the proportion of
patients demonstrating improvement, stability, or worsening in
global health status and functional scale scores (MM-398+5-FU/LV,
n=71; 5-FU/LV, n=57).
[0067] FIG. 27 is a graphical representation of the proportion of
patients demonstrating improvement, stability, or worsening in
symptom scale scores (MM-398+5-FU/LV, n=71; 5-FU/LV, n=57).
[0068] FIG. 28 is a graphical representation of the median change
from baseline to week 12 in global health status and functional
scale scores (MM-398+5-FU/LV, n=71 at baseline; 5-FU/LV, n=57 at
baseline).
[0069] FIG. 29 is a graphical representation of the median change
from baseline to week 12 in symptom scale scores (MM-398+5-FU/LV,
n=71 at baseline; 5-FU/LV, n=57 at baseline).
[0070] FIG. 30 is a table providing Treatment-Emergent Adverse
Events From the Primary Analysis of the NAPOLI-1 Trial. 5-FU is
5-fluorouracil; LC is leucovorin; nal-IRI is liposomal irinotecan.
Data are number of patients (%). The table shows grade 3 and 4
adverse events reported in .gtoreq.5% of patients with .gtoreq.2%
incidence versus 5-FU/LV. .sup.aIncludes agranulocytosis, febrile
neutropenia, granulocytopenia, neutropenia, neutropenic sepsis,
decreased neutrophil count, and pancytopenia.
[0071] FIG. 31 is a table providing Demographics and Baseline
Characteristics (Safety Population). 5-FU is 5-fluorouracil; KPS is
Karnofsky performance status, LV is leucovorin, nal-IRI is
liposomal irinotecan. .sup.aPatients received neoadjuvant,
adjuvant, or locally advanced treatment, but no previous therapy
for metastatic disease. .sup.bColumns add to >100% because some
patients received more than 1 line of therapy, and regimens may
include multiple drug classes.
[0072] FIG. 32 is a table providing TEAEs by Age. 5-FU is
5-fluorouracil; LV is leucovorin; nal-IRI is nanoliposomal
irinotecan; TEAE is treatment-emergent adverse event. .sup.aDose
modification included dose reduction, dose delay, and dose
discontinuation. .sup.bIncludes agranulocytosis, febrile
neutropenia, granulocytopenia, neutropenia, neutrophil sepsis,
neutrophil count decreased, and pancytopenia.
[0073] FIG. 33 is a table providing TEAEs by Ethnicity. 5-FU is
5-fluorouracil; LV is leucovorin; nal-IRI is nanoliposomal
irinotecan; TEAE is treatment-emergent adverse event. .sup.aDose
modification included dose reduction, dose delay, and dose
discontinuation. .sup.bIncludes agranulocytosis, febrile
neutropenia, granulocytopenia, neutropenia, neutrophil sepsis,
neutrophil count decreased, and pancytopenia.
[0074] FIG. 34 is a table providing TEAEs by UGT1A1*28 Allele
(TA7/TA7 Genotype). 5-FU is 5-fluorouracil; LV is leucovorin;
nal-IRI is nanoliposomal irinotecan; TEAE is treatment-emergent
adverse event. .sup.aDose modification included dose reduction,
dose delay, and dose discontinuation. .sup.bIncludes
agranulocytosis, febrile neutropenia, granulocytopenia,
neutropenia, neutrophil sepsis, neutrophil count decreased, and
pancytopenia.
[0075] FIG. 35 is a table providing TEAEs by Albumin Level. 5-FU is
5-fluorouracil; LV is leucovorin; nal-IRI is nanoliposomal
irinotecan; TEAE is treatment-emergent adverse event. .sup.aDose
modification included dose reduction, dose delay, and dose
discontinuation. .sup.bIncludes agranulocytosis, febrile
neutropenia, granulocytopenia, neutropenia, neutrophil sepsis,
neutrophil count decreased, and pancytopenia.
[0076] FIG. 36 is a table providing TEAEs by KPS Score. 5-FU is
5-fluorouracil; KPS is Karnofsky performance status; LV is
leucovorin; nal-IRI is nanoliposomal irinotecan; TEAE is
treatment-emergent adverse event. .sup.aDose modification included
dose reduction, dose delay, and dose discontinuation.
.sup.bIncludes agranulocytosis, febrile neutropenia,
granulocytopenia, neutropenia, neutrophil sepsis, neutrophil count
decreased, and pancytopenia.
DETAILED DESCRIPTION
I. Definitions
[0077] As used herein, the term "subject" or "patient" is a human
cancer patient.
[0078] As used herein, "effective treatment" refers to treatment
producing a beneficial effect, e.g., amelioration of at least one
symptom of a disease or disorder. A beneficial effect can take the
form of an improvement over baseline, i.e., an improvement over a
measurement or observation made prior to initiation of therapy
according to the method. A beneficial effect can also take the form
of arresting, slowing, retarding, or stabilizing of a deleterious
progression of a marker of a cancer. Effective treatment may refer
to alleviation of at least one symptom of a cancer. Such effective
treatment may, e.g., reduce patient pain, reduce the size and/or
number of lesions, may reduce or prevent metastasis of a cancer
tumor, and/or may slow growth of a cancer tumor.
[0079] The term "effective amount" refers to an amount of an agent
that provides the desired biological, therapeutic, and/or
prophylactic result. That result can be reduction, amelioration,
palliation, lessening, delaying, and/or alleviation of one or more
of the signs, symptoms, or causes of a disease, or any other
desired alteration of a biological system. In reference to cancers,
an effective amount comprises an amount sufficient to cause a tumor
to shrink and/or to decrease the growth rate of the tumor (such as
to suppress tumor growth) or to prevent or delay other unwanted
cell proliferation. In some embodiments, an effective amount is an
amount sufficient to delay tumor development. In some embodiments,
an effective amount is an amount sufficient to prevent or delay
tumor recurrence. An effective amount can be administered in one or
more administrations. The effective amount of the drug or
composition may: (i) reduce the number of cancer cells; (ii) reduce
tumor size; (iii) inhibit, retard, slow to some extent and may stop
cancer cell infiltration into peripheral organs; (iv) inhibit
(i.e., slow to some extent and may stop) tumor metastasis; (v)
inhibit tumor growth; (vi) prevent or delay occurrence and/or
recurrence of tumor; and/or (vii) relieve to some extent one or
more of the symptoms associated with the cancer.
[0080] The terms "combination therapy," "co-administration,"
"co-administered" or "concurrent administration" (or minor
variations of these terms) include simultaneous administration of
at least two therapeutic agents to a patient or their sequential
administration within a time period during which the first
administered therapeutic agent is still present in the patient when
the second administered therapeutic agent is administered.
[0081] The term "monotherapy" refers to administering a single drug
to treat a disease or disorder in the absence of co-administration
of any other therapeutic agent that is being administered to treat
the same disease or disorder.
[0082] "Dosage" refers to parameters for administering a drug in
defined quantities per unit time (e.g., per hour, per day, per
week, per month, etc.) to a patient. Such parameters include, e.g.,
the size of each dose. Such parameters also include the
configuration of each dose, which may be administered as one or
more units, e.g., taken at a single administration, e.g., orally
(e.g., as one, two, three or more pills, capsules, etc.) or
injected (e.g., as a bolus). Dosage sizes may also relate to doses
that are administered continuously (e.g., as an intravenous
infusion over a period of minutes or hours). Such parameters
further include frequency of administration of separate doses,
which frequency may change over time.
[0083] "Dose" refers to an amount of a drug given in a single
administration.
[0084] As used herein, "cancer" refers to a condition characterized
by abnormal, unregulated, malignant cell growth. In one embodiment,
the cancer is an exocrine pancreatic cancer. In another embodiment,
the exocrine pancreatic cancer selected from the group consisting
of acinar cell carcinoma, adenocarcinoma, adenosquamous carcinoma,
giant cell tumor, intraductal papillary-mucinous neoplasm (IPMN),
mucinous cystadenocarcinoma, pancreatoblastoma, serous
cystadenocarcinoma, and solid and pseudopapillary tumors.
[0085] The terms "resistant" and "refractory" refer to tumor cells
that survive treatment with a therapeutic agent. Such cells may
have responded to a therapeutic agent initially, but subsequently
exhibited a reduction of responsiveness during treatment, or did
not exhibit an adequate response to the therapeutic agent in that
the cells continued to proliferate in the course of treatment with
the agent.
II. Irinotecan Nanoparticle Formulations
[0086] As provided herein, irinotecan is administered in a
composition of irinotecan nanoparticles with a diameter of about
80-140 nm formulated to provide an irinotecan terminal elimination
half-life in the human patient of at least about 2-fold higher than
that of 125 mg/m.sup.2 free irinotecan as CPT-11 irinotecan
hydrochloride injection, and preferably also include a C.sub.max
and AUC within the ranges specified in Table 4. Preferably, the
irinotecan is contained within a lipid matrix, for example as
described in PCT publication WO2005/107712 (see, e.g., Example 11
describing CPT-11 liposome formulations prepared with TEA-Pn and
TEA-SOS, incorporated herein by reference). The lipid matrix
composition can comprise entrapped irinotecan in a pharmaceutically
acceptable salt form, in 1,2-Distearoyl-SN-phosphatidylcholine
(DSPC) (Mol. wt. 790) 3 molar parts (59.8 mol. %); Cholesterol
(Chol) (Mol. weight 387) 2 molar parts (39.9 mol. %); and
N-(omega-methoxy-poly(ethylene
glycol)-oxycarbonyl)-1,2-distearoylphosphatidyl ethanolamine (Mol.
weight 2787) (PEG-DSPE) 0.015 molar parts (approx. 0.3 mol. %).
[0087] In some embodiments, the irinotecan is administered in a
lipid matrix as a liposomal formulation encapsulating irinotecan
sucrose sulfate liposome. The liposome can have the structure shown
in FIG. 18. For example, the irinotecan nanoparticle can be an
"irinotecan sucrose octasulfate salt liposome injection" or
"irinotecan sucrosofate liposome injection" product, including the
formulation referred to herein as "MM-398" (also known as PEP02 or
nanoliposomal irinotecan or liposomal irinotecan or "nal-IRI").
[0088] For example, an MM-398 liposome is a unilamellar lipid
bilayer vesicle of approximately 80-140 nm in diameter that
encapsulates an aqueous space which contains irinotecan complexed
in a gelated or precipitated state as a salt with sucrose
octasulfate. The lipid membrane of the liposome is composed of
phosphatidylcholine, cholesterol, and a
polyethyleneglycol-derivatized phosphatidyl-ethanolamine in the
amount of approximately one polyethyleneglycol (PEG) molecule for
200 phospholipid molecules.
[0089] This stable liposomal formulation of irinotecan has several
attributes that may provide an improved therapeutic index. The
controlled and sustained release improves activity of this
schedule-dependent drug by increasing duration of exposure of tumor
tissue to drug, an attribute that allows it to be present in a
higher proportion of cells during the S-phase of the cell cycle,
when DNA unwinding is required as a preliminary step in the DNA
replication process. The long circulating pharmacokinetics and high
intravascular drug retention in the liposomes can promote an
enhanced permeability and retention (EPR) effect. EPR allows for
deposition of the liposomes at sites, such as malignant tumors,
where the normal integrity of the vasculature (capillaries in
particular) is compromised resulting in leakage out of the
capillary lumen of particulates such as liposomes. EPR may thus
promote site-specific drug delivery of liposomes to solid tumors.
EPR of MM-398 may result in a subsequent depot effect, where
liposomes accumulate in tumor associated macrophages (TAMs), which
metabolize irinotecan, converting it locally to the substantially
more cytotoxic SN-38. This local bioactivation is believed to
result in reduced drug exposure at potential sites of toxicity and
increased exposure at cancer cells within the tumor.
[0090] The chemical name of irinotecan hydrochloride trihydrate is
(S)
4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxolH-pyrano[3',4':6,7-
]-indolizino[1,2 b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate,
monohydrochloride, trihydrate. The empirical formula is
C.sub.33H.sub.38N.sub.4O.sub.6.HCl.3H.sub.2O and the molecular
weight is 677.19 g/mole. The molecular structure is:
[0091] Structural Formula:
##STR00001##
[0092] The chemical name of irinotecan is (S)
4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxolH-pyrano[3',4':6,7-
]-indolizino[1,2 b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate.
The empirical formula is C.sub.33H.sub.38N.sub.4O.sub.6 and the
molecular weight is 586.68 g/mole. The molecular structure of
irinotecan free base is:
[0093] Structural Formula:
##STR00002##
[0094] MM-398 is a topoisomerase I inhibitor indicated for the
treatment of metastatic adenocarcinoma of the pancreas after
disease progression following gemcitabine-based therapy. MM-398
(irinotecan liposome injection), in combination with 5-fluorouracil
and leucovorin, is indicated for the treatment of patients with
metastatic adenocarcinoma of the pancreas whose disease has
progressed following gemcitabine-based therapy. Administer MM-398
prior to leucovorin and 5-fluorouracil. MM-398 is not indicated as
a single agent for the treatment of metastatic adenocarcinoma of
the pancreas. MM-398 is not substituted for other drugs containing
non-liposome formulations of irinotecan hydrochloride or irinotecan
hydrochloride trihydrate.
[0095] Converting a dose based on irinotecan hydrochloride
trihydrate to a dose based on irinotecan free base is accomplished
by multiplying the dose based on irinotecan hydrochloride
trihydrate with the ratio of the molecular weight of irinotecan
free base (586.68 g/mol) and the molecular weight of irinotecan
hydrochloride trihydrate (677.19 g/mol). This ratio is 0.87 which
can be used as a conversion factor. For example, an 80 mg/m.sup.2
dose based on irinotecan hydrochloride trihydrate is equivalent to
a 69.60 mg/m.sup.2 dose based on irinotecan free base
(80.times.0.87). In the clinic this is rounded to 70
mg/m.sup.2.
[0096] Alternatively, the dose of irinotecan liposome can be
expressed as the amount of irinotecan free base encapsulated in the
irinotecan liposome where indicated ("free base dose"). Unless
otherwise indicated, the irinotecan liposome dose free base dose
recited in MM-398 is expressed in terms of the amount of irinotecan
hydrochloride trihydrate salt (herein referred to as a "(salt)"
dose) containing the same amount of irinotecan free base. Examples
of equivalent MM-398 doses are provided in table 1 below based on
both free base dose and salt based dose.
TABLE-US-00001 TABLE 1 Corresponding MM-398 Irinotecan liposome
irinotecan liposome free base dose in hydrochloride trihydrate
MM-398 (mg/m.sup.2) salt dose (mg/m.sup.2) ("free base") ("salt")
100 120 70 80 60 70 50 60 43 50 35 40
[0097] The recommended dose of MM-398 is 80 mg/m.sup.2 (salt) (70
mg/m.sup.2 free base) intravenous infusion over 90 minutes (i.e.,
70 mg irinotecan free base in the irinotecan liposome per m.sup.2
patient body surface area, containing about the same amount of
irinotecan that would be in 80 mg/m.sup.2 of irinotecan
hydrochloride trihydrate). Preferably, the recommended dose of
MM-398 is 80 mg/m.sup.2 administered by intravenous infusion over
90 minutes every 2 weeks. A corticosteroid and an anti-emetic is
preferably administered to the patient 30 minutes prior to
MM-398.
[0098] Pharmacogenetics of Irinotecan Glucuronidation
[0099] The enzyme produced by the UGT1A1 gene,
UDP-glucuronosyltransferase 1, is responsible for bilirubin
metabolism and also mediates SN-38 glucuronidation, which is the
initial step in the predominant metabolic clearance pathway of this
active metabolite of irinotecan. Besides its anti-tumor activity,
SN-38 is also responsible for the severe toxicity sometimes
associated with irinotecan therapy. Therefore, the glucuronidation
of SN-38 to the inactive form, SN-38 glucuronide, is an important
step in the modulation of irinotecan toxicity.
[0100] Mutational polymorphisms in the promoter of the UGT1A1 gene
have been described in which there is a variable number of thymine
adenine (ta) repeats. Promoters containing seven thymine adenine
(ta) repeats (found in the UGT1A1*28 allele) have been found to be
less active than the wild-type six repeats, resulting in reduced
expression of UDP-glucuronosyltransferase 1. Patients who carry two
deficient alleles of UGT1A1 exhibit reduced glucuronidation of
SN-38. Some case reports have suggested that individuals who are
homozygous for UGT1A1*28 alleles (referred to as having the UGT1A1
7/7 genotype, because both alleles are UGT1A1*28 alleles that
contain 7 ta repeats, as opposed to the wild-type UGT1A1 6/6
genotype in which both alleles contain 6 ta repeats) and who have
fluctuating elevation in serum bilirubin, (e.g., Gilbert's Syndrome
patients), may be at greater risk of toxicity upon receiving
standard doses of irinotecan. This suggests that there is a link
between homozygosity of the UGT1A1*28 allele, bilirubin levels and
irinotecan toxicity.
[0101] The metabolic transformation of MM-398 to SN-38 (e.g., in
plasma) includes two critical steps: (1) the release of irinotecan
from the liposome and (2) the conversion of free irinotecan to
SN-38. While not intending to be limited by theory, it is believed
that once irinotecan leaves the liposomes, it is catabolized by the
same metabolic pathways as conventional (free) irinotecan.
Therefore the genetic polymorphisms in humans predictive for the
toxicity and efficacy of irinotecan and those of MM-398 can be
considered similar. Nonetheless, due to the smaller tissue
distribution, lower clearance, higher systemic exposure and longer
elimination half-life of SN-38 of the MM-398 formulation compared
to free irinotecan, the deficient genetic polymorphisms may show
more association with severe adverse events and/or efficacy.
[0102] Patients with Reduced UGT1A1 Activity
[0103] Individuals who are homozygous for the UGT1A1*28 allele
(UGT1A1 7/7 genotype) have been shown to be at increased risk for
neutropenia following initiation of irinotecan treatment. According
to the prescribing information for irinotecan (Camptosar.RTM.), in
a study of 66 patients who received single-agent irinotecan (350
mg/m.sup.2 once every-3-weeks), the incidence of grade 4
neutropenia in patients homozygous for the UGT1A1*28 allele was as
high as 50%, and in patients heterozygous for this allele (UGT1A1
6/7 genotype) the incidence was 12.5%. Importantly, no grade 4
neutropenia was observed in patients homozygous for the wild-type
allele (UGT1A1 6/6 genotype). In other studies, a lower prevalence
of life threatening neutropenia is described. For this reason,
patients who are enrolled in the phase 3 study described in the
Examples herein and are homozygous for the UGT1A1*28 allele (UGT1A1
7/7 genotype) will have MM-398 treatment initiated at a lower dose
than patients with one (e.g., UGT1A1 6/7) or two (UGT1A1 6/6)
wild-type alleles.
[0104] The recommended starting dose of MM-398 in patients known to
be homozygous for the UGT1A1*28 allele is 60 mg/m.sup.2 (salt)
(equivalent to a dose of 50 mg/m.sup.2 (base)) administered by
intravenous infusion over 90 minutes. Increase the dose of MM-398
to 80 mg/m.sup.2 (salt) as tolerated in subsequent cycles.
[0105] In some embodiments, methods of administering MM-398 to
patients having one or more characteristics can include reducing or
otherwise modifying the dose of MM-398 administered according to
the embodiments herein. In some embodiments, the dose of MM-398 is
modified according to Table 2.
TABLE-US-00002 TABLE 2 Recommended Dose Modifications for MM-398
(salt) MM-398 Patients adjustment in homozygous for patients
UGT1A1*28 Toxicity receiving without previous NCI CTCAE 80
mg/m.sup.2.dagger-dbl. increase to v4.0 Occurrence (salt) 80
mg/m.sup.2 (salt) Grade 3 or 4 Withhold MM-398. adverse reactions
Initiate loperamide for late onset diarrhea of any severity.
Administer intravenous or subcutaneous atropine 0.25 to 1 mg
(unless clinically contraindicated) for early onset diarrhea of any
severity. Upon recovery to .ltoreq. Grade 1 or baseline grade
resume MM-398 at: First 60 mg/m.sup.2 50 mg/m.sup.2 Second 50
mg/m.sup.2 40 mg/m.sup.2 Third Discontinue Discontinue MM-398
MM-398 Interstitial First Discontinue Discontinue Lung Disease
MM-398 MM-398 Anaphylactic First Discontinue Discontinue Reaction
MM-398 MM-398
[0106] Additional Genotypic Modifiers of Irinotecan Metabolism
[0107] Although the UGT1A1*28 allele is relatively common in
Caucasians (estimates 10%), the prevalence is varied in other
ethnic groups. Furthermore, additional UGT1A1 genotypes are found
with higher prevalence for example in Asian populations and these
could be important for the metabolism of irinotecan in these
populations. For example, the UGT1A1*6 allele is more prevalent in
Asians. This allele is not associated with a ta repeat, but with a
Gly71Arg mutation that reduces enzyme activity. In previous and
ongoing studies of MM-398, pharmacogenetic information has been
collected on patients being enrolled. In a study referred to as the
PEP0203 study, the relationship of genetic polymorphism of UGT1A
family and of DPYD (dihydropyrimidine dehydrogenase, an enzyme
associated with catabolism of 5-FU) with pharmacokinetic parameters
of MM-398 and toxicity did not provide a clear correlation with the
small sample size of subjects evaluated. However, it was observed
that patients with UGT1A1*6/*28 combined polymorphism had higher
dose-normalized AUCs of SN-38 and experienced DLT.
III. 5-Fluorouracil (5-FU) and Leucovorin
[0108] 5-Fluorouracil is a pyrimidine antagonist that interferes
with nucleic acid biosynthesis. The deoxyribonucleotide of the drug
inhibits thymidylate synthetase, thus inhibiting the formation of
thymidylic acid from deoxyuridylic acid, thus interfering in the
synthesis of DNA. It also interferes with RNA synthesis.
[0109] Leucovorin (also called folinic acid) acts as a biochemical
cofactor for 1-carbon transfer reactions in the synthesis of
purines and pyrimidines. Leucovorin does not require the enzyme
dihydrofolate reductase (DHFR) for conversion to tetrahydrofolic
acid. The effects of methotrexate and other DHFR-antagonists are
inhibited by leucovorin. Leucovorin can potentiate the cytotoxic
effects of fluorinated pyrimidines (i.e., 5-fluorouracil and
floxuridine). After 5-FU is activated within the cell, it is
accompanied by a folate cofactor, and inhibits the enzyme
thymidylate synthetase, thus inhibiting pyrimidine synthesis.
Leucovorin increases the folate pool, thereby increasing the
binding of folate cofactor and active 5-FU with thymidylate
synthetase.
[0110] Leucovorin has dextro- and levo-isomers, only the latter one
being pharmacologically useful. As such, the bioactive levo-isomer
("levoleucovorin") has also been approved by the FDA for treatment
of cancer. The dosage of levoleucovorin is typically half that of
the racemic mixture containing both dextro (d) and levo (l)
isomers. Unless otherwise indicated, doses requiring 200 mg/m.sup.2
leucovorin are to be understood to require 200 mg/m.sup.2 of the
(l) enantiomer of leucovorin, and doses requiring 400 mg/m.sup.2
leucovorin are to be understood to require 400 mg/m.sup.2 of the
(l+d) racemate of leucovorin. Unless otherwise indicated, a dose
having 200 mg/m.sup.2 of the (l) enantiomer of leucovorin, and a
dose having 400 mg/m.sup.2 of the (l+d) racemate of leucovorin
contain equivalent amounts of the pharmaceutically active (l) form
of leucovorin.
[0111] FU and leucovorin will be stored and handled according to
the country specific package inserts.
IV. Administration
[0112] Liposomal irinotecan is administered intravenously, either
alone or in combination with 5-fluorouracil (5-FU) and/or
leucovorin. In one embodiment, liposomal irinotecan is administered
prior to 5-FU and leucovorin. In another embodiment, leucovorin is
administered prior to 5-FU. In another embodiment, liposomal
irinotecan is administered intravenously over 90 minutes. In
another embodiment, 5-FU is administered intravenously over 46
hours. In another embodiment, leucovorin is administered
intravenously over 30 minutes. In various embodiments the liposomal
irinotecan is MM-398.
V. Patient Populations
[0113] In one embodiment, a patient treated using the methods and
compositions disclosed herein exhibits evidence of recurrent or
persistent pancreatic cancer following primary chemotherapy.
[0114] In another embodiment, the patient has had and failed at
least one prior platinum based chemotherapy regimen for management
of primary or recurrent disease, e.g., a chemotherapy regimen
comprising carboplatin, cisplatin, or another organoplatinum
compound.
[0115] In an additional embodiment, the patient has failed prior
treatment with gemcitabine or become resistant to gemcitabine.
[0116] In one embodiment a resistant or refractory tumor is one
where the treatment-free interval following completion of a course
of therapy for a patient having the tumor is less than 6 months
(e.g., owing to recurrence of the cancer) or where there is tumor
progression during the course of therapy.
[0117] In another embodiment, the pancreatic cancer of the patient
undergoing treatment is advanced pancreatic cancer, which is a
pancreatic tumor that exhibits either or both of distant metastasis
or peripancreatic extension of the tumor.
[0118] The compositions and methods disclosed herein are useful for
the treatment of all pancreatic cancers, including pancreatic
cancers that are refractory or resistant to other anti-cancer
treatments.
VI. Combination Therapy
[0119] In one embodiment, liposomal irinotecan is co-administered
to patients having pancreatic cancer in combination with
5-fluorouracil (5-FU) and leucovorin, according to a particular
clinical dosage regimen, such as those described herein. In one
embodiment, the liposomal irinotecan is MM-398.
[0120] As used herein, adjunctive or combined administration
(coadministration) includes simultaneous administration of the
compounds in the same or different dosage form, or separate
administration of the compounds (e.g., sequential administration).
For example, liposomal irinotecan can be simultaneously
administered with 5-FU and leucovorin. Alternatively, liposomal
irinotecan can be administered in combination with 5-FU and
leucovorin, wherein liposomal irinotecan, 5-FU and leucovorin are
formulated for separate administration and are administered
concurrently or sequentially. For example, liposomal irinotecan can
be administered first followed by (e.g., immediately followed by)
the administration of the 5-FU and leucovorin. Such concurrent or
sequential administration preferably results in liposomal
irinotecan, 5-FU, and leucovorin being simultaneously present in
treated patients. In a particular embodiment, liposomal irinotecan
is administered prior to 5-FU and leucovorin. In another particular
embodiment, leucovorin is administered prior to 5-FU.
[0121] In another embodiment, liposomal irinotecan, 5-FU, and
leucovorin are formulated for intravenous administration. In a
particular embodiment, the patient is administered an effective
amount each of liposomal irinotecan, 5-fluorouracil (5-FU), and
leucovorin, wherein the treatment comprises at least one cycle,
wherein the cycle is a period of 2 weeks, and wherein for each
cycle: (a) liposomal irinotecan is administered on day 1 of the
cycle at a dose of 80 mg/m.sup.2, except if the patient is
homozygous for the UGT1A1*28 allele, wherein liposomal irinotecan
is administered on day 1 of cycle 1 at a dose of 60 mg/m.sup.2; (b)
5-FU is administered at a dose of 2400 mg/m.sup.2; and (c)
leucovorin is administered at a dose of 200 mg/m.sup.2 (l form) or
400 mg/m.sup.2 (l+d racemic form) In a particular embodiment, the
dose of liposomal irinotecan administered to the patient homozygous
for the UGT1A1*28 allele is increased after one cycle to 80
mg/m.sup.2.
[0122] In one embodiment, liposomal irinotecan may be initially
administered at a high dose and may be lowered over time. In
another embodiment, liposomal irinotecan is initially administered
at a low dose and increased over time. In one embodiment, liposomal
irinotecan is administered as a monotherapy.
[0123] In another embodiment, the dose of 5-FU is varied over time.
For example, 5-FU may be initially administered at a high dose and
may be lowered over time. In another embodiment, 5-FU is initially
administered at a low dose and increased over time.
[0124] In another embodiment, the dose of leucovorin is varied over
time. For example, leucovorin may be initially administered at a
high dose and may be lowered over time. In another embodiment,
leucovorin is initially administered at a low dose and increased
over time.
VII. Treatment Protocols
[0125] Other treatment protocols include, for example, those
wherein the patient is administered an effective amount of
liposomal irinotecan, wherein the treatment comprises at least one
cycle, wherein the cycle is a period of 3 weeks, and wherein for
each cycle the liposomal irinotecan is administered on day 1 of the
cycle at a dose of 120 mg/m.sup.2, except if the patient is
homozygous for the UGT1A1*28 allele, wherein liposomal irinotecan
is administered on day 1 of cycle 1 at a dose of 80 mg/m.sup.2. In
one embodiment, the dose of liposomal irinotecan administered to
the patient homozygous for the UGT1A1*28 allele is increased after
one cycle in increments of 20 mg/m.sup.2, up to a maximum of 120
mg/m.sup.2.
[0126] In another embodiment, the treatment protocol includes
administering to the patient an effective amount each of liposomal
irinotecan, 5-fluorouracil (5-FU), and leucovorin, wherein the
treatment comprises at least one cycle, wherein the cycle is a
period of 2 weeks, and wherein for each cycle: (a) liposomal
irinotecan is administered on day 1 of the cycle at a dose of 80
mg/m.sup.2, except if the patient is homozygous for the UGT1A1*28
allele, wherein liposomal irinotecan is administered on day 1 of
cycle 1 at a dose of 60 mg/m.sup.2; (b) 5-FU is administered at a
dose of 2400 mg/m.sup.2; and (c) leucovorin is administered at a
dose of 200 mg/m.sup.2 (l form) or 400 mg/m.sup.2 (l+d racemic
form). In a particular embodiment, the dose of liposomal irinotecan
administered to the patient homozygous for the UGT1A1*28 allele is
increased after one cycle to 80 mg/m.sup.2.
VIII. Outcomes
[0127] Provided herein are methods for treating pancreatic cancer
in a patient comprising administering to the patient liposomal
irinotecan (MM-398), alone or in combination with 5-fluorouracil
(5-FU) and leucovorin, according to a particular clinical dosage
regimen. Preferably, the combination therapy with liposomal
irinotecan with 5-FU and leucovorin exhibits therapeutic
synergy.
[0128] "Therapeutic synergy" refers to a phenomenon where treatment
of patients with a combination of therapeutic agents manifests a
therapeutically superior outcome to the outcome achieved by each
individual constituent of the combination used at its optimum dose
(T. H. Corbett et al., 1982, Cancer Treatment Reports, 66, 1187).
In this context a therapeutically superior outcome is one in which
the patients either a) exhibit fewer incidences of adverse events
while receiving a therapeutic benefit that is equal to or greater
than that where individual constituents of the combination are each
administered as monotherapy at the same dose as in the combination,
or b) do not exhibit dose-limiting toxicities while receiving a
therapeutic benefit that is greater than that of treatment with
each individual constituent of the combination when each
constituent is administered in at the same doses in the
combination(s) as is administered as individual components. In
xenograft models, a combination, used at its maximum tolerated
dose, in which each of the constituents will be present at a dose
generally not exceeding its individual maximum tolerated dose,
manifests therapeutic synergy when decrease in tumor growth
achieved by administration of the combination is greater than the
value of the decrease in tumor growth of the best constituent when
the constituent is administered alone.
[0129] Thus, in combination, the components of such combinations
have an additive or superadditive effect on suppressing pancreatic
tumor growth, as compared to monotherapy with liposome-encapsulated
irinotecan alone or treatment with the chemotherapeutic(s) in the
absence of liposomal irinotecan therapy. By "additive" is meant a
result that is greater in extent (e.g., in the degree of reduction
of tumor mitotic index or of tumor growth or in the degree of tumor
shrinkage or the frequency and/or duration of symptom-free or
symptom-reduced periods) than the best separate result achieved by
monotherapy with each individual component, while "superadditive"
is used to indicate a result that exceeds in extent the sum of such
separate results. In one embodiment, the additive effect is
measured as slowing or stopping of pancreatic tumor growth. The
additive effect can also be measured as, e.g., reduction in size of
a pancreatic tumor, reduction of tumor mitotic index, reduction in
number of metastatic lesions over time, increase in overall
response rate, or increase in median or overall survival.
[0130] One non-limiting example of a measure by which effectiveness
of a therapeutic treatment can be quantified is by calculating the
log 10 cell kill, which is determined according to the following
equation:
log 10 cell kill=TC (days)/3.32.times.Td
[0131] in which T C represents the delay in growth of the cells,
which is the average time, in days, for the tumors of the treated
group (T) and the tumors of the control group (C) to have reached a
predetermined value (1 g, or 10 mL, for example), and Td represents
the time, in days necessary for the volume of the tumor to double
in the control animals. When applying this measure, a product is
considered to be active if log 10 cell kill is greater than or
equal to 0.7 and a product is considered to be very active if log
10 cell kill is greater than 2.8. Using this measure, a
combination, used at its own maximum tolerated dose, in which each
of the constituents is present at a dose generally less than or
equal to its maximum tolerated dose, exhibits therapeutic synergy
when the log 10 cell kill is greater than the value of the log 10
cell kill of the best constituent when it is administered alone. In
an exemplary case, the log 10 cell kill of the combination exceeds
the value of the log 10 cell kill of the best constituent of the
combination by at least 0.1 log cell kill, at least 0.5 log cell
kill, or at least 1.0 log cell kill.
[0132] Responses to therapy may include:
Pathologic complete response (pCR): absence of invasive cancer in
the breast and lymph nodes following primary systemic treatment.
Complete Response (CR): Disappearance of all target lesions. Any
pathological lymph nodes (whether target or non-target) which has
reduction in short axis to <10 mm; Partial Response (PR): At
least a 30% decrease in the sum of dimensions of target lesions,
taking as reference the baseline sum diameters; Stable Disease
(SD): Neither sufficient shrinkage to qualify for partial response,
nor sufficient increase to qualify for progressive disease, taking
as reference the smallest sum diameters while on study; or
[0133] Meanwhile, non-CR/Non-PD denotes a persistence of one or
more non-target lesion(s) and/or maintenance of tumor marker level
above the normal limits.
[0134] Progressive Disease (PD) denotes at least a 20% increase in
the sum of dimensions of target lesions, taking as reference the
smallest sum on study (this includes the baseline sum if that is
the smallest on study). In addition to the relative increase of
20%, the sum must also demonstrate an absolute increase of 5 mm.
The appearance of one or more new lesions is also considered
progression.
[0135] In exemplary outcomes, patients treated according to the
methods disclosed herein may experience improvement in at least one
sign of pancreatic cancer.
[0136] In one embodiment the patient so treated exhibits pCR, CR,
PR, or SD.
[0137] In another embodiment, the patient so treated experiences
tumor shrinkage and/or decrease in growth rate, i.e., suppression
of tumor growth. In another embodiment, unwanted cell proliferation
is reduced or inhibited. In yet another embodiment, one or more of
the following can occur: the number of cancer cells can be reduced;
tumor size can be reduced; cancer cell infiltration into peripheral
organs can be inhibited, retarded, slowed, or stopped; tumor
metastasis can be slowed or inhibited; tumor growth can be
inhibited; recurrence of tumor can be prevented or delayed; one or
more of the symptoms associated with cancer can be relieved to some
extent.
[0138] In other embodiments, such improvement is measured by a
reduction in the quantity and/or size of measurable tumor lesions.
Measurable lesions are defined as those that can be accurately
measured in at least one dimension (longest diameter is to be
recorded) as .gtoreq.10 mm by CT scan (CT scan slice thickness no
greater than 5 mm), 10 mm caliper measurement by clinical exam or
>20 mm by chest X-ray. The size of non-target lesions, e.g.,
pathological lymph nodes can also be measured for improvement. In
one embodiment, lesions can be measured on chest x-rays or CT or
MRI films.
[0139] In other embodiments, cytology or histology can be used to
evaluate responsiveness to a therapy. The cytological confirmation
of the neoplastic origin of any effusion that appears or worsens
during treatment when the measurable tumor has met criteria for
response or stable disease can be considered to differentiate
between response or stable disease (an effusion may be a side
effect of the treatment) and progressive disease.
[0140] In some embodiments, administration of effective amounts of
liposomal irinotecan, 5-FU and leucovorin according to any of the
methods provided herein produce at least one therapeutic effect
selected from the group consisting of reduction in size of a breast
tumor, reduction in number of metastatic lesions appearing over
time, complete remission, partial remission, stable disease,
increase in overall response rate, or a pathologic complete
response. In some embodiments, the provided methods of treatment
produce a comparable clinical benefit rate (CBR=CR+PR+SD.gtoreq.6
months) better than that achieved by the same combinations of
anti-cancer agents administered without concomitant MM-398
administration. In other embodiments, the improvement of clinical
benefit rate is about 20%, 30%, 40%, 50%, 60%, 70%, 80% or more
compared to the same combinations of anti-cancer agents
administered without concomitant MM-398 administration.
[0141] The following examples are illustrative and should not be
construed as limiting the scope of this disclosure in any way; many
variations and equivalents will become apparent to those skilled in
the art upon reading the present disclosure.
EXAMPLES
Example 1: Activity of MM-398 in an Orthotopic Pancreas Tumor Model
Expressing Luciferase (L3.6pl)
[0142] The anti-tumor activity of MM-398 was assessed in an
orthotopic pancreatic cancer model (L3.6pl), a highly hypoxic
preclinical tumor model. Approximately 2.5.times.10.sup.-5 L3.6pl
pancreatic tumor cells were implanted by direct injection into the
pancreas. The bioluminescence images (BLI) were followed over time
for tumor burden detection/quantitation. MM-398 and free irinotecan
were dosed at a dose of 20 mg/kg/dose weekly for three weeks. As
shown in FIG. 1, MM-398 (liposomal CPT11) had significant
anti-tumor activity, as compared to a control (HBS) and free
CPT11.
Example 2: Accumulation of SN-38 in Tumors Following Treatment with
Free Irinotecan or Liposomal Irinotecan (MM-398)
[0143] It was hypothesized that the anti-tumor activity observed in
the orthotopic pancreatic cancer model is due to the effect of
macrophages in converting irinotecan to the more active SN-38
locally. To test this hypothesis, human colon cancer cells (HT-29)
were injected subcutaneously into SCID mice, 40 mg/kg of free
irinotecan or MM-398 was injected intravenously when the tumors
reached 1000 mm.sup.3 in size. Tumor-bearing mice were sacrificed
at different time points, tumors from both groups were extracted
and the concentrations of SN-38 were measured.
[0144] As shown in FIG. 2, there was a 20-fold increase in the
tumor AUC.sub.SN-38 for MM-398 as compared to free irinotecan. The
long duration of exposure allows for prolonged exposure of the slow
proliferating cancer cells to the active metabolite as they
progress through the cell cycle. In addition, this activity was
also hypothesized to result from a reduction in intra-tumoral
hypoxia, and the subsequent downstream effects on angiogenesis,
metastasis, and the immunosuppressive environment in tumors.
Example 3: Effect of MM-398 on Carbonic Anhydrase IX Staining in a
HT29 Xenograft Model
[0145] To test whether MM-398 reduces markers of hypoxia,
experiments were conducted in a human colon cancer cell (HT-29)
model. Specifically, HT-29 cells were injected subcutaneously into
nude mice, on day 13 either PBS control or 1.25, 2.5, 5, 10 or 20
mg/kg MM-398 was injected intravenously. MM-398 was dosed once a
week for 4 weeks at the indicated doses. Tumors from both groups
(n=5) were extracted 24 hours after the last dose. Frozen tumor
sections were used for immunohistochemical staining of Carbonic
Anhydrase IX (CAIX). Quantification of CAIX staining was performed
using Definiens.RTM. (Definiens AG, Munich) software.
[0146] As shown in FIG. 3, MM-398 reduced markers of hypoxia.
Specifically, the graphs in FIG. 3 show the percentage of cells
that stained with medium (middle third) or high (top third)
intensity for CAIX. Representative samples from each group are
shown as well as the group average (mean+/-stdev). MM-398 treatment
modifies the tumor microenvironment by decreasing the percentage of
both medium and high CAIX positive cells in a dose-dependent
manner. As hypoxia is a hallmark of resistant and aggressive
disease, a reduction in hypoxia is expected to make tumor cells
more sensitive to chemotherapies.
Example 4: MM-398 Increases Perfusion of Hoechst Stain
[0147] In addition to changing the chemosensitivity of tumor cells
through modification of the tumor microenvironment, lowering
hypoxia can indicate improved tumor vascularization, which can
facilitate delivery of small molecule therapies. MM-398 treatment
led to increased microvessel density 6 days after treatment as
measured by CD31 (platelet endothelial cell adhesion molecule)
staining in an HT29 xenograft study. To further assess the effect
of MM-398 on small molecule tumor vascularization, a Hoechst 33342
perfusion experiment was conducted. Specifically, a primary
pancreatic tumor was grown in NOD-SCID mice and given one dose of
MM-398 (20 mg/kg). After 24 hours, Hoechst 33342 stain was
administered 20 minutes prior to sacrificing the animal. As shown
in FIG. 4, the increase in stain intensity in treated mice was
statistically significant, p<0.001. These data indicate that
MM-398 modifies the tumor microenvironment in a manner that should
make tumors more susceptible to agents such as 5-FU/LV, through
decreasing tumor hypoxia and increasing small molecule
perfusion.
Example 5A: MM-398 (q3w) Pharmacokinetics in Humans (Phase I)
[0148] The pharmacokinetic profile of MM-398 single agent was
investigated in a phase I clinical study (PEP0201) in patients at
60, 120 or 180 mg/m.sup.2 dose levels and in a phase II clinical
trial in gastric cancer patients (PEP0206) at 120 mg/m.sup.2.
Plasma levels of total irinotecan, SN-38 and encapsulated
irinotecan were measured in these studies.
[0149] The peak serum concentrations of total irinotecan
(C.sub.max) ranged from 48-79 .mu.g/ml for 120 mg/m.sup.2 of
MM-398, which was approximately 50 fold higher than 125 mg/m.sup.2
free irinotecan. The total irinotecan half-life (t.sub.1/2) for
MM-398 ranged from 21 to 48 hours, which was approximately 2-3 fold
higher than 125 mg/m.sup.2 of free irinotecan. Overall, total
irinotecan exposure at one week (AUC 0-T) ranged from 1200-3000
(.mu.g*h/ml) at a dose of 120 mg/m.sup.2 of MM-398, approximately
50-100 fold higher than 300 mg/m.sup.2 of free irinotecan. In
contrast, SN38 C.sub.max levels at 120 mg/m.sup.2 of MM-398 ranged
from 9 to 17 ng/ml, which was approximately 50% less than free
irinotecan at 125 mg/m.sup.2. Overall, exposure of SN38 at one week
(AUC 0-T) ranged from 474 to 997 ng*/ml and was only 1-2 fold
higher than achieved by free irinotecan at 300 mg/m.sup.2. For both
SN38 and total irinotecan, AUC increased less than proportionally
with dose of MM-398. The PK parameters of encapsulated irinotecan
almost matched that of total irinotecan indicates that most of
irinotecan remained encapsulated in the liposomes during
circulation. The MM-398 PK parameters were not significantly
changed when combined with 5-FU/LV. FIGS. 5 and 6 summarize the PK
findings in previous studies of MM 398.
Example 5B: MM-398 (q2w) Pharmacokinetics in Humans (Phase III)
[0150] The plasma pharmacokinetics of total irinotecan and total
SN-38 were evaluated in patients with cancer who received MM-398,
as a single agent or as part of combination chemotherapy, at doses
between 50 and 150 mg/m.sup.2 (free base) and 353 patients with
cancer using population pharmacokinetic analysis. The
pharmacokinetic parameters of total irinotecan and total SN-38
following the administration of MM-398 80 mg/m.sup.2 (salt) as a
single agent or part of combination chemotherapy are presented in
Table 3. Summary of Mean (.+-.Standard Deviation)
TABLE-US-00003 TABLE 3 Total Irinotecan and Total SN-38
Pharmacokinetic Parameters in Patients with Solid Tumors. Total
Irinotecan Total SN-38 Dose C.sub.max AUC.sub.0-.infin. t.sub.1/2
CL V.sub.d C.sub.max AUC.sub.0-.infin. t.sub.1/2 (mg/m.sup.2)
[.mu.g/mL] [h .mu.g/mL] [h] [L/h] [L] [ng/mL] [h ng/mL] [h] (salt)
(n = 25) (n = 23) (n = 23) (n = 23) (n = 23) (n = 25) (n = 13) (n =
13) 80 37.2 1364 25.8 0.20 4.1 5.4 620 67.8 (8.8) (1048) (15.7)
(0.17) (1.5) (3.4) (329) (44.5) C.sub.max: Maximum plasma
concentration AUC.sub.0-.infin.: Area under the plasma
concentration curve extrapolated to time infinity t.sub.1/2:
Terminal elimination half-life V.sub.d: Volume of distribution
[0151] The pharmacokinetic parameters of total irinotecan and total
SN-38 following the administration of MM-398 80 mg/m.sup.2 (salt)
as a single agent or part of combination chemotherapy are presented
in Table 3.
[0152] Over the dose range of 50 to 150 mg/m.sup.2 (free base), the
C.sub.max and AUC of total irinotecan increases with dose.
Additionally, the C.sub.max of total SN-38 increases proportionally
with dose; however, the AUC of total SN-38 increases less than
proportionally with dose. The correlation of SN-38 C.sub.max with
liposomal irinotecan dose had not previously been established.
Higher plasma SN-38 C.sub.max was associated with increased
likelihood of experiencing neutropenia.
[0153] The C.sub.max of SN-38 increases proportionally with
liposomal irinotecan dose but the AUC of SN-38 increases less than
proportionally with dose, enabling new methods of dosage
adjustment. For example, the value of the parameter associated with
adverse effects (C.sub.max) decreases by a relatively greater
extent than the value of the parameter associated with the
effectiveness of treatment (AUC). Accordingly, when an adverse
effect is seen, a reduction in the dosing of the liposomal
irinotecan can be implemented that maximizes the difference between
the reduction in C.sub.max and in AUC. The discovery means that in
treatment regimens, a given SN-38 AUC can be achieved with a
surprisingly low SN-38 C.sub.max. Likewise, a given SN-38 C.sub.max
can be achieved with a surprisingly high SN-38 AUC.
[0154] Direct measurement of irinotecan liposome showed that 95% of
irinotecan remains liposome encapsulated, and the ratios between
total and encapsulated forms did not change with time from 0 to
169.5 hours post-dose. The mean volume of distribution is
summarized in Table 3.
[0155] In some embodiments, the liposomal irinotecan can be MM-398
or a product that is bioequivalent to MM-398. In some embodiments,
the liposomal irinotecan can be characterized by the parameters in
Table 4, including a C.sub.max and/or AUC value that is 80-125% of
the corresponding value in Table 3. The pharmacokinetic parameters
of total irinotecan for various alternative liposomal irinotecan
formulations administering 70 mg/m.sup.2 irinotecan free base once
every two weeks is provided in Table 4.
TABLE-US-00004 TABLE 4 Total Irinotecan Pharmacokinetic Parameters
in Alternative Liposomal Irinotecan Formulations Total Irinotecan
Dose C.sub.max AUC.sub.0-.infin. (mg/m.sup.2) [.mu.g/mL] [h
.mu.g/mL] (salt) (n = 25) (n = 23) 80 29.8-46.5 1091-1705
C.sub.max: Maximum plasma concentration AUC.sub.0-.infin.: Area
under the plasma concentration curve extrapolated to time infinity
t.sub.1/2: Terminal elimination half-life
[0156] Plasma protein binding is <0.44% of the total irinotecan
in MM-398.
[0157] The plasma clearance of total irinotecan from MM-398 80
mg/m.sup.2 (salt) (equivalent to 70 mg/m.sup.2 free base dose) is
0.077 L/h/m.sup.2 with a terminal half live of 26.8 h. Following
administration of irinotecan HCl 125 mg/m.sup.2, the plasma
clearance of irinotecan is 13.3 L/h/m.sup.2 with a terminal half
live of 10.4 h.
Example 6: Phase 1 Dose Escalation Study
[0158] A regimen combining 5-fluorouracil, leucovorin, and MM-398
was studied in a phase 1 trial of solid tumors in 16 subjects, of
whom 5 were patients with pancreatic cancer. The objective tumor
response rate, duration of response, and disease control rate were
efficacy endpoints of the study. Among the 15 efficacy-evaluable
patients, 2 (13.3%) had confirmed PR, 9 (60.0%) had SD, and 4
(26.7%) had PD. The overall disease control rate was 73.3%. Partial
response was observed in one gastric cancer patient (at 80
mg/m.sup.2 dose level) and one breast cancer patient (at 100
mg/m.sup.2 dose level), with the duration of response of 142 and 76
days, respectively. Among the 6 patients who received the MTD dose
of 80 mg/m.sup.2, there were 1 PR, 4 SD and 1 PD. The tumor
response rate and disease control rate were 16.7% and 83.3%,
respectively. The main DLTs were grade 3 diarrhea, leucopenia,
neutropenia and febrile neutropenia. The MTD for MM-398 was 80
mg/m.sup.2.
[0159] In the phase 1 dose-escalation study of MM-398 in
combination with 5-FU/LV in advanced solid tumors (PEP0203), a
total of 401 episodes of AE were reported from the 16 treated
subjects (safety population), of which 74 (18.4%) were of CTC grade
3 or above. Among all AEs, 231 (57.6%) were considered by the
investigators to be treatment-related. The most common
treatment-related AEs, included nausea (81.3%), diarrhea (75.0%),
vomiting (68.8%), fatigue (43.8%), mucositis (43.8%), leucopenia
(37.5%), neutropenia (37.5%), weight loss (37.5%), anemia (31.3%),
and alopecia (31.3%). Acute cholinergic diarrhea was rarely
observed. Table 5 provides the incidence of treatment-emergent
adverse events by maximum CTC grade and by causality
(incidence.gtoreq.20%), as seen in the PEP0203 study. Table 6
provides the incidence of grade 3 or higher treatment-emergent
adverse events seen in the 5 pancreatic cancer patients treated in
the PEP0203 study.
TABLE-US-00005 TABLE 5 Incidence of treatment-emergent adverse
events by maximum CTC grade and by causality (incidence
.gtoreq.20%) in the PEP0203 Study Severity System organ class Total
(Grade).sup.1 Causality.sup.2 Preferred Term (N = 16) I II III IV
Yes No Blood and lymphatic system disorders Anemia 7 (43.8%) 3 2 2
0 5 2 Leucopenia 6 (37.5%) 0 3 2 1 6 0 Neutropenia 6 (37.5%) 0 2 3
1 6 0 Gastrointestinal disorders Abdominal pain 7 (43.8%) 3 2 2 0 3
4 Constipation 6 (37.5%) 3 3 0 0 0 6 Diarrhea 12 (75.0%) 3 4 5 0 12
0 Nausea 13 (81.3%) 6 6 1 0 13 0 Vomiting 12 (75.0%) 3 8 1 0 11 1
General disorders and administration site conditions Fatigue 8
(50.0%) 4 3 1 0 7 1 Mucosal inflammation 7 (43.8%) 4 3 0 0 7 0
Pyrexia 7 (43.8%) 3 4 0 0 2 5 Infections and infestations Infection
6 (37.5%) 0 3 3 0 2 4 Investigations ALT increased 5 (31.3%) 3 2 0
0 4 1 AST increased 4 (25.0%) 3 1 0 0 1 3 Weight decreased 8
(50.0%) 4 4 0 0 6 2 Metabolism and nutrition disorders Anorexia 4
(25.0%) 1 2 1 0 3 1 Hypoalbuminaemia 4 (25.0%) 0 3 1 0 0 4
Hypocalcaemia 5 (31.3%) 1 4 0 0 0 5 Hypokalaemia 8 (50.0%) 2 0 5 1
2 6 Hyponatraemia 4 (25.0%) 2 0 0 2 0 4 Nervous system disorders
Dizziness 4 (25.0%) 4 0 0 0 1 3 Psychiatric disorders Insomnia 4
(25.0%) 4 0 0 0 1 3 Respiratory, thoracic and mediastinal disorders
Cough 5 (31.3%) 3 1 1 0 0 5 Skin and subcutaneous tissue disorders
Alopecia 5 (31.3%) 5 0 0 0 5 0 .sup.1Severity grading used the
highest grading ever rated for each subject if the subject had such
adverse event reported .sup.2Defined as subject ever experienced AE
related to the study drug in causality or not
TABLE-US-00006 TABLE 6 Incidence of Grade 3 or higher
treatment-emergent adverse events in pancreatic cancer patients in
the PEP0203 Study Overall 60 mg/m2 80 mg/m2 120 mg/m2 Primary
system organ class N = 5 N = 1 N = 3 N = 1 Preferred term n (%) n
(%) n (%) n (%) Any primary system organ class Total 3 (60.0) 0 2
(66.7) 1 (100.0) Infections and infestations Total 3 (60.0) 0 2
(66.7) 1 (100.0) Hepatitis viral 1 (20.0) 0 1 (33.3) 0 Infection 1
(20.0) 0 0 1 (100.0) Pneumonia 1 (20.0) 0 1 (33.3) 0 Septic shock 1
(20.0) 0 1 (33.3) 0 Blood and lymphatic system disorders Total 2
(40.0) 0 1 (33.3) 1 (100.0) Lymphopenia 1 (20.0) 0 0 1 (100.0)
Neutropenia 1 (20.0) 0 1 (33.3) 0 White blood cell disorder 1
(20.0) 0 0 1 (100.0) Gastrointestinal disorders -Total 2 (40.0) 0 1
(33.3) 1 (100.0) Diarrhoea 2 (40.0) 0 1 (33.3) 1 (100.0) Abdominal
pain 1 (20.0) 0 0 1 (100.0) Gastrointestinal haemorrhage 1 (20.0) 0
1 (33.3) 0 Investigations -Total 2 (40.0) 0 1 (33.3) 1 (100.0)
Blood bilirubin increased 1 (20.0) 0 1 (33.3) 0 Lipase increased 1
(20.0) 0 0 1 (100.0) Neutrophil count decreased 1 (20.0) 0 0 1
(100.0) White blood cell count decreased 1 (20.0) 0 0 1 (100.0)
Metabolism and nutrition disorders Total 2 (40.0) 0 1 (33.3) 1
(100.0) Hypoalbuminaemia 1 (20.0) 0 1 (33.3) 0 Hypokalaemia 1
(20.0) 0 1 (33.3) 0 Hyponatraemia 1 (20.0) 0 0 1 (100.0)
Hypophosphataemia 1 (20.0) 0 0 1 (100.0) Respiratory, thoracic and
mediastinal disorders Total 2 (40.0) 0 1 (33.3) 1 (100.0) Dyspnoea
1 (20.0) 0 0 1 (100.0) Pleural effusion 1 (20.0) 0 1 (33.3) 0
General disorders and administration site conditions Total 1 (20.0)
0 0 1 (100.0) Death 1 (20.0) 0 0 1 (100.0)
Example 7: Phase 3 NAPOLI-1 Clinical Trial
[0160] The efficacy of MM-398 was evaluated in NAPOLI-1 (also
"Study 1"), a three-arm, randomized, open-label trial in patients
with metastatic pancreatic adenocarcinoma with documented disease
progression, after gemcitabine or gemcitabine-based therapy.
NAPOLI-1 was an international randomized human Phase 3 clinical
trial evaluating the use of the irinotecan liposome MM-398 in
patients with a diagnosis of metastatic pancreatic cancer
previously treated with a gemcitabine based therapy. The NAPOLI-1
trial is summarized below.
[0161] NAPOLI-1 was an open label, randomized, stratified by
albumin (<4.0 g/dL vs.gtoreq.4.0 g/dL), Karnofsky Performance
Status (KPS) (70 & 80 v.gtoreq.90), and ethnicity (Caucasian vs
East Asian vs others). The primary analysis compared each treatment
arm to its corresponding 5-FU/LV control for OS by unstratified
log-rank test; family-wise type I error rate was controlled at the
2-sided 0.05 level using the Bonferroni-Holm method. Primary
analysis planned when at least 305 death events occurred to have
85% power to detect HR=0.67 in the MM-398 arm and 98% power to
detect HR=0.50 in the MM-398+5-FU/LV arm. A supportive stratified
analysis, accounting for the randomization strata, was
performed.
[0162] Key eligibility criteria included Karnofsky Performance
Status (KPS).gtoreq.70, serum bilirubin within institution limits
of normal, and albumin.gtoreq.3.0 g/dL. Patients were randomized to
receive MM-398 plus 5-fluorouracil/leucovorin (MM-398/5-FU/LV),
MM-398, or 5-fluorouracil/leucovorin (5-FU/LV). Randomization was
stratified by ethnicity (White vs. East Asian vs. other), KPS
(70-80 vs. 90-100), and baseline albumin level (.gtoreq.4 g/dL vs.
3.0-3.9 g/dL). Patients randomized to MM-398/5-FU/LV received
MM-398 80 mg/m.sup.2 (salt) as an intravenous infusion over 90
minutes, followed by leucovorin 400 mg/m.sup.2 intravenously over
30 minutes, followed by 5-fluorouracil 2400 mg/m.sup.2
intravenously over 46 hours, every 2 weeks.
[0163] Patients randomized to MM-398 as a single agent received
MM-398 120 mg/m.sup.2 (salt) as an intravenous infusion over 90
minutes every 3 weeks. Patients randomized to 5-FU/LV received
leucovorin 200 mg/m.sup.2 intravenously over 30 minutes, followed
by 5-fluorouracil 2000 mg/m.sup.2 intravenously over 24 hours,
administered on Days 1, 8, 15 and 22 of a 6-week cycle. Patients
homozygous for the UGT1A1*28 allele initiated MM-398 at a reduced
dose (60 mg/m.sup.2 (salt) MM-398, if given with 5-FU/LV or 80
mg/m.sup.2 (salt) MM-398 as a single agent). When MM-398 was
withheld or discontinued for adverse reactions, 5-FU was also
withheld or discontinued. When the dose of MM-398 was reduced for
adverse reactions, the dose of 5-FU was reduced by 25%. Treatment
continued until disease progression or unacceptable toxicity. The
major efficacy outcome measure was overall survival (OS) with two
pair-wise comparisons: MM-398 versus 5-FU/LV and MM-398/5-FU/LV
versus 5-FU/LV. Additional efficacy outcome measures were
progression-free survival (PFS) and objective response rate (ORR).
Tumor status assessments were conducted at baseline and every 6
weeks thereafter. The trial was initiated as a two-arm study and
amended after initiation to include a third arm (MM-398/5-FU/LV).
The comparisons between the MM-398/5-FU/LV and the 5-FU/LV arms are
limited to patients enrolled in the 5-FU/LV arm after this protocol
amendment.
[0164] Four hundred seventeen patients were randomized to:
MM-398/5-FU/LV (N=117), MM-398 (N=151), or 5-FU/LV (N=149).
Baseline demographics and tumor characteristics for the 236
patients randomized to MM-398/5-FU/LV or 5-FU/LV (N=119) after the
addition of the third arm to the study were a median age of 63
years (range 34-81 years) and with 41%.gtoreq.65 years of age; 58%
were men; 63% were White, 30% were Asian, 3% were Black or African
American, and 5% were other. Mean baseline albumin level was 3.97
g/dL, and baseline KPS was 90-100 in 53% of patients. Disease
characteristics included liver metastasis (67%) and lung metastasis
(31%). A total of 13% of patients received gemcitabine in the
neoadjuvant/adjuvant setting only, 55% of patients had 1 prior line
of therapy for metastatic disease, and 33% of patients had 2 or
more prior lines of therapy for metastatic disease. All patients
received prior gemcitabine (alone or in combination with another
agent); 54% received prior gemcitabine in combination with another
agent, and 13% received prior gemcitabine in combination with
nab-paclitaxel.
[0165] NAPOLI-1 demonstrated a statistically significant
improvement in overall survival for the MM-398/5-FU/LV arm over the
5-FU/LV arm as summarized in Table 7 and shown graphically in FIG.
8. There was no improvement in overall survival for the MM-398 arm
over the 5-FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided
log-rank test)).
[0166] The OS and PFS benefits were maintained for MM-398+5-FU/LV
compared with 5-FU/LV alone. Convergence of the OS curves at 20
months (with 19 [16%] patients surviving beyond 20 months) is
likely a reason for the observed attenuation of the OS HR estimate
and unstratified log-rank P value.
TABLE-US-00007 TABLE 7 Efficacy Results from Study
1.dagger..dagger-dbl. MM-398/5-FU/LV 5-FU/LV (N = 117) (N = 119)
Overall Survival Number of Deaths, n (%) 77 (66) 86 (72) Median
Overall Survival (months) 6.1 4.2 (95% CI) (4.8, 8.5) (3.3, 5.3)
Hazard Ratio (95% CI) 0.68 (0.50, 0.93) p-value (log-rank test)
0.014 Progression-Free Survival Death or Progression, n (%) 83 (71)
94 (79) Median Progression-Free Survival 3.1 1.5 (months) (95% CI)
(2.7, 4.2) (1.4, 1.8) Hazard Ratio (95% CI) 0.55 (0.41, 0.75)
p-value (log rank test) p < 0.001 Objective Response Rate
Confirmed complete or partial response 9 (7.7) 1 (0.8) n (%) (95%
CI) (2.9, 12.5) (0, 2.5) .dagger.5-FU/LV =
5-fluorouracil/leucovorin; CI = confidence interval .dagger-dbl.The
MM-398 dose in Study 1, 70 mg/m.sup.2, is based on irinotecan as
the free base (equivalent to 80 mg/m.sup.2 of irinotecan as a
hydrochloride trihydrate).
[0167] Table 7 sets out that the median overall survival of the
MM-398/5-FU/LV is 6.1 months. Median overall survival is used to
express survival rates. It is the amount of time after which, in
the MM-398/5-FU/LV of Study 1 described herein (presented in table
7), 50% of the patients have died and 50% have survived in a study
population. The expected lifetime in months from commencement of
treatment with the MM-398/5-FU/LV treatment regimen as disclosed
herein is defined by the parameter, t.sub.surv. In some
embodiments, the t.sub.surv of an individual being treated is at
least 2/3 of the median overall survival rate (.gtoreq.4.1 months
(to one decimal place (dp))), such as at least of the median
overall survival (.gtoreq.5.1 months (1 dp)) or at least the median
overall survival (.gtoreq.6.1 months). In some embodiments, the
t.sub.surv of an individual being treated is less than 2 times the
median overall survival rate (<12.2 months (1 dp)), such as less
than 1.5 times the median overall survival (<9.15 months (2 dp))
or less than 1.2 times the median overall survival (<7.32 months
(1 dp)). In some embodiments, the t.sub.surv of an individual being
treated is at least 2/3 of the median overall survival rate and
less than 2 times the median overall survival rate, such as less
than 1.5 times the median overall survival or less than 1.2 times
the median overall survival. In some embodiments, the t.sub.surv of
an individual being treated is at least of the median overall
survival rate and less than 2 times the median overall survival
rate, such as less than 1.5 times the median overall survival or
less than 1.2 times the median overall survival. In some
embodiments, the t.sub.surv of an individual being treated is at
least the median overall survival rate and less than 2 times the
median overall survival rate, such as less than 1.5 times the
median overall survival or less than 1.2 times the median overall
survival.
[0168] In NAPOLI-1, analysis of the ITT (intent to treat) patient
group demonstrated statistically significant increase in overall
survival (OS) of MM-398+5-FU/LV (MM-398 80 mg/m.sup.2 (salt) q2w
regimen) over 5-FU/LV alone (FIGS. 11A and 11B) of 6.1 months
versus 4.2 months respectively. In comparison, MM-398, as a single
agent (120 mg/m.sup.2 q3w regimen), did not show a significant
difference in OS. In the Per Protocol (PP) population (described in
FIG. 12) of patients in the NAPOLI-1 human clinical trial (patients
receiving 6 weeks of treatment), the MM-398+5-FU/LV combination
regimen achieved a median OS of 8.9 months versus 5.1 months in the
5-FU/LV arm (stratified Hazard Ratio (HR): 0.47, p=0.0018; FIGS. 13
and 14). The observed patient safety profile was manageable, with
most frequent being grade .gtoreq.3 adverse events including
neutropenia, fatigue and GI effects, such as diarrhea and vomiting
(FIG. 17).
[0169] The primary endpoint of the NAPOLI-1 study was overall
survival; and the key secondary endpoints were Progression Free
Survival (PFS), Objective Response Rate (ORR), Tumor Marker
Response (CA19-9) and Safety. The study was amended to add the
MM-398+5-FU/LV arm once safety data on the combination became
available. Only those patients enrolled in the 5FU/LV arm after the
amendment (N=119), were used as the control for the combination
arm.
[0170] Key Inclusion Criteria for the NAPOLI-1 trial were:
Adenocarcinoma of the exocrine pancreas; Metastatic disease,
measurable or non-measurable; Progressed after prior gemcitabine or
gemcitabine-containing therapy; KPS.gtoreq.70; Adequate bone
marrow, hepatic (bilirubin within normal range for the institution
and albumin.gtoreq.3 g/dL), and renal function.
[0171] Sixty six PP patients were in the MM398+5-FU/LV arm and 71
PP patients were in the 5-FU/LV arm of NAPOLI-1. The NAPOLI-1 study
was well balanced. Patients in the MM-398+5FU/LV and 5FU/LV arms
were consistent across the following patient characteristics:
prognostic factors, demographics (age, sex, race), tumor and pre
and post treatment characteristics. Post-study anticancer therapy
was 31% in the MM-398+5-FU/LV arm and 38% in the 5-FU/LV arm.
[0172] Efficacy Analysis of NAPOLI-1 Clinical Trial (Phase III)
[0173] Overall Survival Results from the ITT patient group in the
NAPOLI-1 clinical trial are shown in FIGS. 11A and 11B. FIG. 11A
shows the median overall survival rate for the MM-398+5-FU/LV arm
was 6.1 months (95% CI 4.8-8.9) and the 5-Fu/LV arm overall
survival rate was 4.2 months (95% CI 3.3-5.3) and the stratified HR
was 0.57 (95 CI 0.41-0.8), p=0.0009. FIG. 11B shows the median
overall survival rate for the MM-398 arm was 4.9 months (95% CI
4.2-5.6) and the 5-FU/LV arm median OS was 4.2 months (95% CI
3.6-4.9) and the stratified HR was 0.93 (95 CI 0.71-1.21),
p=035545.
[0174] The Per Protocol population comprises eligible patients who
received .gtoreq.80% dose density of the protocol defined treatment
during the first 6 weeks of treatment and did not have the
following protocol violations: receipt of any prohibited therapies
as defined in the protocol, not receiving treatment as randomized,
or inclusion/exclusion criteria deviations.
[0175] Overall Survival Results for the PP and Non-PP populations
are shown in FIGS. 13 and 14 respectively. FIG. 13 shows the median
overall survival rate for the PP population; the median OS for the
MM-398+5-FU/LV arm was 8.9 months (95% CI 6.4-10.5) and the median
OS rate for the 5-Fu/LV arm was 5.1 months (95% CI 4.0-7.2) and the
stratified HR was 0.47 (95 CI 0.29-0.77), p=0.0018. FIG. 14 shows
the median overall survival rate for the Non-PP population; the
median OS for the MM-398+5-FU/LV arm was 4.4 months (95% CI
3.3-5.3) and the median OS rate for the 5-Fu/LV arm was 2.8 months
(95% CI 1.7-3.2) and the stratified HR was 0.56 (95 CI 0.33-0.97),
p=0.365.
[0176] After 378 OS events, MM-398+5-FU/LV (n=117) retained an OS
advantage relative to 5-FU/LV (n=119): 6.2 mo (95% confidence
interval [CI], 4.8-8.4) vs 4.2 mo (95% CI, 3.3-5.3) with an
unstratified HR of 0.75 (P=0.0417). In contrast, there was no OS
advantage with MM-398 monotherapy (n=151) vs 5-FU/LV (n=149): 4.9
mo [95% CI, 4.2-5.6] vs 4.2 mo [95% CI, 3.6-4.9], HR=1.08; P=0.5.
Six-month survival estimates were 53% (95% CI, 44-62%) for
MM-398+5-FU/LV vs 38% (95% CI, 29-47%) for 5-FU/LV; 12-month
survival estimates were 26% (95% CI, 18-35%) for MM-398+5-FU/LV vs
16% (95% CI, 10-24%) for 5-FU/LV. With events in nearly all
patients, the OS curves converge at about 20 months with 19
patients (16.2%) surviving beyond 20 months. This is a reason for
attenuation of the HR estimate and unstratified log rank p-value.
The most common grade 3+ adverse events occurring at a .gtoreq.2%
incidence in the MM-398-containing arms were neutropenia, diarrhea,
vomiting, and fatigue. The median OS benefit for MM-398+5FU/LV over
5-FU/LV was maintained, with a similar safety profile.
MM-398+5-FU/LV may be a new standard of care for patients with mPAC
previously treated with gemcitabine-based therapy. The median
overall survival (OS) increased significantly with MM-398+5-FU/LV
relative to 5-FU/LV (6.1 vs 4.2 months; unstratified hazard ratio
[HR]=0.67 [95% confidence interval (CI), 0.49-0.92]; P=0.012). The
median OS did not differ between patients assigned MM-398
monotherapy and those allocated to 5-FU/LV (4.9 vs 4.2 months;
unstratified HR=0.99 [95% CI, 0.77-1.28]; P=0.94). The median
progression-free survival (PFS; 3.1 vs 1.5 months; unstratified
HR=0.56 [95% CI, 0.41-0.75]; P=0.0001) and objective response rate
(ORR; 16% vs 1%; P<0.0001) were also improved with
MM-398+5-FU/LV compared with 5-FU/LV alone.
[0177] The objectives of the current descriptive analysis of the
NAPOLI-1 trial are to evaluate the robustness of the previously
observed OS treatment effect for MM-398+5-FU/LV versus 5-FU/LV
control using data from longer follow-up, and to assess the
long-term safety and tolerability of MM-398. A total of 76 sites in
14 countries enrolled 417 patients between January 2012 and
September 2013. Patient demographics and baseline clinical
characteristics were well balanced across treatment arms (Table
8).
[0178] Treatment Exposure
[0179] The mean duration of treatment exposure was 18.5 weeks
(median, 8.7 weeks; range, 2-115 weeks) in the MM-398+5-FU/LV arm,
12.3 weeks (median, 8.9 weeks; range, 3-69 weeks) in the MM-398
arm, and 10.8 weeks (median, 6.0 weeks; range, 1-68 weeks) in the
5-FU/LV control arm. The mean relative dose intensity of MM-398 was
83% in the combination arm and 90% in the monotherapy arm.
TABLE-US-00008 TABLE 8 Patient Demographic and Baseline Clinical
Characteristics 5-FU/LV 5-FU/LV Nal-IRI + combination Nal-IRI
Monotherapy 5-FU/LV control Monotherapy Control Parameter (n = 117)
(n = 1119) (n = 151) (n = 149) Median age 63 (57-70) 62 (55-69) 65
(58-70) 63 (55-69) (IQR), y KPS, % 100 15 14 15 15 90 44 34 42 36
80 32 43 33 41 70 6 8 10 7 50-60 3 0 0 0 Race, % Caucasian 62 64 59
62 East Asian 29 30 34 34 Other 9 6 7 5 CA19-9.gtoreq.40 U/ 81 80
86 81 mL, %.sup.a Pancreatic head 65 58 66 54 tumor, % Prior lines
of metastatic therapy, % 0.sup.b 13 13 11 13 1 53 56 57 58 2 34 31
32 30
[0180] naI-IRI, nanoliposomal irinotecan; 5-FU, 5-flurouracil; LV,
leucovorin; IQR, interquartile range; KPS, Karnofsky performance
status; CA19-9, carbohydrate antigen 19-9. .sup.aIncludes only
patients who had a measured CA19-9 value prior to treatment. Data
were missing for 3 patients in the MM-398+5-FU/LV group and 5
patients each in the nal-IRI monotherapy and 5-FU/LV groups.
.sup.bPatients received neoadjuvant, adjuvant, or locally advanced
treatment, but had no previous therapy for metastatic disease.
[0181] After 378 events, MM-398+5-FU/LV retained an OS advantage
relative to 5-FU/LV (Table 9 and FIG. 21A). With events in nearly
all patients, the Kaplan-Meier OS curves converge at approximately
20 months, with 19 (16.2%) patients surviving beyond 20 months. No
OS advantage was observed with MM-398 monotherapy versus 5-FU/LV
(FIG. 21B). Median PFS was 3.1 months for MM-398+5-FU/LV versus 1.5
months for the 5-FU/LV combination control, and was 2.6 months for
MM-398 monotherapy compared with 1.6 months for the 5-FU/LV
monotherapy control (Table 9 and FIG. 22). ORR was higher than
5-FU/LV control for both MM-398+5-FU/LV (difference of 16% [95% CI,
9-24]) and MM-398 monotherapy (difference of 5% [95% CI, 1-9];
Table 9)
TABLE-US-00009 TABLE 9 Summary of the Updated Efficacy nal-IRI +
5-FU/LV 5-FU/LV Treatment nal-IRI 5-FU/LV Treatment Endpoint (n =
117) (n = 119) effect.sup.a (n = 151) (n = 149) effect.sup.a Median
OS (95% CI), 6.2 (4.8-8.4) 4.2 (3.5-5.3) HR 0.75 4.9 (4.2-5.6) 4.2
(3.6-4.9) HR 1.08 months P = 0.042 P = 0.513 OS rate at 6 months 53
(44-62) 38 (29-47) -- -- (95% CI), % OS rate at 12 months 26
(18-35) 16 (10-24) -- -- (95% CI), % Median PFS (95% 3.1 (2.7-4.2)
1.5 (1.4-1.8) HR 0.56 2.7 (2.1-2.9) 1.6 (1.4-1.8) HR 0.81 CI), P
< 0.0001 P = 0.111 months ORR (95% CI), %.sup.b 71 (10-24) 1
(0-2) P < 0.0001 6 (2-10) 1 (0-2) P = 0.020 Best overall
response, % Partial response.sup.b 17 1 -- 6 1 -- Stable
disease.sup.c 33 22 -- 36 24 -- Progressive disease 29 47 -- 34 48
-- Other.sup.d 3 2 -- 2 1 -- Not evaluable 19 29 -- 23 27 --
naI-IRI, nanoliposomal irinotecan; 5-FU, 5-flurouracil; LV,
leucovorin; OS, overall survival; CI, confidence interval; HR,
hazard ratio; PFS, progression-free survival; ORR, objective
response rate. .sup.aUnstratified HR and log-rank P value.
.sup.bDesignation of response did not require confirmation and was
based solely on the investigator's assessment using RECIST v1.1
criteria. .sup.cMinimum duration for stable disease from baseline
is 6 weeks from the date of randomization. .sup.dPatients without
measurable (target) disease at baseline may have a best
overall-response of non-complete response/non-partial response.
[0182] After 382 events, median OS was improved with MM-398+5-FU/LV
vs 5-FU/LV (6.2 vs 4.2 mo; HR 0.75; 95% CI 0.57-0.99; P=0.038), but
not for MM-398 vs 5-FU/LV (4.9 vs 4.2 mo; HR 1.07; 95% CI
0.84-1.36; P=0.567). Kaplan-Meier estimates of OS for
MM-398+5-FU/LV and 5-FU/LV, respectively, were 53% and 38% at 6 mo,
and 26% and 16% at 12 mo. Median progression-free survival was
longer for MM-398+5-FU/LV vs 5-FU/LV (3.1 vs 1.5 mo; HR 0.57; 95%
CI 0.43-0.76; P<0.001), but not for MM-398 vs 5-FU/LV (2.7 vs
1.6 mo; HR 0.81; 95% CI 0.63-1.04; P=0.111). Response rates per
RECIST v1.1 were higher for MM-398+5-FU/LV vs 5-FU/LV (17% vs 1%;
P<0.001) and for MM-398 vs 5-FU/LV (6% vs 1%; P=0.020).
Grade.gtoreq.3 treatment-emergent adverse events in .gtoreq.10% of
pts in either MM-398 arm were neutropenia (28%, 15%, and 1% in the
MM-398+5-FU/LV, MM-398, and 5-FU/LV arms, respectively), fatigue
(14%, 6%, and 4%), diarrhea (13%, 21%, and 5%), vomiting (12%, 14%,
and 4%), anemia (9%, 11%, and 7%), and hypokalemia (3%, 12%, and
2%).
[0183] Safety and Tolerability Analysis of NAPOLI-1 Clinical Trial
(Phase III)
[0184] Safety profile was manageable, with most frequent being
grade .gtoreq.3 adverse events including neutropenia, fatigue and
GI effects, such as diarrhea and vomiting (FIG. 17). The safety
data described below are derived from NAPOLI-1. Serum bilirubin
within the institutional normal range, albumin.gtoreq.3 g/dL, and
Karnofsky Performance Status (KPS).gtoreq.70 were required for
study entry. The median duration of exposure was 9 weeks in the
MM-398/5-FU/LV arm, 9 weeks in the MM-398 monotherapy arm, and 6
weeks in the 5-FU/LV arm. Neutropenia, diarrhea, nausea, and
vomiting typically first occur early during the course of treatment
with MM-398+5-FU/LV and tend to decrease in incidence and severity
thereafter.
[0185] The most common adverse reactions (.gtoreq.20%) of MM-398
were diarrhea, fatigue/asthenia, vomiting, nausea, decreased
appetite, stomatitis, and pyrexia. The most common laboratory
abnormalities (.gtoreq.10% Grade 3 or 4) were lymphopenia and
neutropenia. The most common serious adverse reactions (.gtoreq.2%)
of MM-398 were vomiting, diarrhea, neutropenic fever or sepsis,
nausea, pyrexia, anemia, pneumonia, sepsis, dehydration, septic
shock, acute renal failure, thrombocytopenia and ileus.
[0186] The most common adverse reactions (.gtoreq.20%) of patients
receiving MM-398 were diarrhea, fatigue/asthenia, vomiting, nausea,
decreased appetite, stomatitis, and pyrexia. Severe (21%) or
life-threatening (7%) neutropenia or neutropenic sepsis, of which
1% resulted in septic shock, occurred in patients receiving MM-398
in combination with 5-fluorouracil and leucovorin. In some
embodiments, MM-398 is withheld from patients with an absolute
neutrophil count below 1500/mm.sup.3 or neutropenic fever. The
blood cell counts of patients are preferably monitored periodically
during treatment. Severe or life-threatening diarrhea occurred in
13% of patients receiving MM-398 in combination with 5FU and
leucovorin.
[0187] Severe or life threatening neutropenia occurred in 27% of
patients receiving MM-398/5-FU/LV compared to 2% of patients
receiving 5-fluorouracil/leucovorin alone (5-FU/LV) in Study 1
described herein. The expected likelihood of severe or life
threatening neutropenia (as a %) during treatment with
MM-398/5-FU/LV in the protocol used in Study 1, is expressed by the
parameter P.sub.aen. In some embodiments, P.sub.aen is <50%. In
some embodiments it is <45%, such as <40%, <35%, <30%
or .ltoreq.27%.
[0188] In NAPOLI-1 study results, Grade 3 or 4 diarrhea occurred in
13% receiving MM-398/5-FU/LV compared to 4% receiving 5-FU/LV. The
expected likelihood of Grade 3 or 4 diarrhea (as a %) during
treatment with MM-398/5-FU/LV in the protocol used in Study 1, is
expressed by the parameter P.sub.aed. In some embodiments,
P.sub.aed is <50%. In some embodiments it is <45%, such as
<40%, <35%, <30%, <25%, <20%, <15% or
.ltoreq.13%. In some embodiments, t.sub.serv is .gtoreq.6.1 months,
P.sub.aen is .ltoreq.27% and P.sub.aed is .ltoreq.13%.
[0189] Adverse reactions led to permanent discontinuation of MM-398
in 11% of patients receiving MM-398/5-FU/LV; the most frequent
adverse reactions resulting in discontinuation of MM-398 were
diarrhea, vomiting, and sepsis. Dose reductions of MM-398 for
adverse reactions occurred in 33% of patients receiving
MM-398/5-FU/LV; the most frequent adverse reactions requiring dose
reductions were neutropenia, diarrhea, nausea, and anemia. MM-398
was withheld or delayed for adverse reactions in 62% of patients
receiving MM-398/5-FU/LV; the most frequent adverse reactions
requiring interruption or delays were neutropenia, diarrhea,
fatigue, vomiting, and thrombocytopenia.
[0190] Table 10 provides the frequency and severity of adverse
reactions in Study 1 that occurred with higher incidence
(.gtoreq.5% difference for Grades 1-4 or .gtoreq.2% difference for
Grades 3-4) in patients who received MM-398/5 FU/LV compared to
patients who received 5-FU/LV arm.
TABLE-US-00010 TABLE 10 Adverse Reactions with Higher Incidence
(.gtoreq.5% Difference for Grades 1-4* or .gtoreq.2% Difference for
Grades 3 and 4) in the MM-398/5-FU/LV. MM-398/ 5-FU/LV 5-FU/LV N =
117 N = 134 Grades Grades Grades 1-4 3-4 1-4 Grades 3-4 Adverse
Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 59 13
26 4 Diarrhea, early.sup..dagger. 30 3 15 0 Diarrhea,
late.sup..dagger-dbl. 43 9 17 4 Vomiting 52 11 26 3 Nausea 51 8 34
4 Stomatitis.sup..sctn. 32 4 12 1 Infections and infestations
Sepsis 4 3 2 1 Neutropenic 3 3 1 0 fever/neutropenic sepsis
Gastroenteritis 3 3 0 0 Device related infection 3 3 0 0 General
disorders and administration site conditions Fatigue/asthenia 56 21
43 10 Pyrexia 23 2 11 1 Metabolism and nutrition disorders
Decreased appetite 44 4 32 2 Weight loss 17 2 7 0 Dehydration 8 4 7
2 Skin and subcutaneous tissue disorders Alopecia 14 1 5 0 *NCI
CTCAE v4.0 .sup..dagger.Early diarrhea: onset within 24 hours of
MM-398 administration .sup..dagger-dbl.Late diarrhea: onset >1
day after MM-398 administration .sup..sctn.Includes stomatitis,
aphthous stomatitis, mouth ulceration, mucosal inflammation.
Includes febrile neutropenia.
[0191] 398 pts were treated with MM-398+5-FU/LV (n=117), MM-398
(n=147), or 5-FU/LV (n=134). In the MM-398+5-FU/LV arm, most first
occurrences of neutropenia, diarrhea, nausea, and vomiting were
during the first 6 wk of treatment, with incidence and severity
generally decreasing thereafter (Table 11). Similarly, prevalence
and severity were highest in the first 6 wk and tended to decrease
over time. Similar trends were observed in the MM-398 and 5-FU/LV
arms.
TABLE-US-00011 TABLE 11 MM-398 + 5-FU/LV MM-398 5-FU/LV Period
Period Period Incidence, % 1 2 3 1 2 3 1 2 3 Neutropenia n = n = n
= n = n = n = n = n = n = grade 117 73 34 147 95 43 134 111 43 1 1
3 3 1 2 0 1 0 0 2 8 3 3 8 3 0 1 2 2 3 14 4 9 5 1 0 2 0 0 4 7 0 0 6
2 0 0 0 0 5 0 0 0 0 0 0 0 0 0 n = n = n = n = n = n = n = n = n =
Diarrhea grade 117 51 24 147 46 11 134 89 32 1 21 4 0 25 11 18 15 5
6 2 17 12 4 20 7 9 2 1 0 3 12 0 4 16 4 0 2 1 3 4 0 0 0 1 0 0 0 0 0
5 0 0 0 1 0 0 0 0 0 n = n = n = n = n = n = n = n = n = Nausea
grade 117 56 28 147 53 25 134 87 26 1 21 5 7 23 4 8 19 4 12 2 16 0
7 27 4 8 5 4 4 3 7 2 0 5 2 0 2 2 0 4 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0
0 0 0 0 n = n = n = n = n = n = n = n = n = Vomiting grade 117 61
35 147 61 28 134 89 29 1 19 5 11 27 2 7 16 2 4 2 14 0 9 10 3 4 5 1
4 3 10 0 3 12 2 0 1 1 4 4 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0
[0192] Cholinergic Reactions:
[0193] MM-398 can cause cholinergic reactions manifesting as
rhinitis, increased salivation, flushing, bradycardia, miosis,
lacrimation, diaphoresis, and intestinal hyperperistalsis with
abdominal cramping and early onset diarrhea. In Study 1, Grade 1 or
2 cholinergic symptoms other than early diarrhea occurred in 12
(4.5%) MM-398-treated patients. Six of these 12 patients received
atropine; in 1 of the 6 patients who received atropine, the
atropine was administered for cholinergic symptoms other than
diarrhea.
[0194] Infusion Reactions: Infusion reactions, consisting of
allergic reaction, rash, urticaria, periorbital edema, or pruritus,
occurring on the day of MM-398 administration were reported in 3%
of patients receiving MM-398 or MM-398/5-FU/LV.
[0195] Additional clinically significant adverse reactions
occurring in <10% of MM-398/5-FU/LV-treated patients were:
[0196] Cardiovascular: Severe hypotension
[0197] Laboratory abnormalities that occurred with higher incidence
in the MM-398/5 FU/LV arm compared to the 5-FU/LV arm (.gtoreq.5%
difference) are summarized in the following table 12.
TABLE-US-00012 TABLE 12 Laboratory Abnormalities with Higher
Incidence (.gtoreq.5% Difference) in the MM-398/5-FU/LV Arm*#
MM-398/5- FU/LV 5-FU/LV Grades Grades Grades Grades 1-4 3-4 1-4 3-4
Laboratory abnormality (%) (%) (%) (%) Hematology Anemia 97 6 86 5
Decreased lymphocytes 81 27 75 17 Decreased leukocytes 67 16 20 0
Decreased neutrophil counts 52 20 6 2 Decreased platelet counts 41
2 33 0 Hepatic Increased alanine aminotransferase 51 6 37 1 (ALT)
Decreased albumin 43 2 30 0 Metabolic Decreased magnesium 35 0 21 0
Decreased potassium 32 2 19 2 Decreased calcium 32 1 20 0 Decreased
phosphate 29 4 18 1 Decreased sodium 27 5 12 3 Renal Increased
creatinine 18 0 13 0 *NCI CTCAE v4.0, worst grade shown #Percent
based on number of patients with a baseline and at least one
post-baseline measurement.
[0198] Of the 264 patients who received MM-398 as a single agent or
in combination with 5-FU and leucovorin in Study 1, 49% were
.gtoreq.65 years old and 13% were .gtoreq.75 years old. No overall
differences in safety and effectiveness were observed between these
patients and younger patients.
[0199] The safety profiles of MM-398+5-FU/LV and MM-398 monotherapy
described in the current updated analysis did not change
appreciably from that reported in the primary analysis. The most
frequently reported grade .gtoreq.3 TEAEs in the MM-398-containing
arms were neutropenia, diarrhea, vomiting, and fatigue (Table 13).
TEAEs led to dose delay, reduction, and/or discontinuation in 73%
of patients in the MM-398+5-FU/LV arm, 56% of patients in the
MM-398 monotherapy arm, and 37% of patients in the 5-FU/LV arm. The
most common reasons for dose reduction in the MM-398+5-FU/LV and
MM-398 monotherapy arms were gastrointestinal events (12% and 17%,
respectively) and neutropenia (18% and 10%). The rate of treatment
discontinuation due to a TEAE was 12% with MM-398+5-FU/LV, 14% with
MM-398, and 8% with 5-FU/LV; neutropenia, diarrhea, and vomiting
were the most common reasons for discontinuation in the
MM-398-containing arms. Grade.gtoreq.3 febrile neutropenia occurred
in 2 (2%) patients receiving MM-398+5-FU/LV and 6 (4%) patients
receiving MM-398; 1 and 5 patients, respectively, required a dose
reduction but no patient discontinued treatment due to febrile
neutropenia. No additional deaths due to treatment-related TEAEs
have been reported since the primary analysis.
TABLE-US-00013 TABLE 13 Grade .gtoreq.3 TEAE (Treatment Emergent
Adverse Event), % nal-IRI + 5- nal-IRI FU/LV monotherapy 5-FU/LV
Grade .gtoreq.3 TEAE, % (n = 117) (n = 151) (n = 134) Any TEAE 80
76 56 Neutropenia 28 15 2 Fatigue 14 6 4 Diarrhea 13 21 5 Vomiting
12 14 4 Anemia 9 11 7 Asthenia 8 7 7 Nausea 8 5 3 White blood cell
count 8 3 0 Abdominal pain 7 8 7 Decreased appetite 5 9 2
Hypokalemia 3 12 2 Hyponatremia 3 6 2 Hyperglycemia 2 5 2
[0200] TEAE, treatment-emergent adverse event; MM-398,
nanoliposomal irinotecan; 5-FU, 5-fluoruracil; LV, leucovorin. The
table includes all grade .gtoreq.3 TEAEs reported for .gtoreq.5% of
patients in any treatment arm. .sup.aNeutropenia includes
agranulocytosis, febrile neutropenia, granulocytopenia,
neutropenia, neutropenic sepsis, decreased neutrophil count, and
pancytopenia.
[0201] The most common grade .gtoreq.3 treatment-emergent adverse
events (TEAEs) in the MM-398+5-FU/LV arm were neutropenia, fatigue,
diarrhea, and vomiting. Based on NAPOLI-1, the MM-398+5-FU/LV
regimen received regulatory approval from the US Food and Drug
Administration for the treatment of patients with metastatic
adenocarcinoma of the pancreas after disease progression following
gemcitabine-based therapy. Here, we present results of a
prespecified safety analysis by patient subgroup from NAPOLI-1.
[0202] TEAEs were graded by NCI CTCAE v4.0 and coded by MedDRA
v14.1 for the following prespecified subgroups: sex, age (<65 vs
.gtoreq.65 years), ethnicity (white vs Asian), UGT1A1*28 status,
prior conventional irinotecan therapy (yes vs no), and prior 5-FU
therapy (yes vs no). All TEAEs were followed until resolution or
patient discontinuation. Analyses were performed on the safety
population (ie, those who received .gtoreq.1 dose of study
medication). Results herein are for the MM-398+5-FU/LV arm unless
otherwise noted.
[0203] Overall, the incidence and severity of TEAEs were similar
between men (n=67) and women (n=50). Patients aged.gtoreq.65 years
(n=54) generally had a higher incidence of TEAEs than those<65
years (n=63) (eg, stomatitis: 20.4% vs 7.9%; anemia: 46.3% vs
30.2%), although the most common types of TEAEs were similar
regardless of age. Overall, Asian (n=33) patients had a higher
incidence of grade .gtoreq.3 TEAEs than white (n=73) patients
(87.9% vs 69.9%), primarily because of an increased incidence of
neutropenia (24.2% vs 12.3%) and decreased neutrophil counts (33.3%
vs 1.4%); febrile neutropenia was reported in 3.0% of Asian
patients and 0 white patients. Gastrointestinal disorders also
occurred slightly more frequently in Asian patients than white
patients (any grade: 100% vs 87.7%), although diarrhea was less
frequent and less severe among Asian patients (any grade: 48.5% vs
61.6%; grade .gtoreq.3: 3.0% vs 19.2%). The UGT1A1 gene encodes an
enzyme responsible for glucuronidation of the active metabolite of
irinotecan, SN-38. Patients homozygous for the UGT1A1*28 allele
(UGT1A1 7/7 genotype) may be at increased risk for neutropenia
during irinotecan treatment due to reduced glucuronidation of
SN-38. However, in this analysis, there were no differences in
incidence, type, and severity of TEAEs between patients homozygous
(n=7) for the UGT1A1*28 allele and those who were not (n=110).
There were also no notable differences in the incidence or severity
of TEAEs between patients with (n=12) and without (n=105) prior
conventional irinotecan therapy, or between patients with (n=50) or
without (n=67) prior 5-FU therapy.
[0204] Overall, the safety profile of MM-398+5-FU/LV was generally
similar across patient subgroups, apart from an increased risk of
grade .gtoreq.3 neutropenia/reduced neutrophil counts in Asian
patients. The results of this prespecified subgroup analysis
further support the tolerability profile of MM-398+5-FU/LV in
patients with mPAC previously treated with gemcitabine-based
therapy.
[0205] The median overall survival (OS) increased significantly
with MM-398+5-FU/LV relative to 5-FU/LV (6.1 vs 4.2 months;
unstratified hazard ratio [HR], 0.67 [95% confidence interval (CI),
0.49-0.92]; P=0.012), but did not differ significantly between
MM-398 monotherapy and 5-FU/LV (4.9 vs 4.2 months; unstratified HR
0.99 [95% CI, 0.77-1.28]; P=0.94).
[0206] Adverse events that resulted in a dose reduction occurred in
39 (33%) patients in the MM-398+5-FU/LV arm, 46 (31%) patients in
the MM-398 monotherapy arm, and 5 (4%) patients in the 5-FU/LV arm.
Adverse events leading to treatment discontinuation occurred in 13
(11%) patients in the MM-398+5-FU/LV arm, 17 (12%) patients in the
MM-398 monotherapy arm, and 10 (7%) patients in the 5-FU/LV
arm.
[0207] Patients were initially randomized to MM-398 monotherapy
(120 mg/m.sup.2 irinotecan hydrochloride trihydrate salt equivalent
to 100 mg/m.sup.2 irinotecan free base every 3 weeks) or 5-FU/LV
(200 mg/m.sup.2 LV and 2000 mg/m.sup.2 5-FU, every week for the
first 4 weeks of each 6-week cycle). Once safety data for the
combination regimen became available from a concurrent study in
metastatic colorectal cancer, the protocol was amended to include a
third arm, MM-398+5-FU/LV (80 mg/m.sup.2 irinotecan hydrochloride
trihydrate salt [equivalent to 70 mg/m.sup.2 irinotecan free base],
400 mg/m.sup.2 LV, and 2400 mg/m.sup.2 5-FU over 46 hours, every 2
weeks).
[0208] The initial MM-398 dose in the MM-398+5-FU/LV arm was 60
mg/m.sup.2 (salt) for patients homozygous for the UGT1A1*28 allele
(TA7/TA7 genotype) and could be increased to the standard dose (80
mg/m.sup.2 (salt)) in the absence of drug-related toxic effects.
Randomization was stratified by baseline albumin levels
(.gtoreq.4.0 g/dL vs <4.0 g/dL) KPS (70 and 80 vs .gtoreq.90),
and ethnicity (white vs east Asian vs all others).
[0209] TEAEs were graded by National Cancer Institute Common
Terminology Criteria for Adverse Events, version 4.0, and coded by
Medical Dictionary for Regulatory Activities, version 14.1. All
TEAEs were followed until resolution or patient discontinuation.
The safety analysis population included all patients who received
.gtoreq.1 dose of study drug. The presence of the UGT1A1*28 allele
was determined by genotype testing, and homozygous patients were
identified (A7/TA7 genotype)
[0210] Eligibility Criteria:
[0211] Key Inclusion Criteria: Adults.gtoreq.18 years of age;
Histologically or cytologically confirmed PDAC; Documented
measurable or nonmeasurable distant metastatic disease (as defined
by Response Evaluation Criteria in Solid Tumors, version 1.1);
Disease progression after prior gemcitabine or
gemcitabine-containing therapy in a neoadjuvant, adjuvant (only if
distant metastases occurred within 6 months of completing adjuvant
therapy), locally advanced, or metastatic setting; KPS
score.gtoreq.70; Adequate hematologic (including absolute
neutrophil count>1.5.times.109 cells/L), hepatic (including
normal serum total bilirubin and albumin levels.gtoreq.30 g/L), and
renal function.
[0212] Key Exclusion Criteria: Active central nervous system
metastasis; Clinically significant gastrointestinal disorder;
Severe arterial thromboembolic events<6 months before inclusion;
New York Heart Association class III or IV congestive heart
failure, ventricular arrhythmias, or uncontrolled blood pressure;
Active infection or uncontrolled fever.
[0213] Of the 417 patients included in the intention-to-treat
population, 398 (95%) received .gtoreq.1 dose of any study drug
(safety analysis population).
[0214] Median duration of exposure to MM-398 in the MM-398
combination arm was 8.7 weeks (interquartile range [IQR], 5.4-22.0
weeks); mean dose intensity of MM-398 over 6 weeks was 167.5
mg/m.sup.2 (standard deviation [SD], 52.05 mg/m.sup.2). Median
duration of exposure to 5-FU was 8.7 weeks (IQR, 5.4-22.0 weeks) in
the MM-398 combination arm and 6.0 weeks (IQR, 5.9-12.1 weeks) in
the control arm; mean dose intensities of 5-FU over 6 weeks were
5065.0 mg/m.sup.2 (SD, 1539.1 mg/m.sup.2) and 6718.0 mg/m.sup.2
(SD, 1770.18 mg/m.sup.2), respectively. Incidence of any-grade and
grade .gtoreq.3 TEAEs was similar between patients aged<65 years
and those aged.gtoreq.65 years in each treatment arm.
Grade.gtoreq.3 TEAEs of note (difference of .gtoreq.5% between
subgroups): In the MM-398 combination arm, incidence of vomiting
(14.3% vs 7.4%) was higher in patients<65 years; incidence of
nausea (11.1% vs 4.8%) was higher in patients.gtoreq.65 years.
[0215] Incidence of any-grade TEAEs was similar between white and
east Asian patients in each treatment arm, with the exception of
diarrhea, which occurred less frequently in east Asians. Incidence
of grade .gtoreq.3 TEAEs in the control arm was similar between
white and east Asian patients (56.5% vs 54.5%), whereas the
incidence of grade .gtoreq.3 TEAEs in the MM-398 combination arm
was higher for east Asians compared with whites (87.9% vs 69.9%).
Grade.gtoreq.3 TEAEs of note (difference of .gtoreq.5% between
subgroups). In the MM-398 combination arm, incidence of diarrhea
(19.2% vs 3.0%), fatigue (19.2% vs 0%), and vomiting (13.7% vs
6.1%) was higher in white patients; incidence of anemia (21.2% vs
5.5%), neutropenia (54.5% vs 17.8%), and white blood cell decrease
(21.2% vs 2.7%) was higher in east Asian patients. In the control
arm, incidence of abdominal pain (8.2% vs 2.3%) was higher in white
patients; incidence of anemia (13.6% vs 3.5%) was higher in east
Asian patients.
[0216] UGT1A1*28 Allele (TA7/TA7 Genotype): Although the low number
of patients with the TA7/TA7 genotype makes comparison difficult
the incidence of any-grade and grade .gtoreq.3 TEAEs appeared to be
similar between patients with or without the TA7/TA7 genotype. In
the MM-398 combination arm, 3 of the 7 patients with the TA7/TA7
genotype were able to escalate the MM-398 dose to 80 mg/m.sup.2
without needing dose reduction. 1 patient escalated but required
dose reduction back to 60 mg/m.sup.2; 2 patients maintained the
initial dose; 1 patient required dose reduction to 40 mg/m.sup.2; 1
additional patient in the MM-398 combination arm with the TA7/TA7
genotype discontinued treatment (without dose reduction) because of
grade 3 vomiting. Incidence of any-grade and grade .gtoreq.3 TEAEs
was similar between patients with albumin levels.gtoreq.4.0 g/dL or
<4.0 g/dL. Grade.gtoreq.3 TEAEs of note (difference of
.gtoreq.5% between subgroups). In the MM-398 combination arm,
incidence of diarrhea (17.6% vs 6.4%) and fatigue (16.2% vs 10.6%)
was higher in patients with albumin levels.gtoreq.4.0 g/dL. In the
control arm, incidence of diarrhea (8.1% vs 1.4%) was higher in
patients with albumin levels<4.0 g/dL.
[0217] Karnofsky Performance Status: Incidence of any-grade TEAEs
was similar between patients with KPS score of .gtoreq.90 or
<90. Incidence of grade .gtoreq.3 TEAEs was similar between
patients with KPS score of .gtoreq.90 or <90 in the MM-398
combination arm; incidence of grade .gtoreq.3 TEAEs was lower in
patients with KPS score of .gtoreq.90 vs patients with KPS score of
.gtoreq.90 in the control arm (40.9% vs 70.6%). Grade.gtoreq.3
TEAEs of note (difference of .gtoreq.5% between subgroups): In the
MM-398 combination arm, incidence of decreased appetite (8.3% vs
1.4%) and abdominal pain (10.4% vs 4.3%) was higher in patients
with KPS score<90; In the control arm, incidence of abdominal
pain (8.8% vs 3.0%) was higher in patients with KPS
score<90.
[0218] Patient Quality of Life Evaluation
[0219] Patients with mPDAC frequently experience a significant
symptom burden. This in turn negatively impacts their QoL. QoL was
a secondary endpoint of the study.
[0220] QoL was assessed using the European Organization for
Research and Treatment of Cancer quality-of-life core questionnaire
(EORTC-QLQ-C30), which includes functional scales (physical, role,
cognitive, emotional, and social); symptom scales (appetite loss,
constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and
vomiting, and pain); and a global health and quality-of-life scale.
Patients were to complete the questionnaire at treatment start,
every 6 weeks, and 30 days post-follow-up visit. The population
analyzed included all patients who provided baseline and at
.gtoreq.1 subsequent EORTC-QLQ-C30 assessment. Linear
transformations were applied to the raw scores to produce reported
scores in the 0-100 range. In the responder analysis, patients were
classified as improved (.gtoreq.10% increase in scale of breadth at
a post-baseline time point and remained above baseline for
.gtoreq.6 weeks), worsened (did not meet improvement criteria and
died, or had .gtoreq.10% decrease from baseline in scale of breadth
at a post-baseline time point), or stable (did not meet criteria
for improvement or worsening) for each subscale. Pairwise treatment
group comparisons on response classification were performed for
each subscale using Cochran-Mantel-Haenszel testing adjusted for
multiplicity with a Benjamini-Hochberg correction to control false
discovery rate at 0.05 level for the 15 comparisons.
[0221] A total of 154 patients (MM-398+5-FU/LV, n=71; 5-FU/LV,
n=83) comprised the population for this analysis of which 69%
(49/71) of patients in the MM-398+5-FU group and 53% (44/83) in the
5-FU/LV group had evaluable data at 12 weeks. At baseline, median
Global Health Status scores were near the midpoint of the scoring
range, median Functional Scale scores were high, and Symptom Scale
scores were low, with baseline values similar between groups. The
observed median change in score at 12 weeks was 0 for both
treatment groups for Global Health Status and for the following
subscale scores: role functioning, emotional functioning, cognitive
functioning, social functioning, nausea and vomiting, pain,
dyspnea, insomnia, appetite loss, constipation, diarrhea, and
financial difficulties. For subscale scores for which the median
change was not 0 (MM-398+5-FU/LV: physical functioning and
fatigue), the between-group differences were not substantial.
Additionally, there were no significant differences in the
proportion of patients classified as improved, worsened, or stable
between the treatment groups. Across subscales, adjusted P values
for the comparisons were >0.05 (NS).
[0222] In NAPOLI-1, evaluable MM-398+5-FU/LV-treated patients with
data through 12 weeks tended to maintain baseline QoL over 12
weeks, and there were no significant differences versus the
5-FU/LV-treated patients in QoL response despite the addition of a
second cytotoxic agent. These results are limited by the small
number of patients and variability in QoL subscale scores.
[0223] The median overall survival (OS) increased significantly
with MM-398+5-FU/V relative to 5-FU/LV (6.1 vs 4.2 months;
unstratified hazard ratio [HR], 0.67 [95% confidence interval (CI),
0.49-0.92]; P=0.012), but did not differ significantly between
MM-398 monotherapy and 5-FU/LV (4.9 vs 4.2 months; unstratified HR
0.99 [95% CI, 0.77-1.28]; P=0.94).
[0224] Median PFS was significantly longer with MM-398+5-FU/V
compared with 5-FU/LV (3.1 vs 1.5 months; unstratified HR 0.56; 95%
CI, 0.41-0.75; P=0.0001). Median ORR was significantly higher with
MM-398+5-FU/V compared with 5-FU/LV (16% vs 1%; P<0.0001).
[0225] MM-398+5-FU/LV exhibited a manageable safety profile; grade
3/4 adverse events (AEs) occurring more frequently with
MM-398+5-FU/LV vs 5-FU/LV included neutropenia (27% vs 1%), fatigue
(14% vs 4%), diarrhea (13% vs 4%), and vomiting (11% vs 3%). 71
patients (61% of the ITT population randomized under protocol
version 2) in the MM-398+5-FU/LV arm and 57 patients (48% of the
ITT population randomized under protocol version 2) in the 5-FU/LV
arm provided baseline and .gtoreq.1 subsequent EORTC assessment
(PRO population). Patient demographics and baseline characteristics
were similar between the treatment arms. No substantial differences
were identified in the proportion of patients exhibiting improved,
stable, or worsening QoL in symptom scale scores between the
MM-398+5-FU/LV and 5-FU/LV arms.
[0226] Baseline global health status and functional scale scores
ranged from 58-83 and were similar between the treatment arms.
Overall, there were no appreciable changes from baseline in global
health status and functional scale scores between the
MM-398+5-FU/LV and 5-FU/LV arms. The observed median change from
baseline to week 6 in physical functioning score was 6.7 points in
both arms; which corresponds to "a little" decrease. Baseline
symptom scale scores ranged from 0-33 and were similar between the
treatment arms. Overall, there were no appreciable changes from
baseline in symptom scale scores between the MM-398+5-FU/LV and
5-FU/LV arms. The observed median change from baseline to week 6 in
fatigue score was approximately 11 points in the MM-398+5-FU/LV
arm, which corresponds to a "moderate" increase.
[0227] MM-398+5-FU/LV significantly improves OS in patients with
mPDAC previously treated with gemcitabine-based therapy compared
with 5-FU/LV. Global health status and functional scale scores were
not significantly different between treatment arms at baseline, and
showed no appreciable change over 12 weeks. Median symptom scale
scores at baseline ranged from 0-33 (low levels of symptomatology),
and showed no appreciable change over 12 weeks. MM-398+5-FU/LV
provides a new treatment option that does not compromise QoL in
patients with mPDAC previously treated with gemcitabine-based
therapy.
Endnotes
[0228] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features set
forth herein. The disclosure of each and every US, international,
or other patent or patent application or publication referred to
herein is hereby incorporated herein by reference in its
entirety.
* * * * *