U.S. patent application number 17/397221 was filed with the patent office on 2022-01-27 for treatment of hodgkin lymphoma using an anti-pd-1 antibody.
This patent application is currently assigned to Bristol-Myers Squibb Company. The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Benedetto FARSACI.
Application Number | 20220025049 17/397221 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-27 |
United States Patent
Application |
20220025049 |
Kind Code |
A1 |
FARSACI; Benedetto |
January 27, 2022 |
TREATMENT OF HODGKIN LYMPHOMA USING AN ANTI-PD-1 ANTIBODY
Abstract
This disclosure provides to methods for treating Hodgkin
lymphoma in a subject comprising administering to the subject an
anti-Programmed Death-1 (PD-1) antibody to a subject, wherein the
subject has received at least one prior treatment for Hodgkin
lymphoma.
Inventors: |
FARSACI; Benedetto;
(Princeton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Assignee: |
Bristol-Myers Squibb
Company
Princeton
NJ
|
Appl. No.: |
17/397221 |
Filed: |
August 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16306285 |
Nov 30, 2018 |
11083790 |
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PCT/US2017/035492 |
Jun 1, 2017 |
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17397221 |
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62344880 |
Jun 2, 2016 |
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International
Class: |
C07K 16/28 20060101
C07K016/28; A61K 31/704 20060101 A61K031/704; A61K 31/475 20060101
A61K031/475; A61K 31/655 20060101 A61K031/655; A61P 35/00 20060101
A61P035/00; A61K 39/395 20060101 A61K039/395 |
Claims
1. A method of treating a subject afflicted with a tumor derived
from a Hodgkin lymphoma, comprising administering to the subject an
antibody or an antigen-binding portion thereof that binds
specifically to a Programmed Death-1 receptor (PD-1) ("anti-PD-1
antibody"), wherein the subject was not responsive to a prior
treatment comprising (i) an autologous stem cell therapy, and (ii)
brentuximab vedotin.
2. The method of claim 1, wherein (i) the subject failed to achieve
a partial response after the prior treatment, (ii) the subject had
a relapse after a complete response after the prior treatment,
and/or (iii) the subject had progressive disease after a partial
response or stable disease after the prior treatment.
3. The method of claim 1, further comprising administering
doxorubicin, vinblastine, and dacarbazine to the subject.
4. The method of claim 1, wherein the subject is not administered
bleomycin.
5. The method of claim 3, wherein the doxorubicin, vinblastine, and
dacarbazine are administered once about every one, two, three, or
four weeks.
6. The method of claim 3, wherein the doxorubicin is administered
at a dose of about 10 mg/m.sup.2 to about 40 mg/m.sup.2; the
vinblastine is administered at a dose of about 0.1 mg/m.sup.2 to
about 10 mg/m.sup.2; and/or the dacarbazine is administered at a
dose of about 200 mg/m.sup.2 to about 500 mg/m.sup.2.
7. The method of claim 3, wherein the doxorubicin is administered
at a dose of 25 mg/m.sup.2, the vinblastine is administered at a
dose of 6 mg/m.sup.2, and the dacarbazine is administered at a dose
of 375 mg/m.sup.2 once about every 2 weeks.
8. The method of claim 1, wherein the anti-PD-1 antibody is
nivolumab.
9. The method of claim 1, wherein the anti-PD-1 antibody is
administered at ci) a dose ranging from about 0.1 mg/kg to about
10.0 mg/kg body weight once about every 1, 2, or 3 weeks; or (ii) a
flat dose of about 200 mg, about 220 mg, about 240 mg, about 260
mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about
360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg,
about 460 mg, about 480 mg, about 500 mg, or about 550 mg, about
once every 1, 2, 3 or 4 weeks.
10. The method of claim 1, wherein the Hodgkin lymphoma has a
genetic alteration at 9p24.1.
11. The method of claim 1, wherein the Hodgkin lymphoma expresses
PD-L1 and/or PD-L2.
12. The method of claim 11, wherein the PD-L1 and/or PD-L2
expression is at least about 1%.
13. The method of claim 1, wherein the subject exhibits
progression-free survival of at least about one month, at least
about 2 months, at least about 3 months, at least about 4 months,
at least about 5 months, at least about 6 months, at least about 7
months, at least about 8 months, at least about 9 months, at least
about 10 months, at least about 11 months, at least about one year,
at least about eighteen months, at least about two years, at least
about three years, at least about four years, or at least about
five years after the initial administration.
14. The method of claim 1, wherein the subject exhibits an overall
survival of at least about one month, at least about 2 months, at
least about 3 months, at least about 4 months, at least about 5
months, at least about 6 months, at least about 7 months, at least
about 8 months, at least about 9 months, at least about 10 months,
at least about 11 months, at least about one year, at least about
eighteen months, at least about two years, at least about three
years, at least about four years, or at least about five years
after the initial administration.
15. A kit comprising: (a) an anti-PD-1 antibody; and (b)
instructions for using the anti-PD-1 antibody in the method of
claim 1.
16. The method of claim 1, wherein the anti-PD-1 antibody is
pembrolizumab.
17. The method of claim 1, wherein the anti-PD-1 antibody is
administered at a dose of about 3 mg/kg body weight once about
every 2 weeks.
18. The method of claim 8, wherein the anti-PD-1 antibody is
administered at a flat dose of about 240 mg once every 2 weeks.
19. The method of claim 8, wherein the anti-PD-1 antibody is
administered at a flat dose of about 480 mg once every 4 weeks.
20. The method of claim 16, wherein the anti-PD-1 antibody is
administered at a flat dose of about 200 mg once every 3 weeks.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/306,285, which is the national phase entry of International
Application No. PCT/US2017/035492, filed Jun. 1, 2017, which claims
the priority benefit of U.S. Provisional Application No.
62/344,880, filed Jun. 2, 2016, each of which is incorporated by
reference herein in its entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure relates to methods for treating Hodgkin
lymphoma in a subject in need thereof comprising administering to
the subject an anti-Programmed Death-1 (PD-1) antibody or an
antigen binding portion thereof, wherein the subject has received
at least one prior treatment for Hodgkin lymphoma selected from the
group consisting of an autologous stem cell therapy, brentuximab
vedotin, and both.
BACKGROUND OF THE DISCLOSURE
[0003] Human cancers harbor numerous genetic and epigenetic
alterations, generating neoantigens potentially recognizable by the
immune system (Sjoblom et al., (2006) Science 366:268-74). The
adaptive immune system, comprised of T and B lymphocytes, has
powerful anti-cancer potential, with a broad capacity and exquisite
specificity to respond to diverse tumor antigens. Further, the
immune system demonstrates considerable plasticity and a memory
component. The successful harnessing of all these attributes of the
adaptive immune system would make immunotherapy unique among all
cancer treatment modalities.
[0004] Until recently, cancer immunotherapy had focused substantial
effort on approaches that enhance anti-tumor immune responses by
adoptive-transfer of activated effector cells, immunization against
relevant antigens, or providing non-specific immune-stimulatory
agents such as cytokines. In the past decade, however, intensive
efforts to develop specific immune checkpoint pathway inhibitors
have begun to provide new immunotherapeutic approaches for treating
cancer
[0005] Nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or
ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint
inhibitor antibody that selectively prevents interaction with PD-1
ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of
antitumor T-cell functions (U.S. Pat. No. 8,008,449; Wang et al.,
(2014) Cancer Immunol Res 2:846-56). Nivolumab has shown activity
in a variety of advanced solid tumors including renal cell
carcinoma (renal adenocarcinoma, or hypernephroma), melanoma, and
non-small cell lung cancer (NSCLC) (Topalian et al., (2012) N Engl
J Med 366:2443-54; Topalian et al., (2014) J Clin Oncol 32:1020-30;
Drake et al., (2013) BJU Int 112:1-17; Ansell et al., (2015) Blood
126:583 [Abstract]; PCT Publication No. WO 2013/173223).
[0006] In order to survive in an immunocompetent host, many human
cancers have evolved mechanisms to disable immune responses against
tumor neoantigens. For instance, classical Hodgkin lymphoma (cHL),
a B-cell malignancy that commonly affects young adults, is
characterized by small numbers of neoplastic Reed-Sternberg (RS)
cells within an extensive inflammatory/immune cell infiltrate.
(Green et al., (2010) Blood 116:3268-77). However, there is little
evidence of an effective antitumor immune response, suggesting that
immune evasion pathways may play a role in the tumor's survival in
the host. Indeed, the Hodgkin RS (HRS) cells express molecules that
limit the efficacy of T cell responses. (Juszczynski et al., (2007)
Proc Natl Acad Sci USA 104:13134-9; and Kuppers, (2009) Nat Rev
Cancer 9:15-27).
[0007] Classic Hodgkin's lymphomas include small numbers of
malignant Reed-Sternberg cells within an extensive but ineffective
inflammatory and immune-cell infiltrate. (Taube et al., (2014) Clin
Cancer Res 20:5064-74; Topalian et al., (2014) J Clin Oncol
32:1020-30). The genes encoding the PD-1 ligands, PD-L1 and PD-L2
(also called CD274 and PDCD1LG2, respectively), are key targets of
chromosome 9p24.1 amplification, a recurrent genetic abnormality in
Hodgkin lymphoma. (Taube et al., (2014) Clin Cancer Res
20:5064-74). The 9p24.1 amplicon also includes JAK2, and gene
dosage-dependent JAK-STAT activity further induces PD-1 ligand
transcription. (Green et al., (2010) Blood 116:3268-77). The genes
encoding the PD-1 ligands, PDL1 and PDL2 (also called CD274 and
PDCD1LG2, respectively), are key targets of chromosome 9p24.1
amplification, a recurrent genetic abnormality in the
nodular-sclerosis type of Hodgkin lymphoma. (Taube et al., (2014)
Clin Cancer Res 20:5064-74), and recent analysis integrating
high-resolution copy-number data and transcriptional profiles
identified PD-L1 and PD-L2 as key targets of chromosome 9p24.1
amplification. (Green et al., (2010) Blood 116:3268-77). These
copy-number-dependent mechanisms, as well as other less frequent
rearrangements, lead to genetically determined overexpression of
the PD-1 ligands on the HRS cell surface. (Steidl et al., (2011)
Nature 471:377-81; Andorsky et al., (2011) Clin Cancer Res
17:4232-44).
[0008] Epstein-Barr virus (EBV) infection, also common in cHL, is
an additional mechanism of PD-L1 overexpression, consistent with
the virus's known ability to usurp the PD-1 pathway to allow viral
persistence in the host. (Green et al., (2012) Clin Cancer Res
18:1611-8). Therefore, Epstein-Barr virus (EBV) infection also
increases the expression of PD-1 ligands in EBV-positive Hodgkin
lymphomas. (Armand et al., (2013) Clin Oncology 31:4199-206). As a
result of the two complementary pathways of 9p24.1 alterations and
EBV infection, over 80% of cHL cases have increased surface
expression of PD-L1, suggesting a central role for the PD-1 pathway
in this disease. (Chen et al., (2013) Clin Cancer Res
19:3462-73).
[0009] Current treatments for cHL primarily include chemotherapy,
radiation therapy, and stem cell/bone marrow transplantation.
Despite such treatment options, many cHL patients fail to achieve
complete remission or subsequently relapse after treatment.
(Kuruvilla et al., (2011) Blood 117:4208-17). Therefore, a more
effective treatment option is required for cHL and other human
cancers.
SUMMARY OF THE DISCLOSURE
[0010] The present disclosure relates to a method for treating a
subject afflicted with a tumor derived from a Hodgkin lymphoma
comprising administering to the subject a therapeutically effective
amount of an antibody or an antigen-binding portion thereof that
binds specifically to a Programmed Death-1 receptor (PD-1)
("anti-PD-1 antibody"), wherein the subject was not responsive to a
prior treatment selected from (i) an autologous stem cell therapy,
(ii) brentuximab vedotin, and both (i) and (ii).
[0011] In some embodiments, the subject failed to achieve a partial
response after the prior treatment. In certain embodiments, the
subject had a relapse after a complete response after the prior
treatment. In one embodiment, the subject had progressive disease
after a partial response or stable disease after the prior
treatment. In an embodiment, the subject is further administered
doxorubicin, vinblastine, and dacarbazine.
[0012] The present disclosure relates to a method for treating a
subject afflicted with a tumor derived from a Hodgkin lymphoma
comprising administering to the subject a therapeutically effective
amount of an anti-PD-1 antibody in combination with doxorubicin,
vinblastine, and dacarbazine.
[0013] In further embodiments, the subject is not administered
bleomycin. In certain embodiments, the doxorubicin, vinblastine,
and dacarbazine are administered once about every one, two, three,
or four weeks. In some embodiments, the doxorubicin is administered
at a dose of about 10 mg/m.sup.2 to about 40 mg/m.sup.2, about 10
mg/m.sup.2 to about 30 mg/m.sup.2, or about 20 mg/m.sup.2 to about
30 mg/m.sup.2, the vinblastine is administered at a dose of about
0.1 mg/m.sup.2 to about 10 mg/m.sup.2, about 1 mg/m.sup.2 to about
10 mg/m.sup.2, or about 5 mg/m.sup.2 to about 10 mg/m.sup.2, and/or
the dacarbazine is administered at a dose of about 200 mg/m.sup.2
to about 500 mg/m.sup.2, about 250 mg/m.sup.2 to about 500
mg/m.sup.2, or about 300 mg/m.sup.2 to about 400 mg/m.sup.2. In
particular embodiments, the doxorubicin is administered at a dose
of 25 mg/m.sup.2, the vinblastine is administered at a dose of 6
mg/m.sup.2, and the dacarbazine is administered at a dose of 375
mg/m.sup.2 once about every 2 weeks.
[0014] In some embodiments, the anti-PD-1 antibody cross-competes
with nivolumab for binding to human PD-1. In other embodiments, the
anti-PD-1 antibody binds to the same epitope as nivolumab. In
further embodiments, the anti-PD-1 antibody is a chimeric,
humanized, or human monoclonal antibody or a portion (e.g., an
antigen-binding portion) thereof. In still further embodiments, the
anti-PD-1 antibody comprises a heavy chain constant region which is
of a human IgG1 or IgG4 isotype. In some embodiments, the anti-PD-1
antibody is nivolumab. In other embodiments, the anti-PD-1 antibody
is pembrolizumab.
[0015] In particular embodiments, the anti-PD-1 antibody is
administered at a dose ranging from at least about 0.1 mg/kg to at
least about 10.0 mg/kg body weight once about every 1, 2, or 3
weeks. In further embodiments, the anti-PD-1 antibody (e.g.,
nivolumab) is administered at a dose of at least about 3 mg/kg body
weight once about every 2 weeks. In other embodiments, the
anti-PD-1 antibody (e.g., pembrolizumab) is administered at a dose
of at least about 200 mg every 3 weeks or 2 mg/kg (up to 200 mg)
every three weeks. In some embodiments, the anti-PD-1 antibody
(e.g., avelumab) is administered at a dose of 10 mg/kg every two
weeks. In certain embodiments, the anti-PD-1 antibody is
administered at a flat dose. In embodiments, the anti-PD-1 antibody
is administered at a flat dose of at least about 200 mg, at least
about 220 mg, at least about 240 mg, at least about 260 mg, at
least about 280 mg, at least about 300 mg, at least about 320 mg,
at least about 340 mg, at least about 360 mg, at least about 380
mg, at least about 400 mg, at least about 420 mg, at least about
440 mg, at least about 460 mg, at least about 480 mg, at least
about 500 mg, at least about 550 mg, at least about 600 mg, at
least about 650 mg, at least 700 mg, at least 750 mg, or at least
800 mg. In some embodiments, the anti-PD-1 antibody is administered
at a flat dose about once every 1, 2, 3, or 4 weeks. In particular
embodiments, the anti-PD-1 antibody is administered at a
subtherapeutic dose. In some embodiments, the anti-PD-1 antibody is
administered for as long as clinical benefit is observed or until
unmanageable toxicity or disease progression occurs. In certain
embodiments, the anti-PD-1 antibody is formulated for intravenous
administration.
[0016] In some embodiments, the method further comprises
administering one or more additional anti-cancer agents.
[0017] In some embodiments, the Hodgkin lymphoma has a genetic
alteration at 9p24.1. In particular embodiments, the Hodgkin
lymphoma expresses PD-L1 and/or PD-L2.
[0018] In some embodiments, the PD-L1 and/or PD-L2 expression is at
least about 1%. In other embodiments, the PD-L1 and/or PD-L2
expression of the tumor is at least about 5%. In further
embodiments, the PD-L1 and/or PD-L2 expression of the tumor is at
least about 10%. In embodiments, the PD-L1 and/or PD-L2 expression
is measured by automated immunohistochemistry (IHC) or fluorescent
in situ hybridization.
[0019] In particular embodiments, the subject exhibits
progression-free survival of at least about one month, at least
about 2 months, at least about 3 months, at least about 4 months,
at least about 5 months, at least about 6 months, at least about 7
months, at least about 8 months, at least about 9 months, at least
about 10 months, at least about 11 months, at least about one year,
at least about eighteen months, at least about two years, at least
about three years, at least about four years, or at least about
five years after the initial administration. In other embodiments,
the subject exhibits an overall survival of at least about one
month, at least about 2 months, at least about 3 months, at least
about 4 months, at least about 5 months, at least about 6 months,
at least about 7 months, at least about 8 months, at least about 9
months, at least about 10 months, at least about 11 months, at
least about one year, at least about eighteen months, at least
about two years, at least about three years, at least about four
years, or at least about five years after the initial
administration.
[0020] The disclosure relates to a kit for treating a subject
afflicted with a tumor derived from a Hodgkin lymphoma who has
received at least one prior treatment for Hodgkin lymphoma, the kit
comprising: (a) an anti-PD-1 antibody; and (b) instructions for
administering the anti-PD-1 antibody to the subject in any method
disclosed herein.
[0021] In certain embodiments, the kit optionally comprises an
additional step between (a) and (b): instructions for determining
the PD-L1 and/or PD-L2 expression of the tumor. In some
embodiments, the kit comprises an agent to determine the PD-L1
and/or PD-L2 expression of the tumor. In some embodiments, the
PD-L1 and/or PD-L2 expression is measured by an anti-PD-L1 and/or
PD-L2 antibody.
[0022] Other features and advantages of the instant disclosure will
be apparent from the following detailed description and examples
which should not be construed as limiting. The contents of all
cited references, including scientific articles, newspaper reports,
GenBank entries, patents and patent applications cited throughout
this application are expressly incorporated herein by
reference.
EMBODIMENTS
[0023] E1. A method for treating a subject afflicted with a tumor
derived from a Hodgkin's lymphoma comprising administering to the
subject a therapeutically effective amount of an antibody or an
antigen-binding portion thereof that binds specifically to a
Programmed Death-1 receptor (PD-1) ("anti-PD-1 antibody"), wherein
the subject was not responsive to a prior treatment selected from
(i) an autologous stem cell therapy, (ii) brentuximab vedotin, and
both (i) and (ii).
[0024] E2. The method of embodiment E1, wherein the subject failed
to achieve a partial response after the prior treatment.
[0025] E3. The method of embodiment E1 or E2, wherein the subject
had a relapse after a complete response after the prior
treatment.
[0026] E4. The method of any one of embodiments E1 to E3, wherein
the subject had progressive disease after a partial response or
stable disease after the prior treatment.
[0027] E5. The method of any one of embodiments E1 to E4, wherein
the subject is further administered doxorubicin, vinblastine, and
dacarbazine.
[0028] E6. A method for treating a subject afflicted with a tumor
derived from a Hodgkin's lymphoma comprising administering to the
subject a therapeutically effective amount of an anti-PD-1 antibody
in combination with doxorubicin, vinblastine, and dacarbazine.
[0029] E7. The method of any one of embodiments E1-E6, wherein the
subject is not administered bleomycin.
[0030] E8. The method of any one of embodiments E5 to E7, wherein
the doxorubicin, vinblastine, and dacarbazine are administered once
about every one, two, three or four weeks.
[0031] E9. The method of any one of embodiments E5 to E8, wherein
the doxorubicin is administered at a dose of about 10 mg/m.sup.2 to
about 40 mg/m.sup.2, about 10 mg/m.sup.2 to about 30 mg/m.sup.2, or
about 20 mg/m.sup.2 to about 30 mg/m.sup.2, the vinblastine is
administered at a dose of about 0.1 mg/m.sup.2 to about 10
mg/m.sup.2, about 1 mg/m.sup.2 to about 10 mg/m.sup.2, or about 5
mg/m.sup.2 to about 10 mg/m.sup.2, and/or the dacarbazine is
administered at a dose of about 200 mg/m.sup.2 to about 500
mg/m.sup.2, about 250 mg/m.sup.2 to about 500 mg/m.sup.2, or about
300 mg/m.sup.2 to about 400 mg/m.sup.2.
[0032] E10. The method of any one of embodiments E5 to E9, wherein
the doxorubicin is administered at a dose of 25 mg/m.sup.2, the
vinblastine is administered at a dose of 6 mg/m.sup.2, and the
dacarbazine is administered at a dose of 375 mg/m.sup.2 once about
every 2 weeks.
[0033] E11. The method of any one of embodiments E1 to E10, wherein
the anti-PD-1 antibody cross-competes with nivolumab for binding to
human PD-1.
[0034] E12. The method of any one of embodiments E1 to E11, wherein
the anti-PD-1 antibody binds to the same epitope as nivolumab.
[0035] E13. The method of any one of embodiments E1 to E12, wherein
the anti-PD-1 antibody is a chimeric, humanized or human monoclonal
antibody or a portion thereof.
[0036] E14. The method of any one of embodiments E1 to E13, wherein
the anti-PD-1 antibody comprises a heavy chain constant region
which is of a human IgG1 or IgG4 isotype.
[0037] E15. The method of any one of embodiments E1 to E14, wherein
the anti-PD-1 antibody is nivolumab.
[0038] E16. The method of any one of embodiments E1 to E14, wherein
the anti-PD-1 antibody is pembrolizumab.
[0039] E17. The method of any one of embodiments E1 to E16, wherein
the anti-PD-1 antibody is administered at a dose ranging from at
least about 0.1 mg/kg to at least about 10.0 mg/kg body weight once
about every 1, 2 or 3 weeks.
[0040] E18. The method of any one of embodiments E1 to E17, wherein
the anti-PD-1 antibody is administered at a dose of at least about
3 mg/kg body weight once about every 2 weeks.
[0041] E19. The method of any one of embodiments E1 to E16, wherein
the anti-PD-1 antibody is administered at a flat dose.
[0042] E20. The method of embodiment E19, wherein the anti-PD-1
antibody is administered at a flat dose of at least about 200 mg,
at least about 220 mg, at least about 240 mg, at least about 260
mg, at least about 280 mg, at least about 300 mg, at least about
320 mg, at least about 340 mg, at least about 360 mg, at least
about 380 mg, at least about 400 mg, at least about 420 mg, at
least about 440 mg, at least about 460 mg, at least about 480 mg,
at least about 500 mg, or at least about 550 mg.
[0043] E21. The method of embodiment E19 or E20, wherein the
anti-PD-1 antibody is administered at a flat dose about once every
1, 2, 3 or 4 weeks.
[0044] E22. The method of any one of embodiments E1 to E16, wherein
the anti-PD-1 antibody is administered at a subtherapeutic
dose.
[0045] E23. The method of any one of embodiments E1 to E22, wherein
the anti-PD-1 antibody is administered for as long as clinical
benefit is observed or until unmanageable toxicity or disease
progression occurs.
[0046] E24. The method of any one of embodiments E1 to E23, wherein
the anti-PD-1 antibody is formulated for intravenous
administration.
[0047] E25. The method of any one of embodiments E1 to E24, which
further comprises administering one or more additional anti-cancer
agents.
[0048] E26. The method of any one of embodiments E1 to E25, wherein
the Hodgkin's lymphoma has a genetic alteration at 9p24.1.
[0049] E27. The method of any one of embodiments E1 to E26, wherein
the Hodgkin's lymphoma expresses PD-L1 and/or PD-L2.
[0050] E28. The method of any one of embodiments E1 to E27, wherein
the PD-L1 and/or PD-L2 expression is at least about 1%.
[0051] E29. The method of any one of embodiments E1 to E28, wherein
the PD-L1 and/or PD-L2 expression of the tumor is at least about
5%.
[0052] E30. The method of any one of embodiments E1 to E29, wherein
the PD-L1 and/or PD-L2 expression of the tumor is at least about
10%.
[0053] E31. The method of any one of embodiments E1 to E30, wherein
the PD-L1 and/or PD-L2 expression is measured by automated
immunohistochemistry (IHC) or fluorescent in situ
hybridization.
[0054] E32. The method of any one of embodiments E1 to E31, wherein
the subject exhibits progression-free survival of at least about
one month, at least about 2 months, at least about 3 months, at
least about 4 months, at least about 5 months, at least about 6
months, at least about 7 months, at least about 8 months, at least
about 9 months, at least about 10 months, at least about 11 months,
at least about one year, at least about eighteen months, at least
about two years, at least about three years, at least about four
years, or at least about five years after the initial
administration.
[0055] E33. The method of any one of embodiments E1 to E32, wherein
the subject exhibits an overall survival of at least about one
month, at least about 2 months, at least about 3 months, at least
about 4 months, at least about 5 months, at least about 6 months,
at least about 7 months, at least about 8 months, at least about 9
months, at least about 10 months, at least about 11 months, at
least about one year, at least about eighteen months, at least
about two years, at least about three years, at least about four
years, or at least about five years after the initial
administration.
[0056] E34. A kit for treating a subject afflicted with a tumor
derived from a Hodgkin's lymphoma who has received at least one
prior treatment for Hodgkin's lymphoma, the kit comprising: (a) an
anti-PD-1 antibody; and (b) instructions for administering the
anti-PD-1 antibody to the subject in the methods of embodiments E1
to E33.
[0057] E35. The kit of embodiment E34, optionally comprising an
additional step between (a) and (b): instructions for determining
the PD-L1 and/or PD-L2 expression of the tumor.
[0058] E36. The kit of embodiment E35, further comprising an agent
to determine the PD-L1 and/or PD-L2 expression of the tumor.
[0059] E37. The kit of embodiment E35 or E36, wherein the PD-L1
and/or PD-L2 expression is measured by an anti-PD-L1 and/or PD-L2
antibody.
BRIEF DESCRIPTION OF THE DRAWINGS
[0060] FIG. 1 shows a study design schematic for a Multicenter,
Non-Comparative Phase 2 Registrational Study assessing the efficacy
and safety of nivolumab monotherapy in classical Hodgkin lymphoma
(cHL) patients after failed treatment with autologous stem cell
transplantation and brentuximab vedotin.
[0061] FIGS. 2A-2C show a summary of the response and the change in
tumor burden in cHL patients after nivolumab monotherapy. FIG. 2A
shows the response characteristics in all responders (n=53) per
IRRC assessment. Of the responders, 62% continued to respond at
time of analysis (denoted by a black arrow). The median time to
response was 2.1 months (1.6-5.7 months) and the median duration of
response was 7.8 months (6.6 months--not estimable). FIG. 2B shows
the independent radiologic review committee (IRRC) assessment of
the best change from baseline in tumor burden for all
response-evaluable patients. All but one responder had a reduction
of greater than 50% from baseline in tumor burden, and the patient
who didn't had a negative CDG-PET scan. FIG. 2C shows the change in
tumor burden in patients treated with nivolumab beyond progression.
Of the 9 patients analyzed, 6 patients maintained tumor reduction,
per investigator assessment.
[0062] FIG. 3 shows the probability of progression free survival
(PFS) over a course of 12 months in cHL patients treated with
nivolumab. The median PFS was 10 months (95% CI 8.41 months--NA).
The PFS at 6 months was 76.9% (95% CI 64.9%-85.3%) with an overall
survival rate of 99% at 6 months.
[0063] FIG. 4 shows a study design schematic for the single-arm,
open-label, phase 2 study assessing the safety and tolerability of
nivolumab monotherapy followed by nivolumab in combination with
doxorubicin (25 mg/m2), vinblastine (6 mg/m2), dacarbazine (375
mg/m2) ("AVD") in newly diagnosed advanced-stage cHL. C means cycle
(dose on day 1 and day 15) every 28 days of therapy. FU/OBS means
follow-up and observation phase.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0064] The present disclosure relates to the superior effects of an
anti-PD-1 antibody or anti-PD-L1 antibody in treating a patient
with Classical Hodgkin Lymphoma (cHL) who has received at least one
prior treatment. The present methods for treating a Classical
Hodgkin Lymphoma (cHL) patient comprise administering to the
patient an anti-PD-1 antibody or an anti-PD-L1 antibody.
Terms
[0065] In order that the present disclosure can be more readily
understood, certain terms are first defined. As used in this
application, except as otherwise expressly provided herein, each of
the following terms shall have the meaning set forth below.
Additional definitions are set forth throughout the
application.
[0066] "Administering" refers to the physical introduction of a
composition comprising a therapeutic agent to a subject, using any
of the various methods and delivery systems known to those skilled
in the art. Routes of administration for the anti-PD-1 antibody
include intravenous, intramuscular, subcutaneous, intraperitoneal,
spinal, or other parenteral routes of administration, for example
by injection or infusion. The phrase "parenteral administration" as
used herein means modes of administration other than enteral and
topical administration, usually by injection, and includes, without
limitation, intravenous, intramuscular, intraarterial, intrathecal,
intralymphatic, intralesional, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal, epidural, and intrasternal injection and
infusion, as well as in vivo electroporation. In some embodiments,
a composition is administered via a non-parenteral route, in some
embodiments, orally. Other non-parenteral routes include a topical,
epidermal or mucosal route of administration, for example,
intranasally, vaginally, rectally, sublingually or topically.
Administering can also be performed, for example, once, a plurality
of times, and/or over one or more extended periods.
[0067] An "adverse event" (AE) as used herein is any unfavorable
and generally unintended or undesirable sign (including an abnormal
laboratory finding), symptom, or disease associated with the use of
a medical treatment. For example, an adverse event can be
associated with activation of the immune system or expansion of
immune system cells (e.g., T cells) in response to a treatment. A
medical treatment can have one or more associated AEs and each AE
can have the same or different level of severity. Reference to
methods capable of "altering adverse events" means a treatment
regime that decreases the incidence and/or severity of one or more
AEs associated with the use of a different treatment regime.
[0068] An "antibody" (Ab) shall include, without limitation, a
glycoprotein immunoglobulin which binds specifically to an antigen
and comprises at least two heavy (H) chains and two light (L)
chains interconnected by disulfide bonds, or an antigen-binding
portion thereof. Each H chain comprises a heavy chain variable
region (abbreviated herein as V.sub.H) and a heavy chain constant
region. The heavy chain constant region comprises at least three
constant domains, C.sub.H1, C.sub.H2 and C.sub.H3. Each light chain
comprises a light chain variable region (abbreviated herein as
V.sub.L) and a light chain constant region. The light chain
constant region is comprises one constant domain, C.sub.L. The
V.sub.H and V.sub.L regions can be further subdivided into regions
of hypervariability, termed complementarity determining regions
(CDRs), interspersed with regions that are more conserved, termed
framework regions (FRs). Each V.sub.H and V.sub.L comprises three
CDRs and four FRs, arranged from amino-terminus to carboxy-terminus
in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
The variable regions of the heavy and light chains contain a
binding domain that interacts with an antigen. The constant regions
of the antibodies can mediate the binding of the immunoglobulin to
host tissues or factors, including various cells of the immune
system (e.g., effector cells) and the first component (C1q) of the
classical complement system.
[0069] An immunoglobulin can derive from any of the commonly known
isotypes, including but not limited to IgA, secretory IgA, IgG, and
IgM. IgG subclasses are also well known to those in the art and
include but are not limited to human IgG1, IgG2, IgG3, and IgG4.
"Isotype" refers to the antibody class or subclass (e.g., IgM or
IgG1) that is encoded by the heavy chain constant region genes. The
term "antibody" includes, by way of example, both naturally
occurring and non-naturally occurring antibodies; monoclonal and
polyclonal antibodies; chimeric and humanized antibodies; human or
non-human antibodies; wholly synthetic antibodies; and single chain
antibodies. A non-human antibody can be humanized by recombinant
methods to reduce its immunogenicity in man. Where not expressly
stated, and unless the context indicates otherwise, the term
"antibody" also includes an antigen-binding fragment or an
antigen-binding portion of any of the aforementioned
immunoglobulins, and includes a monovalent and a divalent fragment
or portion, and a single chain antibody.
[0070] An "isolated antibody" refers to an antibody that is
substantially free of other antibodies having different antigenic
specificities (e.g., an isolated antibody that binds specifically
to PD-1 is substantially free of antibodies that bind specifically
to antigens other than PD-1). An isolated antibody that binds
specifically to PD-1 can, however, have cross-reactivity to other
antigens, such as PD-1 molecules from different species. Moreover,
an isolated antibody can be substantially free of other cellular
material and/or chemicals.
[0071] The term "monoclonal antibody" (mAb) refers to a
non-naturally occurring preparation of antibody molecules of single
molecular composition, i.e., antibody molecules whose primary
sequences are essentially identical, and which exhibits a single
binding specificity and affinity for a particular epitope. A
monoclonal antibody is an example of an isolated antibody and can
be produced by hybridoma, recombinant, transgenic, or other
techniques known to those skilled in the art.
[0072] A "human antibody" (HuMAb) refers to an antibody having
variable regions in which both the framework and CDRs are derived
from human germline immunoglobulin sequences. Furthermore, if the
antibody contains a constant region, the constant region also is
derived from human germline immunoglobulin sequences. The human
antibodies of the disclosure can include amino acid residues not
encoded by human germline immunoglobulin sequences (e.g., mutations
introduced by random or site-specific mutagenesis in vitro or by
somatic mutation in vivo). However, the term "human antibody," as
used herein, is not intended to include antibodies in which CDR
sequences derived from the germline of another mammalian species,
such as a mouse, have been grafted onto human framework sequences.
The terms "human antibodies" and "fully human antibodies" are used
synonymously.
[0073] A "humanized antibody" refers to an antibody in which some,
most, or all of the amino acids outside the CDRs of a non-human
antibody are replaced with corresponding amino acids derived from
human immunoglobulins. In one embodiment of a humanized form of an
antibody, some, most or all of the amino acids outside the CDRs
have been replaced with amino acids from human immunoglobulins,
whereas some, most or all amino acids within one or more CDRs are
unchanged. Small additions, deletions, insertions, substitutions or
modifications of amino acids are permissible as long as they do not
abrogate the ability of the antibody to bind to a particular
antigen. A "humanized antibody" retains an antigenic specificity
similar to that of the original antibody. In some embodiments, the
CDRs of a humanized antibody contain CDRs from a non-human,
mammalian antibody. In other embodiments, the CDRs of a humanized
antibody contain CDRs from an engineered, synthetic antibody.
[0074] A "chimeric antibody" refers to an antibody in which the
variable regions are derived from one species and the constant
regions are derived from another species, such as an antibody in
which the variable regions are derived from a mouse antibody and
the constant regions are derived from a human antibody.
[0075] An "anti-antigen" antibody refers to an antibody that binds
specifically to the antigen. For example, an anti-PD-1 antibody
binds specifically to PD-1 and an anti-CTLA-4 antibody binds
specifically to CTLA-4.
[0076] An "antigen-binding portion" of an antibody (also called an
"antigen-binding fragment") refers to one or more fragments of an
antibody that retain the ability to bind specifically to the
antigen bound by the whole antibody.
[0077] A "cancer" refers a broad group of various diseases
characterized by the uncontrolled growth of abnormal cells in the
body. A "cancer" or "cancer tissue" can include a tumor.
Unregulated cell division and growth results in the formation of
malignant tumors that invade neighboring tissues and may also
metastasize to distant parts of the body through the lymphatic
system or bloodstream. Following metastasis, the distal tumors can
be said to be "derived from" the original, pre-metastasis tumor.
For example, a "tumor derived from" a non-Hodgkin Lymphoma refers
to a tumor that is the result of a metastasized non-Hodgkin
Lymphoma. Because the distal tumor is derived from the
pre-metastasis tumor, the "derived from" tumor can also comprise
the pre-metastasis tumor, e.g., a tumor derived from a non-Hodgkin
Lymphoma can comprise a non-Hodgkin Lymphoma. In some embodiments,
the cancer is Hodgkin lymphoma (also referring to as Hodgkin
lymphoma, Classical Hodgkin Lymphoma and CHL).
[0078] "Cytotoxic T-Lymphocyte Antigen-4" (CTLA-4) refers to an
immunoinhibitory receptor belonging to the CD28 family. CTLA-4 is
expressed exclusively on T cells in vivo, and binds to two ligands,
CD80 and CD86 (also called B7-1 and B7-2, respectively). The term
"CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants,
isoforms, and species homologs of hCTLA-4, and analogs having at
least one common epitope with hCTLA-4. The complete hCTLA-4
sequence can be found under GenBank Accession No. AAB59385.
[0079] The term "immunotherapy" refers to the treatment of a
subject afflicted with, or at risk of contracting or suffering a
recurrence of, a disease by a method comprising inducing,
enhancing, suppressing or otherwise modifying an immune
response.
[0080] "Treatment" or "therapy" of a subject refers to any type of
intervention or process performed on, or the administration of an
active agent to, the subject with the objective of reversing,
alleviating, ameliorating, inhibiting, slowing down or preventing
the onset, progression, development, severity or recurrence of a
symptom, complication or condition, or biochemical indicia
associated with a disease.
[0081] "PD-L1 positive" or "PD-L2 positive" as used herein can be
interchangeably used with "PD-L1 and/or PD-L2 expression of at
least about 1%." In one embodiment, the PD-L1 and/or PD-L2
expression can be used by any methods known in the art. In another
embodiment, the PD-L1 and/or PD-L2 expression is measured by an
automated in situ hybridization (IHC). A PD-L1 and/or PD-L2
positive tumor can thus have at least about 1%, at least about 2%,
at least about 5%, at least about 10%, or at least about 20%, at
least about 25%, at least about 30%, at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least about
75%, at least about 80%, at least about 85%, at least about 90%, at
least about 95%, or about 100% of tumor cells expressing PD-L1
and/or PD-L2 as measured by an automated IHC. In certain
embodiments, "PD-L1 positive" means that there are at least 100
cells that express PD-L1 on the surface of the cells. In other
embodiments, "PD-L2 positive" means that there are at least 100
cells that express PD-L2 on the surface of the cells.
[0082] "Programmed Death-1" (PD-1) refers to an immunoinhibitory
receptor belonging to the CD28 family. PD-1 is expressed
predominantly on previously activated T cells in vivo, and binds to
two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein
includes human PD-1 (hPD-1), variants, isoforms, and species
homologs of hPD-1, and analogs having at least one common epitope
with hPD-1. The complete hPD-1 sequence can be found under GenBank
Accession No. U64863.
[0083] "Programmed Death Ligand-1" (PD-L1) is one of two cell
surface glycoprotein ligands for PD-1 (the other being PD-L2) that
downregulate T cell activation and cytokine secretion upon binding
to PD-1. The term "PD-L1" as used herein includes human PD-L1
(hPD-L1), variants, isoforms, and species homologs of hPD-L1, and
analogs having at least one common epitope with hPD-L1. The
complete hPD-L1 sequence can be found under GenBank Accession No.
Q9NZQ7.
[0084] A "subject" includes any human or non-human animal. The term
"non-human animal" includes, but is not limited to, vertebrates
such as non-human primates, sheep, dogs, and rodents such as mice,
rats and guinea pigs. In some embodiments, the subject is a human.
The terms, "subject" and "patient" are used interchangeably
herein.
[0085] A "therapeutically effective amount" or "therapeutically
effective dosage" of a drug or therapeutic agent is any amount of
the drug that, when used alone or in combination with another
therapeutic agent, protects a subject against the onset of a
disease or promotes disease regression evidenced by a decrease in
severity of disease symptoms, an increase in frequency and duration
of disease symptom-free periods, or a prevention of impairment or
disability due to the disease affliction. The ability of a
therapeutic agent to promote disease regression can be evaluated
using a variety of methods known to the skilled practitioner, such
as in human subjects during clinical trials, in animal model
systems predictive of efficacy in humans, or by assaying the
activity of the agent in in vitro assays.
[0086] As used herein, "subtherapeutic dose" means a dose of a
therapeutic compound (e.g., an antibody) that is lower than the
usual or typical dose of the therapeutic compound when administered
alone for the treatment of a hyperproliferative disease (e.g.,
cancer).
[0087] By way of example, an "anti-cancer agent" promotes cancer
regression in a subject or prevents further tumor growth. In
certain embodiments, a therapeutically effective amount of the drug
promotes cancer regression to the point of eliminating the cancer.
"Promoting cancer regression" means that administering an effective
amount of the drug, alone or in combination with an anti-neoplastic
agent, results in a reduction in tumor growth or size, necrosis of
the tumor, a decrease in severity of at least one disease symptom,
an increase in frequency and duration of disease symptom-free
periods, or a prevention of impairment or disability due to the
disease affliction. In addition, the terms "effective" and
"effectiveness" with regard to a treatment includes both
pharmacological effectiveness and physiological safety.
Pharmacological effectiveness refers to the ability of the drug to
promote cancer regression in the patient. Physiological safety
refers to the level of toxicity, or other adverse physiological
effects at the cellular, organ and/or organism level (adverse
effects) resulting from administration of the drug.
[0088] By way of example for the treatment of tumors, a
therapeutically effective amount of an anti-cancer agent can
inhibit cell growth or tumor growth by at least about 10%, at least
about 20%, by at least about 30%, by at least about 40%, by at
least about 50%, by at least about 60%, by at least about 70%, by
at least about 80%, by at least about 90%, at least about 95%, or
about 100% relative to untreated subjects or, in certain
embodiments, relative to patients treated with a standard-of-care
therapy. In other embodiments of the disclosure, tumor regression
can be observed and continue for a period of at least about 20
days, at least about 30 days, at least about 40 days, at least
about 50 days, or at least about 60 days. Notwithstanding these
ultimate measurements of therapeutic effectiveness, evaluation of
immunotherapeutic drugs must also make allowance for
"immune-related response patterns".
[0089] An "immune-related response pattern" refers to a clinical
response pattern often observed in cancer patients treated with
immunotherapeutic agents that produce antitumor effects by inducing
cancer-specific immune responses or by modifying native immune
processes. This response pattern is characterized by a beneficial
therapeutic effect that follows an initial increase in tumor burden
or the appearance of new lesions, which in the evaluation of
traditional chemotherapeutic agents would be classified as disease
progression and would be synonymous with drug failure. Accordingly,
proper evaluation of immunotherapeutic agents can require long-term
monitoring of the effects of these agents on the target
disease.
[0090] A therapeutically effective amount of a drug includes a
"prophylactically effective amount," which is any amount of the
drug that, when administered alone or in combination with an
anti-neoplastic agent to a subject at risk of developing a cancer
(e.g., a subject having a pre-malignant condition) or of suffering
a recurrence of cancer, inhibits the development or recurrence of
the cancer. In certain embodiments, the prophylactically effective
amount prevents the development or recurrence of the cancer
entirely. "Inhibiting" the development or recurrence of a cancer
means either lessening the likelihood of the cancer's development
or recurrence, or preventing the development or recurrence of the
cancer entirely.
[0091] The term "weight-based dose" as referred to herein means
that a dose that is administered to a patient is calculated based
on the weight of the patient. For example, when a patient with 60
kg body weight requires 3 mg/kg of an anti-PD-1 antibody, one can
calculate and use the appropriate amount of the anti-PD-1 antibody
(i.e., 180 mg) for administration.
[0092] The use of the term "fixed dose" with regard to a method of
the disclosure means that two or more different antibodies in a
single composition (e.g., anti-PD-1 antibody and anti-CTLA-4
antibody) are present in the composition in particular (fixed)
ratios with each other. In some embodiments, the fixed dose is
based on the weight (e.g., mg) of the antibodies. In certain
embodiments, the fixed dose is based on the concentration (e.g.,
mg/ml) of the antibodies. In some embodiments, the ratio is at
least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about
1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about
1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70,
about 1:80, about 1:90, about 1:100, about 1:120, about 1:140,
about 1:160, about 1:180, about 1:200, about 200:1, about 180:1,
about 160:1, about 140:1, about 120:1, about 100:1, about 90:1,
about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about
30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1,
about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1
mg first antibody (e.g., anti-PD-1 antibody) to mg second antibody
(e.g., anti-CTLA-4 antibody). For example, the 3:1 ratio of an
anti-PD-1 antibody and an anti-CTLA-4 antibody can mean that a vial
can contain about 240 mg of the anti-PD-1 antibody and 80 mg of the
anti-CTLA-4 antibody or about 3 mg/ml of the anti-PD-1 antibody and
1 mg/ml of the anti-CTLA-4 antibody.
[0093] The use of the term "flat dose" with regard to the methods
and dosages of the disclosure means a dose that is administered to
a patient without regard for the weight or body surface area (BSA)
of the patient. The flat dose is therefore not provided as a mg/kg
dose, but rather as an absolute amount of the agent (e.g., the
anti-PD-1 antibody). For example, a 60 kg person and a 100 kg
person would receive the same dose of an antibody (e.g., 240 mg of
an anti-PD-1 antibody).
[0094] The use of the alternative (e.g., "or") should be understood
to mean either one, both, or any combination thereof of the
alternatives. As used herein, the indefinite articles "a" or "an"
should be understood to refer to "one or more" of any recited or
enumerated component.
[0095] The terms "about" or "comprising essentially of" refer to a
value or composition that is within an acceptable error range for
the particular value or composition as determined by one of
ordinary skill in the art, which will depend in part on how the
value or composition is measured or determined, i.e., the
limitations of the measurement system. For example, "about" or
"comprising essentially of" can mean within 1 or more than 1
standard deviation per the practice in the art. Alternatively,
"about" or "comprising essentially of" can mean a range of up to
10% or 20% (i.e., .+-.10% or .+-.20%). For example, about 3 mg can
include any number between 2.7 mg and 3.3 mg (for 10%) or between
2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect
to biological systems or processes, the terms can mean up to an
order of magnitude or up to 5-fold of a value. When particular
values or compositions are provided in the application and claims,
unless otherwise stated, the meaning of "about" or "comprising
essentially of" should be assumed to be within an acceptable error
range for that particular value or composition.
[0096] The terms "once about every week," "once about every two
weeks," or any other similar dosing interval terms as used herein
mean approximate numbers. "Once about every week" can include every
seven days.+-.one day, i.e., every six days to every eight days.
"Once about every two weeks" can include every fourteen
days.+-.three days, i.e., every eleven days to every seventeen
days. Similar approximations apply, for example, to once about
every three weeks, once about every four weeks, once about every
five weeks, once about every six weeks and once about every twelve
weeks. In some embodiments, a dosing interval of once about every
six weeks or once about every twelve weeks means that the first
dose can be administered any day in the first week, and then the
next dose can be administered any day in the sixth or twelfth week,
respectively. In other embodiments, a dosing interval of once about
every six weeks or once about every twelve weeks means that the
first dose is administered on a particular day of the first week
(e.g., Monday) and then the next dose is administered on the same
day of the sixth or twelfth weeks (i.e., Monday), respectively.
[0097] As described herein, any concentration range, percentage
range, ratio range or integer range is to be understood to include
the value of any integer within the recited range and, when
appropriate, fractions thereof (such as one tenth and one hundredth
of an integer), unless otherwise indicated.
[0098] Various aspects of the disclosure are described in further
detail in the following subsections.
TABLE-US-00001 TABLE 1 List of Abbreviations Term Definition AEs
adverse events ASCT autologous stem cell transplantation BMS
Bristol-Myers Squibb cHL classical Hodgkin lymphoma CI confidence
interval CR complete remission CT computerized tomography (CT) scan
DOR duration of response EBV Epstein-Barr virus FDG
fluorodeoxyglucose IRRC independent radiologic review committee Kg
kilogram mAB monoclonal antibody Mg milligram MRI magnetic
resonance imaging N number of subjects or observations NE not
evaluable ORR overall response rate OS overall survival PD
progressive disease PD-1 programmed death-1 PD-L1 programmed
death-ligand 1 PD-L2 programmed death-ligand 2 PET positron
emission tomography PFS progression-free survival PR partial
remission QoL quality of life SAE serious adverse event SCT stem
cell transplantation SD stable disease SOP Standard Operating
Procedures Subj subject
Methods of the Disclosure
[0099] This disclosure provides a method of treating a subject
afflicted with a tumor derived from Hodgkin lymphoma, wherein the
subject has received (e.g., not responded to) at least one prior
treatment for Hodgkin lymphoma selected from the group consisting
of (i) an autologous stem cell therapy, (ii) brentuximab vedotin,
and both (i) and (ii), wherein the method comprises administering
to the subject a therapeutically effective amount of an antibody or
an antigen-binding portion thereof that specifically binds to and a
PD-1 receptor and inhibits PD-1 activity ("anti-PD-1 antibody") or
an antibody or an antigen-binding portion thereof that specifically
binds to and a PD-L1 receptor and inhibits PD-L1 activity
("anti-PD-L1 antibody").
[0100] In certain embodiments, the disclosure is directed to a
method for treating a subject afflicted with a tumor derived from
Hodgkin lymphoma wherein the subject has received at least one
prior treatment for Hodgkin lymphoma selected from the group
consisting of (i) an autologous stem cell therapy, (ii) an
anti-CD30 antibody (e.g., brentuximab vedotin), and both (i) and
(ii), comprising administering to the subject a therapeutically
effective amount of: an anti-PD-1 antibody or an antigen-binding
portion thereof or anti-PD-L1 antibody or an antigen binding
portion thereof.
[0101] In some embodiments, the subject has received at least two
prior treatments for Hodgkin lymphoma. In some embodiments, the
prior treatment received by the patient was autologous stem cell
transplantation. In other embodiments, the prior treatment received
by the patient was an anti-CD30 antibody, e.g., brentuximab
vedotin. In yet other embodiments, the patient received both
autologous stem cell transplantation and an anti-CD30 antibody,
e.g., brentuximab vedotin, as prior treatments. In further
embodiments, an anti-CD30 antibody, e.g., brentuximab vedotin, was
administered simultaneously with the autologous stem cell
transplant. In some embodiments, the patient was first treated with
an autologous stem cell transplant and then treated with an
anti-CD30 antibody, e.g., brentuximab vedotin. In other
embodiments, the patient was first treated with an anti-CD30
antibody, e.g., brentuximab vedotin and then treated with an
autologous stem cell transplant. Brentuximab vedotin is also known
as ADCETRIS.RTM..
[0102] In particular embodiments, the at least one prior treatment
failed. In embodiments, the subject failed to achieve a partial
response after the at least one prior treatment. In other
embodiments, the subject had a relapse after a complete response
after the at least one prior treatment. In still other embodiments,
the patient had progressive disease after a partial response or
stable disease after the at least one prior treatment.
[0103] In other embodiments, the disclosure includes a method of
treating a subject afflicted with a tumor derived from Hodgkin
lymphoma wherein the subject has received at least one prior
treatment for Hodgkin lymphoma selected from the group consisting
of (i) an autologous stem cell therapy, (ii) an anti-CD30 antibody,
e.g., brentuximab vedotin, and both (i) and (ii), comprising: (i)
measuring a PD-L1 expression level on the tumor, wherein the tumor
has a PD-L1 or PD-L2 expression level of at least 1%, and (ii)
administering to the subject a therapeutically effective amount of
an anti-PD-1 antibody or antigen-binding portion thereof or an
anti-PD-L1 antibody or antigen-binding portion thereof.
[0104] In further embodiments, the disclosure includes a method for
treating a subject afflicted with a tumor derived from a Hodgkin
lymphoma comprising administering to the subject a therapeutically
effective amount of an anti-PD-1 antibody or an antigen-binding
portion thereof or an anti-PD-L1 antibody or antigen-binding
portion thereof in combination with doxorubicin, vinblastine, and
dacarbazine. In embodiments, the disclosure includes a method for
treating a subject afflicted with a tumor derived from a Hodgkin
lymphoma comprising administering to the subject a therapeutically
effective amount of an anti-PD-1 antibody or an antigen-binding
portion thereof or an anti-PD-L1 antibody or antigen-binding
portion thereof in combination with doxorubicin, vinblastine, and
dacarbazine, but not bleomycin.
[0105] In certain embodiments, the therapy of the present
disclosure (e.g., administration of an anti-PD-1 antibody or an
anti-PD-L1 antibody and, optionally, another anti-cancer agent)
effectively increases the duration of survival of the subject. In
some embodiments, the anti-PD-1 antibody therapy or anti-PD-L1
antibody therapy of the present disclosure increases the duration
of survival of the subject in comparison to standard-of-care
therapies (i.e., brentuximab vedotin or AVD chemotherapy). After
the administration of an anti-PD-1 antibody or anti-PD-L1 antibody
therapy, the subject having Hodgkin lymphoma tumor can exhibit an
overall survival of at least about 10 months, at least about 11
months, at least about 12 months, at least about 13 months, at
least about 14 months at least about 15 months, at least about 16
months, at least about 17 months, at least about 18 months, at
least about 19 months, at least about 20 months, at least about 21
months, at least about 22 months, at least about 23 months, at
least about 2 years, at least about 3 years, at least about 4
years, or at least about 5 years after the administration.
[0106] In other embodiments, the duration of survival or the
overall survival of the subject is increased by at least about 1
month, at least about 2 months, at least about 3 months, at least
about 4 months, at least about 5 months, at least about 6 months,
at least about 7 months, at least about 8 months, at least about 9
months or at least about 1 year when compared to another subject
treated with only a standard-of-care therapy (e.g., brentuximab
vedotin or AVD chemotherapy). In some embodiments, the overall
survival is increased by at least about 4 months, at least about 5
months, at least about 6 months, at least about 7 months, at least
about 8 months, at least about 9 months, at least about 10 months,
at least about 11 months, at least about 1 year, at least about 18
months, or at least about 2 years when the tumor is PD-L1 positive
when compared to another subject treated with only a
standard-of-care therapy (e.g., brentuximab vedotin or AVD
chemotherapy). For example, the duration of survival or the overall
survival of the subject is increased by at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 40%, at least about 50%, or
at least about 75% when compared to another subject treated with
only a standard-of-care therapy (e.g., brentuximab vedotin or AVD
chemotherapy).
[0107] In certain embodiments, the therapy of the present
disclosure effectively increases the duration of progression free
survival of the subject. For example, the progression free survival
of the subject treated with a method of the disclosure is at least
about 1 month, 2 months, 3 months, at least about 4 months, at
least about 5 months, at least about 6 months, at least about 7
months, at least about 8 months, at least about 9 months, at least
about 10 months, at least about 11 months, at least about 12
months, at least about 1 year, at least about eighteen months, at
least about 2 years, at least about 3 years, at least about 4
years, or at least about 5 years.
[0108] In other embodiments, the subject is a human patient. In
some embodiments, the subject has received another cancer therapy
(e.g., brentuximab vedotin or chemotherapy), but is resistant or
refractory to such another cancer therapy. In certain embodiments,
the subject has a genetic alteration of the PD-1 ligand loci. In
one embodiment, the subject has a 9p24.1 amplification. In other
embodiments, the subject is PD-L1 positive. In some embodiments,
the subject is PD-L2 positive.
[0109] The PD-L1 or PD-L2 status of a tumor (e.g., a tumor derived
from HL) in a subject can be measured prior to administering any
composition or utilizing any method disclosed herein. PD-L1 or
PD-L2 expression can be determined by any methods known in the
art.
[0110] In order to assess the PD-L1 and/or PD-L2 expression, in one
embodiment, a test tissue sample can be obtained from the patient
who is in need of the therapy. In another embodiment, the
assessment of PD-L1 and/or PD-L2 expression can be achieved without
obtaining a test tissue sample. In some embodiments, selecting a
suitable patient includes (i) optionally providing a test tissue
sample obtained from a patient with cancer of the tissue, the test
tissue sample comprising tumor cells and/or tumor-infiltrating
inflammatory cells; and (ii) assessing the proportion of cells in
the test tissue sample that express PD-L1 and/or PD-L2 on the
surface of the cells based on an assessment that the proportion of
cells in the test tissue sample that express PD-L1 and/or PD-L2 on
the cell surface is higher than a predetermined threshold
level.
[0111] In any of the methods comprising the measurement of PD-L1
expression in a test tissue sample, however, it should be
understood that the step comprising the provision of a test tissue
sample obtained from a patient is an optional step. It should also
be understood that in certain embodiments the "measuring" or
"assessing" step to identify, or determine the number or proportion
of, cells in the test tissue sample that express PD-L1 on the cell
surface is performed by a transformative method of assaying for
PD-L1 expression, for example by performing a reverse
transcriptase-polymerase chain reaction (RT-PCR) assay or an IHC
assay. In certain other embodiments, no transformative step is
involved and PD-L1 expression is assessed by, for example,
reviewing a report of test results from a laboratory. In certain
embodiments, the steps of the methods up to, and including,
assessing PD-L1 expression provides an intermediate result that may
be provided to a physician or other healthcare provider for use in
selecting a suitable candidate for the anti-PD-1 antibody or
anti-PD-L1 antibody therapy. In certain embodiments, the steps that
provide the intermediate result is performed by a medical
practitioner or someone acting under the direction of a medical
practitioner. In other embodiments, these steps are performed by an
independent laboratory or by an independent person such as a
laboratory technician.
[0112] In certain embodiments of any of the present methods, the
proportion of cells that express PD-L1 is assessed by performing an
assay to determine the presence of PD-L1 RNA. In further
embodiments, the presence of PD-L1 RNA is determined by RT-PCR, in
situ hybridization or RNase protection. In other embodiments, the
proportion of cells that express PD-L1 is assessed by performing an
assay to determine the presence of PD-L1 polypeptide. In further
embodiments, the presence of PD-L1 polypeptide is determined by
immunohistochemistry (IHC), enzyme-linked immunosorbent assay
(ELISA), in vivo imaging, or flow cytometry. In some embodiments,
PD-L1 expression is assayed by IHC. In other embodiments of all of
these methods, cell surface expression of PD-L1 is assayed using,
e.g., IHC or in vivo imaging. Chen et al., (2013) Clin Cancer Res
19(13): 3462-3473.
[0113] Imaging techniques have provided important tools in cancer
research and treatment. Recent developments in molecular imaging
systems, including positron emission tomography (PET),
single-photon emission computed tomography (SPECT), fluorescence
reflectance imaging (FM), fluorescence-mediated tomography (FMT),
bioluminescence imaging (BLI), laser-scanning confocal microscopy
(LSCM) and multiphoton microscopy (MPM), will likely herald even
greater use of these techniques in cancer research. Some of these
molecular imaging systems allow clinicians to not only see where a
tumor is located in the body, but also to visualize the expression
and activity of specific molecules, cells, and biological processes
that influence tumor behavior and/or responsiveness to therapeutic
drugs (Condeelis and Weissleder, "In vivo imaging in cancer," Cold
Spring Harb. Perspect. Biol. 2(12): a003848 (2010)). Antibody
specificity, coupled with the sensitivity and resolution of PET,
makes immunoPET imaging particularly attractive for monitoring and
assaying expression of antigens in tissue samples (McCabe and Wu,
"Positive progress in immunoPET--not just a coincidence," Cancer
Biother. Radiopharm. 25(3):253-61 (2010); Olafsen et al.,
"ImmunoPET imaging of B-cell lymphoma using 124I-anti-CD20 scFv
dimers (diabodies)," Protein Eng. Des. Sel. 23(4):243-9 (2010)). In
certain embodiments of any of the present methods, PD-L1 expression
is assayed by immunoPET imaging. In certain embodiments of any of
the present methods, the proportion of cells in a test tissue
sample that express PD-L1 is assessed by performing an assay to
determine the presence of PD-L1 polypeptide on the surface of cells
in the test tissue sample. In certain embodiments, the test tissue
sample is a FFPE tissue sample. In other embodiments, the presence
of PD-L1 polypeptide is determined by IHC assay. In further
embodiments, the IHC assay is performed using an automated process.
In some embodiments, the IHC assay is performed using an anti-PD-L1
monoclonal antibody to bind to the PD-L1 polypeptide.
[0114] In one embodiment of the present methods, an automated IHC
method is used to assay the expression of PD-L1 on the surface of
cells in FFPE tissue specimens. This disclosure provides methods
for detecting the presence of human PD-L1 antigen in a test tissue
sample, or quantifying the level of human PD-L1 antigen or the
proportion of cells in the sample that express the antigen, which
methods comprise contacting the test sample, and a negative control
sample, with a monoclonal antibody that specifically binds to human
PD-L1, under conditions that allow for formation of a complex
between the antibody or portion thereof and human PD-L1. In certain
embodiments, the test and control tissue samples are FFPE samples.
The formation of a complex is then detected, wherein a difference
in complex formation between the test sample and the negative
control sample is indicative of the presence of human PD-L1 antigen
in the sample. Various methods are used to quantify PD-L1
expression.
[0115] In a particular embodiment, the automated IHC method
comprises: (a) deparaffinizing and rehydrating mounted tissue
sections in an autostainer; (b) retrieving antigen using a
decloaking chamber and pH 6 buffer, heated to 110.degree. C. for 10
min; (c) setting up reagents on an autostainer; and (d) running the
autostainer to include steps of neutralizing endogenous peroxidase
in the tissue specimen; blocking non-specific protein-binding sites
on the slides; incubating the slides with primary antibody;
incubating with a post primary blocking agent; incubating with
NovoLink Polymer; adding a chromogen substrate and developing; and
counterstaining with hematoxylin.
[0116] For assessing PD-L1 expression in tumor tissue samples, a
pathologist examines the number of membrane PD-L1.sup.+ tumor cells
in each field under a microscope and mentally estimates the
percentage of cells that are positive, then averages them to come
to the final percentage. The different staining intensities are
defined as 0/negative, 1+/weak, 2+/moderate, and 3+/strong.
Typically, percentage values are first assigned to the 0 and 3+
buckets, and then the intermediate 1+ and 2+ intensities are
considered. For highly heterogeneous tissues, the specimen is
divided into zones, and each zone is scored separately and then
combined into a single set of percentage values. The percentages of
negative and positive cells for the different staining intensities
are determined from each area and a median value is given to each
zone. A final percentage value is given to the tissue for each
staining intensity category: negative, 1+, 2+, and 3+. The sum of
all staining intensities needs to be 100%. In one embodiment, the
threshold number of cells that needs to be PD-L1 positive is at
least about 100, at least about 125, at least about 150, at least
about 175, or at least about 200 cells. In certain embodiments, the
threshold number or cells that needs to be PD-L1 positive is at
least about 100 cells.
[0117] Staining is also assessed in tumor-infiltrating inflammatory
cells such as macrophages and lymphocytes. In most cases
macrophages serve as an internal positive control since staining is
observed in a large proportion of macrophages. While not required
to stain with 3+ intensity, an absence of staining of macrophages
should be taken into account to rule out any technical failure.
Macrophages and lymphocytes are assessed for plasma membrane
staining and only recorded for all samples as being positive or
negative for each cell category. Staining is also characterized
according to an outside/inside tumor immune cell designation.
"Inside" means the immune cell is within the tumor tissue and/or on
the boundaries of the tumor region without being physically
intercalated among the tumor cells. "Outside" means that there is
no physical association with the tumor, the immune cells being
found in the periphery associated with connective or any associated
adjacent tissue.
[0118] In certain embodiments of these scoring methods, the samples
are scored by two pathologists operating independently, and the
scores are subsequently consolidated. In certain other embodiments,
the identification of positive and negative cells is scored using
appropriate software.
[0119] A histoscore is used as a more quantitative measure of the
IHC data. The histoscore is calculated as follows:
Histoscore=[(% tumor.times.1(low intensity))+(%
tumor.times.2(medium intensity))+(% tumor.times.3(high
intensity)]
[0120] To determine the histoscore, the pathologist estimates the
percentage of stained cells in each intensity category within a
specimen. Because expression of most biomarkers is heterogeneous
the histoscore is a truer representation of the overall expression.
The final histoscore range is 0 (no expression) to 300 (maximum
expression).
[0121] An alternative means of quantifying PD-L1 expression in a
test tissue sample IHC is to determine the adjusted inflammation
score (AIS) score defined as the density of inflammation multiplied
by the percent PD-L1 expression by tumor-infiltrating inflammatory
cells (Taube et al., "Colocalization of inflammatory response with
B7-hl expression in human melanocytic lesions supports an adaptive
resistance mechanism of immune escape," Sci. Transl. Med.
4(127):127ra37 (2012)).
[0122] In one embodiment, the PD-L1 expression level of a tumor
(e.g., a tumor derived from HL) is at least about 1%, at least
about 2%, at least about 3%, at least about 4%, at least about 5%,
at least about 6%, at least about 7%, at least about 8%, at least
about 9%, at least about 10%, at least about 11%, at least about
12%, at least about 13%, at least about 14%, at least about 15%, at
least about 20%, at least about 25%, at least about 30%, at least
about 40%, at least about 50%, at least about 60%, at least about
70%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or about 100%. In another
embodiment, the PD-L1 status of a tumor is at least about 1%. In
other embodiments, the PD-L1 status of the subject is at least
about 5%. In a certain embodiment, the PD-L1 status of a tumor is
at least about 10%. In one embodiment, the PD-L1 status of the
tumor is at least about 25%. In a particular embodiment, the PD-L1
status of the tumor is at least about 50%.
[0123] The present methods can treat any type of Hodgkin lymphoma
(also referred to as Classical Hodgkin lymphoma). In certain
embodiments, the Hodgkin lymphoma is cHL or nodular lymphocyte
predominant type Hodgkin lymphoma. In certain embodiments, the
Hodgkin lymphoma is a Hodgkin lymphoma selected from the group
consisting of nodular sclerosing, mixed cellularity, lymphocyte
rich, lymphocyte depleted, or lymphocyte-predominant. In certain
embodiments, the subject has had an illness or been infected by the
Epstein Barr virus (EBV).
[0124] The present methods can treat a Hodgkin lymphoma of any
stage. There are at least four stages used for Hodgkin lymphoma:
Stage I, Stage II, Stage III, and Stage IV. In Stage I, the cancer
is limited to one lymph node region or a single organ. In Stage II,
the cancer is in two lymph node regions or the cancer has invaded
one organ and the nearby lymph nodes, but the cancer is still
limited to a section of the body either above or below the
diaphragm. In Stage III, the cancer has moved to lymph nodes both
above and below the diaphragm, and the cancer may also be in one
portion of tissue or an organ near the lymph nodes groups or in the
spleen. In Stage IV, cancer cells are in several portions of one or
more tissues. Stage IV Hodgkin lymphoma affects not only the lymph
nodes but also other parts of the body, such as the liver, lungs or
bones. Hodgkin lymphoma is also divided into the categories "A" and
"B." A means that a subject doesn't have any significant symptoms
as a result of the cancer. B indicates that a subject may have
significant signs and symptoms, such as a persistent fever,
unintended weight loss or severe night sweats.
Anti-PD-1 Antibodies and Anti-PD-L1 Antibodies
[0125] Anti-PD-1 antibodies suitable for use in the disclosed
methods are antibodies that bind to PD-1 with high specificity and
affinity, block the binding of PD-L1, and inhibit the
immunosuppressive effect of the PD-1 signaling pathway. In any of
the therapeutic methods disclosed herein, an anti-PD-1 or
anti-PD-L1 "antibody" includes an antigen-binding portion that
binds to the PD-1 or PD-L1 receptor, respectively, and exhibits the
functional properties similar to those of whole antibodies in
inhibiting ligand binding and upregulating the immune system. In
certain embodiments, the anti-PD-1 antibody or antigen-binding
portion thereof cross-competes with nivolumab for binding to human
PD-1. In other embodiments, the anti-PD-L1 antibody or
antigen-binding fragment thereof competes for binding with
BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C for binding to
human PD-L1.
[0126] In other embodiments, the anti-PD-1 antibody or anti-PD-L1
antibody, or antigen-binding portions thereof is a chimeric,
humanized, or human monoclonal antibody or a portion thereof. In
certain embodiments for treating a human subject, the antibody is a
humanized antibody. In other embodiments for treating a human
subject, the antibody is a human antibody of an IgG1, IgG2, IgG3,
or IgG4 isotype can be used.
[0127] In certain embodiments, the anti-PD-1 antibody, or
anti-PD-L1 antibody, or antigen-binding portions thereof comprises
a heavy chain constant region which is of a human IgG1 or IgG4
isotype. In certain other embodiments, the sequence of the IgG4
heavy chain constant region of the anti-PD-1 antibody or anti-PD-L1
antibody, or antigen-binding portions thereof, contains an S228P
mutation which replaces a serine residue in the hinge region with
the proline residue normally found at the corresponding position in
IgG1 isotype antibodies. This mutation, which is present in
nivolumab, prevents Fab arm exchange with endogenous IgG4
antibodies, while retaining the low affinity for activating Fc
receptors associated with wild-type IgG4 antibodies (Wang et al.,
In vitro characterization of the anti-PD-1 antibody nivolumab,
BMS-936558, and in vivo toxicology in non-human primates, Cancer
Imm Res, 2(9):846-56 (2014)). In yet other embodiments, the
antibody comprises a light chain constant region which is a human
kappa or lambda constant region. In other embodiments, the
anti-PD-1 antibody, or anti-PD-L1 antibody, or antigen-binding
portions thereof is a monoclonal antibody or an antigen-binding
portion thereof.
[0128] Human monoclonal antibodies that bind specifically to PD-1
with high affinity have been disclosed in U.S. Pat. No. 8,008,449.
Other anti-PD-1 monoclonal antibodies have been described in, for
example, U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757, and
8,354,509, and PCT Publication No. WO 2012/145493. Each of the
anti-PD-1 human monoclonal antibodies disclosed in U.S. Pat. No.
8,008,449 has been demonstrated to exhibit one or more of the
following characteristics: (a) binds to human PD-1 with a K.sub.D
of 1.times.10.sup.-7 M or less, as determined by surface plasmon
resonance using a Biacore biosensor system; (b) does not
substantially bind to human CD28, CTLA-4 and/or ICOS; (c) increases
T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay;
(d) increases interferon-.gamma. production in an MLR assay; (e)
increases IL-2 secretion in an MLR assay; (f) binds to human PD-1
and cynomolgus monkey PD-1; (g) inhibits the binding of PD-L1
and/or PD-L2 to PD-1; (h) stimulates antigen-specific memory
responses; (i) stimulates antibody responses; and (j) inhibits
tumor cell growth in vivo. Anti-PD-1 antibodies usable in the
present disclosure include monoclonal antibodies that bind
specifically to human PD-1 and exhibit at least one, in some
embodiments, at least five, of the preceding characteristics. In
some embodiments, the anti-PD-1 antibody is nivolumab. In one
embodiment, the anti-PD-1 antibody is pembrolizumab.
[0129] In one embodiment, the anti-PD-1 antibody is nivolumab.
Nivolumab (also known as "OPDIVO.RTM."; formerly designated 5C4,
BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P)
PD-1 immune checkpoint inhibitor antibody that selectively prevents
interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking
the down-regulation of antitumor T-cell functions (U.S. Pat. No.
8,008,449; Wang et al., In vitro characterization of the anti-PD-1
antibody nivolumab, BMS-936558, and in vivo toxicology in non-human
primates, Cancer Imm Res, 2(9):846-56 (2014)). In another
embodiment, the anti-PD-1 antibody or fragment thereof
cross-competes with nivolumab. In other embodiments, the anti-PD-1
antibody or fragment thereof binds to the same epitope as
nivolumab. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as nivolumab.
[0130] In another embodiment, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with pembrolizumab.
In some embodiments, the anti-PD-1 antibody binds to the same
epitope as pembrolizumab. In certain embodiments, the anti-PD-1
antibody has the same CDRs as pembrolizumab. In another embodiment,
the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also known
as "KEYTRUDA.RTM.", lambrolizumab, and MK-3475) is a humanized
monoclonal IgG4 antibody directed against human cell surface
receptor PD-1 (programmed death-1 or programmed cell death-1).
Pembrolizumab is described, for example, in U.S. Pat. Nos.
8,354,509 and 8,900,587; see also
http://www.cancer.gov/drugdictionary?cdrid=695789 (last accessed:
Dec. 14, 2014). Pembrolizumab has been approved by the FDA for the
treatment of relapsed or refractory melanoma.
[0131] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with MEDI0680. In
still other embodiments, the anti-PD-1 antibody binds to the same
epitope as MEDI0680. In certain embodiments, the anti-PD-1 antibody
has the same CDRs as MEDI0680. In other embodiments, the anti-PD-1
antibody is MEDI0680 (formerly AMP-514), which is a monoclonal
antibody MEDI0680 is described, for example, in U.S. Pat. No.
8,609,089B2 or in http://www.cancer.gov/drugdictionary?cdrid=756047
(last accessed Dec. 14, 2014).
[0132] In certain embodiments, the first antibody is an anti-PD-1
antagonist. One example of the anti-PD-1 antagonist is AMP-224,
which is a B7-DC Fc fusion protein. AMP-224 is discussed in U.S.
Publ. No. 2013/0017199 or in
http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=700595
(last accessed Jul. 8, 2015).
[0133] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with BGB-A317. In
some embodiments, the anti-PD-1 antibody binds the same epitope as
BGB-A317. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as BGB-A317. In certain embodiments, the anti-PD-1
antibody is BGB-A317, which is a humanized monoclonal antibody.
BGB-A317 is described in U.S. Publ. No. 2015/0079109.
[0134] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with INCSHR1210
(SHR-1210). In some embodiments, the anti-PD-1 antibody binds to
the same epitope as INCSHR1210 (SHR-1210). In certain embodiments,
the anti-PD-1 antibody has the same CDRs as INCSHR1210 (SHR-1210).
In certain embodiments, the anti-PD-1 antibody is INCSHR1210
(SHR-1210), which is a human monoclonal antibody. INCSHR1210
(SHR-1210) is described in WO2015/085847.
[0135] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with REGN-2810. In
some embodiments, the anti-PD-1 antibody binds to the same epitope
as REGN-2810. In certain embodiments, the anti-PD-1 antibody has
the same CDRs as REGN-2810. In certain embodiments, the anti-PD-1
antibody is REGN-2810, which is a human monoclonal antibody.
REGN-2810 is described in WO2015/112800.
[0136] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with PDR001. In
some embodiments, the anti-PD-1 antibody binds to the same epitope
as PDR001. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as PDR001. In certain embodiments, the anti-PD-1 antibody
is PDR001, which is a humanized monoclonal antibody. PDR001 is
described in WO2015/112900.
[0137] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with TSR-042
(ANB011). In some embodiments, the anti-PD-1 antibody binds to the
same epitope as TSR-042 (ANB011). In certain embodiments, the
anti-PD-1 antibody has the same CDRs as TSR-042 (ANB011). In
certain embodiments, the anti-PD-1 antibody is TSR-042 (ANB011),
which is a humanized monoclonal antibody. TSR-042 (ANB011) is
described in WO2014/179664.
[0138] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with STI-1110. In
some embodiments, the anti-PD-1 antibody binds to the same epitope
as STI-1110. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as STI-1110. In certain embodiments, the anti-PD-1
antibody is STI-1110, which is a human monoclonal antibody.
STI-1110 is described in WO2014/194302.
[0139] Anti-PD-1 antibodies usable in the disclosed methods also
include isolated antibodies that bind specifically to human PD-1
and cross-compete for binding to human PD-1 with nivolumab (see,
e.g., U.S. Pat. Nos. 8,008,449 and 8,779,105; WO 2013/173223). The
ability of antibodies to cross-compete for binding to an antigen
indicates that these antibodies bind to the same epitope region of
the antigen and sterically hinder the binding of other
cross-competing antibodies to that particular epitope region. These
cross-competing antibodies are expected to have functional
properties very similar to those of nivolumab by virtue of their
binding to the same epitope region of PD-1. Cross-competing
antibodies can be readily identified based on their ability to
cross-compete with nivolumab in standard PD-1 binding assays such
as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO
2013/173223).
[0140] In certain embodiments, the antibodies that cross-compete
for binding to human PD-1 with, or bind to the same epitope region
of human PD-1 as, nivolumab are monoclonal antibodies. For
administration to human subjects, these cross-competing antibodies
are chimeric antibodies, or humanized or human antibodies. Such
chimeric, humanized, or human monoclonal antibodies can be prepared
and isolated by methods well known in the art.
[0141] Anti-PD-1 antibodies usable in the methods of the disclosed
disclosure also include antigen-binding portions of the above
antibodies. It has been amply demonstrated that the antigen-binding
function of an antibody can be performed by fragments of a
full-length antibody. Examples of binding fragments encompassed
within the term "antigen-binding portion" of an antibody include
(i) a Fab fragment, a monovalent fragment consisting of the
V.sub.L, V.sub.H, C.sub.L and C.sub.H1 domains; (ii) a F(ab')2
fragment, a bivalent fragment comprising two Fab fragments linked
by a disulfide bridge at the hinge region; (iii) a Fd fragment
consisting of the V.sub.H and C.sub.H1 domains; (iv) a Fv fragment
consisting of the V.sub.L and V.sub.H domains of a single arm of an
antibody; or any combination thereof.
[0142] Anti-PD-1 antibodies suitable for use in the disclosed
compositions are antibodies that bind to PD-1 with high specificity
and affinity, block the binding of PD-L1 and or PD-L2, and inhibit
the immunosuppressive effect of the PD-1 signaling pathway. In any
of the compositions or methods disclosed herein, an anti-PD-1
"antibody" includes an antigen-binding portion or fragment that
binds to the PD-1 receptor and exhibits the functional properties
similar to those of whole antibodies in inhibiting ligand binding
and upregulating the immune system. In certain embodiments, the
anti-PD-1 antibody or antigen-binding portion thereof
cross-competes with nivolumab for binding to human PD-1. In other
embodiments, the anti-PD-1 antibody or antigen-binding portion
thereof is a chimeric, humanized or human monoclonal antibody or a
portion thereof. In certain embodiments, the antibody is a
humanized antibody. In other embodiments, the antibody is a human
antibody. Antibodies of an IgG1, IgG2, IgG3, or IgG4 isotype can be
used.
[0143] In certain embodiments of any of the therapeutic methods
described herein comprising administration of an anti-PD-1
antibody, the anti-PD-1 antibody is nivolumab. In other
embodiments, the anti-PD-1 antibody is pembrolizumab. In other
embodiments, the anti-PD-1 antibody is chosen from the human
antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in U.S. Pat.
No. 8,008,449. In still other embodiments, the anti-PD-1 antibody
is MEDI0608 (formerly AMP-514), or AMP-224.
[0144] In certain embodiments, an anti-PD-1 antibody used in the
methods can be replaced with another PD-1 or anti-PD-L1 antagonist.
For example, because an anti-PD-L1 antibody prevents interaction
between PD-1 and PD-L1, thereby exerting similar effects to the
signaling pathway of PD-1, an anti-PD-L1 antibody can replace the
use of an anti-PD-1 antibody in the methods disclosed herein.
Therefore, in one embodiment, the present disclosure is directed to
a method for treating a subject afflicted with a Hodgkin lymphoma
comprising administering to the subject a therapeutically effective
amount an anti-PD-L1 antibody. In certain embodiments, the
anti-PD-L1 antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see,
e.g., U.S. Pat. No. 7,943,743; WO 2013/173223). In other
embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as
RG7446 or atezolizumab) (see, e.g., Herbst et al. (2013) J Clin
Oncol 31(suppl):3000. Abstract; U.S. Pat. No. 8,217,149), MEDI4736
(also called Durvalumab; Khleif (2013) In: Proceedings from the
European Cancer Congress 2013; Sep. 27-Oct. 1, 2013; Amsterdam, The
Netherlands. In other embodiments, the anti-PD-L1 antibody is
CX-072 (also called CytomX; See WO2016/149201). In certain
embodiments, the antibodies that cross-compete for binding to human
PD-L1 with, or bind to the same epitope region of human PD-L1 as
the above-references PD-L1 antibodies are monoclonal antibodies.
For administration to human subjects, these cross-competing
antibodies can be chimeric antibodies, or can be humanized or human
antibodies. Such chimeric, humanized or human monoclonal antibodies
can be prepared and isolated by methods well known in the art.
Abstract 802, See U.S. Pat. No. 8,779,108 or US 2014/0356353, filed
May 6, 2014), or MSB0010718C (also called Avelumab; See US
2014/0341917).
[0145] Because anti-PD-1 and anti-PD-L1 target the same signaling
pathway and have been shown in clinical trials to exhibit similar
levels of efficacy in a variety of cancers, (see Brahmer et al.,
(2012) N Engl J Med 366:2455-65; Topalian et al., (2012a) N Engl J
Med 366:2443-54; WO 2013/173223), an anti-PD-L1 antibody can be
substituted for the anti-PD-1 antibody in any of the therapeutic
methods disclosed herein. In certain embodiments, the anti-PD-L1
antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see, e.g., U.S.
Pat. No. 7,943,743; WO 2013/173223). In other embodiments, the
anti-PD-L1 antibody is MPDL3280A (also known as RG7446 or
atezolizumab) (see, e.g., Herbst et al., (2013) J Clin Oncol
31(suppl):3000. Abstract; U.S. Pat. No. 8,217,149) or MEDI4736
(Khleif (2013) In: Proceedings from the European Cancer Congress
2013; Sep. 27-Oct. 1, 2013; Amsterdam, The Netherlands. Abstract
802). In certain embodiments, the antibodies that cross-compete for
binding to human PD-L1 with, or bind to the same epitope region of
human PD-L1 as the above-references PD-L1 antibodies are monoclonal
antibodies. For administration to human subjects, these
cross-competing antibodies can be chimeric antibodies, or can be
humanized or human antibodies. Such chimeric, humanized, or human
monoclonal antibodies can be prepared and isolated by methods well
known in the art.
Combination Therapies with Anti-PD-1 or Anti-PD-L1 Antibodies
[0146] In certain embodiments, an anti-PD-1 antibody or anti-PD-L1
antibody is administered in combination with one or more other
anti-cancer agents. In some embodiments, the anti-PD-1 antibody or
anti-PD-L1 antibody is initially administered as a monotherapy for
one or more doses, and is then administered in combination with an
additional anti-cancer agent. In some embodiments, the other
anti-cancer agent is any anti-cancer agent described herein or
known in the art. In certain embodiments, the other anti-cancer
agent is an anti-CTLA-4 antibody. In embodiments, the additional
anti-cancer agent is a combination of doxorubicin, vinblastine, and
dacarbazine. In one embodiment, the other anti-cancer agent is a
chemotherapy or a platinum-based doublet chemotherapy (PT-DC). In
other embodiments, the anti-cancer agent is a platinum agent (e.g.,
cisplatin, carboplatin), a mitotic inhibitor (e.g., paclitaxel,
albumin-bound paclitaxel, docetaxel, taxotere, docecad), a
fluorinated Vinca alkaloid (e.g., vinflunine, javlor), vinorelbine,
vinblastine, etoposide, or pemetrexed gemcitabin.
[0147] In an embodiment, the other anti-cancer agent is Adcetris
(Brentuximab Vedotin), Ambochlorin (Chlorambucil), Amboclorin
(Chlorambucil), Becenum (Carmustine), BiCNU (Carmustine), Blenoxane
(Bleomycin), Bleomycin, Brentuximab Vedotin, Carmubris
(Carmustine), Carmustine, Chlorambucil, Clafen (Cyclophosphamide),
Cyclophosphamide, Cytoxan (Cyclophosphamide), Dacarbazine,
Doxorubicin Hydrochloride, DTIC-Dome (Dacarbazine), Leukeran
(Chlorambucil), Linfolizin (Chlorambucil), Lomustine, Matulane
(Procarbazine Hydrochloride), Mechlorethamine Hydrochloride,
Mustargen (Mechlorethamine Hydrochloride), Neosar
(Cyclophosphamide), Prednisone, Procarbazine Hydrochloride, Velban
(Vinblastine Sulfate), Velsar (Vinblastine Sulfate), Vinblastine
Sulfate, Vincasar PFS (Vincristine Sulfate), and/or Vincristine
Sulfate. In other embodiments, the other anti-cancer agent is any
combination of drugs from ABVD, ABVE, ABVE-PC, BEACOPP, COPDAC,
COPP, COPP-ABV, ICE, MOPP, OEPA, OPPA, STANFORD V, and/or VAMP.
(See
http://www.cancer.gov/about-cancer/treatment/drugs/hodgkin-lymphoma,
last visited May 27, 2016).
[0148] In a particular embodiment, the anti-cancer agents to be
administered in combination with an anti-PD-1 antibody or an
anti-PD-L1 antibody are doxorubicin, vinblastine, and dacarbazine.
In other embodiments, the anti-cancer agents to be administered in
combination with an anti-PD-1 antibody or an anti-PD-L1 antibody
are doxorubicin, vinblastine, and dacarbazine, but not including
bleomycin.
[0149] In certain embodiments, the other anti-cancer agent is any
other anti-cancer agent known in the art. In some embodiments, two
or more additional anti-cancer agents are administered in
combination with the anti-PD-1 or anti-PD-L1 antibody. In some
embodiments, the PD-1 or PD-L1 antibody is combined with surgical
resection, radiation therapy, and/or a step cell transplant.
[0150] In certain embodiments, the anti-PD-1 antibody or anti-PD-L1
antibody can be combined with another immunotherapy. In certain
embodiments, immunotherapy involving blockade of immune checkpoints
is administered as a monotherapy. In other embodiments,
immunotherapy involving blockade of immune checkpoints is
administered in combination with other therapies. In some
embodiments, Hodgkin lymphoma patients can benefit from the
combination of different immunotherapeutic drugs.
Anti-CTLA-4 Antibodies
[0151] In certain embodiments, an anti-PD-1 antibody or anti-PD-L1
antibody is combined with an anti-CTLA-4 antibody. Anti-CTLA-4
antibodies useful for the instant combination can bind to human
CTLA-4 so as to disrupt the interaction of CTLA-4 with a human B7
receptor. Because the interaction of CTLA-4 with B7 transduces a
signal leading to inactivation of T-cells bearing the CTLA-4
receptor, disruption of the interaction effectively induces,
enhances or prolongs the activation of such T cells, thereby
inducing, enhancing or prolonging an immune response.
[0152] Human monoclonal antibodies that bind specifically to CTLA-4
with high affinity have been disclosed in U.S. Pat. Nos. 6,984,720
and 7,605,238. Other anti-CTLA-4 monoclonal antibodies have been
described in, for example, U.S. Pat. Nos. 5,977,318, 6,051,227,
6,682,736, and 7,034,121. The anti-CTLA-4 human monoclonal
antibodies disclosed in U.S. Pat. Nos. 6,984,720 and 7,605,238 have
been demonstrated to exhibit one or more of the following
characteristics: (a) binds specifically to human CTLA-4 with a
binding affinity reflected by an equilibrium association constant
(K.sub.a) of at least about 10.sup.7 M.sup.-1, or about 10.sup.9
M.sup.-1, or about 10.sup.10 M.sup.-1 to 10.sup.11 M.sup.-1 or
higher, as determined by Biacore analysis; (b) a kinetic
association constant (k.sub.a) of at least about 10.sup.3, about
10.sup.4, or about 10.sup.5 m.sup.-1 s.sup.-1; (c) a kinetic
disassociation constant (k.sub.d) of at least about 10.sup.3, about
10.sup.4, or about 10.sup.5 m.sup.-1 s.sup.-1; and (d) inhibits the
binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4
antibodies usable in the present disclosure include monoclonal
antibodies that bind specifically to human CTLA-4 and exhibit at
least one, at least two or, in one embodiment, at least three of
the preceding characteristics. An exemplary clinical anti-CTLA-4
antibody is the human monoclonal antibody 10D1 (now known as
ipilimumab and marketed as YERVOY.RTM.) as disclosed in U.S. Pat.
No. 6,984,720. Ipilimumab is an anti-CTLA-4 antibody for use in the
methods disclosed herein. Another anti-CTLA-4 antibody usable in
the present methods is tremelimumab.
[0153] An exemplary clinical anti-CTLA-4 antibody useful for the
combination is the human monoclonal antibody 10D1 (now known as
ipilimumab and marketed as YERVOY.RTM.) as disclosed in U.S. Pat.
No. 6,984,720. Ipilimumab is an anti-CTLA-4 antibody for use in the
methods disclosed herein. Ipilimumab is a fully human, IgG1
monoclonal antibody that blocks the binding of CTLA-4 to its B7
ligands, thereby stimulating T cell activation and improving
overall survival (OS) in patients with advanced melanoma.
[0154] Another anti-CTLA-4 antibody useful for the present methods
is tremelimumab (also known as CP-675,206). Tremelimumab is human
IgG2 monoclonal anti-CTLA-4 antibody. Tremelimumab is described in
WO/2012/122444, U.S. Publ. No. 2012/263677, or WO Publ. No.
2007/113648 A2.
[0155] Anti-CTLA-4 antibodies usable in the disclosed methods also
include isolated antibodies that bind specifically to human PD-1
and cross-compete for binding to human CTLA-4 with ipilimumab or
tremelimumab or bind to the same epitope region of human CTLA-4 as
ipilimumab or tremelimumab. In certain embodiments, the antibodies
that cross-compete for binding to human CTLA-4 with, or bind to the
same epitope region of human PD-1 as does ipilimumab or
tremelimumab, are antibodies comprising a heavy chain of the human
IgG1 isotype. For administration to human subjects, these
cross-competing antibodies are chimeric antibodies, or humanized or
human antibodies. Usable anti-CTLA-4 antibodies also include
antigen-binding portions of the above antibodies such as Fab,
F(ab')2, Fd, or Fv fragments.
[0156] Ipilimumab (YERVOY.RTM.) is a fully human, IgG1 monoclonal
antibody that blocks the binding of CTLA-4 to its B7 ligands,
thereby stimulating T cell activation and improving overall
survival (OS) in patients with advanced melanoma (Hodi et al.,
(2010) N Engl J Med 363:711-23). Concurrent therapy with nivolumab
and ipilimumab in a Phase 1 clinical trial produced rapid and deep
tumor regression in a substantial proportion of patients with
advanced melanoma, and was significantly more effective than either
antibody alone (Wolchok et al., (2013) N Engl J Med 369(2):122-33;
WO 2013/173223).
Chemotherapy
[0157] In some embodiments, the anti-PD-1 antibody is administered
in combination with any chemotherapy known in the art. In
embodiments, the anti-PD-1 antibody is administered in combination
with doxorubicin, vinblastine, and dacarbazine. In embodiments, the
combination of doxorubicin, vinblastine, and dacarbazine is
administered once about every one, two, three or four weeks. In
embodiments, doxorubicin is administered at a dose of about 10
mg/m.sup.2-about 40 mg/m.sup.2, about 10 mg/m.sup.2-about 30
mg/m.sup.2, or about 20 mg/m.sup.2-about 30 mg/m.sup.2. In other
embodiments, vinblastine is administered at a dose of about 0.1
mg/m.sup.2 to about 10 mg/m.sup.2, about 1 mg/m.sup.2 to about 10
mg/m.sup.2, or about 5 mg/m.sup.2 to about 10 mg/m.sup.2. In some
embodiments, dacarbazine is administered at a dose of about 200
mg/m.sup.2-about 500 mg/m.sup.2, about 250 mg/m.sup.2 to about 500
mg/m.sup.2, or about 300 mg/m.sup.2-about 400 mg/m.sup.2. In some
embodiments, doxorubicin is administered at a dose of about 10
mg/m.sup.2, about 15 mg/m.sup.2, about 20 mg/m.sup.2, about 25
mg/m.sup.2, about 30 mg/m.sup.2, about 35 mg/m.sup.2, about 40
mg/m.sup.2, about 45 mg/m.sup.2, or about 50 mg/m.sup.2. In certain
embodiments, vinblastine is administered at a dose of about 0.1
mg/m.sup.2, about 1 mg/m.sup.2, about 2 mg/m.sup.2, about 3
mg/m.sup.2, about 4 mg/m.sup.2, about 5 mg/m.sup.2, about 6
mg/m.sup.2, about 7 mg/m.sup.2, about 8 mg/m.sup.2, about 9
mg/m.sup.2, about 10 mg/m.sup.2, about 11 mg/m.sup.2, about 12
mg/m.sup.2, about 13 mg/m.sup.2, about 14 mg/m.sup.2, about 15
mg/m.sup.2, or about 20 mg/m.sup.2. In some embodiments,
dacarbazine is administered at a dose of about 200 mg/m.sup.2,
about 225 mg/m.sup.2, about 250 mg/m.sup.2, about 275 mg/m.sup.2,
about 300 mg/m.sup.2, about 325 mg/m.sup.2, about 350 mg/m.sup.2,
about 375 mg/m.sup.2, about 400 mg/m.sup.2, about 425 mg/m.sup.2,
about 450 mg/m.sup.2, about 475 mg/m.sup.2, or about 500
mg/m.sup.2. In further embodiments, doxorubicin is administered at
a dose of 25 mg/m.sup.2, vinblastine is administered at a dose of 6
mg/m.sup.2, and dacarbazine is administered at a dose of 375
mg/m.sup.2 once about every 2 weeks. In still further embodiments,
the subject is not administered bleomycin.
[0158] In certain embodiments, the chemotherapy is a platinum
based-chemotherapy. Platinum-based chemotherapies are coordination
complexes of platinum. In some embodiments, the platinum-based
chemotherapy is a platinum-doublet chemotherapy. In one embodiment,
the chemotherapy is administered at the approved dose for the
particular indication. In other embodiments, the chemotherapy is
administered at any dose disclosed herein. In some embodiments, the
platinum-based chemotherapy is cisplatin, carboplatin, oxaliplatin,
satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or
combinations thereof. In certain embodiments, the platinum-based
chemotherapy is any other platinum-based chemotherapy known in the
art. In some embodiments, the chemotherapy is the nucleotide analog
gemcitabine. In an embodiment, the chemotherapy is a folate
antimetabolite. In an embodiment, the folate antimetabolite is
pemetrexed. In certain embodiments the chemotherapy is a taxane. In
other embodiments, the taxane is paclitaxel. In other embodiments,
the chemotherapy is a nucleoside analog. In one embodiment, the
nucleoside analog is gemcitabine. In some embodiments, the
chemotherapy is any other chemotherapy known in the art. In certain
embodiments, at least one, at least two or more chemotherapeutic
agents are administered in combination with the anti-PD-1 antibody.
In some embodiments, the anti-PD-1 antibody is administered in
combination with gemcitabine and cisplatin. In some embodiments,
the anti-PD-1 antibody is administered in combination with
pemetrexed and cisplatin. In certain embodiments, the anti-PD-1
antibody is administered in combination with gemcitabine and
pemetrexed. In one embodiment, the anti-PD-1 antibody is
administered in combination with paclitaxel and carboplatin. In an
embodiment, an anti-CTLA-4 antibody is additionally
administered.
Pharmaceutical Compositions and Dosages
[0159] Therapeutic agents of the present disclosure can be
constituted in a composition, e.g., a pharmaceutical composition
containing an antibody and a pharmaceutically acceptable carrier.
As used herein, a "pharmaceutically acceptable carrier" includes
any and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the
like that are physiologically compatible. In one embodiment, the
carrier for a composition containing an antibody is suitable for
intravenous, intramuscular, subcutaneous, parenteral, spinal or
epidermal administration (e.g., by injection or infusion), whereas
the carrier for some compositions is suitable for non-parenteral,
e.g., oral, administration. A pharmaceutical composition of the
disclosure can include one or more pharmaceutically acceptable
salts, anti-oxidant, aqueous and non-aqueous carriers, and/or
adjuvants such as preservatives, wetting agents, emulsifying agents
and dispersing agents.
[0160] Dosage regimens are adjusted to provide the optimum desired
response, e.g., a maximal therapeutic response and/or minimal
adverse effects. In some embodiments, the anti-PD-1 antibody or
antigen binding portion thereof is administered at a weight-based
dose. For administration of an anti-PD-1 antibody at a weight-based
dose, as a monotherapy or in combination with another anti-cancer
agent, the dosage can range from about 0.01 mg/kg to about 20
mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about
5 mg/kg, about 1 mg/kg to about 5 mg/kg, about 2 mg/kg to about 5
mg/kg, about 7.5 mg/kg to about 12.5 mg/kg, or about 0.1 mg/kg to
about 30 mg/kg of the subject's body weight. For example, dosages
can be about 0.1 mg/kg, about 0.3 mg/kg, about 1 mg/kg, about 2
mg/kg, about 3 mg/kg, about 5 mg/kg, or about 10 mg/kg body weight,
or about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, or
about 5 mg/kg body weight. The dosing schedule is typically
designed to achieve exposures that result in sustained receptor
occupancy (RO) based on typical pharmacokinetic properties of an
antibody. An exemplary treatment regime entails administration
about once per week, once about every 2 weeks, once about every 3
weeks, once about every 4 weeks, once about a month, once about
every 3-6 months or longer. In certain embodiments, an anti-PD-1
antibody such as nivolumab is administered to the subject once
about every 2 weeks. In other embodiments, the antibody is
administered once about every 3 weeks. The dosage and scheduling
can change during a course of treatment. For example, a dosing
schedule for anti-PD-1 monotherapy can comprise administering the
antibody: (i) about every 2 weeks in about 6-week cycles; (ii)
about every 4 weeks for about six dosages, then about every three
months; (iii) about every 3 weeks; (iv) about 3 mg/kg to about 10
mg/kg once followed by about 1 mg/kg every about 2-3 weeks.
Considering that an IgG4 antibody typically has a half-life of 2-3
weeks, a dosage regimen for an anti-PD-1 antibody of the disclosure
comprises at least about 0.3 mg/kg to at least about 10 mg/kg body
weight, at least about 1 mg/kg to at least about 5 mg/kg body
weight, or at least about 1 mg/kg to at least about 3 mg/kg body
weight via intravenous administration, with the antibody being
given every about 14-21 days in up to about 6-week or about 12-week
cycles until complete response or confirmed progressive disease. In
certain embodiments, an anti-PD-1 monotherapy is administered at 3
mg/kg every 2 weeks until progressive disease or unacceptable
toxicity. In some embodiments, the antibody treatment, or any
combination treatment disclosed herein, is continued for at least
about 1 month, at least about 3 months, at least about 6 months, at
least about 9 months, at least about 1 year, at least about 18
months, at least about 24 months, at least about 3 years, at least
about 5 years, or at least about 10 years.
[0161] When used in combinations with other cancer agents, the
dosage of an anti-PD-1 antibody can be lowered compared to the
monotherapy dose. Dosages of nivolumab that are lower than the
typical 3 mg/kg, but not less than 0.001 mg/kg, are subtherapeutic
dosages. The subtherapeutic doses of an anti-PD-1 antibody used in
the methods herein are higher than 0.001 mg/kg and lower than 3
mg/kg. In some embodiments, a subtherapeutic dose is about 0.001
mg/kg to about 1 mg/kg, about 0.01 mg/kg to about 1 mg/kg, about
0.1 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg
body weight. In some embodiments, the subtherapeutic dose is at
least about 0.001 mg/kg, at least about 0.005 mg/kg, at least about
0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.1 mg/kg, at
least about 0.5 mg/kg, or at least about 1.0 mg/kg body weight.
Receptor-occupancy data from 15 subjects who received 0.3 mg/kg to
10 mg/kg dosing with nivolumab indicate that PD-1 occupancy appears
to be dose-independent in this dose range. Across all doses, the
mean occupancy rate was 85% (range, 70% to 97%), with a mean
plateau occupancy of 72% (range, 59% to 81%). In some embodiments,
0.3 mg/kg dosing can allow for sufficient exposure to lead to
maximal biologic activity. Receptor-occupancy data from 15 subjects
who received 0.3 mg/kg to 10 mg/kg dosing with nivolumab indicate
that PD-1 occupancy appears to be dose-independent in this dose
range. Across all doses, the mean occupancy rate was 85% (range,
70% to 97%), with a mean plateau occupancy of 72% (range, 59% to
81%) (Brahmer et al., (2010)J Clin Oncol 28:3167-75). Thus, 0.3
mg/kg dosing can allow for sufficient exposure to lead to maximal
biologic activity.
[0162] Although higher nivolumab monotherapy dosing up to about 10
mg/kg every two weeks has been achieved without reaching the
maximum tolerated dose (MTD), the significant toxicities reported
in other trials of checkpoint inhibitors plus anti-angiogenic
therapy (see, e.g., Johnson et al. (2013) Cancer Immunol Res
1:373-77; Rini et al. (2011) Cancer 117:758-67) support the
selection of a nivolumab dose lower than 10 mg/kg.
[0163] In certain embodiments, the dose of an anti-PD-1 antibody
(or an anti-PD-L1 antibody) is a fixed dose in a pharmaceutical
composition. In other embodiments, the method of the present
disclosure can be used with a flat dose (a dose given to a patient
irrespective of the body weight of the patient). In embodiments,
the flat dose of the anti-PD-1 antibody or antigen binding portion
thereof is at least about 100 mg, 120 mg, 140 mg, 160 mg, 180 mg,
200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 400 mg, 420 mg, 440
mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, or 600 mg. For
example, a flat dose of a nivolumab can be about 240 mg. For
example, a flat dose of pembrolizumab can be about 200 mg. In
embodiments, the anti-PD-1 antibody or antigen-binding portion
thereof is administered at a dose of about 240 mg. In embodiments,
the anti-PD-1 antibody or antigen-binding portion thereof is
administered at a dose of about 360 mg. In embodiments, the
anti-PD-1 antibody or antigen-binding portion thereof is
administered at a dose of about 480 mg. In embodiments, the flat
dose of the anti-PD-1 antibody or antigen binding portion thereof
is administered once about every week, every two weeks, every three
weeks, every four weeks, every five weeks, or every six weeks. In
one embodiment, 360 mg of the anti-PD-1 antibody or antigen binding
fragment is administered once every 3 weeks. In another embodiment,
480 mg of the anti-PD-1 antibody or antigen binding fragment is
administered once every 4 weeks.
[0164] Ipilimumab (YERVOY.RTM.) is approved for the treatment of
melanoma at 3 mg/kg given intravenously once every 3 weeks for 4
doses. Thus, in some embodiments, about 3 mg/kg is the highest
dosage of ipilimumab used in combination with the anti-PD-1
antibody though, in certain embodiments, an anti-CTLA-4 antibody
such as ipilimumab can be dosed within the range of about 0.3 mg/kg
to about 10 mg/kg, about 0.5 mg/kg to about 10 mg/kg, about 0.5
mg/kg to about 5 mg/kg, or about 1 mg/kg to about 5 mg/kg body
weight about every two or three weeks when combined with nivolumab.
In other embodiments, ipilimumab is administered on a different
dosage schedule from nivolumab. In some embodiments, ipilimumab is
administered about every week, about every two weeks, about every
three weeks, about every 4 weeks, about every five weeks, about
every six weeks, about every seven weeks, about every eight weeks,
about every nine weeks, about every ten weeks, about every eleven
weeks, about every twelve weeks or about every fifteen weeks.
Dosages of ipilimumab that are lower than the typical 3 mg/kg every
3 weeks, but not less than 0.001 mg/kg, are subtherapeutic dosages.
The doses of an anti-CTLA-4 antibody used in the methods herein are
higher than 0.001 mg/kg and lower than 3 mg/kg. In some
embodiments, a dose of an anti-CTLA-4 antibody is about 0.001
mg/kg-about 1 mg/kg, about 0.01 mg/kg to about 1 mg/kg, about 0.1
mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg
body weight. In some embodiments, the dose of an anti-CTLA-4
antibody is at least about 0.001 mg/kg, at least about 0.005 mg/kg,
at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least
about 0.1 mg/kg, at least about 0.5 mg/kg, or at least about 1.0
mg/kg body weight. In some embodiments, although nivolumab is
tolerated up to 10 mg/kg given intravenously every 2 weeks, doses
of the anti-PD-1 antibody do not exceed about 3 mg/kg when combined
with ipilimumab. In certain embodiments, based on risk-benefit and
PK-PD assessments, the dosage useful for the disclosed methods
comprises a combination of nivolumab at about 1 mg/kg plus
ipilimumab at about 3 mg/kg, nivolumab at about 3 mg/kg plus
ipilimumab at about 1 mg/kg, or nivolumab at about 3 mg/kg plus
ipilimumab at about 3 mg/kg, each administered at a dosing
frequency of once about every 2-4 weeks, in certain embodiments,
once about every 2 weeks or once about every 3 weeks. In certain
other embodiments, nivolumab is administered at a dosage of about
0.1 mg/kg, about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3
mg/kg or about 5 mg/kg in combination with ipilimumab administered
at a dosage of about 0.1 mg/kg, about 0.3 mg/kg, about 1 mg/kg,
about 2 mg/kg, about 3 mg/kg or about 5 mg/kg, once about every 2
weeks, once about every 3 weeks, or once about every 4 weeks.
[0165] In certain embodiments, the combination of an anti-PD-1
antibody and an anti-CTLA-4 antibody is administered intravenously
to the subject in an induction phase about every 2 or 3 weeks for
1, 2, 3, or 4 administrations. In certain embodiments, the
combination of nivolumab and ipilimumab is administered
intravenously in the induction phase about every 2 weeks or about
every 3 weeks for about 4 administrations. The induction phase is
followed by a maintenance phase during which only the anti-PD-1
antibody is administered to the subject at a dosage of about 0.1
mg/kg, about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3
mg/kg, about 5 mg/kg, or about 10 mg/kg about every two or three
weeks for as long as the treatment proves efficacious or until
unmanageable toxicity or disease progression occurs. In certain
embodiments, nivolumab is administered during the maintenance phase
at a dose of about 3 mg/kg body about every 2 weeks.
[0166] In certain embodiments, the anti-PD-1 antibody and the
anti-CTLA-4 antibody is formulated as a single composition, wherein
the dose of the anti-PD-1 antibody and the dose of the anti-CTLA-4
antibody are combined in a fixed-dose at a ratio of 1:50, 1:40,
1:30, 1:20, 1:10. 1:5, 1:3, 1:1, 3:1, 5:1, 10:1, 20:1, 30:1, 40:1,
or 50:1. In certain embodiments, the dose of the anti-CTLA-4
antibody is a flat dose, which is given to a patient irrespective
of the body weight. In some embodiments, the flat dose of the
anti-CTLA-4 antibody is at least about 40 mg, 50 mg, 60 mg, 70 mg,
80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg. In
a specific embodiment, the flat dose of the anti-CTLA-4 antibody is
about 80 mg.
[0167] For combination of nivolumab with other anti-cancer agents,
these agents are administered at their approved dosages. Treatment
is continued as long as clinical benefit is observed or until
unacceptable toxicity or disease progression occurs. Nevertheless,
in certain embodiments, the dosages of these anti-cancer agents
administered are significantly lower than the approved dosage,
i.e., a subtherapeutic dosage, of the agent is administered in
combination with the anti-PD-1 antibody. The anti-PD-1 antibody can
be administered at the dosage that has been shown to produce the
highest efficacy as monotherapy in clinical trials, e.g., about 3
mg/kg of nivolumab administered once about every three weeks
(Topalian et al., (2012a) N Engl J Med 366:2443-54; Topalian et
al., (2012b) Curr Opin Immunol 24:207-12), or at a significantly
lower dose, i.e., at a subtherapeutic dose. In certain embodiments,
the anti-PD-1 antibody is administered at about 3 mg/kg once about
every two weeks.
[0168] Dosage and frequency vary depending on the half-life of the
antibody in the subject. In general, human antibodies show the
longest half-life, followed by humanized antibodies, chimeric
antibodies, and non-human antibodies. The dosage and frequency of
administration can vary depending on whether the treatment is
prophylactic or therapeutic. In prophylactic applications, a
relatively low dosage is typically administered at relatively
infrequent intervals over a long period of time. Some patients
continue to receive treatment for the rest of their lives. In
therapeutic applications, a relatively high dosage at relatively
short intervals is sometimes required until progression of the
disease is reduced or terminated, or until the patient shows
partial or complete amelioration of symptoms of disease.
Thereafter, the patient can be administered a prophylactic
regime.
[0169] Actual dosage levels of the active ingredient or ingredients
in the pharmaceutical compositions of the present disclosure can be
varied so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration,
without being unduly toxic to the patient. The selected dosage
level will depend upon a variety of pharmacokinetic factors
including the activity of the particular compositions of the
present disclosure employed, the route of administration, the time
of administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compositions employed, the age, sex, weight, condition, general
health and prior medical history of the patient being treated, and
like factors well known in the medical arts. A composition of the
present disclosure can be administered via one or more routes of
administration using one or more of a variety of methods well known
in the art. As will be appreciated by the skilled artisan, the
route and/or mode of administration will vary depending upon the
desired results.
Kits
[0170] Also within the scope of the present disclosure are kits
comprising an anti-PD-1 antibody and, optionally, another
anti-cancer agent for therapeutic uses. Kits typically include a
label indicating the intended use of the contents of the kit and
instructions for use. The term label includes any writing, or
recorded material supplied on or with the kit, or which otherwise
accompanies the kit. Accordingly, this disclosure provides a kit
for treating a subject afflicted with a Hodgkin lymphoma, the kit
comprising: (a) any dosage described herein of an anti-cancer agent
which is an antibody or an antigen-binding portion thereof that
specifically binds to the PD-1 receptor and inhibits PD-1 activity;
and, optionally, (b) instructions for using the anti-PD-1 antibody
and in any of the therapy methods disclosed herein. In some
embodiments, the kit contains, optionally, another anti-cancer
agent(s) (e.g., doxorubicin, vinblastine, and dacarbazine) and
instructions for the use of that agent. In certain embodiments, the
kit comprises additional step between (a) and (b): instructions for
determining the PD-L1 and/or PD-L2 expression of the tumor. In some
embodiments, the kit comprises an agent to determine the PD-L1
and/or PD-L2 expression of the tumor. In one embodiment, the PD-L1
and/or PD-L2 expression is measured by an anti-PD-L1 and/or PD-L2
antibody or antigen-binding portion thereof.
[0171] The present disclosure is further illustrated by the
following example, which should not be construed as further
limiting. The contents of all references cited throughout this
application are expressly incorporated herein by reference.
[0172] Cross-reference to earlier filed applications: the present
application claims benefit to U.S. provisional application No.
62/344,880 filed Jun. 2, 2017, which is incorporated by reference
herein by reference in its entirety.
EXAMPLES
Example 1
Treatment of cHL with Nivolumab Monotherapy after Failure of
Autologous Stem Cell Transplantation (ASCT) and Subsequent
Brentuximab Vedotin
[0173] In a phase 2 study, the efficacy and safety of nivolumab
monotherapy in patients with cHL after failure of ASCT and
subsequent brentuximab vedotin was determined. The primary endpoint
of the study included the objective response rate (ORR) as assessed
by the Independent Radiologic Review Committee (IRRC). The
secondary endpoints included 1) IRRC-assessed complete remission
(CR), partial remission (PR), and duration of response (DOR); 2)
investigator-assessed ORR and DOR; 3) safety; and 4) quality of
life (QoL).
Methods
Study Design
[0174] The study was part of an ongoing,
multicenter-non-comparative, multicohort, phase 2 registrational
study in patients with cHL from 34 study centers across Europe,
Canada, and the US.
[0175] As shown in FIG. 1, key inclusion criteria included 1) prior
treatment with ASCT followed by brentuximab vedotin; and 2) (i)
failure to achieve greater than PR after the most recent treatment,
(ii) relapse after CR, or (iii) progressive disease (PD) after PR
or stable disease (SD).
[0176] Patients meeting the above inclusion criteria received
nivolumab every 2 weeks at a dosage of 3 mg/kg. Treatment continued
until disease progression or unacceptable toxicity occurred. At any
time, patients had the option to elect to discontinue nivolumab
treatment and proceed to hematopoietic stem cell transplantation
(SCT). (See FIG. 1).
Assessment
[0177] Patients were assessed for efficacy, safety, and quality of
life (QoL) associated with nivolumab treatment.
[0178] Efficacy was determined by assessing tumor response per 2007
IWG criteria. During the first year, tumor response was measured
using CT or MRI at baseline and at Weeks 9, 17, 25, 37, and 49.
Afterwards, tumor response was measured every 16 weeks until Week
97. After Week 97, the response was measured every 26 weeks.
FDG-PET scan was also performed at baseline and Weeks 17 and
25.
[0179] Safety was determined by assessing all adverse events (AEs)
that occurred as a result of the treatment. AEs were categorized
based on their severity and included: fatigue, infusion-related
reaction, rash, pyrexia, arthralgia, nausea, diarrhea, pruritus,
and pneumonitis. (See Table 4).
[0180] Quality of life was determined using the EQ-5D and European
Organization for Research and Treatment of Cancer Quality-of-Life
Questionnaire-Core 30 (EORTC QLQ-C30).
Statistical Analysis
[0181] The initial planned sample size of the study was 60
patients, which would provide approximately 93% power to reject the
null hypothesis that the ORR is .ltoreq.20%, assuming an ORR of 40%
and given a 2-sided alpha of 5%. However, 80 patients were enrolled
due to high demand from investigators and also to account for the
possibility of a high rate of screening failures.
[0182] Time-to-response assessments were summarized using the
Kaplan-Meier method.
Results
Patients
[0183] A total of 80 patients with cHL were enrolled and received
nivolumab treatment. The baseline characteristics of the enrolled
patients are provided in Table 2. At database lock, 51 of the 80
patients (64%) remained on nivolumab treatment. The median number
of doses received was 17 (range of 3-25). Among the 29 patients who
discontinued the nivolumab treatment, primary reasons for the
discontinuation included: disease progression (n=13) and SCT
(allogeneic SCT, n=5; autologous SCT, n=1). At time of the
transplantation, the best responses were CR (n=1), PR (n=3), and SD
(n=2). All patients were alive at data cut-off.
TABLE-US-00002 TABLE 2 Patient characteristics at baseline (N = 80)
Characteristics Value Age (years), median (range) 37 (18-72) Age
<65 years 77 (96) Male sex 51 (64) Previous lines of
therapy,.sup.a median (range) 4 (3-15) .gtoreq.5 lines of therapy
39 (49) Previous radiation therapy 59 (74) Previous ASCT 80 (100) 1
74 (93) .gtoreq.2 6 (8) Data shown as n (%) unless indicated
otherwise .sup.aExcluding high-dose preparative regimen prior to
ASCT
Efficacy
Objective Response Rate (ORR)
[0184] The ORR as assessed by the IRRC and investigators are
provided in Table 3. The median time to first objective response
was 2.1 months (range 1.6-5.7 months). As assessed by the IRRC, 53
of the 80 patients (66%) had reduction in tumor burden, with 7
patients having complete remission. Under investigator assessment,
58 patients (73%) showed reduced tumor burden and of those
patients, 22 patients had complete remission. This discordance in
complete remission was largely based on FDG-PET scan interpretation
and was not considered to meaningfully impact clinical activity
interpretation, as 13/19 investigator assessed complete remission
were assessed at least as partial remission by the IRRC. IRRC ORR
was 72% in patients (n=43) with no prior response to their most
recent brentuximab vedotin.
TABLE-US-00003 TABLE 3 ORR as assessed by IRRC and investigators
IRRC (n = 80) Investigator (n = 80) ORR, 95% CI 53 (66); 55-76 58
(73); 61-82 Best overall response Complete remission 7 (9) 22 (28)
Partial remission 46 (58) 36 (45) Stable disease 18 (23) 18 (23)
Progressive disease 6 (8) 3 (4) Unable to determine 3 (4).sup.a 1
(1).sup.b Data shown as n (%) unless indicated otherwise .sup.aNo
post-baseline tumor assessment available before or on the day of
subsequent therapy (if any) or assessment not available .sup.bNo
radiographic assessment after the first dose
Duration of Response (DOR)
[0185] After a median follow-up of 8.9 months, the median DOR was
7.8 months (95% CI 6.6--not estimable (NE)).
Response Characteristics and Change in Target Lesion
[0186] At time of analysis, 62% of the responders, as determined by
the IRRC, continued to respond to nivolumab treatment. (See FIG.
2A). All but 1 responder had a reduction of .gtoreq.50% from
baseline in tumor burden. (See FIG. 2B). This patient had a
negative FDG-PET scan.
[0187] A total of 9 patients continued nivolumab beyond
progression. As shown in FIG. 2C, 6 of the 9 patients maintained
tumor reduction in target lesions, per investigator assessment.
Progression Free Survival (PFS) and Overall Survival (OS)
[0188] As shown in FIG. 3, the median PFS among patients treated
with nivolumab was 10 months. At 6 months, the PFS was 77% (95% CI
65%-85%) and the OS rate was 99% (95% CI 91%-100%).
Safety
[0189] All-cause adverse events (AEs) were reported in 79 of the 80
patients (99%), with serious AEs (grade 3-4) reported in 20
patients (25%). Drug-related AEs were reported in 72 patients. (See
Table 4). Pneumonitis was reported in 2 patients (3%; grade 1/2 and
grade 3) between the first dose and the 35 days after the last
dose, which were considered drug-related.
[0190] All-cause AEs requiring discontinuation of nivolumab
treatment included: autoimmune hepatitis (n=1), increased alanine
aminotransferase and aspartate aminotransferase levels (n=1), and
multi-organ failure (n=1). Three deaths have also been reported due
to disease progression (n=1), an undetermined cause after lost
follow-up (n=1), and multi-organ failure due to Epstein-Barr
virus-positive T-cell lymphoma (n=1).
[0191] The most frequently reported AEs of special interest,
regardless of causality, included skin (41%); gastrointestinal
(26%); hypersensitivity/infusion-related reaction (21%); and
endocrine (18%), hepatic (10%), renal (5%), and pulmonary (1%)
events.
TABLE-US-00004 TABLE 4 Drug-related AEs in >10% of
patients.sup.a (N = 80) Any grade Grade 3-4 Patients with a
drug-related event 72 (90) 20 (25) Fatigue 20 (25) 0
Infusion-related reaction 16 (20) 0 Rash 13 (16) 1 (1) Pyrexia 11
(14) 0 Arthralgia 11 (14) 0 Nausea 10 (13) 0 Diarrhea 8 (10) 0
Pruritus 8 (10) 0 Data shown as n (%) .sup.aAEs occurring within 30
days of last dose
Quality of Life
[0192] Over time on treatment with nivolumab, the mean EQ-5D visual
analog score increased. The EORTC QLQ-C30 also showed a trend
towards improvement from baseline across functional, symptom, and
global health scores.
Conclusions
[0193] In this registrational study in patients with cHL who had
failed ASCT and brentuximab vedotin, nivolumab monotherapy resulted
in the following observations: 1) 66.3% of patients had an
objective response rate (ORR) per IRRC assessment; 2) preliminary
durability of response was encouraging, with 62% of the patients
continuing to respond at data cutoff (median duration of response
of 7.8 months) and a median PFS of 10.0 months; and 3) acceptable
safety profile with mostly grade 1 or 2 AEs and no new safety
concerns versus solid tumors.
Example 2
A Phase 2 Study of a Nivolumab-Containing Regimen in Patients with
Newly Diagnosed Classical Hodgkin Lymphoma
Objectives
[0194] The primary objective of this study is to assess overall
safety and tolerability of nivolumab monotherapy followed by
nivolumab in combination with AVD (doxorubicin, vinblastine, and
dacarbazine) in newly diagnosed patients with advanced-stage cHL.
This will be measured as patients who experienced .gtoreq.graded
3-5 treatment-related AE between the first dose and 30 days after
the last dose.
[0195] The secondary objectives of this study include: 1) safety
and tolerability of nivolumab as monotherapy and in combination
with AVD; 2) treatment discontinuation rate during monotherapy, in
combination with AVD, and overall; and 3) clinical activity as
measured by complete response (CR) rate, assessed by independent
radiologic review committee using 2007 International Working Group
criteria.
[0196] The exploratory objectives of this study include: 1)
objective response rate, and 2) progression-free survival
(PFS).
Study Design
[0197] This is a single-arm, open-label, phase 2 study assessing
the safety and tolerability of nivolumab monotherapy followed by
nivolumab in combination with AVD in newly diagnosed patients with
advanced-stage cHL. The study is conducted in 8 countries in North
America and the EU with a planned enrollment of 50 patients with
newly diagnosed advanced-stage cHL.
[0198] As described in Table 5, the key inclusion criteria for
enrollment in this study include: 1) newly diagnosed, previously
untreated cHL (except corticosteroid use); 2) adults aged
.gtoreq.18 years; 3) advanced-stage (IIB, III, and IV) disease; 4)
presence of .gtoreq.1 lesion .gtoreq.15 mm diameter; and 5) ECOG
performance status .ltoreq.1. The exclusion criteria are: 1) known
CNS lymphoma; 2) known nodular lymphocyte-predominant HL; 3) active
interstitial pneumonitis; 4) active or suspected autoimmune
disease; and 5) HIV.sup.+ or hepatitis B/C.
TABLE-US-00005 TABLE 5 Key Inclusion/Exclusion Criteria Inclusion
Exclusion Newly diagnosed, previously untreated Known CNS lymphoma
cHL (except corticosteroid use) Adults aged .gtoreq.18 years Known
nodular lymphocyte- predominant HL Advanced-stage (IIB, III, and
IV) disease Active interstitial Stage IIB disease must have bulky
disease pneumonitis or extranodal disease Presence of .gtoreq.1
lesion > 15 mm diameter Active or suspected autoimmune disease
ECOG performance status .ltoreq.1 HIV.sup.+ or hepatitis B/C CNS =
central nervous system
[0199] As shown in FIG. 4, patients meeting the above inclusion
criteria first receive nivolumab alone (240 mg) every 2 weeks for 4
doses ("monotherapy phase"). Then, the patients receive nivolumab
(240 mg) in combination with AVD every 2 weeks for 6 combo-cycles
("combination phase"). Patients are initially observed for a
maximum of 2 years after last treatment ("observation phase"). If
no relapse occurs during the observation phase, patients are
followed for up to an additional 5 years for survival analysis.
* * * * *
References