U.S. patent application number 17/715875 was filed with the patent office on 2022-09-22 for anti-pd-1 antibody in combination with an anti-cd30 antibody in cancer treatment.
This patent application is currently assigned to Bristol-Myers Squibb Company. The applicant listed for this patent is Bristol-Myers Squibb Company, Seattle Genetics, Inc.. Invention is credited to Anthony CAO, Benedetto FARSACI, Ryan HEISER, Neil JOSEPHSON.
Application Number | 20220298243 17/715875 |
Document ID | / |
Family ID | 1000006381287 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220298243 |
Kind Code |
A1 |
FARSACI; Benedetto ; et
al. |
September 22, 2022 |
ANTI-PD-1 ANTIBODY IN COMBINATION WITH AN ANTI-CD30 ANTIBODY IN
CANCER TREATMENT
Abstract
This disclosure provides methods for treating a tumor in a
subject comprising administering to the subject an anti-PD-1
antibody and an anti-CD30 antibody. In some embodiments, the tumor
is derived from a lymphoma (e.g., a Hodgkin lymphoma or a
non-Hodgkin lymphoma). In certain embodiments, the anti-CD30
antibody is an antibody-drug conjugate, e.g., brentuximab
vedotin.
Inventors: |
FARSACI; Benedetto;
(Princeton, NJ) ; JOSEPHSON; Neil; (Bothell,
WA) ; CAO; Anthony; (Sammamish, WA) ; HEISER;
Ryan; (Lake Stevens, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company
Seattle Genetics, Inc. |
Princeton
Bothell |
NJ
WA |
US
US |
|
|
Assignee: |
Bristol-Myers Squibb
Company
Princeton
NJ
Seattle Genetics, Inc.
Bothell
WA
|
Family ID: |
1000006381287 |
Appl. No.: |
17/715875 |
Filed: |
April 7, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16306282 |
Nov 30, 2018 |
11299543 |
|
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PCT/US2017/035521 |
Jun 1, 2017 |
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17715875 |
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62344866 |
Jun 2, 2016 |
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62382839 |
Sep 2, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/2878 20130101;
A61K 2039/507 20130101; C07K 16/2818 20130101; C07K 2317/76
20130101; A61P 35/00 20180101; A61K 2039/505 20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method of treating a human subject afflicted with a tumor
derived from a non-Hodgkin lymphoma or a tumor derived from a
Hodgkin lymphoma, comprising administering to the human subject a
combination of: (a) an antibody or an antigen-binding portion
thereof that binds specifically to a Programmed Death-1 receptor
(PD-1) and inhibits PD-1 activity ("anti-PD-1 antibody"); and (b)
an antibody or an antigen-binding portion thereof that specifically
binds to CD30 ("anti-CD30 antibody").
2. The method of claim 1, wherein (i) the non-Hodgkin lymphoma is
relapsed or refractory non-Hodgkin lymphoma; (ii) the non-Hodgkin
lymphoma is selected from diffuse large B-cell lymphoma (DLBCL),
peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma
(CTCL), and any combination thereof (iii) the Hodgkin lymphoma is
classical Hodgkin lymphoma (cHL); or (iv) the Hodgkin lymphoma is
relapsed or refractory Hodgkin lymphoma, optionally relapsed HL
after autologous stem cell transplant (ASCT) or relapsed HL in a
human subject ineligible for ASCT.
3. The method of claim 1, wherein the non-Hodgkin lymphoma is
selected from the group consisting of diffuse large B-cell lymphoma
(DLBCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell
lymphoma (CTCL), and any combination thereof.
4. The method of claim 1, wherein the tumor comprises one or more
cells that express CD30.
5. The method of claim 4, wherein at least about 0.1%, 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
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 60%, at least about 70%, or at least
about 80% of the tumor cells express CD30.
6. The method of claim 5, wherein (i) the anti-CD30 antibody
cross-competes for binding to CD30 with cAC10, (ii) the anti-CD30
antibody comprises cAC10, or (iii) the anti-CD30 antibody is an
anti-CD30 antibody conjugated to a therapeutic agent, optionally
comprising an anti-neoplastic agent, such as an anti-mitotic agent,
or monomethyl auristatin E (MMAE), and further optionally
comprising a linker, such as a cleavable linker, between the
therapeutic agent and the CD30 antibody.
7. The method of claim 1, wherein the anti-CD30 antibody is
brentuximab vedotin.
8. The method of claim 1, wherein (i) the anti-PD-1 antibody
cross-competes with nivolumab for binding to human PD-1; (ii) the
anti-PD-1 antibody binds to the same epitope as nivolumab; (iii)
the anti-PD-1 antibody is nivolumab; or (iv) the anti-PD-1 antibody
is pembrolizumab.
9. The method of claim 1, wherein (i) 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; (ii) the anti-PD-1 antibody is administered at a dose of at
least about 3 mg/kg body weight once about every 2 weeks; (iii) the
anti-PD-1 antibody is administered at a dose of at least about 3
mg/kg body weight once about every 3 weeks; (iv) the anti-PD-1
antibody or antigen-binding portion thereof is administered at a
flat dose, optionally, 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 administered about once every 1, 2, 3,
or 4 weeks.
10. The method of claim 1, wherein (i) the anti-CD30 antibody is
administered at a dose ranging from at least about 0.1 mg/kg to at
least about 180 mg/kg body weight once about every 1, 2 or 3 weeks;
(ii) the anti-CD30 antibody is administered at a dose ranging from
at least about 1.0 mg/kg to at least about 10 mg/kg body weight
once about every 1, 2 or 3 weeks; (iii) the anti-CD30 antibody is
administered at a dose of at least about 2 mg/kg body weight once
about every 3 weeks; or (iv) the anti-CD30 antibody is administered
at a dose of 1.8 mg/kg body weight once about every 3 weeks.
11. The method of claim 1, wherein (a) the anti-CD30 antibody is
administered to the human subject on day 1 of a first 21-day cycle
and the anti-PD-1 antibody is administered to the human subject on
day 8 of the first 21-day cycle; and (b) optionally, a combination
of the anti-CD30 antibody and the anti-PD-1 antibody is
administered on day 1 of each of a second 21-day cycle, a third
21-day cycle, and a fourth 21-day cycle, wherein the second 21-day
cycle, the third 21-day cycle, and the fourth 21-day cycle follow
in succession after the first 21-day cycle, and wherein the
anti-CD30 antibody is administered at a dose of about 1.8 mg/kg and
the anti-PD-1 antibody is administered at a dose of about 3
mg/kg.
12. The method of claim 1, wherein the anti-PD-1 antibody and the
anti-CD30 antibody are administered sequentially.
13. The method of claim 1, wherein the tumor comprises one or more
cells that express PD-L1, PD-L2, or both PD-L1 and PD-L2.
14. The method of claim 1, wherein the human 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.
15. A kit comprising: (a) a dosage ranging from about 4 mg to about
500 mg of an anti-PD-1 antibody; (b) a dosage ranging from about
0.1 mg to about 500 mg of an anti-CD30 antibody; and (c)
instructions for using the anti-PD-1 antibody and the anti-CD30
antibody according to the method of claim 1.
16. A method of treating a human subject afflicted with a tumor
derived from a Hodgkin lymphoma, comprising administering to the
human subject a combination of: (a) an anti-PD-1 antibody; and (b)
an anti-CD30 antibody.
17. The method of claim 16, wherein (i) the Hodgkin lymphoma is
classical Hodgkin lymphoma (cHL); or (ii) the Hodgkin lymphoma is
relapsed or refractory Hodgkin lymphoma, optionally relapsed HL
after autologous stem cell transplant (ASCT) or relapsed HL in a
human subject ineligible for ASCT.
18. The method of claim 16, wherein the tumor comprises one or more
cells that express CD30.
19. The method of claim 16, wherein (i) the anti-CD30 antibody
cross-competes for binding to CD30 with cAC10, (ii) the anti-CD30
antibody comprises cAC10, or (iii) the anti-CD30 antibody is an
anti-CD30 antibody conjugated to a therapeutic agent, optionally
comprising an anti-neoplastic agent, such as an anti-mitotic agent,
or monomethyl auristatin E (MMAE), and further optionally
comprising a linker, such as a cleavable linker, between the
therapeutic agent and the anti-CD30 antibody.
20. The method of claim 16, wherein the anti-CD30 antibody is
brentuximab vedotin.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 16/306,282, which is the U.S. National Phase
of International Application No. PCT/US2017/035521, filed on Jun.
1, 2017, which claims the benefit of U.S. Provisional Application
Nos. 62/344,866, filed Jun. 2, 2016, and 62/382,839, filed on Sep.
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 a tumor in a
subject comprising administering to the subject an anti-Programmed
Death-1 (PD-1) antibody and an anti-CD30 antibody. In some
embodiments, the tumor is derived from a lymphoma. In certain
embodiments, the tumor is derived from a Hodgkin lymphoma, a
non-Hodgkin lymphoma, or a combination thereof.
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 314:268-74). 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, including the development of an antibody, ipilimumab
(YERVOY.RTM.), that binds to and inhibits CTLA-4 for the treatment
of patients with advanced melanoma (Hodi et al., 2010 N Engl J Med
363:711-23) and the development of antibodies, such as nivolumab
and pembrolizumab (formerly lambrolizumab; USAN Council Statement,
2013), that bind specifically to the Programmed Death-1 (PD-1)
receptor and block the inhibitory PD-1/PD-1 ligand pathway
(Topalian et al., N Engl J Med 366:2443-54 (2012a); Topalian et
al., Curr Opin Immunol 24:207-12 (2012b); Topalian et al., J Clin
Oncol 32(10):1020-30 (2014); Hamid et al., N Engl J Med 369:134-144
(2013); Hamid and Carvajal, Expert Opin Biol Ther 13(6):847-61
(2013); and McDermott and Atkins, Cancer Med 2(5):662-73
(2013)).
[0005] Targeted therapy of multiple non-redundant molecular
pathways regulating immune responses can enhance antitumor
immunotherapy. However, not all combinations have acceptable safety
and/or efficacy. There remains a need for combination therapies
with an acceptable safety profile and high efficacy that enhance
antitumor immune responses compared to monotherapy and other
immunotherapy combinations.
SUMMARY OF THE DISCLOSURE
[0006] The present disclosure relates to a method of treating a
subject afflicted with a tumor derived from a non-Hodgkin lymphoma
comprising administering to the subject: (a) an antibody or an
antigen-binding portion thereof that binds specifically to a
Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity
("anti-PD-1 antibody"); and (b) an antibody or an antigen-binding
portion thereof that specifically binds to CD30 ("anti-CD30
antibody"). In some embodiments, the non-Hodgkin lymphoma is
relapsed or refractory non-Hodgkin lymphoma. In certain
embodiments, the non-Hodgkin lymphoma is selected from the group
consisting of diffuse large B-cell lymphoma (DLBCL), peripheral
T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and any
combination thereof.
[0007] The present disclosure further relates to a method of
treating a subject afflicted with a tumor derived from a Hodgkin
lymphoma comprising administering to the subject: (a) an anti-PD-1
antibody; and (b) an anti-CD30 antibody. In some embodiments, the
Hodgkin lymphoma is classical Hodgkin lymphoma (cHL).
[0008] In some embodiments, the tumor comprises one or more cells
that express CD30. In certain embodiments, at least 1% of the tumor
cells express CD30.
[0009] In some embodiments, the anti-CD30 antibody cross-competes
for binding to CD30 with cAC10. In some embodiments, the anti-CD30
antibody comprises cAC10. In some embodiments, the anti-CD30
antibody is an anti-CD30 antibody conjugated to a therapeutic agent
("anti-CD30 antibody-drug conjugate"). In certain embodiments, the
therapeutic agent comprises monomethyl auristatin E (MMAE). In one
particular embodiment, the anti-CD30 antibody is brentuximab
vedotin.
[0010] In some embodiments, the anti-PD-1 antibody cross-competes
with nivolumab for binding to human PD-1. In some embodiments, the
anti-PD-1 antibody binds to the same epitope as nivolumab. In one
particular embodiment, the anti-PD-1 antibody is nivolumab.
[0011] In certain embodiments, the anti-PD-1 antibody is
administered at a dose of at least about 3 mg/kg body weight once
about every 2 weeks. In some embodiments, the anti-CD30 antibody is
administered at a dose of 1.8 mg/kg body weight once about every 3
weeks.
[0012] In some embodiments, the tumor comprises one or more cells
that express PD-L1, PD-L2, or both.
[0013] In some embodiments, the subject received at least one prior
chemotherapy treatment. In certain embodiments, the subject was not
responsive to a prior chemotherapy treatment.
[0014] In some embodiments, the method further comprises
administering a stem cell transplant to the patient after
administering the anti-PD-1 antibody and the anti-CD30
antibody.
[0015] The present disclosure is further directed to a kit for
treating a subject afflicted with a cancer, the kit comprising: (a)
a dosage ranging from about 4 mg to about 500 mg of an anti-PD-1
antibody; (b) a dosage ranging from about 0.1 mg to about 500 mg of
an anti-CD30 antibody; and (c) instructions for using the anti-PD-1
antibody and the anti-CD30 antibody in the method.
[0016] The present disclosure is further directed to a kit for
treating a subject afflicted with a lymphoma, the kit comprising:
(a) a dosage ranging from about 4 mg to about 500 mg of an
anti-PD-1 antibody; (b) a dosage ranging from about 0.1 mg to about
500 mg of brentuximab vedotin; and (c) instructions for using the
anti-PD-1 antibody and the brentuximab vedotin in the method.
EMBODIMENTS
[0017] E1. A method of treating a subject afflicted with a tumor
derived from a non-Hodgkin lymphoma comprising administering to the
subject: (a) an antibody or an antigen-binding portion thereof that
binds specifically to a Programmed Death-1 (PD-1) receptor and
inhibits PD-1 activity ("anti-PD-1 antibody"); and (b) an antibody
or an antigen-binding portion thereof that specifically binds to
CD30 ("anti-CD30 antibody").
[0018] E2. The method of embodiment E1, wherein the non-Hodgkin
lymphoma is relapsed or refractory non-Hodgkin lymphoma.
[0019] E3. The method of embodiment E1 or E2, wherein the
non-Hodgkin lymphoma is selected from the group consisting of
diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma
(PTCL), cutaneous T-cell lymphoma (CTCL), and any combination
thereof.
[0020] E4. A method of treating a subject afflicted with a tumor
derived from a Hodgkin lymphoma comprising administering to the
subject: (a) an anti-PD-1 antibody; and (b) an anti-CD30
antibody.
[0021] E5. The method of embodiment E4, wherein the Hodgkin
lymphoma is classical Hodgkin lymphoma (cHL).
[0022] E6. The method of any one of embodiments E1 to E5, wherein
the tumor comprises one or more cells that express CD30.
[0023] E7. The method of embodiment E6, wherein at least about
0.1%, 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 15%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 60%, at least about
70%, or at least about 80% of the tumor cells express CD30.
[0024] E8. The method of embodiment E6 or E7, wherein about at
least 1% of the tumor cells express CD30.
[0025] E9. The method of any one of embodiments E1 to E8, wherein
the administering treats the tumor.
[0026] E10. The method of any one of embodiments E1 to E9, wherein
the anti-CD30 antibody cross-competes for binding to CD30 with
cAC10.
[0027] E11. The method of any one of embodiments E1 to E9, wherein
the anti-CD30 antibody comprises cAC10.
[0028] E12. The method of any one of embodiments E1 to E11, wherein
the anti-CD30 antibody is an anti-CD30 antibody conjugated to a
therapeutic agent ("anti-CD30 antibody-drug conjugate").
[0029] E13. The method of embodiment E12, wherein the therapeutic
agent comprises an anti-neoplastic agent.
[0030] E14. The method of embodiment E13, wherein the
anti-neoplastic agent is an anti-mitotic agent.
[0031] E15. The method of any one of embodiments E12 to E14,
wherein the therapeutic agent comprises monomethyl auristatin E
(MMAE).
[0032] E16. The method of anyone of embodiments E12 to E15, wherein
the anti-CD30 antibody-drug conjugate further comprises a linker
between the therapeutic agent and the antibody.
[0033] E17. The method of embodiment E16, wherein the linker is a
cleavable linker.
[0034] E18. The method of anyone of embodiments E1 to E17, wherein
the anti-CD30 antibody is brentuximab vedotin.
[0035] E19. The method of any one of embodiments E1 to E18, wherein
the anti-PD-1 antibody cross-competes with nivolumab for binding to
human PD-1.
[0036] E20. The method of any one of embodiments E1 to E19, wherein
the anti-PD-1 antibody binds to the same epitope as nivolumab.
[0037] E21. The method of any one of embodiments E1 to E20, wherein
the anti-PD-1 antibody is a chimeric antibody, a humanized
antibody, a human monoclonal antibody, or a portion thereof.
[0038] E22. The method of any one of embodiments E1 to E21, wherein
the anti-PD-1 antibody comprises a heavy chain constant region
which is of a human IgG1 or IgG4 isotype.
[0039] E23. The method of any one of embodiments E1 to E22, wherein
the anti-PD-1 antibody is nivolumab.
[0040] E24. The method of any one of embodiments E1 to E22, wherein
the anti-PD-1 antibody is pembrolizumab.
[0041] E25. The method of any one of embodiments E1 to E24, 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.
[0042] E26. The method of embodiment E25, 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.
[0043] E27. The method of any one of embodiments E1 to E24, wherein
the anti-PD-1 antibody is administered at a flat dose.
[0044] E28. The method of any one of embodiments E1 to E24 and E27,
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.
[0045] E29. The method of any one of embodiments E1 to E24, E27,
and E28, wherein the anti-PD-1 antibody is administered at a flat
dose about once every 1, 2, 3, or 4 weeks.
[0046] E30. The method of any one of embodiments E1 to E29, wherein
the anti-PD-1 antibody is administered for as long as clinical
benefit is observed or until unmanageable toxicity or disease
progression occurs.
[0047] E31. The method of any one of embodiments E1 to E30, wherein
the anti-CD30 antibody is administered at a dose ranging from at
least about 0.1 mg/kg to at least about 180 mg/kg body weight once
about every 1, 2, or 3 weeks.
[0048] E32. The method of any one of embodiments E1 to E31, wherein
the anti-CD30 antibody is administered at a dose ranging from at
least about 1.0 mg/kg to at least about 10 mg/kg body weight once
about every 1, 2, or 3 weeks.
[0049] E33. The method of any one of embodiments E1 to E32, wherein
the anti-CD30 antibody is administered at a dose of at least about
2 mg/kg body weight once about every 3 weeks.
[0050] E34. The method of any one of embodiments E1 to E32, wherein
the anti-CD30 antibody is administered at a dose of 1.8 mg/kg body
weight once about every 3 weeks.
[0051] E35. The method of any of embodiments E1 to E34, wherein the
anti-CD30 antibody is administered for as long as clinical benefit
is observed or until unmanageable toxicity or disease progression
occurs.
[0052] E36. The method of any one of embodiments E1 to E35, wherein
the anti-PD-1 and anti-CD30 antibodies are formulated for
intravenous administration.
[0053] E37. The method of any one of embodiments E1 to E36, wherein
the anti-PD-1 and anti-CD30 antibodies are administered
sequentially.
[0054] E38. The method of any one of embodiments E1 to E37, wherein
the anti-PD-1 and anti-CD30 antibodies are administered within 30
minutes of each other.
[0055] E39. The method of any one of embodiments E1 to E38, wherein
the anti-PD-1 antibody is administered before the anti-CD30
antibody.
[0056] E40. The method of any one of embodiments E1 to E39, wherein
the anti-CD30 antibody is administered before the anti-PD-1
antibody.
[0057] E41. The method of any one of embodiments E1 to E36, wherein
the anti-PD-1 antibody and the anti-CD30 antibody are administered
concurrently in separate compositions.
[0058] E42. The method of any one of embodiments E1 to E36, wherein
the anti-PD-1 antibody and the anti-CD30 antibody are admixed as a
single composition for concurrent administration.
[0059] E43. The method of any one of embodiments E1 to E42, wherein
the anti-PD-1 antibody is administered at a subtherapeutic
dose.
[0060] E44. The method any one of embodiments E1 to E43, wherein
the anti-CD30 antibody is administered at a subtherapeutic
dose.
[0061] E45. The method any one of embodiments E1 to E44, wherein
the anti-PD-1 antibody and the anti-CD30 antibody are each
administered at a subtherapeutic dose.
[0062] E46. The method of any one of embodiments E1 to E45, wherein
the tumor comprises one or more cells that express PD-L1, PD-L2, or
both.
[0063] E47. The method of any one of embodiments E1 to E46, 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.
[0064] E48. The method of any one of embodiments E1 to E47, wherein
the anti-CD30 antibody is ADCETRIS.RTM..
[0065] E49. The method of any one of embodiments E1 to E48, wherein
the anti-PD-1 antibody is OPDIVO.RTM..
[0066] E50. The method of any one of embodiments E1 to E49, wherein
the subject received at least one prior chemotherapy treatment.
[0067] E51. The method of any one of embodiments E1 to E50, wherein
the subject received at least two prior chemotherapy
treatments.
[0068] E52. The method of any one of embodiments E1 to E51, wherein
the subject was not responsive to a prior chemotherapy
treatment.
[0069] E53. The method of any one of embodiments E1 to E52, further
comprising administering a stem cell transplant to the patient
after administering the anti-PD-1 antibody and the anti-CD30
antibody.
[0070] E54. The method of embodiment E53, wherein the stem cell
transplant comprises autologous stem cells.
[0071] E55. A kit for treating a subject afflicted with a cancer,
the kit comprising: (a) a dosage ranging from about 4 mg to about
500 mg of an anti-PD-1 antibody; (b) a dosage ranging from about
0.1 mg to about 500 mg of an anti-CD30 antibody; and (c)
instructions for using the anti-PD-1 antibody and the anti-CD30
antibody in the method of any of embodiments E1 to E54.
[0072] E56. A kit for treating a subject afflicted with a lymphoma,
the kit comprising: (a) a dosage ranging from about 4 mg to about
500 mg of an anti-PD-1 antibody; (b) a dosage ranging from about
0.1 mg to about 500 mg of brentuximab vedotin; and (c) instructions
for using the anti-PD-1 antibody and the brentuximab vedotin in the
method of any of embodiments E1 to E54.
[0073] E57. The method of any one of embodiments E4 to E54, wherein
the Hodgkin lymphoma is relapsed or refractory Hodgkin
lymphoma.
[0074] E58. The method of embodiment E25, wherein the anti-PD-1
antibody is administered at a dose of at least about 3 mg/kg body
weight once about every 3 weeks.
[0075] E59. The method of any one of embodiments E1 to E24, wherein
the anti-CD30 antibody is administered to the subject on day 1 of a
first 21-day cycle and the anti-PD-1 antibody is administered to
the subject on day 8 of the first 21-day cycle.
[0076] E60. The method of embodiment E59, further comprising
administering a combination of the anti-CD30 antibody and the
anti-PD-1 antibody on day 1 of each of a second 21-day cycle, a
third 21-day cycle, and a fourth 21-day cycle, wherein the second
21-day cycle, the third 21-day cycle, and the fourth 21-day cycle
follow in succession after the first 21-day cycle.
[0077] E61. The method of embodiment E59 or E60, wherein the
anti-CD30 antibody is administered at a dose of about 1.8
mg/kg.
[0078] E62. The method of any one of embodiments E59 to E61,
wherein the anti-PD-1 antibody is administered at a dose of about 3
mg/kg.
[0079] E63. The method of any one of embodiments E59 to E62,
wherein the anti-CD30 antibody, the anti-PD-1 antibody, or both the
anti-CD30 antibody and the anti-PD-1 antibody are administered to
the subject intravenously.
[0080] E64. The method of any one of embodiments E59 to E63,
wherein the anti-CD30 antibody comprises brentuximab vedotin.
[0081] E65. The method of any one of embodiments E59 to E64,
wherein the anti-PD-1 antibody comprises nivolumab.
BRIEF DESCRIPTION OF THE DRAWINGS
[0082] FIG. 1 shows a schematic drawing of the PD-1 pathway and the
mode of action of nivolumab. MEW=major histocompatibility complex;
NFKB=nuclear factor kappa B; PI3K=phosphoinositide-3 kinase;
Shp2=Src homology 2 domain-containing tyrosine phosphatase.
[0083] FIG. 2 shows a schematic drawing of the mechanism of action
of brentuximab vedotin and secondary effects.
[0084] FIG. 3 shows the study design and treatment schedule for a
Phase I/II clinical trial of brentuximab vedotin (BV) in
combination with nivolumab.
[0085] FIG. 4 shows the treatment schedule for a Phase I/II
clinical trial of brentuximab vedotin (BV) in combination with
nivolumab.
[0086] FIGS. 5A and 5B show the tumor response of patients treated
with brentuximab vedotin (BV) in combination with nivolumab. CR
means complete response; PR means partial response; SD means no
metabolic response; and PD means progressive disease.
[0087] FIGS. 6A-6D show priming of the immune system of patients
treated with brentuximab vedotin (BV) in combination with
nivolumab. Serum TARC levels were significantly lower compared to
baseline following single agent BV administration and following BV
and nivolumab dosing (FIG. 6A). T-cell chemokine IP10 levels were
significantly higher after C1D1 BV and following C1D8 nivolumab
dosing (FIG. 6B). Pro-inflammatory cytokine IL-18 levels were
significantly higher after C1D1 BV dosing and remained stable with
BV and nivolumab dosing (FIG. 6C). Pro-inflammatory cytokines such
as IFN.gamma. were significantly higher after BV and nivolumab
dosing (C1D15) compared to baseline (FIG. 6D).
[0088] FIGS. 7A-7C show peripheral blood immunophenotyping. T
helper subsets, such as Tregs, (FIG. 7A), activated CD4.sup.+ T
cells (FIG. 7B), and proliferating CD4.sup.+ T cells (FIG. 7C),
which were reduced after single agent BV dosing, expanded after BV
and nivolumab combination dosing.
[0089] FIG. 8 shows adverse events associated with BV and nivolumab
dosing.
[0090] FIG. 9 shows infusion-related reactions (IRRs) associated
with BV and nivolumab dosing.
[0091] FIG. 10 shows the study design and treatment schedule for a
Phase III clinical trial of brentuximab vedotin (BV) in combination
with nivolumab.
[0092] FIG. 11 shows BV-killed A20 mouse lymphoma immunization
confers anti-tumor protection.
[0093] FIGS. 12A and 12B show T cell transfer from mice immunized
with BV-killed cells provides protective immunity.
[0094] FIG. 13 shows improved tumor clearance and survival
associated with BV and nivolumab combination therapy.
[0095] FIGS. 14A-14D show immune cell infiltration into autologous
tumors following BV and nivolumab combination therapy. CD8+ T cell
and NK cell counts relative to tumor mass (FIG. 14A) and total cell
count (FIG. 14B) were increased after BV and nivolumab combination
dosing. CD8+ T cells and LCL tumor cells expressed increased levels
of PD-1 (FIG. 14C) and PD-L1 (FIG. 14D). TIL=tumor infiltrating
lymphocyte; PBMC=peripheral blood mononuclear cell.
[0096] FIGS. 15A-15B show BV enhances immune-mediated tumor
clearance alone and in combination with nivolumab. Relative tumor
volume decreased over time following treatment (FIG. 15A), and mean
tumor volume substantially decreased after treatment with BV and
nivolumab in combination (FIG. 15B). BV=brentuximab vedotin;
Nivo=nivolumab; PBMC=peripheral blood mononuclear cell;
hIgG-MMAE=control.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0097] This disclosure relates to methods for treating a tumor in a
subject comprising administering to the subject an anti-Programmed
Death-1 (PD-1) antibody and an anti-CD30 antibody. In some
embodiments, the tumor is derived from a lymphoma. In certain
embodiments, the tumor is derived from a Hodgkin lymphoma, a
non-Hodgkin lymphoma, or a combination thereof.
Terms
[0098] 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.
[0099] The term "and/or" where used herein is to be taken as
specific disclosure of each of the two specified features or
components with or without the other. Thus, the term "and/or" as
used in a phrase such as "A and/or B" herein is intended to include
"A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the
term "and/or" as used in a phrase such as "A, B, and/or C" is
intended to encompass each of the following aspects: A, B, and C;
A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B (alone); and C (alone).
[0100] It is understood that wherever aspects are described herein
with the language "comprising," otherwise analogous aspects
described in terms of "consisting of" and/or "consisting
essentially of" are also provided.
[0101] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure is related. For
example, the Concise Dictionary of Biomedicine and Molecular
Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of
Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the
Oxford Dictionary Of Biochemistry And Molecular Biology, Revised,
2000, Oxford University Press, provide one of skill with a general
dictionary of many of the terms used in this disclosure.
[0102] Units, prefixes, and symbols are denoted in their Systeme
International de Unites (SI) accepted form. Numeric ranges are
inclusive of the numbers defining the range. The headings provided
herein are not limitations of the various aspects of the
disclosure, which can be had by reference to the specification as a
whole. Accordingly, the terms defined immediately below are more
fully defined by reference to the specification in its
entirety.
[0103] "Administering" refers to the physical introduction of a
therapeutic agent to a subject, using any of the various methods
and delivery systems known to those skilled in the art. Exemplary
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. A therapeutic agent
can be administered via a non-parenteral route, or 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.
[0104] 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. 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.
[0105] 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 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 (Clq) of the
classical complement system.
[0106] 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.
[0107] 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. In one embodiment, an antibody includes
a conjugate attached to another agent (e.g., small molecule drug).
In some embodiments, an anti-CD30 antibody includes a conjugate of
an anti-CD30 antibody with a small molecule drug (e.g., MMAE).
[0108] 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.
Monoclonal antibodies can be produced by hybridoma, recombinant,
transgenic, or other techniques known to those skilled in the
art.
[0109] A "human antibody" (HuMAb) refers to an antibody having
variable regions in which both the FRs 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" and are
used synonymously.
[0110] 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.
[0111] 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.
[0112] 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-CD30 antibody binds
specifically to CD30.
[0113] 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.
[0114] 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 can 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 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.
[0115] "CD30" or "TNFRSF8" refers to a receptor that is a member of
the tumor necrosis factor receptor superfamily. CD30 is a
transmembrane glycoprotein expressed on activated CD4.sup.+ and
CD8.sup.+ T cells and B cells, and virally-infected lymphocytes.
CD30 interacts with TRAF2 and TRAF3 to mediate signal transduction
that leads to activation of NF-.kappa.B. CD30 acts as a positive
regulator of apoptosis, and it has been shown to limit the
proliferative potential of auto-reactive CD8 effector T cells. CD30
is also expressed by various forms of lymphoma, including Hodgkin
lymphoma (CD30 is expressed by Reed-Sternberg cells) and
non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL),
peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma
(CTCL).
[0116] The term "immunotherapy" refers to the treatment of a
subject afflicted with, at risk of contracting, or suffering a
recurrence of a disease by a method comprising inducing, enhancing,
suppressing, or otherwise modifying an immune response.
[0117] "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, condition, or biochemical indicia associated
with a disease.
[0118] "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.
[0119] "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.
[0120] A "subject" includes any human or non-human animal. The term
"nonhuman animal" includes, but is not limited to, vertebrates such
as nonhuman 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.
[0121] 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.
[0122] 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).
[0123] By way of example, an "anti-cancer agent" promotes cancer
regression in a subject. In some 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-cancer 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.
[0124] By way of example for the treatment of tumors, a
therapeutically effective amount of an anti-cancer agent inhibits
cell growth or tumor growth by at least about 10%, by 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%, or
by at least about 80%, by at least about 90%, at least about 95%,
or at least about 100% relative to untreated subjects.
[0125] 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".
[0126] 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.
[0127] 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-cancer 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 some 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.
[0128] The term "weight-based dose", as referred to herein, means
that a dose 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.
[0129] 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-CD30
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-CD30 antibody). For example, the 3:1 ratio of an
anti-PD-1 antibody and an anti-CD30 antibody can mean that a vial
can contain about 240 mg of the anti-PD-1 antibody and 80 mg of the
anti-CD30 antibody or about 3 mg/ml of the anti-PD-1 antibody and 1
mg/ml of the anti-CD30 antibody.
[0130] 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-CD30 antibody and/or 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).
[0131] 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.
[0132] 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
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.
[0133] 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.
[0134] 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.
[0135] Various aspects of the disclosure are described in further
detail in the following subsections.
Methods of the Disclosure
[0136] The present disclosure is directed to a method for treating
a tumor or a subject afflicted with a tumor 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 (PD-1) receptor and inhibits
PD-1 activity ("anti-PD-1 antibody") or an antibody or an
antigen-binding portion thereof that binds specifically to a
Programmed Death Ligand1 (PD-L1) receptor and inhibits PD-L1
activity ("anti-PD-L1 antibody") and a therapeutically effective
amount of an antibody or an antigen-binding portion thereof that
binds specifically to CD30 ("anti-CD30 antibody").
[0137] In some embodiments, the tumor is derived from a Hodgkin
lymphoma (HL), a non-Hodgkin lymphoma (NHL), or a combination
thereof. In certain embodiments, the subject has received one, two,
three, four, five or more prior cancer treatments. In other
embodiments, the subject is treatment-naive. In some embodiments,
the subject has progressed on other cancer treatments. In some
embodiments, the tumor has reoccurred. In some embodiments, the
tumor is metastatic. In other embodiments, the tumor is not
metastatic.
[0138] In certain embodiments, the tumor is derived from an HL
(e.g., a tumor comprising an HL). In certain embodiments, the HL is
a classical HL (cHL; e.g., a nodular sclerosing HL, a mixed
cellularity HL, a lymphocyte rich HL, or a lymphocyte depleted HL).
In other embodiments, the HL is a nodular lymphocyte predominant
type HL.
[0139] In other embodiments, the tumor is derived from a NHL. In
some embodiments, the tumor comprises an NHL. In certain
embodiments, the NHL is a relapsed or refractor NHL. In some
embodiments, the NHL is a B-cell lymphoma, e.g., a diffuse large
B-cell lymphoma (DLBCL), a follicular lymphoma (FL), a Burkitt
lymphoma, an immunoblastic large cell lymphoma, a precursor
B-lymphoblastic lymphoma, a mantle cell lymphoma, or any
combination thereof. In some embodiments, the NHL is a T-cell
lymphoma, e.g., a cutaneous T-cell lymphoma (CTCL), a peripheral
T-cell lymphoma (PTCL), a mycosis fungoides, an anaplastic large
cell lymphoma, a precursor T-lymphoblastic lymphoma, or any
combination thereof. In certain embodiments, the NHL is selected
from a DLBCL, a PTCL, a CTCL, and any combination thereof.
[0140] In other embodiments, the present methods comprise
administering an effective amount of an anti-PD-1 antibody and an
effective amount of an anti-CD30 antibody. An effective amount of
an anti-PD-1 antibody and/or an anti-CD30 antibody can be a flat
dose or a weight based dose.
[0141] In some embodiments, the disclosure includes a method of
treating a cancer or a subject afflicted with cancer comprising
administering an anti-PD-1 antagonist in combination with an
anti-CD30 antibody to treat cancer. An "anti-PD-1 antagonist" as
referred herein includes any molecule that inhibits interaction
between PD-1 (receptor) and PD-L1 (ligand) such that the signal
pathway of PD-1/PD-L1 is blocked. In other embodiments, an
anti-PD-1 antagonist is a PD-1-Fc fusion protein. In certain
embodiments, an anti-PD-1 antagonist includes an anti-PD-1 fusion
protein, an antisense molecule, a small molecule, a ribozyme, or a
nanobody that inhibits or prevents interaction between PD-1 and
PD-L1.
[0142] In certain embodiments, the therapy of the present
disclosure (e.g., administration of an anti-PD-1 antibody the
anti-CD30 antibody) effectively increases the duration of survival
of the subject. For example, the duration of 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, at least about 10
months, at least about 11 months, or at least about 1 year or more
when compared to another subject treated with only either another
therapy or, only one of the two members of the combination therapy
alone (e.g., an anti-PD-1 antibody alone) or an alternative
combination therapy. In other embodiments, the combination therapy
of an anti-PD-1 antibody and an anti-CD30 antibody increases the
duration of survival of the subject at a level similar to the
duration of survival of the subject using a combination therapy of
an anti-PD-L1 antibody and brentuximab vedotin (anti-CD30
antibody). In still other embodiments, the combination therapy of
an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) and an
anti-CD30 antibody (e.g., brentuximab vedotin) increases the
duration of survival of the subject at a level higher than (about
one month higher than, about two months higher than, about three
months higher than, about four months higher than, about five
months higher than, about six months higher than, about seven
months higher than, about eight months higher than, about nine
months higher than, about ten months higher than, about eleven
months higher than, or about one year higher than the duration of
survival of the subject using a combination therapy of an
anti-PD-L1 antibody (e.g., MPDL3280A or atezolizumab) and
brentuximab vedotin (anti-CD30 antibody).
[0143] 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 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, at least
about 10 months, at least about 11 months, or at least about 1 year
when compared to another subject treated with only either another
therapy or only one of the two members of the combination therapy
alone (e.g., an anti-PD-1 antibody alone) or an alternative
combination therapy.
[0144] In certain embodiments, the therapy of the present
disclosure effectively increases the response rate in a group of
subjects. For example, the response rate in a group of subjects is
increased by at least about 2%, at least about 3%, at least about
4%, 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 last
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, 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%, at least about 99% or at least about
100% when compared to another group of subjects treated with only
either another therapy or, only one of the two members of the
combination therapy alone (e.g., an anti-PD-1 antibody alone) or an
alternative combination therapy.
[0145] In certain embodiments, the methods of the present
disclosure lower a serum thymus and activation-regulated chemokine
(TARC) level in the subject after the administration of the
anti-PD-1 antibody and the anti-CD30 antibody in combination,
compared to the serum TARC level at the baseline (no administration
or before the administration) or after the administration of the
anti-PD-1 antibody or the anti-CD30 antibody alone (monotherapy).
In some embodiments, the serum TARC level is lowered after the
administration at least one fold, at least 1.5 fold, at least two
fold, at least three fold, at least four fold, at least five fold,
at least six fold, at least seven fold, at least eight fold, at
least nine fold, at least ten fold, at least 11 fold, at least 12
fold, at least 13 fold, at least 14 fold, at least 15 fold, at
least 16 fold, at least 17 fold, at least 18 fold, at least 19
fold, or at least 20 fold compared to the serum TARC level at the
baseline (no administration or before the administration) or after
the monotherapy. In other embodiments, the methods of the present
disclosure increase the level of a pro-inflammatory cytokine, e.g.,
Interleukin-18 (IL-18) and/or Interferon-.gamma., in the subject
after the administration of the anti-PD-1 antibody and the
anti-CD30 antibody in combination, compared to the level of the
pro-inflammatory cytokine at the baseline (no administration or
before the administration) or after the administration of the
anti-PD-1 antibody or the anti-CD30 antibody alone (monotherapy).
The level of the pro-inflammatory cytokine can be increased at
least 1 fold, at least 1.5 fold, at least 2 fold, at least 3 fold,
at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold,
at least 9 fold, at least 10 fold, at least 11 fold, at least 12
fold, at least 13 fold, at least 14 fold, at least 15 fold, at
least 16 fold, at least 17 fold, at least 18 fold, at least 19
fold, or at least 20 fold after the administration of the
combination therapy. In yet other embodiments, the methods of the
present disclosure increase the level of a T cell chemokine, e.g.,
IP10, in the subject after the administration of the anti-PD-1
antibody and the anti-CD30 antibody in combination, compared to the
level of the T cell chemokine at the baseline (no administration or
before the administration) or after the administration of the
anti-PD-1 antibody or the anti-CD30 antibody alone (monotherapy).
In some embodiments, the level of the T cell chemokine is increased
at least 1 fold, at least 1.5 fold, at least 2 fold, at least 3
fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8
fold, at least 9 fold, at least 10 fold, at least 11 fold, at least
12 fold, at least 13 fold, at least 14 fold, at least 15 fold, at
least 16 fold, at least 17 fold, at least 18 fold, at least 19
fold, or at least 20 fold after the administration of the
combination therapy.
[0146] In other embodiments, the present method provides a method
of reducing the serum level of TARC in a subject afflicted with a
tumor derived from a Hodgkin lymphoma (HL), a non-Hodgkin lymphoma
(NHL), or a combination thereof comprising administering to the
subject a therapeutically effective amount of an anti-PD-1 antibody
and an anti-CD30 antibody. In some embodiments, the serum TARC
level is lowered after the administration at least one fold, at
least 1.5 fold, at least two fold, at least three fold, at least
four fold, at least five fold, at least six fold, at least seven
fold, at least eight fold, at least nine fold, at least ten fold,
at least 11 fold, at least 12 fold, at least 13 fold, at least 14
fold, at least 15 fold, at least 16 fold, at least 17 fold, at
least 18 fold, at least 19 fold, or at least 20 fold compared to
the serum TARC level at the baseline (no administration or before
the administration) or after the monotherapy.
[0147] In some embodiments, the present method provides a method of
increasing the level of a pro-inflammatory cytokine (e.g., IL-18
and/or IFN.gamma.) and/or a T cell chemokine (e.g., IP10) in a
subject afflicted with a tumor derived from a Hodgkin lymphoma
(HL), a non-Hodgkin lymphoma (NHL), or a combination thereof
comprising administering to the subject a therapeutically effective
amount of an anti-PD-1 antibody and an anti-CD30 antibody. In some
embodiments, the level of the pro-inflammatory cytokine and/or T
cell chemokine is increased at least 1 fold, at least 1.5 fold, at
least 2 fold, at least 3 fold, at least 5 fold, at least 6 fold, at
least 7 fold, at least 8 fold, at least 9 fold, at least 10 fold,
at least 11 fold, at least 12 fold, at least 13 fold, at least 14
fold, at least 15 fold, at least 16 fold, at least 17 fold, at
least 18 fold, at least 19 fold, or at least 20 fold after the
administration of the combination therapy.
[0148] In certain embodiments, the present methods (e.g.,
combination therapy of an anti-PD-1 antibody and an anti-CD30
antibody) also activate and/or proliferate T cells, e.g., CD4+ T
cells, e.g., Follicular helper CD4 T cells (Tfh), T helper cells
(Th1 and/or Th2), T helper 17 (T17) cells, and/or regulatory T
cells (Tregs), or CD8+ T cells, compared to the administration of
the anti-CD30 antibody alone or the baseline (no administration or
before the administration). In some embodiments, the present
methods increase the number of T cells, e.g., CD4.sup.+ T cells,
regulatory T cells (Tregs) compared to the administration of the
anti-CD30 antibody alone or the baseline (no administration or
before the administration).
[0149] In some embodiments, the anti-PD-1 and anti-CD30 antibodies
are formulated for intravenous administration. In certain
embodiments, the anti-PD-1 and anti-CD30 antibodies are
administered sequentially. In certain embodiments, the anti-PD-1
and anti-CD30 antibodies are administered within 30 minutes of each
other. In one embodiment, the anti-PD-1 antibody or antigen-binding
portion thereof is administered before the anti-CD30 antibody or
antigen-binding portion thereof. In another embodiment, the anti
CD30 antibody or antigen-binding portion thereof is administered
before the anti-PD-1 antibody or antigen-binding portion thereof.
In another embodiment, the anti-PD-1 antibody or antigen-binding
portion thereof and the anti-CD30 antibody or antigen-binding
portion thereof are administered concurrently in separate
compositions. In a further embodiment, the anti-PD-1 antibody or
antigen-binding portion thereof and the anti-CD30 antibody or
antigen-binding portion thereof are admixed as a single composition
for concurrent administration.
[0150] In some embodiments, the anti-PD-1 antibody and anti-CD30
antibody are administered in a fixed dose.
Anti-PD-1 and Anti-PD-L1 Antibodies
[0151] The combination therapy of the present disclosure can
utilize an anti-PD-1 antibody or an antigen-binding fragment
thereof. PD-1 is a key immune checkpoint receptor expressed by
activated T and B cells and mediates immunosuppression. PD-1 is a
member of the CD28 family of receptors, which includes CD28,
CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands
for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1)
and Programmed Death Ligand-2 (PD-L2), that are expressed on
antigen-presenting cells as well as many human cancers and have
been shown to down regulate T cell activation and cytokine
secretion upon binding to PD-1. Inhibition of the PD-1/PD-L1
interaction mediates potent antitumor activity in preclinical
models.
[0152] 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 mABs 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.-7M or less, as determined by surface plasmon
resonance using a Biacore biosensor system; (b) does not
substantially bind to human CD28, CTLA-4 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/or (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, at least two,
at least three, at least four, or at least five of the preceding
characteristics.
[0153] 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., 2014 Cancer Immunol Res. 2(9):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., 2012a; Topalian et al., 2014; Drake et al., 2013;
WO 2013/173223). In another embodiment, the anti-PD-1 antibody or
fragment thereof cross-competes with nivolumab. In some
embodiments, the anti-PD-1 antibody binds to the same epitope as
nivolumab. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as nivolumab.
[0154] 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. No.
8,900,587; see also 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 and
advanced NSCLC.
[0155] In other embodiments, the anti-PD-1 antibody (or
antigen-binding portion thereof) cross-competes with MEDI0680. In
some 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
against the PD-1 receptor. MEDI0680 is described, for example, in
U.S. Pat. No. 8,609,089B2 or in
cancer.gov/drugdictionary?cdrid=756047 (last accessed Dec. 14,
2014).
[0156] In certain embodiments, an immune checkpoint inhibitor is
AMP-224, which is a B7-DC Fc fusion protein. AMP-224 is discussed
in U.S. Publ. No. 2013/0017199 or in
cancer.gov/publications/dictionaries/cancer-drug?cdrid=700595 (last
accessed Jul. 8, 2015).
[0157] 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 to 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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. No. 8,008,449; 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).
[0164] 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
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.
[0165] 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.
[0166] In certain embodiments, the anti-PD-1 antibody or
antigen-binding portion 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 antigen-binding portion 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., 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 antigen-binding portion thereof is a monoclonal
antibody or an antigen-binding portion thereof. 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 MEDI0680 (formerly AMP-514), AMP-224, or
BGB-A317.
[0167] 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
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. Antibodies of an IgG1, IgG2, IgG3, or IgG4
isotype can be used.
[0168] 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 tumor comprising
administering to the subject a therapeutically effective amount an
anti-PD-L1 antibody and an anti-CD30 antibody.
[0169] 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).
[0170] In other embodiments, the anti-PD-L1 antibody is MPDL3280A
(also known as RG7446 and atezolizumab) (see, e.g., Herbst et al.
(2013) J Clin Oncol 31(suppl):3000. Abstract.; U.S. Pat. No.
8,217,149).
[0171] In other embodiments, the anti-PD-L1 antibody is MEDI4736
(also called Durvalumab; Khleif (2013) In: Proceedings from the
European Cancer Congress 2013; Sep. 27-Oct. 1, 2013; Amsterdam, The
Netherlands. Abstract 802, See U.S. Pat. No. 8,779,108 or US
2014/0356353, filed May 6, 2014).
[0172] In further embodiments, the anti-PD-L1 antibody is
MSB0010718C (also called Avelumab; See US 2014/0341917).
[0173] In other embodiments, the anti-PD-L1 antibody is CX-072
(also called CytomX; See WO2016/149201).
[0174] In certain embodiments, the anti-PD-L1 antibodies
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. In other embodiments, the anti-PD-L1 antibodies useful
for the combination therapy with an anti-CD30 antibody 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.
Anti-CD30 Antibodies
[0175] The combination therapy of the present disclosure also
utilizes an anti-CD30 antibody or an antigen-binding fragment
thereof. CD30 receptors are members of the tumor necrosis factor
receptor superfamily involved in limiting the proliferative
potential of autoreactive CD8 effector T cells. Antibodies
targeting CD30 can potentially be either agonists or antagonists of
these CD30 activities.
[0176] In some embodiments, the anti-CD30 antibody is cAC10. cAC10
is a chimeric IgG1 monoclonal antibody that specifically binds
CD30. cAC10 induces growth arrest of CD30.sup.+ cell lines in vitro
and has pronounced antitumor activity in severe combined
immunodeficiency (SCID) mouse xenograft models of Hodgkin disease.
See Francisco et al., Blood 102(4):1458-64 (2003).
[0177] In some embodiments, the anti-CD30 antibody is conjugated to
a therapeutic agent, e.g., the anti-CD30 antibody comprises an
anti-CD30 antibody-drug conjugate. In some embodiments, the
therapeutic agent comprises an anti-neoplastic agent (e.g., an
anti-mitotic agent). In certain embodiments, the therapeutic agent
is selected from the group consisting of monomethyl auristatin E
(MMAE), auristatin drug analogues, can tansinoids (maytansine;
DMs), dolastatins, cryptophycin, duocarmycin, duocarmycin
derivatives, esperamicin, calicheamicin, pyrolobenodiazepine (PBD),
and any combination thereof. In one particular embodiment, the
anti-CD30 antibody is conjugated to MMAE. The antibody can be
conjugated to at least one, at least two, at least three, at least
four, at least five, at least six, at least seven, at least eight,
at least nine, or at least ten molecules of the therapeutic agent.
In one embodiment, the anti-CD30 antibody is conjugated to four
molecules of the therapeutic agent, e.g., four molecules of
MMAE.
[0178] In some embodiments, the anti-CD30 antibody-drug conjugate
further comprises a linker between the therapeutic agent and the
antibody. In some embodiments, the linker comprises one or more
naturally occurring amino acids, one or more non-naturally
occurring (e.g., synthetic) amino acids, a chemical linker, or any
combination thereof. In certain embodiments, the linker is a
cleavable linker, e.g., a protease cleavable linker. In certain
embodiments, the linker is specifically cleaved upon uptake by a
target cell, e.g., upon uptake by a cell expressing CD30. In some
embodiments, cleavage of the linker activates a cytotoxic activity
of the therapeutic agent.
[0179] In one embodiment, the anti-CD30 antibody comprises
brentuximab vedotin. In one particular embodiment, the anti-CD30
antibody is brentuximab vedotin. Brentuximab vedotin (BV; also
known as "ADCETRIS.RTM.") is a CD30-directed antibody-drug
conjugate (ADC) comprising a chimeric anti-CD30 antibody (cAC10), a
therapeutic agent (MMAE), and a protease-cleavable linker between
the cAC10 and the MMAE. BV comprises approximately four molecules
of MMAE linked to each cAC10 antibody molecule. In one embodiment,
the anti-CD30 antibody is ADCETRIS.RTM.. ADCETRIS.RTM. is approved
by the FDA for treatment of patients with Hodgkin lymphoma after
failure of autologous stem cell transplant (ASCT) or after failure
of at least two prior multi-agent chemotherapy regimens in patients
who are not ASCT candidates and for the treatment of patients with
systemic anaplastic large cell lymphoma after failure of at least
one prior multi-agent chemotherapy regimen.
[0180] In one embodiment, the anti-CD30 antibody is an anti-CD30
antibody or fragment thereof that binds to the same epitope as
cAC10, e.g., the same epitope as brentuximab vedotin. In certain
embodiments, the anti-CD30 antibody is an antibody that has the
same CDRs as cAC10, e.g., the same CDRs as brentuximab vedotin.
Antibodies that bind to the same epitope are expected to have
functional properties very similar to those of cAC10 by virtue of
their binding to the same epitope region of CD30. These antibodies
can be readily identified based on their ability to, for example,
cross-compete with cAC10 in standard CD30 binding assays such as
Biacore analysis, ELISA assays, or flow cytometry.
[0181] In certain embodiments, the antibodies that cross-compete
for binding to human CD30 with, or bind to the same epitope region
of human CD30 as cAC10 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. Anti-CD30 antibodies usable in the methods of the
disclosed disclosure also include antigen-binding portions of the
above antibodies.
[0182] In other embodiments, the anti-CD30 antibody or
antigen-binding portion 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. Antibodies of an IgG1, IgG2, IgG3, or IgG4
isotype can be used.
Cancer and Standard-of-Care Therapies
[0183] In some embodiments, the methods disclosed herein are used
in place of standard of care therapies. In certain embodiments, a
standard of care therapy is used in combination with any method
disclosed herein. Standard-of-care therapies for different types of
cancer are well known by persons of skill in the art. For example,
the National Comprehensive Cancer Network (NCCN), an alliance of 21
major cancer centers in the USA, publishes the NCCN Clinical
Practice Guidelines in Oncology (NCCN GUIDELINES.RTM.) that provide
detailed up-to-date information on the standard-of-care treatments
for a wide variety of cancers (see NCCN GUIDELINES.RTM., 2014,
available at:
nccn.org/professionals/physician_gls/f_guidelines.asp, last
accessed May 14, 2014).
Lymphoma
[0184] The combination therapy of the present disclosure can be
used to treat a tumor derived from a lymphoma. Lymphoma is a form
of cancer that affects the immune system. The majority of lymphomas
fall within two categories: Hodgkin lymphoma (HL) and non-Hodgkin
lymphoma (NHL). NHL is the most common form of lymphoma, accounting
for about 90% of all cases of lymphoma, whereas HL accounts for
only about 10% of all cases of lymphoma. Accordingly, in some
embodiments, the lymphoma is an HL. In other embodiments, the
lymphoma is an NHL.
[0185] NHL will account for an estimated 72,000 new cases (4.3% of
all new cancer cases) and 20,000 deaths (3.4% of all cancer-related
deaths) in the U.S. in 2017. Howlader N et al., SEER Cancer
Statistics Review, 1975-2014, based on November 2016 SEER data
submission. Diffuse large B-cell lymphoma (DLBCL), the most common
NHL subtype, has an incidence rate of 7.14 per 100,000 persons per
year (P-Y), including up to 10% primary mediastinal B-cell lymphoma
(PMBL). Dunleavy K et al., Blood 2015; 125:33-39. Incidence rates
of peripheral T-cell lymphoma (PTCL) and mycosis fungoides/Sezary
syndrome (MF/SS) are 0.60 and 0.52 per 100,000 P-Y. Morton L M et
al., Blood 2006; 107:265-276. Within the two main categories of
lymphoma, HL and NHL, there are several specific subgroups of
lymphomas. Hodgkin lymphomas can include, but are not limited to,
classical HL (cHL; e.g., nodular sclerosing HL, mixed cellularity
HL, lymphocyte rich HL, and lymphocyte depleted HL) and nodular
lymphocyte predominant type HL. Non-Hodgkin Lymphomas can include,
but are not limited to, B-cell lymphomas (e.g., diffuse large
B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt
lymphoma, immunoblastic large cell lymphoma, precursor
B-lymphoblastic lymphoma, and mantle cell lymphoma) and T cell
lymphomas (e.g., a cutaneous T-cell lymphoma (CTCL), a peripheral
T-cell lymphoma (PTCL), a mycosis fungoides, an anaplastic large
cell lymphoma, and a precursor T-lymphoblastic lymphoma).
[0186] Treatment guidelines for relapsed/refractory (R/R) NHL
recommend multi-agent chemotherapy (combined with targeted therapy
for B-cell lymphomas), brentuximab vedotin (BV), autologous or
allogeneic hematopoietic stem cell transplantation (HSCT), and/or
radiotherapy, with addition of topical therapies for MF/SS.
National Comprehensive Cancer Network, Non-Hodgkin Lymphoma
(version 3.2016). 5-year relative survival rates are 48%, 44%, and
86% in DLBCL, PTCL, and MF/SS, respectively. Han X et al., Cancer
Causes Control 2008; 19:841-858.
[0187] In certain aspects, the present disclosure is directed to a
method of treating a subject afflicted with a tumor derived from a
Hodgkin lymphoma (HL) comprising administering to the subject (a)
an anti-PD-1 antibody, and (b) an anti-CD30 antibody. In some
embodiments, the tumor comprises an HL. In one particular
embodiment, the HL is classical HL (cHL).
[0188] In certain aspects, the present disclosure is directed to a
method of treating a subject afflicted with a tumor derived from a
non-Hodgkin lymphoma (NHL) comprising administering to the subject
(a) an anti-PD-1 antibody, and (b) an anti-CD30 antibody. In some
embodiments, the tumor comprises an NHL. In certain embodiments,
the NHL is a relapsed or refractory NHL. In some embodiments, the
NHL is a B-cell lymphoma, e.g., a diffuse large B-cell lymphoma
(DLBCL), a follicular lymphoma (FL), a Burkitt lymphoma, an
immunoblastic large cell lymphoma, a precursor B-lymphoblastic
lymphoma, a mantle cell lymphoma, or any combination thereof. In
some embodiments, the NHL is a T-cell lymphoma, e.g., a cutaneous
T-cell lymphoma (CTCL), a peripheral T-cell lymphoma (PTCL), a
mycosis fungoides, an anaplastic large cell lymphoma, a precursor
T-lymphoblastic lymphoma, or any combination thereof. In particular
embodiments, the NHL is selected from the group consisting of a
DLBCL, a PTCL, a CTCL, and any combination thereof.
[0189] Various lymphomas are known to express CD30. For example,
CD30 is expressed by Reed-Sternberg cells typical of HL, and CD30
expression has been observed in various forms of NHL, including,
but not limited to, diffuse large B-cell lymphoma (DLBCL),
peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma
(CTCL). Accordingly, in some embodiments, the tumor comprises one
or more cells that express CD30. In some embodiments, at least
about 0.01%, at least about 0.1%, 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 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about
70%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, or at least about 95% of the tumor cells express
CD30. In one particular embodiment, at least about 1% of the tumor
cells express CD30. In another embodiment, at least about 10% of
the tumor cells express CD30. In another embodiment, at least about
20% of the tumor cells express CD30. In another embodiment, at
least about 30% of the tumor cells express CD30. In another
embodiment, at least about 40% of the tumor cells express CD30. In
another embodiment, at least about 50% of the tumor cells express
CD30.
[0190] The PD-L1 status of a tumor (e.g., a tumor derived from a
NHL and/or a HL) in a subject can be measured prior to
administering any composition or utilizing any method disclosed
herein. PD-L1 expression can be determined by any methods known in
the art.
[0191] In order to assess the PD-L1 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
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 on the surface of the cells based on an assessment
that the proportion of cells in the test tissue sample that express
PD-L1 on the cell surface is higher than a predetermined threshold
level.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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.
[0198] 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.
[0199] 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.
[0200] 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)]
[0201] 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).
[0202] 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)).
[0203] In one embodiment, the PD-L1 expression level of a tumor
(e.g., a tumor derived from a NHL and/or a 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 a tumor
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%.
[0204] "PD-L1 positive" as used herein can be interchangeably used
with "PD-L1 expression of at least about 1%". In one embodiment,
the PD-L1 positive tumors can thus have at least about 1%, at least
about 2%, at least about 5%, at least about 10%, 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 the tumor cells
expressing PD-L1 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.
Pharmaceutical Compositions and Dosages
[0205] 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 some embodiments, 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). A
pharmaceutical composition of the disclosure can include one or
more pharmaceutically acceptable salts, anti-oxidants, aqueous and
non-aqueous carriers, and/or adjuvants such as preservatives,
wetting agents, emulsifying agents, and dispersing agents.
[0206] 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 is
administered at a weight-based dose. For administration of an
anti-PD-1 antibody, the dosage can range from at least about 0.01
mg/kg to at least about 20 mg/kg, from at least about 0.1 mg/kg to
at least about 10 mg/kg, from about 0.01 mg/kg to about 5 mg/kg,
from about 1 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 5
mg/kg, from about 1 mg/kg to about 3 mg/kg, from about 7.5 mg/kg to
about 12.5 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg of the
subject's body weight. For example, dosages can be at least about
0.1 mg/kg, at least about 0.3 mg/kg, at least about 1 mg/kg, at
least about 2 mg/kg, at least about 3 mg/kg, at least about 5
mg/kg, or at least about 10 mg/kg body weight. In certain
embodiments, the dosage of the anti-PD-1 antibody is 3 mg/kg body
weight.
[0207] In one embodiment, a dosage regimen for an anti-PD-1
antibody comprises about 0.3-1 mg/kg body weight, about 5 mg/kg
body weight, 1-5 mg/kg body weight, or about 1-3 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 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.
[0208] 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 once per week, once every 2
weeks, once every 3 weeks, once every 4 weeks, once a month, once
every 3-6 months or longer. In certain embodiments, an anti-PD-1
antibody such as nivolumab is administered to the subject once
every 2 weeks. In other embodiments, the antibody is administered
once every 3 weeks. The dosage and scheduling can change during a
course of treatment. The anti-PD-1 antibody can be administered in
at least two doses, each of the doses is at an amount of about 0.01
mg/kg to about 5 mg/kg, e.g., 3 mg/kg, at a dosing interval of
every two weeks between the two doses. In some embodiments, the
anti-PD-1 antibody is administered in at least three, four, five,
six, or seven doses (i.e., multiple doses), each of the doses is at
an amount of about 0.01 mg/kg to about 5 mg/kg, e.g., 3 mg/kg, at a
dosing interval of every two weeks between two adjacently given
doses. The dosage and scheduling may change during a course of
treatment. For example, a dosing schedule for anti-PD-1 monotherapy
can comprise administering the antibody: (i) every 2 weeks in
6-week cycles; (ii) every 4 weeks for six dosages, then every three
months; (iii) every 3 weeks; or (iv) 3-10 mg/kg once followed by 1
mg/kg every 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 0.3-10 mg/kg body weight,
e.g., 1-5 mg/kg body weight, e.g., 1-3 mg/kg body weight via
intravenous administration, with the antibody being given every
14-21 days in up to 6-week or 12-week cycles until complete
response or confirmed progressive disease.
[0209] 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.
[0210] In certain embodiments, an anti-PD-1 antibody is
administered at a flat dose. In embodiments, the flat dose of the
anti-PD-1 antibody is a dose (e.g., flat dose) of at least about
100-600 mg, at least about 400-500 mg, such as, at least about 480
mg, or at least about 100-300 mg, such as, at least about 200-300
mg, at least about 220-260 mg, at least about 230-250 mg or at
least about 240 mg, such as at least about 60 mg, at least about 80
mg, at least about 100 mg, at least about 120 mg, at least about
140 mg, at least about 160 mg, at least about 180 mg, 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 360 mg, at least about 400
mg, at least about 440 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 about 700 mg, at least about 750 mg, or at
least about 800 mg. In one embodiment, the anti-PD-1 antibody is a
dose (e.g., flat dose) of at least about 240 mg or at least about
480 mg, e.g., 240 mg to 480 mg, once about every 2 to 4 weeks. In
other embodiments, the anti-PD-1 antibody or antigen-binding
portion thereof is administered at a dose higher than, i.e., at
least about, 240 mg. In a particular embodiment, the anti-PD-1
antibody is administered a flat dose of about 360 mg once about
every 3 weeks.
[0211] In certain embodiments, an anti-PD-1 antibody is
administered at a flat dose. In embodiments, the flat dose of the
anti-PD-1 antibody is a dose (e.g., flat dose) of about 100-600 mg,
about 400-500 mg, such as, about 480 mg, or about 100-300 mg, such
as, about 200-300 mg, about 220-260 mg, about 230-250 mg or about
240 mg, such as about 60 mg, about 80 mg, about 100 mg, about 120
mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about
220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg,
about 320 mg, about 360 mg, about 400 mg, about 440 mg, about 480
mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about
720 mg, about 750 mg, or about 800 mg. In one embodiment, the
anti-PD-1 antibody is a dose (e.g., flat dose) of about 240 mg or
about 480 mg, e.g., 240 mg to 480 mg, once about every 2 to 4
weeks. In other embodiments, the anti-PD-1 antibody or
antigen-binding portion thereof is administered at a dose higher
than, i.e., about 240 mg. In a particular embodiment, the anti-PD-1
antibody is administered a flat dose of about 360 mg once about
every 3 weeks.
[0212] In some embodiments, the anti-PD-1 antibody is administered
in a fixed dose with the anti-CD30 antibody. 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 anti-PD-1 antibody to anti-CD30 antibody.
[0213] When used in combinations with other anti-cancer agents, the
dosage of an anti-PD-1 antibody can be lowered compared to the
monotherapy dose. For example, a dosage of nivolumab that is
significantly lower than the typical 3 mg/kg, but not less than
0.001 mg/kg, for instance 0.1 mg/kg or less every 3 or 4 weeks, is
regarded as a subtherapeutic dosage. 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%). (Brahmer et al., J Clin Oncol 28:3167-75 2010). In
some embodiments, 0.3 mg/kg dosing can allow for sufficient
exposure to lead to maximal biologic activity. In a particular
embodiment, the anti-CD30 antibody, e.g., BV, is administered at a
dose of 1.8 mg/kg once every 3 weeks.
[0214] Although higher nivolumab monotherapy dosing up to 10 mg/kg
every two weeks has been achieved without reaching the maximum
tolerated does (MTD), the significant toxicities reported in other
trials of checkpoint inhibitors plus anti-angiogenic therapy (see,
e.g., Johnson et al., 2013; Rini et al., 2011) support the
selection of a nivolumab dose lower than 10 mg/kg.
[0215] In some embodiments, the anti-CD30 antibody (e.g.,
brentuximab vedotin) is administered at a weight-based dose. For
administration of an anti-CD30 antibody (e.g., brentuximab
vedotin), the dosage can range from about 0.01 mg/kg to about 20
mg/kg, about 0.05 mg/kg to about 20 mg/kg, about 0.1 mg/kg to about
20 mg/kg, about 0.1 mg/kg to about 15 mg/kg, about 0.1 mg/kg to
about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg
to about 4 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.1 to
about 2 mg/kg, about 1 to about 10 mg/kg, about 1 to about 10
mg/kg, about 1 to about 8 mg/kg, about 1 to about 5 mg/kg, about 1
to about 3 mg/kg, about 1 to about 2 mg/kg of the subject's body
weight. For example, dosages can be about 0.05 mg/kg, about 0.1
mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5
mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9
mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3
mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7
mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1
mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5
mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9
mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg,
about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about
11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15
mg/kg, or about 20 mg/kg of the subject's body weight.
[0216] In some embodiments, the dosage of the anti-CD30 antibody
(e.g., brentuximab vedotin) is 0.1 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.2 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.3 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.4 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.5 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.6 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.7 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.8 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 0.9 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.0 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.1 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.2 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.3 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.4 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.5 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.6 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.7 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.8 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 1.9 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.0 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.1 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.2 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.3 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.4 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is 2.5 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is about 5 mg/kg body weight. In other
embodiments, the dosage of the anti-CD30 antibody (e.g.,
brentuximab vedotin) is about 10 mg/kg body weight.
[0217] In certain embodiments, an anti-CD30 antibody (e.g.,
brentuximab vedotin) is administered at a flat dose. In some
embodiments, the flat dose of the anti-CD30 antibody is a dose
(e.g., flat dose) of at least about 1-1500 mg, at least about
10-1000 mg, such as, at least about 50-800 mg, at least about
100-600 mg, at least about 100-400 mg or at least about 100-200 mg,
such as at least about 1 mg, at least about 3 mg, at least about 5
mg, at least about 8 mg, at least about 10 mg, at least about 20
mg, at least about 30 mg, at least about 40 mg, at least about 50
mg, at least about 60 mg, at least about 70 mg, at least about 80
mg, at least about 90 mg, at least about 100 mg, at least about 110
mg, at least about 120 mg, at least about 130 mg, at least about
140 mg, at least about 150 mg, at least about 160 mg, at least
about 170 mg, at least about 180 mg, at least about 190 mg, 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 600 mg,
at least about 700 mg, at least about 800 mg, at least about 900
mg, at least about 1000 mg, at least about 1100 mg, at least about
1200 mg, at least about 1300 mg, at least about 1400 mg, or at
least about 1500 mg.
[0218] In certain embodiments, an anti-CD30 antibody (e.g.,
brentuximab vedotin) is administered at a flat dose. In some
embodiments, the flat dose of the anti-CD30 antibody is a dose
(e.g., flat dose) of about 1-1500 mg, about 10-1000 mg, such as,
about 50-800 mg, about 100-600 mg, about 100-400 mg or about
100-200 mg, such as about 1 mg, about 3 mg, about 5 mg, about 8 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,
about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150
mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, 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, about 600 mg, about 700 mg, about 800 mg,
about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about
1300 mg, about 1400 mg, or about 1500 mg.
[0219] An exemplary treatment regime entails administration 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, the anti-CD30 antibody
(e.g., brentuximab vedotin) is administered once about every 3
weeks.
[0220] In some embodiments, a subtherapeutic dose of an anti-CD30
antibody (e.g., brentuximab vedotin) is used in the methods herein.
The subtherapeutic dosages of an anti-CD30 antibody (e.g.,
brentuximab vedotin) used in the methods herein are higher than
0.001 mg/kg and lower than 10 mg/kg. In some embodiments, the
subtherapeutic dose is about 0.001 mg/kg-about 10 mg/kg, about 0.01
mg/kg-about 10 mg/kg, about 0.01 mg/kg-about 1 mg/kg, about 0.1
mg/kg-about 1 mg/kg, or about 0.001 mg/kg-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 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4
mg/kg, at least about 0.5 mg/kg, at least about 0.6 mg/kg, at least
about 0.7 mg/kg, at least about 0.8 mg/kg, at least about 0.9
mg/kg, at least about 1 mg/kg, at least about 1.1 mg/kg, at least
about 1.2 mg/kg, at least about 1.3 mg/kg, at least about 1.4
mg/kg, at least about 1.5 mg/kg, at least about 1.6 mg/kg, or at
least about 1.7 mg/kg body weight.
[0221] In certain embodiments, at least about 0.1 mg/kg to about 5
mg/kg of the anti-CD30 antibody (e.g., brentuximab vedotin) and at
least about 240 mg of the anti-PD-1 antibody are administered to
the subject once about every three weeks. In certain embodiments,
at least about 0.1 mg/kg of the anti-CD30 antibody (e.g.,
brentuximab vedotin) and at least about 240 mg of the anti-PD-1
antibody are administered to the subject once about every three
weeks. In certain embodiments, at least about 0.2 mg/kg of the
anti-CD30 antibody (e.g., brentuximab vedotin) and at least about
240 mg of the anti-PD-1 antibody are administered to the subject
once about every three weeks. In certain embodiments, at least
about 0.3 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 0.4 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 0.5 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 0.6 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 0.7 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 0.8 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 0.9 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 1 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 1.1 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 1.2 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 1.3 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 1.4 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 1.5 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 1.6 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 1.7 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 1.8 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 1.9 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 2 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 3 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
certain embodiments, at least about 4 mg/kg of the anti-CD30
antibody (e.g., brentuximab vedotin) and at least about 240 mg of
the anti-PD-1 antibody are administered to the subject once about
every three weeks. In certain embodiments, at least about 5 mg/kg
of the anti-CD30 antibody (e.g., brentuximab vedotin) and at least
about 240 mg of the anti-PD-1 antibody are administered to the
subject once about every three weeks. In certain embodiments, at
least about 10 mg/kg of the anti-CD30 antibody (e.g., brentuximab
vedotin) and at least about 240 mg of the anti-PD-1 antibody are
administered to the subject once about every three weeks. In
embodiments, the anti-CD30 antibody is brentuximab vedotin. In some
embodiments, the anti-PD-1 antibody is nivolumab.
[0222] In certain embodiments, the combination of an anti-PD-1
antibody (e.g., nivolumab) and an anti-CD30 antibody (e.g.,
brentuximab vedotin) is administered intravenously to the subject
once about every 3 weeks for a total of nine weeks. In some
embodiments, the nine week cycle is repeated 3 or 4 times. In
embodiments, the subject is treated with a combination of an
anti-PD-1 antibody (e.g., nivolumab) and an anti-CD30 antibody
(e.g., brentuximab vedotin) every 3 weeks for a total of nine weeks
and 3 nine-week cycles are performed. In embodiments, the subject
is treated with a combination of an anti-PD-1 antibody (e.g.,
nivolumab) and an anti-CD30 antibody (e.g., brentuximab vedotin)
every 3 weeks for a total of nine weeks and 4 nine-week cycles are
performed. In embodiments, a subject is treated with the anti-PD-1
antibody for 12 nine-week cycles.
[0223] In certain embodiments, the anti-CD30 antibody (e.g.,
brentuximab vedotin) is administered (e.g., intravenously) to a
subject on day 1 of the first cycle (cycle 1 day 1); the anti-PD-1
antibody (e.g., Nivolumab) is administered (e.g., intravenously) to
the subject on day 8 of the cycle (cycle 1 day 8); and a
combination of an anti-CD30 antibody (e.g., brentuximab vedotin)
and an anti-PD-1 antibody (e.g., Nivolumab) is administered (e.g.,
intravenously) on day 1 of each of cycles 2-4. In some embodiments,
each cycle is two weeks, 15 days, three weeks, four weeks, a month,
five weeks, or six weeks. In one particular embodiment, the subject
is treated with about 1.8 mg/kg of an anti-CD30 antibody (e.g.,
brentuximab vedotin) on cycle 1 day 1 (e.g., 21 day cycle); about 3
mg/kg of an anti-PD-1 antibody (e.g., Nivolumab) on cycle 1 day 8;
and a combination of an anti-CD30 antibody (e.g., brentuximab
vedotin) and an anti-PD-1 antibody (e.g., Nivolumab) on day 1 of
each of cycles 2-4. In one particular embodiment, the combination
of an anti-CD30 antibody (e.g., brentuximab vedotin) and an
anti-PD-1 antibody (e.g., Nivolumab) comprises a dose of about 1.8
mg/kg of an anti-CD30 antibody (e.g., brentuximab vedotin) and a
dose of about 3 mg/kg of an anti-PD-1 antibody (e.g.,
Nivolumab).
[0224] Treatment is continued as long as clinical benefit is
observed or until unacceptable toxicity or disease progression
occurs. In certain embodiments, 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., 2012 N Engl J Med 366:2443-54; Topalian et al.,
2012 Curr Opin Immunol 24:207-12), at a flat dose of 240 mg, or at
a significantly lower dose, i.e., at a subtherapeutic dose.
[0225] In certain embodiments, the subject is treated with a
combination of an anti-PD-1 antibody and an anti-CD30 antibody once
about every 3 weeks for a set period of time followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. In some embodiments, the subject is treated
with a combination of an anti-PD-1 antibody and an anti-CD30
antibody once about every 3 weeks for about 6 weeks followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. In some embodiments, the subject is treated
with a combination of an anti-PD-1 antibody and an anti-CD30
antibody once about every 3 weeks for about 9 weeks followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. In some embodiments, the subject is treated
with a combination of an anti-PD-1 antibody and an anti-CD30
antibody once about every 3 weeks for about 12 weeks followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. In some embodiments, the subject is treated
with a combination of an anti-PD-1 antibody and an anti-CD30
antibody once about every 3 weeks for about 24 weeks followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. In some embodiments, the subject is treated
with a combination of an anti-PD-1 antibody and an anti-CD30
antibody once about every 3 weeks for about 48 weeks followed by a
monotherapy of an anti-PD-1 antibody or a monotherapy of an
anti-CD30 antibody. The monotherapy of the anti-PD-1 antibody can
be administered by any route disclosed herein at any dose disclosed
herein. In one embodiment, the monotherapy of the anti-PD-1
antibody is administered intravenously at a flat dose of 240 mg. In
another embodiment, the monotherapy of the anti-PD-1 antibody is
administered intravenously at a dose of 3 mg/kg or 6 mg/kg. The
monotherapy of the anti-CD30 antibody can be administered by any
route disclosed herein at any dose disclosed herein. In one
embodiment, the monotherapy of the anti-CD30 antibody, e.g.,
brentuximab vedotin, is administered intravenously at a dose of 1.8
mg/kg.
[0226] 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 nonhuman 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, and until the patient shows
partial or complete amelioration of symptoms of disease.
Thereafter, the patient can be administered a prophylactic
regime.
[0227] Actual dosage levels of the active 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
[0228] Also within the scope of the present disclosure are kits
comprising an anti-PD-1 antibody and an anti-CD30 antibody 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 cancer, the kit comprising: (a) a dosage ranging
from about 4 mg to about 500 mg of an anti-PD-1 antibody or
antigen-binding portion thereof; (b) a dosage ranging from about
0.1 mg to about 500 mg of an anti-CD30 antibody or antigen-binding
portion thereof; and (c) instructions for using the anti-PD-1
antibody and the anti-CD30 antibody in any of the combination
therapy methods disclosed herein. In certain embodiments, the
anti-PD-1 antibody, the anti-CD30 can be co-packaged in unit dosage
form. In certain embodiments for treating human patients, the kit
comprises an anti-human PD-1 antibody disclosed herein, e.g.,
nivolumab, pembrolizumab, MEDI0680 (formerly AMP-514), AMP-224, or
BGB-A317. In other embodiments, the kit comprises an anti-human
CD30 antibody disclosed herein, e.g., brentuximab vedotin.
[0229] The present disclosure is further illustrated by the
following examples which should not be construed as further
limiting. The contents of all references cited throughout this
application are expressly incorporated herein by reference.
EXAMPLES
Example 1
[0230] A phase 1/2 open-label, international, multicenter study
(NCT02581631), is underway to investigate the safety and efficacy
of nivolumab combined with BV in patients with relapsed/refractory
NHL.
BACKGROUND
[0231] Treatment options for patients with relapsed, refractory
non-Hodgkin lymphoma (NHL) are limited. Nivolumab is a fully human
IgG4 monoclonal antibody immune checkpoint inhibitor that targets
programmed death receptor-1 (PD-1) to restore active T-cell immune
responses against the tumor (FIG. 1). Nivolumab has approval in the
United States as treatment for metastatic melanoma, metastatic
non-small cell lung cancer, and advanced renal cell carcinoma.
Safety and tolerability of nivolumab is consistent across both
solid and hematologic tumor types. While PD-1 blockade has shown
encouraging activity in aggressive B-cell and T-cell NHL--a phase 1
trial demonstrated an objective response rate (ORR) of 36% in
heavily pretreated patients with relapsed, refractory diffuse large
B-cell lymphoma (DLBCL)--the majority of patients either do not
respond or progress after an initial response. Combination therapy
with therapeutic agents such as antibody-drug conjugates can
increase the frequency and durability of responses, through both
direct cell killing and immunogenic consequences of cell death.
[0232] Brentuximab vedotin (BV) is a CD30-directed antibody--drug
conjugate that has shown anti-tumor activity in a range of lymphoid
malignancies. BV works primarily by inducing cell cycle arrest and
apoptotic death in CD30-expressing cells. BV may also mediate
immunogenic cell death, bystander-killing effects, and
antibody-dependent cellular phagocytosis (FIG. 2). Gardai S J, et
al. Cancer Res 2015; 75(Suppl. 15):2469 [abstract]; Li F et al.
Cancer Res 2016; 76:2710-2719; and Oflazoglu E, et al. Blood 2007;
110:4370-4372.
[0233] In studies of patients with CD30+ relapsed, refractory
DLBCL, CD30+ relapsed, refractory peripheral T-cell lymphoma
(PTCL), and CD30+ cutaneous T-cell lymphoma (CTCL) treated with BV,
ORR observed was 44%, 41%, and 73%, respectively. BV is approved in
the United States as treatment for cHL after autologous stem cell
transplant (ASCT) failure, or after failure of .gtoreq.2 prior
chemotherapy regimens in non-ASCT candidates, and for systemic
anaplastic large cell lymphoma after failure of .gtoreq.1
chemotherapy regimen. BV elicits its effect by inducing cell cycle
arrest and apoptotic death in CD30-expressing cells, and can also
mediate immunogenic cell death, bystander effects, and
antibody-dependent cellular phagocytosis. As BV can mediate
immunogenic cell death, it could synergize with PD-1 blockade. We
hypothesize that nivolumab and BV can induce frequent and durable
responses in patients with CD30+ relapsed, refractory T-cell NHL
and diffuse large B-cell lymphoma (DLBCL).
Study Rationale
[0234] Patients with relapsed, refractory NHLs after progression
following systemic therapy represent an area of substantial unmet
medical need. BV can provide synergy with immune checkpoint
inhibitors by inducing immunogenic cell death, which can upregulate
the expression of the costimulatory molecule CD86 and MHC class II
antigens on antigen-presenting cells in the tumor microenvironment.
We hypothesize that the complementary mechanisms of actions of
nivolumab in combination with BV could provide frequent and durable
responses for patients with CD30+ relapsed, refractory NHL.
Study Design
[0235] The design of the present single-arm, phase 1/2 multicenter
study is shown in FIG. 3. Treatment continues in 3-week cycles
until disease progression or unacceptable toxicity. Both nivolumab
and BV are administered as 30-minute IV infusions. For cycles in
which both treatments are given on the same day, the schedule is as
follows: BV infusion, 30-minute rest, nivolumab infusion. Planned
enrollment is for 96 patients: 6 in phase 1 and 90 in phase 2;
recruitment will be equal across the 3 subtypes. Key inclusion and
exclusion criteria are shown in Table 1.
TABLE-US-00001 TABLE 1 Key Inclusion/Exclusion Criteria Inclusion
Exclusion Patients with relapsed, refractory NHLs, NHL involving
the CNS including DLBCL, PTCL, CTCL, PMBL, and MGZL Expression of
CD30 on .gtoreq.1% of tumor cells, History of progressive
multifocal confirmed via immunohistochemical leukoencephalopathy
analysis Age .gtoreq.15 years for patients with PMBL, .gtoreq.18
Any active grade 3+ infection within 2 years for other histologies
weeks prior to the first dose of BV ECOG PS score of 0 or 1
Pre-existing neuropathy of grade >2 Tumor tissue (biopsy) for
biomarker Prior BV exposure analysis Measurable disease according
to 2014 Prior exposure to immune checkpoint Lugano Classification
for patients with inhibitor DLBCL, PTCL, PMBL, and MGZL Suspected
or known autoimmune disease CNS = central nervous system; ECOG PS =
Eastern Cooperative Oncology Group Performance Status; IHC =
immunohistochemistry
Objectives
[0236] The primary objectives of the present study are two-fold.
First, safety and tolerability of nivolumab in combination with BV
will be evaluated in patients with relapsed, refractory NHLs.
Second, the clinical benefit of nivolumab in combination with BV
will be assessed in patients with relapsed, refractory NHLs, as
measured by objective response rate (ORR; patients achieving a best
overall response of either partial response or complete
response).
[0237] The secondary objectives are to measure the duration of
response, the complete response (CR) rate and duration of CR, and
the progression free survival (PFS) and overall survival rate. In
addition, exploratory objectives include (i) indeterminate response
(IR) per Lymphoma Response to Immunomodulatory therapy Criteria
(LYRIC); (ii) assessment of CD30 expression and PD-L1/2 status, and
correlation with response, and (iii) identification of biomarkers
of response or resistance to the BV and nivolumab combination
regimen.
[0238] After the administration of BV and nivolumab, the patients
will show improved overall response rates, increased overall
survival, increased progression free survival, decreased tumor
burden, decreased occurrence of drug-related adverse events or any
combination thereof.
Example 2
[0239] A phase 1/2 study (NCT02572167) is ongoing to assess the
safety profile and antitumor activity of BV administered in
combination with nivolumab in patients with relapsed or refractory
Hodgkin lymphoma (HL). Patients will be treated for up to four
21-day cycles with BV 1.8 mg/kg and nivolumab 3 mg/kg. Patients
will be administered 1.8 mg/kg BV on Cycle 1 Day 1, and 3 mg/kg
nivolumab on Cycle 1 Day 8. For cycles 2 through 4, BV and
nivolumab will be administered on Day 1 of each cycle at the same
doses, e.g., 1.8 mg/kg BV and 3 mg/kg nivolumab. Both BV and
nivolumab will be administered by IV injection. After completion of
the Cycle 4 response assessment (EOT), patients will be eligible to
undergo ASCT. Responses were assessed using the 2014 Lugano
classification (Cheson et al., J Clin Oncol 2014;
32(27):3059-68).
[0240] There will be two parts to this study. In Part 1, the safety
of combination treatment will be evaluated by a Safety Monitoring
Committee (SMC) prior to expansion of enrollment to evaluate
treatment effect in Part 2. Part 2 of the study will further
characterize safety and evaluate the antitumor activity of BV
combined with nivolumab by enrolling patients at the recommended
dose schedule determined in Part 1. Key inclusion and exclusion
criteria are shown in Table 2. Patients were excluded if they
previously received more than one line of anti-cancer therapy; BV
or any immuno-oncology therapy affecting the PD-1, CTLA4, or CD137
pathways; and/or Allogeneic or autologous stem cell transplant
(ASCT).
TABLE-US-00002 TABLE 2 Key Inclusion/Exclusion Criteria Inclusion
Exclusion Relapsed or refractory Hodgkin lymphoma Previously
treated with BV, immune- following failure of standard frontline
oncology agents, or received an allogeneic chemotherapy for the
treatment of classical or autologous stem cell transplant Hodgkin
lymphoma Documented history of a cerebral vascular event Eastern
Cooperative Oncology Group History of another invasive malignancy
that (ECOG) performance status of 0 or 1 has not been in remission
for at least 3 years Age 18 years or older History of progressive
multifocal leukoencephalopathy (PML)
[0241] The primary outcome measures of the present study are
two-fold. First, safety and tolerability of nivolumab in
combination with BV will be evaluated in patients with relapsed or
refractory HL. Second, the clinical benefit of nivolumab in
combination with BV will be assessed in patients with relapsed or
refractory HL, as measured by complete response (CR) rate (CRR;
patients achieving a best overall response of complete response)
following the completion of study treatment, AE incidence, and
severity.
[0242] The secondary outcome measures are to measure objective
response rate (ORR), the duration of response, the duration of
complete response (CR) and objective response, and the progression
free survival (PFS) post-autologous stem cell transplant. In
addition, exploratory objectives include assessment of CD30
expression and correlation with response and to identification of
biomarkers of response or resistance to the BV and nivolumab
combination regimen.
[0243] After the administration of BV and nivolumab, the patients
will show improved overall response rates, increased overall
survival, increased progression free survival, decreased tumor
burden, decreased occurrence of drug-related adverse events or any
combination thereof.
Results
[0244] Target enrollment of approximately 55 adult patients with
classical Hodgkin lymphoma (cHL) that had relapsed or was
refractory (RR) to frontline chemotherapy was met and patient
information is provided below in Tables 3 and 4.
TABLE-US-00003 TABLE 3 Patient Characteristics Patient demographics
and disease characteristics N = 62 Median age, years (range) 36
(18-69) Gender (M/F) 30/32 Disease status relative to frontline tx,
n (%) Primary refractory 28 (45) Relapsed, remission duration
.ltoreq.1 year 19 (31) Bulky disease at baseline, n (%) 8 (13)
Extranodal disease at baseline, n (%) 16 (26) Disease stage at
initial diagnosis, n (%) I/II 37 (60) III/IV 24 (39) Unknown 1 (2)
Median prior therapies.sup.a (range) 1 (1-3) Prior chemotherapy
regimens, n (%) ABVD 56 (90) BEACOPP 2 (3) Stanford V 2 (3)
Other.sup.b 6 (10) Prior radiation 9 (15)
TABLE-US-00004 TABLE 4 Patient Disposition N = 62 Patient
disposition.sup.c n (%) Received .gtoreq.1 dose of both study
drugs, n (%) 61 (98) Remain on tx 0 Completed tx 58 (94) Reason for
tx discontinuation.sup.d Patient decision 2 (3) Adverse event 1 (2)
Investigator decision 1 (2) Received alternative salvage regimen 12
(19) ICE.sup.e 9 (15) GEMOX 1 (2) BeGEV 1 (2) Nivolumab 1 (2) a
Includes radiation b ABVD + AVD (3 pts), ABVE-PC (2 pts), R-ABVD (1
pt) .sup.c1 pt discontinued before receiving study drug .sup.dPts
who did not receive study drug still provided a reason for tx
discontinuation .sup.e2 of 9 pts who received ICE also received
other regimens; 1 pt received 3 other salvage regimens:
carboplatin/gemcitabine/decadron (not evaluable), followed by BV
(PD), followed by gemcitabine/oxaliplatin (PD), and 1 pt had HL and
FL and received bendamustine/rituximab
[0245] Initially, twenty-five patients (60% female) with a median
age of 32 years (range, 18-69) were enrolled to date. Sixty percent
of patients have relapsed disease, 36% have primary refractory
disease (failure to achieve complete response (CR) with frontline
therapy, or relapse within 3 months of completing frontline
therapy), and 1 patient (4%) has unknown status. At the time of
enrollment, 32% of patients presented with extranodal disease and
16% with bulky disease.
[0246] Currently, sixty-two patients (52% female) with a median age
of 36 years (range, 18-69) have been enrolled to date. Thirty-one
percent of patients have relapsed disease, and forty-five percent
of patients have primary refractory disease. At the time of
enrollment, 26% of patients presented with extranodal disease and
13% with bulky disease.
[0247] At the time of the previous data extract, 23 patients had
received treatment. An increased incidence of infusion-related
reactions (IRRs) was observed at the start of combination treatment
in Cycle 2 during the BV infusion leading to 1 dose delay.
Premedication with corticosteroids (hydrocortisone 100 mg or
equivalent) and antihistamines at Cycles 2-4 was instituted through
a protocol amendment.
[0248] At the time of the previous data extract, six patients have
completed combination treatment, and all have achieved an objective
response rate (ORR, 100%), with 3 of 6 achieving a complete
metabolic response (CmR, 50%). All 6 patients have proceeded
directly to ASCT. The median number of CD34.sup.+ cells collected
was 12.9.times.10.sup.6 cells/kg (range, 5-26) in a mean number of
1.7 apheresis sessions (range, 1-2).
[0249] Currently, fifty-nine patients (95%) have completed
combination treatment, with a high objective response rate (85%)
with 63% complete responses (FIGS. 5A and 5B). Additional
information about patient responses is provided in Table 5 below.
Thirty-seven patients have proceeded to ASCT.
TABLE-US-00005 TABLE 5 N = 59 n (%) Complete response (CR) 37 (63)
Deauville .ltoreq.2 29 (49) Deauville 3 7 (12) Deauville 5.sup.a 1
(2) Partial response (PR) 13 (22) Deauville 4 7 (12) Deauville 5 6
(10) No metabolic response (SD) 5 (8) Deauville 5 5 (8) Progressive
disease (PD) 3 (5) Deauville 5 2 (3) Missing 1 (2) Clinical
Progression (CP) 1 (2) .sup.a1 patient had uptake in lymph node,
but no evidence of disease was found on biopsy
[0250] Priming of the immune system was indicated by an increase in
pro-inflammatory cytokine and chemokine levels after BV dosing with
high levels maintained following concurrent BV and nivolumab
administration (FIGS. 6A-6D).
[0251] Additionally, an initial reduction in some T helper subsets
(including Tregs) (FIG. 7A) and activated and proliferating
CD4.sup.+ T cells (FIGS. 7B and 7C) after single agent BV
administration, is followed by an expansion after combination
dosing.
[0252] BV and nivolumab in combination were well tolerated in
patients with relapsed refractory cHL. Potential immune-mediated
AEs requiring steroids occurred in <10% of patients (FIG. 8).
And although IRRs occurred relatively frequently (41% of patients),
most frequently during the Cycle 2 BV infusion and required dose
interruptions in 25% of patients, the maximum severity was Grade 3
which occurred in less than 5% of patients (FIG. 9).
[0253] Mandatory premedication with low-dose corticosteroids
(hydrocortisone 100 mg or equivalent) and antihistamine at Cycles
2-4 was instituted. The rate of IRRs at Cycle 2 was equivalent
before and after instituting premedication, i.e., 5 of 15 patients
(33%) developed IRRs without premedication, whereas 15 of 45
patients (33%) developed IRRs with premedication. The rate of IRRs
at Cycles 3-4 was low irrespective of premedication
requirements.
[0254] Pre-ASCT treatment-emergent AEs occurred in 98% of patients
at the following frequencies: Grade 1 (25%), Grade 2 (36%), Grade 3
(33%; anemia most frequent at 8%), and Grade 4 (5%).
Treatment-related SAEs occurred in 5 patients (8%): pneumonitis and
pyrexia each occurred in 2 patients; and colitis, malaise, nausea,
pneumonia, respiratory failure, and sepsis each occurred in 1
patient. No unusual post-ASCT toxicities were reported.
[0255] Systemic steroids for potential immune-mediated AEs were
required in 7% of patients. Each of the following was experience by
1 patient: Grade 4 pneumonitis and colitis (related to BV and
nivolumab, 2 patients or 3%), Grade 2 pneumonitis (id.), Grade 3
diarrhea and Grade 2 colitis, and Grade 3 AST elevation.
[0256] Preliminary biomarker data indicate a BV-induced decrease in
the percentage of CD4.sup.+ T regulatory (T.sub.reg) cells at Cycle
1 Day 8, with no effect on proliferating CD8.sup.+ T cells. At
Cycle 1, nivolumab induced a robust expansion of T cells one week
after dosing (2 weeks after BV dosing), with no significant change
observed in the percentage of CD4.sup.+ Th1 cells compared to
baseline for most patients (5 of 6, 83%).
[0257] Early data suggest the combination of BV and nivolumab is an
active and well-tolerated salvage therapy in patients with relapsed
or refractory (R/R) Hodgkin lymphoma (HL). While an elevated
incidence of IRRs has been observed, toxicities with this regimen
appear to be tolerable overall. The preliminary antitumor activity
suggests this combination can be a promising option for R/R HL
patients.
[0258] The promising activity of the BV and nivolumab combination
supports further exploration of this novel regimen for RR cHL
patients.
Example 3
[0259] A randomized, open-label, Phase 3 trial of nivolumab plus
brentuximab vedotin versus brentuximab vedotin alone in
participants with relapsed refractory or ineligible for autologous
stem cell transplant (ASCT) advanced stage classical Hodgkin
Lymphoma is planned.
Background
[0260] The programmed death-1 (PD-1) cell surface membrane receptor
is a member of the CD28 family of T-cell co-stimulatory receptors.
PD-1 expression is a marker of T cell exhaustion and is associated
with immune evasion in tumors. Hodgkin Lymphoma (HL) is
characterized by genetic predisposition for over expression of
programmed death (PD)-1 ligands. There are multiple mechanisms
identified for upregulation of PD-L1 and PD-L2 in HL. Additionally
CD30 is a cell membrane protein of the tumor necrosis factor
family. CD30 is highly expressed in HL on the Reed Sternberg cells.
Given the abundant expression of PD-1 ligands and CD30 in HL, the
two proteins provide opportunity to target specific molecules
associated with tumor growth and progression. Ongoing trials with
the combination of brentuximab vedotin (BV) and nivolumab appear
promising. Nivolumab and BV have demonstrated encouraging single
agent activity in the treatment of relapsed HL. Since both drugs
are effective as single agents, it is likely that the combination
may have better efficacy as compared to either agent alone. A Phase
1/2 trial of the BV and nivolumab combination is ongoing in adults
with Relapsed/Refractory Hodgkin Lymphoma after failure of
first-line therapy. In this study, patients have been treated for a
total of 4 cycles with combination regimen. Overall, the
combination has been well tolerated with none of the participants
requiring dose discontinuation due to toxicities. All patients were
able to tolerate 4 cycles of combination regimen. The majority of
adverse events including immune-related adverse events were low
grades (1 and 2). Preliminary results are indicative of a highly
efficacious regimen in a sample size n=20, with an Objective
Overall Response Rate of 90% and Complete Metabolic Response of
62%. Similar findings have been observed in another ongoing trial.
The preliminary data from the E4412 trial with a sample size (N=10)
for relapsed/refractory patients has demonstrated an ORR of 100%
and CR of 63%. Although the studies are ongoing and numbers are
small, preliminary findings are suggestive of an effective and
tolerable regimen in a refractory patient population with high
unmet need.
[0261] It is therefore anticipated that combination therapy could
potentially be more effective in the salvage treatment setting than
administration of either agent alone. The combination may result in
demonstrating higher clinical benefit, which can translate into
improved disease control in a patient population where outcome is
poor. Moreover, both agents are well tolerated, have few
overlapping toxicities, and can be infused in the outpatient
setting.
Study Population
[0262] Males and females, ages 18 and above with
relapsed/refractory cHL and with one of the following:
a) Autologous Stem Cell Transplant (ASCT) Ineligible Patients
[0263] Chemo-resistant disease (unable to achieve CR or PR to
salvage chemotherapy) or any significant coexisting medical
condition (cardiac, renal, pulmonary, or hepatic dysfunction) are
likely to have a negative impact on tolerability of ASCT. Note:
Sponsor review and approval of participants <65 years of age who
are not ASCT candidates is required before randomization.
Participants must have received at least 2 prior chemotherapy
regimens (BV can be included as one regimen).
b) Patients after Failure of ASCT: [0264] Documented absence of CR
after 90 days from stem cell infusion for the most recent ASCT
[0265] Documented relapsed disease (after CR) or disease
progression (after PR or SD)
[0266] Both for a) and b), participants who are naive to BV or who
were sensitive to the most recent BV treatment are eligible.
Participants must demonstrate BV sensitivity as defined by
documented PR or CR from the most recent BV treatment, and by no
disease progression during the most recent BV treatment or no early
relapse within 3 months after last dose of the most recent BV based
on medical record. For b), prior treatment with BV may have been as
a single agent or in combination with chemotherapy and may have
occurred during any line of therapy (e.g., induction, salvage, or
consolidation post-ASCT). Of note, documentation of response
following consolidation therapy with BV is not required, as it is
assumed that the patients are in remission at the time of
consolidation.
[0267] Other key inclusion criteria include ECOG PS 0-1 and biopsy
confirmation of cHL prior to initiation of study drug. Key
exclusion criteria include known CNS lymphoma, nodular
lymphocyte-predominant HL, and active interstitial pneumonitis or
CT evidence of Grade 1 pneumonitis.
Objectives and Endpoints
[0268] The primary and secondary objectives of the study, and the
endpoints of the study, are set forth in Table 6 below. The primary
objectives in the study will be measured by the primary endpoint of
PFS assessed by BICR. The secondary objectives in the study will be
measured by: (1) CRR, ORR, DOR, and DOCR assessed by BICR; (2) PFS
assessed by investigator; and (3) OS.
TABLE-US-00006 TABLE 6 Objectives/Endpoints Objectives Endpoints
Primary To compare progression free survival Progression Free
Survival (PFS): of nivolumab + BV vs. BV based on defined as time
from date of BICR assessments randomization to death, or disease
progression. Secondary To compare the complete response rate
Complete Response Rate (CRR): of nivolumab + BV vs. BV based on
defined as proportion of participants BICR assessments who have
achieved complete response To assess objective response rate and
(Lugano 2014 conference) duration of response based on BICR
Objective Response Rate (ORR): To assess duration of complete
defined as the proportion of participants response based on BICR
who have achieved complete response To assess overall survival of
or partial response (Lugano 2014 participants treated with
nivolumab + classification) BV vs BV Duration of response or
duration of To assess PFS based on investigator complete response
(DOR or DOCR): assessments defined as the time from first response
or complete response to the date of initial objectively documented
progression as determined using the 2014 Lugano classification or
death due to any cause Overall Survival (OS): defined as the time
between the date of randomization and the date of death. PFS
defined as the above but assessed by investigator.
[0269] The primary endpoint PFS based on BICR assessment will be
compared in two randomized arms via a two-sided, log-rank test
stratified by the same factors used in randomization. Participants
who die without a reported progression will be considered to have
progressed on the date of their
Overall Design
[0270] This is a 1:1 randomized, open-label phase 3 study in
advanced cHL participants 18 years old who are relapsed refractory
or ineligible for autologous stem cell transplant (ASCT). Patients
will be balanced in the 2 groups in regards to prior therapies.
Approximately 340 participants will be treated in one of two arms:
(1) nivolumab 360 mg IV every 3 weeks until progression or
unacceptable toxicity (except for patients in CR who can
discontinue at 2 years) plus BV 1.8 mg/kg IV every 3 weeks for 16
cycles, or until progression or unacceptable toxicity, whichever
occurs first, or (2) BV alone 1.8 mg/kg every 3 weeks for 16
cycles, or until progression or unacceptable toxicity, whichever
occurs first. Treatment may also be discontinued if the participant
meets other criteria for discontinuation of study drug outlined in
Section 8.1 of the protocol. Participants receiving nivolumab who
achieve CR may discontinue treatment after a maximum of 2 years of
therapy, provided that there is no prohibitive toxicity.
Participants can be BV-naive, or can have prior BV treatment as a
single agent or in combination in any line of therapy.
Randomization stratification will be performed on the following two
factors: (1) Prior ASCT status (YES/NO); (2) Prior BV use (YES/NO).
Participants will be balanced based on the stratification factors
per arm.
[0271] Participants will undergo screening evaluations to determine
eligibility within 28 days prior to first dose. Each 21-day dosing
period will constitute a cycle.
[0272] Any participant who discontinues the study treatment prior
to progression will be followed for progression, then survival, in
the follow up phase of the study.
[0273] Approximately 400 participants will be screened and then,
with an estimated screen failure rate of 15%, the planned sample
size for this study will be approximately 340 randomized
participants. The sample size of the study accounts for the primary
efficacy endpoint, PFS. PFS will be evaluated for treatment effect
at the overall alpha level of 0.05 (two-sided) with 90% power.
[0274] Sample size determination for PFS provides approximately 340
participants will be randomized to nivolumab+BV and BV arms in a
1:1 ratio, i.e., such that 170 participants will be assigned to the
nivolumab+BV arm, and 170 participants will be assigned to the BV
arm. For the comparison of PFS between the two treatment arms, the
study requires at least 187 PFS events to ensure that a two-sided
5% type I error sequential test procedure will have 90% power to
detect a hazard ratio (HR) of 0.62, corresponding to a median PFS
of 15 vs 9.3 months for the nivolumab+BV and BV arms,
respectively.
[0275] One formal PFS interim analysis will be conducted when at
least 131 PFS events (70% of the final PFS events) have been
observed and also requires a minimum follow-up of 9 months from
Last Patient First Visit (LPFV).
[0276] Assuming an accrual rate of 10 participants enrolled per
month, the accrual will take approximately 30.5 months. The final
analysis for PFS is expected to take place 46 months after the
first participant's randomization date (30.5 months of accrual+15.5
months of follow-up). This projection is based on an assumption
that the progression free survival rates are 28% and 45.4% at 24
months in BV arm and nivolumab+BV arm, and very few events will
occur after two years of treatment in both arms. The interim
analysis for PFS is expected to take place 40 months after the
first participant's randomization date.
[0277] East version 6.3 was used for sample size/power
computations.
[0278] The treatment arms and duration are shown in FIG. 10. The
study treatment includes (1) a Randomized Investigational Arm:
Nivolumab (360 mg flat dose) every 3 weeks until progression or
unacceptable toxicity+BV (1.8 mg/kg) every 3 weeks for 16 cycles,
progression, or unacceptable toxicity, whichever occurs first; and
(2) a Randomized Control Arm: BV (1.8 mg/kg) every 3 weeks for 16
cycles, progression, or unacceptable toxicity, whichever occurs
first. Further information about preparations and routes of
administration for nivolumab and BV is provided in Table 7
below.
TABLE-US-00007 TABLE 7 Study Drug Medication Potency IP/Non-IP
Nivolumab (BMS-936558) 100 mg (10 mg/mL) IP Solution for Injection
and 40 mg (10 mg/mL) Brentuximab Vedotin Powder 50 mg IP for
Solution for Injection
[0279] Other medications used as support medication for
preventative, diagnostic, or therapeutic reasons, as components of
the standard of care for a given diagnosis, may be considered as
non-investigational products.
Example 4
BV-Killed A20 Mouse Lymphoma Immunization Confers Anti-Tumor
Protection
[0280] A20 mouse lymphoma cells were transfected with plasmid
constructs encoding human TNFRSF8 (NM 001243.4) and sgRNA/Cas9 for
control under the endogenous promoter of murine Tnfrsf8.
Fluorescence activated cell sorting (FACS) yielded a clonal
population of A20 cells that stably expressed human CD30, to be
referenced as A20.sup.hCD30, in order to be susceptible to
brentuximab vedotin treatment.
[0281] A20.sup.hCD30 cells were cultured in RPMI 1640 with 10% FBS,
10 mM HEPES, 1 mM sodium pyruvate, penicillin (100 U/ml), and
streptomycin (100 .mu.g/ml). A20.sup.hCD30 cells were treated with
1 .mu.g/ml BV or 100 nM mc-vc-MMAE for 4 days. In order to prepare
dying cells for immunization, treated A20.sup.hCD30 cells were
overlaid atop Histopaque, and centrifuged at 2000 g for 30 minutes.
Dead and dying cells were pelleted underneath the Histopaque layer,
and viability was assessed to be <20% live cells by trypan blue
exclusion. Flash-frozen A20.sup.hCD30 cells were prepared by
submerging cells in liquid nitrogen for 10 seconds, followed by
immersion in 37.degree. C. water until completely thawed. The
liquid nitrogen freeze-thaw process was repeated 5 times. Dead and
dying A20.sup.hCD30 cells were resuspended in PBS and
2.times.10.sup.6 cells were injected into the peritoneum of
immune-competent Balb/c mice. 7 days later, mice received a second
immunization with dead and dying cells prepared in the same
manner.
[0282] 14 days after initial immunization, mice were subcutaneously
implanted with 5.times.10.sup.6 wild-type A20 cells and monitored
for tumor growth. As shown in FIG. 11, mice that were immunized
with BV-killed or mc-vc-MMAE-killed A20.sup.hCD30 cells delayed
tumor growth, and increased survival of tumor-bearing mice. As
these effects occurred in the absence of any administered
therapeutic, the presence of cells killed by BV or MMAE were
sufficient to generate long-lasting protective immune memory
against subsequent A20 lymphoma challenge.
T Cell Transfer Provides Protective Immunity
[0283] Immune-competent Balb/c mice were immunized with BV-killed
or flash-frozen-killed A20.sup.hCD30 cells as previously described.
16 weeks after initial immunization, spleens were harvested from
immunized mice or naive Balb/c mice, and manually homogenized.
Splenic homogenates were combined from 4 mice per immunization, and
CD3.sup.+ T cells were isolated using EasySep Mouse T cell
Enrichment Kit (Stem Cell Technologies). 1.times.10.sup.6 CD3+ T
cells were administered intravenously into A20 tumor-bearing
mice.
[0284] 4.times.10.sup.6 wild-type A20 cells were subcutaneously
implanted into immunodeficient NOD/SCID/.gamma.-chain-deficient
(NSG) mice. 5 days after implant, mice harboring tumors .about.100
mm.sup.3 were randomized, and received 1.times.10.sup.6T cells from
mice as described above. As shown in FIG. 12A, NSG mice that
received T cells from mice immunized with BV-killed cells slowed
tumor growth, as well as increased CD8 T cells within the tumor
(FIG. 12B). The capacity of T cells to provide robust anti-tumor
immunity long after immunization demonstrates that tumor death from
BV elicits strong immune memory that is mediated by T cells.
PD-1 Inhibition Potentiates Protective Immunity Conferred by BV
[0285] Balb/c mice were immunized with BV- or MMAE-killed
A20.sup.hCD30 cells as described above. 14 days after initial
immunization, mice were subcutaneously implanted with
5.times.10.sup.6 wild-type A20 cells. Anti-murine PD-1 (1 mg/kg,
BioLegend) was administered intravenously on days 6, 9, 14, and 17
after A20 tumor challenge. Immunization with BV- or MMAE-killed
A20.sup.hCD30 cells conferred protective anti-tumor immunity. As
shown in FIG. 13, combination with anti-PD-1 therapy augmented
protective immunity and improved tumor clearance and survival.
T Cell and NK Cell Infiltration into Autologous Tumors in a
Humanized Mouse Model.
[0286] Epstein Barr virus (EBV) transformed lymphoblastoid cell
Lines (LCL) were implanted subcutaneously into NSG mice. When LCL
tumor volumes reached 250 mm.sup.3, mice received a single
suboptimal dose of BV or control hIgG-MMAE (1 mg/kg, i.p). Three
days following dosing, 2.0.times.10.sup.6 autologous peripheral
blood mononuclear cells (PBMC) were adoptively transferred to mice
via tail vein injection. Eleven days following transfer of PBMC,
tumors were harvested, weighed, and manually dissociated through a
70 .mu.m cell strainer. Following centrifugation, individual tumor
cell pellets were resuspended in 4 ml of RPMI+10% FCS, and 200 ul
of the cell suspension was used for staining and analysis by flow
cytometry (FACS). Tumor cell suspensions were stained with Zombie
Aqua Viability Dye (Biolegend) followed by staining with
fluorescently labeled antibodies targeting human CD19, CD2, CD8,
CD4, CD56, human CD45, PD-L1, PD-1, and murine CD45.1 (1:50
dilution, Biolegend) in staining buffer (SB: PBS, 2% FCS, 1% NRS,
0.05% NaN.sub.3) at 4.degree. C. for 30 minutes. Cells were washed
and resuspended in 120 .mu.l of SB for plate-based FACS using an
Attune NXT flow cytometer. All events were collected from 80 .mu.l
of sample, and FACS-measured cell concentrations were used to
calculate numbers of infiltrating immune cells. CD8.sup.+ T cells
were identified as viability dye.sup.neg, hCD45.sup.+,
mCD45.1.sup.-, CD2.sup.+, CD8.sup.+ cells. NK cells were identified
as viability dye.sup.neg, hCD45.sup.+, mCD45.1.sup.-, CD2.sup.+,
CD56.sup.+ cells. FIG. 14A shows calculated cell counts relative to
tumor mass, or alternatively, as a calculated total cell count
(FIG. 14B). FIG. 14C shows CD8.sup.+ T cells recovered from tumors
expressed increased levels of PD-1, and LCL tumor cells expressed
heightened levels of PD-L1 relative to their resting/normal PBMC
counterparts (FIG. 14D). Treatment of mice harboring established
LCL tumors with a suboptimal dose of BV enhanced intratumoral
accumulation of human cytotoxic cells consistent with the induction
of an anti-tumor inflammatory response.
BV Enhances Immune-Mediated Tumor Clearance Alone and in
Combination with Nivolumab in the Humanized LCL Tumor Model.
[0287] Epstein Barr virus (EBV) transformed lymphoblastoid cell
lines (LCL) were implanted subcutaneously into NSG mice. When LCL
tumors averaged 250 mm.sup.3, mice received a single suboptimal
dose of BV or control hIgG-MMAE (1 mg/kg, i.p). Three days
following dosing, 2.times.10.sup.6 autologous PBMC were adoptively
transferred to mice via tail vein injection. Mice received two
doses of nivolumab (10 mg/kg, i.p.) 2 and 7 days after adoptive
transfer of PBMC. FIG. 15A shows treatment group tumor volume over
time, relative to untreated (no drug) control. Notably, mice
receiving a suboptimal dose of BV without the addition of PBMC
(solid line, top) did not reject tumors and were removed from the
study when tumors exceeded 2000 mm.sup.3. All other treatment
groups received autologous PBMC and showed tumor regression,
highlighting the role of immune-mediated tumor clearance in this
model. A single, suboptimal dose of BV administered 3 days prior to
transfer of PBMC resulted in enhanced immune-mediated tumor
clearance compared to mice receiving control hIgG-MMAE or nivolumab
alone. Importantly, mice receiving a combination of BV and
nivolumab showed the most rapid tumor clearance of any treatment
group. The significance of these differences is reflected in a
comparison of mean tumor volumes at day 50, during active tumor
clearance (FIG. 15B). Taken together, results obtained from this
humanized model support the conclusion that in addition to direct
tumor cell killing, BV drives an inflammatory response that
enhances immune-mediated cellular cytotoxicity and pairs well with
nivolumab.
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