NZ737018B2 - Pd-l1 antagonist combination treatments - Google Patents
Pd-l1 antagonist combination treatments Download PDFInfo
- Publication number
- NZ737018B2 NZ737018B2 NZ737018A NZ73701816A NZ737018B2 NZ 737018 B2 NZ737018 B2 NZ 737018B2 NZ 737018 A NZ737018 A NZ 737018A NZ 73701816 A NZ73701816 A NZ 73701816A NZ 737018 B2 NZ737018 B2 NZ 737018B2
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- NZ
- New Zealand
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- cancer
- antibody
- avelumab
- antagonist
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Abstract
The present disclosure describes combination therapies comprising an antagonist of Programmed Death Ligand 1 receptor (PD-L1) (Avelumab) and a VEFGR inhibitor that is is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide (axitinib) for the treatment of cancer.
Description
PD-L1 ANTAGONIST COMBINATION TREATMENTS
Field
The present invention relates to combination therapies useful for the treatment
of cancer. In particular, the invention relates to a combination therapy which comprises
an antagonist of a Programmed Death-Ligand 1 protein (PD-L1) and one or more
additional therapeutic agent(s).
Background
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes
about 3% of all malignant tumors in adults. Until 2005, interferon-alpha (IFN-α) and
high-dose interleukin (IL)-2 therapies were the standards of care for patients with
advanced RCC (aRCC), albeit with modest efficacy. Since then, development and
approval of multiple vascular endothelial growth factor (VEGF) pathway and
mammalian target of rapamycin (mTOR) inhibitors have significantly improved the
outcomes of aRCC patients. These agents include the VEGF receptor (VEGFR)
tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and sorafenib, the mTOR
inhibitors temsirolimus and everolimus, and the anti-VEGF monoclonal antibody
bevacizumab. However, despite the substantial improvement of patient outcomes with
these agents, durable and complete responses in aRCC patients are uncommon; the
majority of patients will eventually develop resistance, exhibit disease progression
while on therapy, and succumb to death due to metastatic disease.
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1 and
PD-L2, respectively) play integral roles in immune regulation. Expressed on activated
T cells, PD-1 is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by
stromal cells, tumor cells, or both, initiating T-cell death and localized immune
suppression (Dong et al., Nat Med 1999; 5:1365-69; Freeman et al. J Exp Med 2000;
192:1027-34), potentially providing an immune-tolerant environment for tumor
development and growth. Conversely, inhibition of this interaction can enhance local
T-cell responses and mediate antitumor activity in nonclinical animal models (Iwai Y,
et al. Proc Natl Acad Sci USA 2002; 99:12293-97). Avelumab is a fully human mAb of
the IgG1 isotype that specifically targets and blocks PD-L1. Avelumab is the
International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody
MSB0010718C.
Axitinib is a VEGF receptor (VEGFR) TKI. The antitumor activity of single-agent
axitinib 5 mg twice daily (BID) in previously untreated patients with clear cell aRCC
was assessed against sorafenib in a randomized, open-label, Phase 3 trial. Although
the study did not demonstrate a statistically significant difference in progression-free
survival (PFS) between patients treated with axitinib or sorafenib, axitinib was
associated with a longer median PFS (mPFS) time (mPFS of 10.1 months (95% CI
7.2,12.1) with axitinib vs. 6.5 months (95% CI 4.7, 8.3) with sorafenib, stratified hazard
ratio 0.77 (95% CI 0.56, 1.05)).
4-1BB (CD137 and TNFRSF9), which was first identified as an inducible
costimulatory receptor expressed on activated T cells, is a membrane spanning
glycoprotein of the Tumor Necrosis Factor (TNF) receptor superfamily. Current
understanding of 4-1BB indicates that expression is generally activation dependent
and encompasses a broad subset of immune cells including activated NK and NKT
cells; regulatory T cells; dendritic cells (DC) including follicular DC; stimulated mast
cells, differentiating myeloid cells, monocytes, neutrophils, eosinophils, and activated
B cells. 4-1BB expression has also been demonstrated on tumor vasculature (19-20)
and atherosclerotic endothelium. The ligand that stimulates 4-1BB (4-1BBL) is
expressed on activated antigen presenting cells (APCs), myeloid progenitor cells and
hematopoietic stem cells. 4-1BB agonist mAbs increase costimulatory molecule
expression and markedly enhance cytolytic T lymphocyte responses, resulting in anti-
tumor efficacy in various models. 4-1BB agonist mAbs have demonstrated efficacy in
prophylactic and therapeutic settings and both monotherapy and combination therapy
tumor models and have established durable anti-tumor protective T cell memory
responses
Macrophage colony stimulating factor (M-CSF) is a member of the family of
proteins referred to as colony stimulating factors (CSFs). M-CSF, also known as CSF-
1, is a secreted or a cell surface glycoprotein comprised of two subunits that are joined
by a disulfide bond with a total molecular mass varying from 40 to 90 kD (Stanley E.
R., et al., Mol. Reprod. Dev., 46:4-10 (1997)). Similar to other CSFs, M-CSF is
produced by macrophages, monocytes, and human joint tissue cells, such as
chondrocytes and synovial fibroblasts, in response to proteins such as interleukin-1 or
tumor necrosis factor-alpha. M-CSF stimulates the formation of macrophage colonies
from pluripotent hematopoietic progenitor stem cells (Stanley E. R., et al., Mol. Reprod.
Dev., 46:4-10 (1997)). M-CSF typically bind to its receptor, c-fms, in order to exert a
biological effect. c-fms contains five extracellular Ig domains, one transmembrane
domain, and an intracellular domain with two kinase domains. Upon M-CSF binding to
c-fms, the receptor homo-dimerizes and initiates a cascade of signal transduction
pathways including the JAK/STAT, PI3K, and ERK pathways.
The OX40 receptor (OX40, also known as CD134, TNFRSF4, ACT-4, ACT35,
and TXGP1L) is a member of the TNF receptor superfamily. OX40 is found to be
expressed on activated CD4+ T-cells. High numbers of OX40+ T cells have been
demonstrated within tumors (tumor infiltrating lymphocytes) and in the draining lymph
nodes of cancer patients (Weinberg, A. et al., J. Immunol. 164: 2160-69, 2000; Petty,
J. et al., Am. J. Surg. 183: 512-518, 2002). It was shown in tumor models in mice that
engagement of OX40 in vivo during tumor priming significantly delayed and prevented
the appearance of tumors as compared to control treated mice (Weinberg et al., 2000).
Therefore, it has been contemplated to enhance the immune response of a mammal
to an antigen by engaging OX40 through the use of an OX40 binding agent (WO
99/42585; Weinberg et al., 2000).
The rituximab antibody is a genetically engineered chimeric murine/human
monoclonal antibody directed against the CD20 antigen. Rituximab is the antibody
called “C2B8” in U.S. Pat. No. 5,736,137 issued Apr. 7, 1998 (Anderson et al.).
rituximab is indicated for the treatment of patients with relapsed or refractory low-grade
or follicular, CD20 positive, B cell non-Hodgkin's lymphoma. In vitro mechanism of
action studies have demonstrated that rituximab binds human complement and lyses
lymphoid B cell lines through complement-dependent cytotoxicity (CDC) (Reff et al.
Blood 83(2):435-445 (1994)). Additionally, it has significant activity in assays for
antibody-dependent cellular cytotoxicity (ADCC).
There is a need for improved therapies for the treatment of cancers.
Furthermore, there is a need for therapies having greater efficacy than existing
therapies. Preferred combination therapies of the present invention show greater
efficacy than treatment with either therapeutic agent alone.
Summary
This invention relates to therapeutic regimens for treatment of cancer. In
particular the present invention provides:
1. The use of an antagonist of a Programmed Death Ligand 1 protein (PD-L1) in
the manufacture of a medicament for treating a cancer in a subject, said treating
comprising combination therapy with the antagonist of PD-L1 antagaonist and
a VEGFR inhibitor, wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal
antibody comprising: three CDRs in the heavy chain variable region, having
amino acid sequences according to SEQ ID NO’s 2, 3 and 4, and three CDRs
in the light chain variable region, having amino acid sequences according to
SEQ ID NO’s 5, 6, and 7, and wherein the VEGFR inhibitor is N-methyl-
2-[3-((E)pyridinyl-vinyl)-1H-indazolylsulfanyl]-benzamide (axitinib) or a
pharmaceutically acceptable salt thereof.
2. The use of a VEGFR inhibitor in the manufacture of a medicament for treating
a cancer in a subject, said treating comprising combination therapy with the
VEGFR inhibitor and a PD-L1 antagonist, wherein the PD-L1 antagonist is an
anti-PD-L1 monoclonal antibody comprising: three CDRs in the heavy chain
variable region, having amino acid sequences according to SEQ ID NO’s 2, 3
and 4, and three CDRs in the light chain variable region, having amino acid
sequences according to SEQ ID NO’s 5, 6, and 7, and wherein the VEGFR
inhibitor is N-methyl[3-((E)pyridinyl-vinyl)-1H-indazolylsulfanyl]-
benzamide (axitinib) or a pharmaceutically acceptable salt thereof.
3. The use of 1 or 2 in which both the VEGFR inhibitor and PD-L1 antagonist are
used in the manufacture of the medicament.
4. The use of any one of 1 to 3, wherein the PD-L1 antagonist is avelumab.
. The use of any one of 1 to 4, wherein the combination therapy comprises
administering the PD-L1 antagonist as an initial dose of at least 5 mg/kg, or 10
mg/kg, and the VEGFR inhibitor as an initial dose of at least 3 mg/kg or 5 mg/kg.
6. The use of any one of 1 to 5, wherein the combination therapy comprises
administering the PD-L1 antagonist once every two weeks, and the VEGFR
inhibitor twice daily.
7. The use of 4, wherein the combination therapy comprises administration of the
avelumab as a 1-hour intravenous infusion, and the axitinib orally.
8. The use of 7, wherein the combination therapy comprises administration of the
axitinib is with or without food.
9. The use of 7 or 8, wherein the combination therapy comprises administration of
the axitinib on a continuous dosing schedule.
. The use of any one of 1 to 9, wherein the axitinib is formulated as a 5 mg tablet.
11. The use of any one of 1 to 10, wherein the cancer is bladder cancer, breast
cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung
squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer
(NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell
carcinoma, small-cell lung cancer (SCLC), triple negative breast cancer, acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-
cell lymphoma (DLBCL), follicular lymphoma, Hodgkin’s lymphoma (HL), mantle
cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein
(Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL),
Squamous Cell Carcinoma of the Head and Neck (SCCHN), or small
lymphocytic lymphoma (SLL).
12. The use of 11, wherein the cancer is renal cell carcinoma.
13. The use of 11 or 12, wherein the cancer is advanced renal cell carcinoma.
14. The use of 12 or 13, wherein the renal cell carcinoma is previously untreated
advanced renal cell carcinoma.
. The use of any one of 1 to 14, wherein the cancer tests positive for PD-L1
expression.
16. A kit which comprises a first container, a second container and a package insert,
wherein the first container comprises at least one dose of a medicament
comprising an antagonist of a Programmed Death 1 protein (PD-L1), the second
container comprises at least one dose of a medicament comprising a VEGFR
inhibitor, and the package insert comprises instructions for treating a subject for
cancer using the medicaments, wherein the PD-L1 antagonist is an anti-PD-L1
monoclonal antibody comprising three CDRs in the heavy chain variable region,
having amino acid sequences according to SEQ ID NO’s 2, 3 and 4 and three
CDRs in the light chain variable region, having amino acid sequences according
to SEQ ID NO’s 5, 6 and 7, and further wherein the VEGFR inhibitor is N-methyl-
2-[3-((E)pyridinyl-vinyl)-1H-indazolylsulfanyl]-benzamide (axitinib) or a
pharmaceutically acceptable salt thereof.
17. The kit of 16, wherein the instructions state that the medicaments are intended
for use in treating a subject having a cancer that tests positive for PD-L1
expression by an immunohistochemical (IHC) assay.
18. The kit of 16 or 17, wherein the PD-L1 antagonist is avelumab formulated as a
liquid medicament and the VEGFR inhibitor is axitinib formulated as a 1 mg
tablet or a 5 mg tablet.
19. The kit of any one of 16 to 18, wherein the cancer is bladder cancer, breast
cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung
squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer
(NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell
carcinoma, small-cell lung cancer (SCLC), triple negative breast cancer, acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-
cell lymphoma (DLBCL), follicular lymphoma, Hodgkin’s lymphoma (HL), mantle
cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein
(Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL),
Squamous Cell Carcinoma of the Head and Neck (SCCHN), or small
lymphocytic lymphoma (SLL).
. The kit according to 18, wherein the cancer is renal cell carcinoma.
21. The kit of 19 or 20, wherein the cancer is advanced renal cell carcinoma.
22. The kit of 20 or 21, wherein the renal cell carcinoma is previously untreated
advanced renal cell carcinoma.
The invention is described further below with reference to the above and other
embodiments which are provided herein for completeness.
Thus provided herein are methods for treating a cancer in a subject. Also
provided are methods of inhibiting tumor growth or progression in a subject who has
malignant cells. Also provided are methods of inhibiting metastasis of malignant cells
in a subject. Also provided are methods of inducing tumor regression in a subject who
has malignant cells.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist and a VEGFR inhibitor. In
some embodiments, the invention provides a medicament comprising a PD-L1
antagonist for use in combination with a VEGFR inhibitor for treating a cancer. In
some embodiments, the invention provides a medicament comprising a VEGFR
inhibitor for use in combination with a PD-L1 antagonist for treating a cancer. Other
embodiments provide use of a PD-L1 antagonist in the manufacture of medicament
for treating a cancer in a subject when administered in combination with a VEGFR
inhibitor and use of a VEGFR inhibitor in the manufacture of a medicament for
treating a cancer in a subject when administered in combination with a PD-L1
antagonist. In some embodiments, the invention provides use of a PD-L1 antagonist
and a VEGFR inhibitor in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with a VEGFR inhibitor to treat a cancer in a subject. In all of the above
embodiments of the treatment method, medicaments and uses herein, the VEGFR
inhibitor is N-methyl[3-((E)pyridinyl-vinyl)-1H-indazolylsulfanyl]-benzamide
or a pharmaceutically acceptable salt thereof.
Also provided are kits comprising a first container, a second container and a
package insert, wherein the first container comprises at least one dose of a
medicament comprising an anti-PD-L1 antagonist, the second container comprises at
least one dose of a medicament comprising a VEGFR inhibitor, and the package insert
comprises instructions for treating a subject for cancer using the medicaments.
In some embodiments of the above methods, medicaments, uses or kits, the
VEGFR inhibitor can be axitinib and can be formulated as a 1 mg tablet, 3 mg tablet,
or a 5 mg tablet.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist and an anti1BB antibody.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist and an anti-M-CSF
antibody. In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist and an anti-OX40 antibody.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist, an anti1BB antibody, and
an anti-M-CSF antibody. In some embodiments, the method comprises administering
to the subject a combination therapy which comprises a PD-L1 antagonist, an anti
1BB antibody, and an anti-OX40 antibody.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist and a CD20 antagonist. In
some embodiments, the method comprises administering to the subject a combination
therapy which comprises a PD-L1 antagonist, a CD20 antagonist, and an anti1BB
antibody. In some embodiments, the PD-L1 antagonist is avelumab and the CD20
antagonist is rituximab. In some embodiments, the anti1BB antibody is PF-
05082566. In some embodiments, the method comprises administering rituximab at a
dose of 375 mg/m IV on Day 1 of a 28 day cycle, PF-05082566 at a fixed dose of 100
mg as a 1 hour IV infusion on Day 2 of each cycle, and avelumab as a 1 hour IV infusion
on Day 2 and Day 16 of each cycle at a dose of 10 mg/kg. In some embodiments, the
method comprises administering rituximab at a dose of 375 mg/m IV on Day 1 of a 28
day cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV infusion on Day 1 of
each cycle, and avelumab as a 1 hour IV infusion on Day 2 and Day 16 of each cycle
at a dose of 10 mg/kg. In some embodiments, the method comprises administering
rituximab at a dose of 375 mg/m IV on Day 1 of a 28 day cycle, PF-05082566 at a
fixed dose of 100 mg as a 1 hour IV infusion on Day 1 of each cycle, and avelumab as
a 1 hour IV infusion on Day 1 and Day 15 of each cycle at a dose of 10 mg/kg. In some
embodiments, the method comprises administering rituximab at a dose of 375 mg/m
IV on Day 1 of a 28 day cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV
infusion on Day 2 of each cycle, and avelumab as a 1 hour IV infusion on Day 1 and
Day 15 of each cycle at a dose of 10 mg/kg. In some embodiments, avelumab is
administered at least 3 hours after PF-05082566 when avelumab and PF-05082566
are administered on the same day. In some embodiments, avelumab is administered
about 60 minutes after PF-05082566 when avelumab and PF-05082566 are
administered on the same day. In some embodiments, avelumab is administered about
minutes after PF-05082566 when avelumab and PF-05082566 are administered on
the same day. In some embodiments, the cancer is R/R DLBCL.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist, a CD20 antagonist, and
bendamustine. In some embodiments, the method comprises administering to the
subject a combination therapy which comprises a PD-L1 antagonist, a CD20
antagonist, and bendamustine. In some embodiments, the PD-L1 antagonist is
avelumab and the CD20 antagonist is rituximab. In some embodiments, the method
comprises administering rituximab at a dose of 375 mg/m IV on Day 1 of a 28 day
cycle, bendamustine at a dose of 90 mg/m IV on Day 2 and Day 3 of each 28 day
cycle, and avelumab as a 1 hour IV infusion on Day 2 and Day 16 of each cycle at a
dose of 10 mg/kg. In some embodiments, the method comprises administering
rituximab at a dose of 375 mg/m IV on Day 1 of a 28 day cycle, bendamustine at a
dose of 90 mg/m IV on Day 1 and Day 2 of each 28 day cycle, and avelumab as a 1
hour IV infusion on Day 2 and Day 16 of each cycle at a dose of 10 mg/kg. In some
embodiments, the method comprises administering rituximab at a dose of 375 mg/m
IV on Day 1 of a 28 day cycle, bendamustine at a dose of 90 mg/m IV on Day 2 and
Day 3 of each 28 day cycle, and avelumab as a 1 hour IV infusion on Day 1 and Day
of each cycle at a dose of 10 mg/kg. In some embodiments, the method comprises
administering rituximab at a dose of 375 mg/m IV on Day 1 of a 28 day cycle,
bendamustine at a dose of 90 mg/m IV on Day 1 and Day 2 of each 28 day cycle, and
avelumab as a 1 hour IV infusion on Day 1 and Day 15 of each cycle at a dose of 10
mg/kg. In some embodiments, avelumab is administered at least 3 hours after
bendamustine when avelumab and bendamustine are administered on the same day.
In some embodiments, the cancer is R/R DLBCL.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises a PD-L1 antagonist, azacitidine, and an anti
1BB antibody. In some embodiments, the method comprises administering to the
subject a combination therapy which comprises avelumab, azacitidine, and PF-
05082566. In some embodiments, the method comprises administering azacitidine at
a daily dose of 75 mg/m subcutaneously (SC) each day from Day 1 to Day 7 of a 28
day cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV infusion on Day 2 of
each cycle, and avelumab as a 1 hour IV infusion on Day 2 and Day 16 of each cycle
at a dose of 10 mg/kg. In some embodiments, the method comprises administering
azacitidine at a daily dose of 75 mg/m SC each day from Day 1 to Day 7 of a 28 day
cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV infusion on Day 1 of each
cycle, and avelumab as a 1 hour IV infusion on Day 2 and Day 16 of each cycle at a
dose of 10 mg/kg. In some embodiments, the method comprises administering
azacitidine at a daily dose of 75 mg/m SC each day from Day 1 to Day 7 of a 28 day
cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV infusion on Day 1 of each
cycle, and avelumab as a 1 hour IV infusion on Day 1 and Day 15 of each cycle at a
dose of 10 mg/kg. In some embodiments, the method comprises administering
azacitidine at a daily dose of 75 mg/m SC each day from Day 1 to Day 7 of a 28 day
cycle, PF-05082566 at a fixed dose of 100 mg as a 1 hour IV infusion on Day 2 of each
cycle, and avelumab as a 1 hour IV infusion on Day 1 and Day 15 of each cycle at a
dose of 10 mg/kg. In some embodiments, on the days when avelumab is administered
on the same day as azacitidine, avelumab is administered at least 3 hours after
administration of azacitidine. In some embodiments, avelumab is administered at least
3 hours after PF-05082566 when avelumab and PF-05082566 are administered on the
same day. In some embodiments, avelumab is administered about 60 minutes after
PF-05082566 when avelumab and PF-05082566 are administered on the same day.
In some embodiments, avelumab is administered about 30 minutes after PF-05082566
when avelumab and PF-05082566 are administered on the same day. In some
embodiments, the cancer is R/R DLBCL.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises avelumab and PF-05082566. In some
embodiments, the cancer is advanced NSCLC, RCC, or urothelial cancer which was
resistant (responded and then progressed) or refractory (never responded) to prior
therapy(ies), including for example a single-agent immune checkpoint inhibitor (e.g.,
anti-PD-1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody treatment). In some
embodiments, avelumab is administered as a 1 hour IV infusion every 2 weeks at a
dose of 10 mg/kg, PF-05082566 is administered at fixed dose of 10 mg as a 1 hour IV
infusion once every four weeks on Day 1 of each cycle, and on days when both
avelumab and PF-05082566 are administered, PF-05082566 is administered first,
followed by avelumab infusion within 30 mintues after the end of the PF-05082566
infusion.
In some embodiments, the method comprises administering to the subject a
combination therapy which comprises avelumab and chemoradiotherapy. In some
embodiments, the chemoradiotherapy comprises cisplatin and definitive radiation
therapy. In some embodiments, subject has locally-advanced squamous cell
carcinoma of the head and neck (SCCHN). In some embodiments, the SCCHN is
localized to the oral cavity, oropharynx, larynx, or hypopharynx. In some embodiments,
the method comprises a lead-in phase and a chemoradiotherapy (CRT) phase,
wherein the lead-in phase begins seven days prior to initiation of the CRT phase. In
some embodiments, avelumab is administered at a dose of 10 mg/kg on Day 1 of the
lead-in phase and on Day 8, Day 29, and Day 39 of the CRT phase; cisplatin is
administered at a dose of 100 mg/m on Day 1, Day 22, and Day 23 of the CRT phase;
and radiation therapy is 70 Gy/33-35 fractions/day, 5 fractions/week intensity
modulated radiation therapy (IMRT). In some embodiments, the method comprises a
maintenance phase which begins two weeks after completion of the CRT phase. In
some embodiments the maintenance phase comprises administration of avelumab at
a dose of 10 mg/kg every two weeks (Q2W) after completion of the CRT phase.
In all of the above treatment methods, medicaments and uses, the PD-L1
antagonist inhibits the binding of PD-L1 to PD-1. In some embodiments of the above
treatment methods, medicaments and uses, the PD-L1 antagonist is a monoclonal
antibody, or an antigen binding fragment thereof, which specifically binds to PD-L1 or
to PD-1 and blocks the binding of PD-L1 to PD-1. In some embodiments, the PD-L1
antagonist is an anti-PD-L1 antibody which comprises three complementarity
determining regions (CDRs) from a heavy chain variable region comprising the amino
acid sequence shown in SEQ ID NO: 8 and three CDRs from a light chain variable
region comprising the amino acid sequences shown in SEQ ID NO: 9. In some
embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody which comprises heavy
and light chain variable regions comprising the amino acid sequences shown in SEQ
ID NO: 8 and SEQ ID NO: 9, respectively.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti1BB antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
4-1BB antibody for use in combination with a PD-L1 antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti1BB antibody and use of an anti1BB antibody in the manufacture of a
medicament for treating a cancer in a subject when administered in combination with
a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti1BB antibody in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with an anti1BB antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti-M-CSF antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
M-CSF antibody for use in combination with a PD-L1 antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti-M-CSF antibody and use of an anti-M-CSF antibody in the manufacture of a
medicament for treating a cancer in a subject when administered in combination with
a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti-M-CSF antibody in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with an anti-M-CSF antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti-OX40 antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
OX40 antibody for use in combination with a PD-L1 antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti-OX40 antibody and use of an anti-OX40 antibody in the manufacture of a
medicament for treating a cancer in a subject when administered in combination with
a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti-OX40 antibody in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with an anti-OX40 antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti-M-CSF antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
M-CSF antibody for use in combination with a PD-L1 antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti-M-CSF antibody and use of an anti-M-CSF antibody in the manufacture of a
medicament for treating a cancer in a subject when administered in combination with
a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti-M-CSF antibody in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with an anti-M-CSF antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti-OX40 antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
OX40 antibody for use in combination with a PD-L1 antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti-OX40 antibody and use of an anti-OX40 antibody in the manufacture of a
medicament for treating a cancer in a subject when administered in combination with
a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti-OX40 antibody in the manufacture of medicaments for treating a cancer in a
subject. In some embodiments, the medicaments comprise a kit, and the kit also
comprises a package insert comprising instructions for using the PD-L1 antagonist in
combination with an anti-OX40 antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti1BB antibody and an anti-M-CSF
antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
4-1BB antibody and an anti-M-CSF antibody for use in combination with a PD-L1
antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti1BB antibody and an anti-M-CSF antibody and use of an anti1BB antibody
and an anti-M-CSF antibody in the manufacture of a medicament for treating a cancer
in a subject when administered in combination with a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti1BB antibody and an anti-M-CSF antibody in the manufacture of
medicaments for treating a cancer in a subject. In some embodiments, the
medicaments comprise a kit, and the kit also comprises a package insert comprising
instructions for using the PD-L1 antagonist in combination with an anti1BB antibody
and an anti-M-CSF antibody to treat a cancer in a subject.
In some embodiments, the invention provides a medicament comprising a PD-
L1 antagonist for use in combination with an anti1BB antibody and an anti-OX40
antibody for treating a cancer.
In some embodiments, the invention provides a medicament comprising an anti-
4-1BB antibody and an anti-OX40 antibody for use in combination with a PD-L1
antagonist for treating a cancer.
Other embodiments provide use of a PD-L1 antagonist in the manufacture of
medicament for treating a cancer in a subject when administered in combination with
an anti1BB antibody and an anti-OX40 antibody and use of an anti1BB antibody
and an anti-OX40 antibody in the manufacture of a medicament for treating a cancer
in a subject when administered in combination with a PD-L1 antagonist.
In some embodiments, the invention provides use of a PD-L1 antagonist and
an anti1BB antibody and an anti-OX40 antibody in the manufacture of medicaments
for treating a cancer in a subject. In some embodiments, the medicaments comprise a
kit, and the kit also comprises a package insert comprising instructions for using the
PD-L1 antagonist in combination with an anti1BB antibody and an anti-OX40
antibody to treat a cancer in a subject.
In all of the above treatment methods, medicaments and uses, the PD-L1
antagonist inhibits the binding of PD-L1 to PD-1. In some embodiments of the above
treatment methods, medicaments and uses, the PD-L1 antagonist is a monoclonal
antibody, or an antigen binding fragment thereof, which specifically binds to PD-L1 or
to PD-1 and blocks the binding of PD-L1 to PD-1. In some embodiments, the PD-L1
antagonist is an anti-PD-L1 antibody which comprises three CDRs from a heavy chain
variable region comprising the amino acid sequence shown in SEQ ID NO: 8 and three
CDRs from a light chain variable region comprising the amino acid sequence shown in
SEQ ID NO: 9. In some embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody
which comprises heavy and light chain variable regions comprising the amino acid
sequences shown in SEQ ID NO: 8 and SEQ ID NO: 9, respectively. In some
embodiments, the anti-PD-L1 antibody is Avelumab.
In some embodiments, the anti1BB antibody can comprise a heavy chain
variable region comprising three CDRs from the heavy chain variable region having
the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region
comprising three CDRs from the light chain variable region having the amino acid
sequence shown in SEQ ID NO: 19. In some embodiments, the anti1BB antibody
can comprise heavy and light chain variable regions comprising the amino acid
sequences shown in SEQ ID NO: 18 and SEQ ID NO: 19, respectively. In some
embodiments, the anti1BB antibody is PF-05082566.
In some embodiments, the anti-M-CSF antibody can comprise a heavy chain
variable region comprising three CDRs from the heavy chain variable region having
the amino acid sequence shown in SEQ ID NO: 30, and a light chain variable region
comprising three CDRs from the light chain variable region having the amino acid
sequence shown in SEQ ID NO: 31. In some embodiments, the anti-M-CSF antibody
can comprise heavy and light chain variable regions comprising the amino acid
sequences shown in SEQ ID NO: 30 and SEQ ID NO: 31, respectively. In some
embodiments, the anti-M-CSF antibody is PD-0360324.
In some embodiments, the anti-OX40 antibody can comprise a heavy chain
variable region comprising three CDRs from the heavy chain variable region having
the amino acid sequence shown in SEQ ID NO: 38, and a light chain variable region
comprising three CDRs from the light chain variable region having the amino acid
sequence shown in SEQ ID NO: 39. In some embodiments, the anti-OX40 antibody
can comprise a heavy chain variable region comprising the amino acid sequence
shown in SEQ ID NO: 38, and a light chain variable region comprising the amino acid
sequence shown in SEQ ID NO: 39. In some embodiments, the anti-OX40 antibody is
PF-04518600.
In some embodiments of the above treatment methods, medicaments and uses
of the invention, the individual is a human and the cancer is a solid tumor. In some
embodiments, the solid tumor is renal cell carcinoma (RCC), bladder cancer, breast
cancer, clear cell kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung
squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC),
ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or
triple negative breast cancer.
In other embodiments of the above treatment methods, medicaments and uses
of the invention, the individual is a human and the cancer is a Heme malignancy and
in some embodiments, the Heme malignancy is acute lymphoblastic leukemia (ALL),
acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid
leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL,
primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell
lymphoma, follicular lymphoma, Hodgkin’s lymphoma (HL), mantle cell lymphoma
(MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1),
myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), or small
lymphocytic lymphoma (SLL).
Also, in some embodiments of any of the above treatment methods,
medicaments and uses, the cancer tests positive for the expression of one or both of
PD-L1 and PD-L2. In still other embodiments, the cancer has elevated PD-L1
expression.
In some embodiments of the above treatment methods, medicaments and uses,
the subject is a human and the cancer is RCC that tests positive for human PD-L1.
In some embodiments of the above treatment methods, medicaments and uses,
the cancer is advanced RCC with clear cell subtype and is present in a human who
has not been previously treated for RCC.
In some embodiments of the above treatment methods, medicaments and uses,
the cancer is relapsed or refractory (R/R) cancer. In some embodiments, the R/R
cancer is R/R DLBCL.
In some embodiments of the above treatment methods, medicaments and uses,
the cancer is locally advanced cancer. In some embodiments, the locally advanced
cancer is locally advanced SCCHN. In some embodiments, the SCCHN is localized to
the oral cavity, oropharynx, larynx, or hypopharynx.
.Brief Description of the Figures/Drawings
Figure 1 depicts a graph summarizing infiltration of T cells in response to
treatment.
Figure 2 depicts a graph summarizing ratio of CD8+ T cells/Treg in response to
treatment.
Figure 3 depicts a graph summarizing Eomes induction in response to
treatment.
Detailed Description
I. Definitions
So that the invention may be more readily understood, certain technical and
scientific terms are specifically defined below. Unless specifically defined elsewhere in
this document, all other technical and scientific terms used herein have the meaning
commonly understood by one of ordinary skill in the art to which this invention belongs.
“About” when used to modify a numerically defined parameter (e.g., the dose of
a PD-L1 antagonist or VEGFR inhibitor, or the length of treatment time with a
combination therapy described herein) means that the parameter may vary by as much
as 10% below or above the stated numerical value for that parameter. For example, a
dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg.
As used herein, including the appended claims, the singular forms of words
such as "a," "an," and "the," include their corresponding plural references unless the
context clearly dictates otherwise.
"Administration" and "treatment," as it applies to an animal, human,
experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an
exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the
animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell
encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid,
where the fluid is in contact with the cell. "Administration" and "treatment" also means
in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding
compound, or by another cell. The term "subject" includes any organism, preferably an
animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most
preferably a human.
An “antibody” is an immunoglobulin molecule capable of specific binding to a
target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least
one antigen recognition site, located in the variable region of the immunoglobulin
molecule. As used herein, the term encompasses not only intact polyclonal or
monoclonal antibodies, but also fragments thereof (such as Fab, Fab’, F(ab’)2, Fv),
single chain (scFv) and domain antibodies (including, for example, shark and camelid
antibodies), and fusion proteins comprising an antibody, and any other modified
configuration of the immunoglobulin molecule that comprises an antigen recognition
site. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-
class thereof), and the antibody need not be of any particular class. Depending on the
antibody amino acid sequence of the constant region of its heavy chains,
immunoglobulins can be assigned to different classes. There are five major classes of
immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further
divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The
heavy-chain constant regions that correspond to the different classes of
immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The
subunit structures and three-dimensional configurations of different classes of
immunoglobulins are well known.
The term "antigen binding fragment" or “antigen binding portion” of an antibody,
as used herein, refers to one or more fragments of an intact antibody that retain the
ability to specifically bind to a given antigen (e.g., PD-L1). Antigen binding functions of
an antibody can be performed by fragments of an intact antibody. Examples of binding
fragments encompassed within the term "antigen binding fragment" of an antibody
include Fab; Fab’; F(ab’)2; an Fd fragment consisting of the VH and CH1 domains; an
Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a
single domain antibody (dAb) fragment (Ward et al., Nature 341:544-546, 1989), and
an isolated complementarity determining region (CDR).
An antibody, an antibody conjugate, or a polypeptide that “preferentially binds”
or “specifically binds” (used interchangeably herein) to a target (e.g., PD-L1 protein) is
a term well understood in the art, and methods to determine such specific or
preferential binding are also well known in the art. A molecule is said to exhibit “specific
binding” or “preferential binding” if it reacts or associates more frequently, more rapidly,
with greater duration and/or with greater affinity with a particular cell or substance than
it does with alternative cells or substances. An antibody “specifically binds” or
“preferentially binds” to a target if it binds with greater affinity, avidity, more readily,
and/or with greater duration than it binds to other substances. For example, an
antibody that specifically or preferentially binds to a PD-L1 epitope is an antibody that
binds this epitope with greater affinity, avidity, more readily, and/or with greater
duration than it binds to other PD-L1 epitopes or non-PD-L1 epitopes. It is also
understood that by reading this definition, for example, an antibody (or moiety or
epitope) that specifically or preferentially binds to a first target may or may not
specifically or preferentially bind to a second target. As such, “specific binding” or
“preferential binding” does not necessarily require (although it can include) exclusive
binding. Generally, but not necessarily, reference to binding means preferential
binding.
A “variable region” of an antibody refers to the variable region of the antibody
light chain or the variable region of the antibody heavy chain, either alone or in
combination. As known in the art, the variable regions of the heavy and light chain each
consist of four framework regions (FR) connected by three complementarity
determining regions (CDRs) also known as hypervariable regions. The CDRs in each
chain are held together in close proximity by the FRs and, with the CDRs from the other
chain, contribute to the formation of the antigen binding site of antibodies. There are
at least two techniques for determining CDRs: (1) an approach based on cross-species
sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest,
(5th ed., 1991, National Institutes of Health, Bethesda MD)); and (2) an approach
based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al.,
1997, J. Molec. Biol. 273:927-948). As used herein, a CDR may refer to CDRs defined
by either approach or by a combination of both approaches.
A “CDR” of a variable domain are amino acid residues within the variable region
that are identified in accordance with the definitions of the Kabat, Chothia, the
accumulation of both Kabat and Chothia, AbM, contact, and/or conformational
definitions or any method of CDR determination well known in the art. Antibody CDRs
may be identified as the hypervariable regions originally defined by Kabat et al. See,
e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed.,
Public Health Service, NIH, Washington D.C. The positions of the CDRs may also be
identified as the structural loop structures originally described by Chothia and others.
See, e.g., Chothia et al., Nature 342:877-883, 1989. Other approaches to CDR
identification include the “AbM definition,” which is a compromise between Kabat and
Chothia and is derived using Oxford Molecular's AbM antibody modeling software (now
Accelrys®), or the “contact definition” of CDRs based on observed antigen contacts,
set forth in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach,
referred to herein as the “conformational definition” of CDRs, the positions of the CDRs
may be identified as the residues that make enthalpic contributions to antigen binding.
See, e.g., Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still
other CDR boundary definitions may not strictly follow one of the above approaches,
but will nonetheless overlap with at least a portion of the Kabat CDRs, although they
may be shortened or lengthened in light of prediction or experimental findings that
particular residues or groups of residues or even entire CDRs do not significantly
impact antigen binding. As used herein, a CDR may refer to CDRs defined by any
approach known in the art, including combinations of approaches. The methods used
herein may utilize CDRs defined according to any of these approaches. For any given
embodiment containing more than one CDR, the CDRs may be defined in accordance
with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.
"Isolated antibody" and “isolated antibody fragment” refers to the purification
status and in such context means the named molecule is substantially free of other
biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other
material such as cellular debris and growth media. Generally, the term "isolated" is not
intended to refer to a complete absence of such material or to an absence of water,
buffers, or salts, unless they are present in amounts that substantially interfere with
experimental or therapeutic use of the binding compound as described herein.
"Monoclonal antibody" or “mAb” or “Mab”, as used herein, refers to a population
of substantially homogeneous antibodies, i.e., the antibody molecules comprising the
population are identical in amino acid sequence except for possible naturally occurring
mutations that may be present in minor amounts. In contrast, conventional (polyclonal)
antibody preparations typically include a multitude of different antibodies having
different amino acid sequences in their variable domains, particularly their CDRs,
which are often specific for different epitopes. The modifier "monoclonal" indicates the
character of the antibody as being obtained from a substantially homogeneous
population of antibodies, and is not to be construed as requiring production of the
antibody by any particular method. For example, the monoclonal antibodies to be used
in accordance with the present invention may be made by the hybridoma method first
described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant
DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may
also be isolated from phage antibody libraries using the techniques described in
Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222:
581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
"Chimeric antibody" refers to an antibody in which a portion of the heavy and/or
light chain is identical with or homologous to corresponding sequences in an antibody
derived from a particular species (e.g., human) or belonging to a particular antibody
class or subclass, while the remainder of the chain(s) is identical with or homologous
to corresponding sequences in an antibody derived from another species (e.g., mouse)
or belonging to another antibody class or subclass, as well as fragments of such
antibodies, so long as they exhibit the desired biological activity.
“Human antibody” refers to an antibody that comprises human immunoglobulin
protein sequences only. A human antibody may contain murine carbohydrate chains if
produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only
mouse or rat immunoglobulin sequences, respectively.
"Humanized antibody" refers to forms of antibodies that contain sequences from
non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies
contain minimal sequence derived from non-human immunoglobulin. In general, the
humanized antibody will comprise substantially all of at least one, and typically two,
variable domains, in which all or substantially all of the hypervariable loops correspond
to those of a non-human immunoglobulin and all or substantially all of the FR regions
are those of a human immunoglobulin sequence. The humanized antibody optionally
also will comprise at least a portion of an immunoglobulin constant region (Fc), typically
that of a human immunoglobulin. The prefix “hum”, “hu” or “h” is added to antibody
clone designations when necessary to distinguish humanized antibodies from parental
rodent antibodies. The humanized forms of rodent antibodies will generally comprise
the same CDR sequences of the parental rodent antibodies, although certain amino
acid substitutions may be included to increase affinity, increase stability of the
humanized antibody, or for other reasons.
The terms “cancer”, “cancerous”, or “malignant” refer to or describe the
physiological condition in mammals that is typically characterized by unregulated cell
growth. Examples of cancer include but are not limited to, carcinoma, lymphoma,
leukemia, blastoma, and sarcoma. More particular examples of such cancers include
squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer,
glioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute myeloid leukemia
(AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer,
liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer,
endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma,
chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical
cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon
carcinoma, and head and neck cancer. Another particular example of cancer includes
renal cell carcinoma.
“Biotherapeutic agent” means a biological molecule, such as an antibody or
fusion protein, that blocks ligand / receptor signaling in any biological pathway that
supports tumor maintenance and/or growth or suppresses the anti-tumor immune
response.
“Chemotherapeutic agent” is a chemical compound useful in the treatment of
cancer. Classes of chemotherapeutic agents include, but are not limited to: alkylating
agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids,
cytotoxic/antitumor antibiotics, topisomerase inhibitors, photosensitizers, anti-
estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones,
estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing
hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR
inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of
genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic
agents useful in the treatment methods of the present invention include cytostatic
and/or cytotoxic agents.
"Conservatively modified variants" or "conservative substitution" refers to
substitutions of amino acids in a protein with other amino acids having similar
characteristics (e.g. charge, side-chain size, hydrophobicity/hydrophilicity, backbone
conformation and rigidity, etc.), such that the changes can frequently be made without
altering the biological activity or other desired property of the protein, such as antigen
affinity and/or specificity. Those of skill in this art recognize that, in general, single
amino acid substitutions in non-essential regions of a polypeptide do not substantially
alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene,
The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of
structurally or functionally similar amino acids are less likely to disrupt biological
activity. Exemplary conservative substitutions are set forth in Table 1 below.
TABLE 1. Exemplary Conservative Amino Acid Substitutions
Original residue Conservative substitution
Ala (A) Gly; Ser
Arg (R) Lys; His
Asn (N) Gln; His
Asp (D) Glu; Asn
Cys (C) Ser; Ala
Gln (Q) Asn
Glu (E) Asp; Gln
Gly (G) Ala
His (H) Asn; Gln
Ile (I) Leu; Val
Leu (L) Ile; Val
Lys (K) Arg; His
Met (M) Leu; Ile; Tyr
Phe (F) Tyr; Met; Leu
Pro (P) Ala
Ser (S) Thr
Thr (T) Ser
Trp (W) Tyr; Phe
Tyr (Y) Trp; Phe
Val (V) Ile; Leu
"Consists essentially of," and variations such as "consist essentially of" or
"consisting essentially of," as used throughout the specification and claims, indicate
the inclusion of any recited elements or group of elements, and the optional inclusion
of other elements, of similar or different nature than the recited elements, that do not
materially change the basic or novel properties of the specified dosage regimen,
method, or composition. As a non-limiting example, a PD-L1 antagonist that consists
essentially of a recited amino acid sequence may also include one or more amino
acids, including substitutions of one or more amino acid residues, which do not
materially affect the properties of the binding compound.
“Diagnostic anti-PD-L1 monoclonal antibody” means a mAb which specifically
binds to PD-L1 that is expressed on the surface of certain mammalian cells. A mature
PD-L1 lacks the presecretory leader sequence, also referred to as leader peptide The
terms "PD-L1" and "mature PD-L1" are used interchangeably herein, and shall be
understood to mean the same molecule unless otherwise indicated or readily apparent
from the context.
As used herein, an anti-human PD-L1 mAb or a diagnostic anti-hPD-L1 mAb
refers to a monoclonal antibody that specifically binds to mature human PD-L1. A
mature human PD-L1 molecule consists of amino acids 19-290 of the following
sequence (SEQ ID NO: 1): MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIEC
KFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNA
ALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTC
QAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRR
LDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKC
GIQDTNSKKQSDTHLEET (SEQ ID NO: 1).
"Homology" refers to sequence similarity between two polypeptide sequences
when they are optimally aligned. When a position in both of the two compared
sequences is occupied by the same amino acid monomer subunit, e.g., if a position in
a light chain CDR of two different Abs is occupied by alanine, then the two Abs are
homologous at that position. The percent of homology is the number of homologous
positions shared by the two sequences divided by the total number of positions
compared ×100. For example, if 8 of 10 of the positions in two sequences are matched
or homologous when the sequences are optimally aligned then the two sequences are
80% homologous. Generally, the comparison is made when two sequences are
aligned to give maximum percent homology. For example, the comparison can be
performed by a BLAST algorithm wherein the parameters of the algorithm are selected
to give the largest match between the respective sequences over the entire length of
the respective reference sequences.
The following references relate to BLAST algorithms often used for sequence
analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-
410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996)
Meth. Enzymol. 266:131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-
3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993)
Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-
70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., "A model of evolutionary
change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl.
3. M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC;
Schwartz, R.M., et al., "Matrices for detecting distant relationships." in Atlas of Protein
Sequence and Structure, (1978) vol. 5, suppl. 3." M.O. Dayhoff (ed.), pp. 353-358, Natl.
Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-
565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl.
Acad. Sci. USA 89:10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300;
ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA
87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877;
Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. "Evaluating the
statistical significance of multiple distinct local alignments." in Theoretical and
Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14,
Plenum, New York.
"Patient" or "subject" refers to any single subject for which therapy is desired or
that is participating in a clinical trial, epidemiological study or used as a control,
including humans and mammalian veterinary patients such as cattle, horses, dogs,
and cats.
"PD-L1 antagonist" means any chemical compound or biological molecule that
blocks binding of PD-L1 expressed on a cancer cell to PD-1. In any of the treatment
method, medicaments and uses of the present invention in which a human subject is
being treated, the PD-L1 antagonist blocks binding of human PD-L1 to human PD-1.
PD-L1 antagonists useful in the any of the treatment methods, medicaments,
and uses of the present invention include a monoclonal antibody (mAb) which
specifically binds to PD-L1, and preferably specifically binds to human PD-L1. The
mAb may be a human antibody, a humanized antibody or a chimeric antibody, and
may include a human constant region. In some embodiments the human constant
region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant
regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4
constant region. In some embodiments, the antigen binding fragment is selected from
the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
Examples of mAbs that bind to human PD-L1, and useful in the treatment
method, medicaments and uses of the present invention, are described in
WO2013079174, WO2015061668, WO2010089411, WO/2007/005874,
WO/2010/036959, WO/2014/100079, WO2013/019906, WO/2010/077634, and US
Patent Nos. 8552154, 8779108, and 8383796. Specific anti-human PD-L1 mAbs useful
as the PD-L1 antagonist in the treatment method, medicaments and uses of the
present invention include, for example without limitation: avelumab (MSB0010718C),
nivolumab (BMS-936558), MPDL3280A (an IgG1-engineered, anti–PD-L1 antibody),
BMS-936559 (a fully human, anti–PD-L1, IgG4 monoclonal antibody), MEDI4736 (an
engineered IgG1 kappa monoclonal antibody with triple mutations in the Fc domain to
remove antibody-dependent, cell-mediated cytotoxic activity), and an antibody which
comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ
ID NO:21, respectively, of WO2013/019906.
Other PD-L1 antagonists useful in the any of the treatment method,
medicaments and uses of the present invention include an immunoadhesin that
specifically binds to PD-L1, and preferably specifically binds to human PD-L1, e.g., a
fusion protein containing the PD-L1 binding portion of PD-1 fused to a constant region
such as an Fc region of an immunoglobulin molecule.
Table 2 below provides exemplary anti-PD-L1 antibody sequences for use in
the treatment method, medicaments and uses of the present invention.
Table 2. EXEMPLARY ANTI-HUMAN PD-L1 MONOCLONAL ANTIBODY SEQUENCES
Heavy chain CDR1 SYIMM (SEQ ID NO:2)
(CDRH1)
Heavy chain CDR2 SIYPSGGITFY (SEQ ID NO:3)
(CDRH2)
Heavy chain CDR3 IKLGTVTTVDY (SEQ ID NO:4)
(CDRH3)
Light chain CDR1 TGTSSDVGGYNYVS (SEQ ID NO:5)
(CDRL1)
Light chain CDR2 DVSNRPS (SEQ ID NO:6)
(CDRL2)
Light chain CDR3 SSYTSSSTRV (SEQ ID NO:7)
(CDRL3)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGL
Heavy chain
EWVSSIYPSGGITFYADKGRFTISRDNSKNTLYLQMNSLRAEDTAVY
variable region (VR)
YCARIKLGTVTTVDYWGQGTLVTVSS (SEQ ID NO: 8)
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKA
Light chain VR PKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCS
SYTSSSTRVFGTGTKVTVL (SEQ ID NO: 9)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGL
EWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTA
Heavy chain
VYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
Table 2. EXEMPLARY ANTI-HUMAN PD-L1 MONOCLONAL ANTIBODY SEQUENCES
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP
CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF
NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD
KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 10)
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKA
PKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCS
Light chain SYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVC
LISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 11)
“PD-L1” expression as used herein means any detectable level of expression of
PD-L1 protein on the cell surface or of PD-L1 mRNA within a cell or tissue. PD-L1
protein expression may be detected with a diagnostic PD-L1 antibody in an IHC assay
of a tumor tissue section or by flow cytometry. Alternatively, PD-L1 protein expression
by tumor cells may be detected by PET imaging, using a binding agent (e.g., antibody
fragment, affibody and the like) that specifically binds to PD-L1. Techniques for
detecting and measuring PD-L1 mRNA expression include RT-PCR and real-time
quantitative RT-PCR.
Several approaches have been described for quantifying PD-L1 protein
expression in IHC assays of tumor tissue sections. See, e.g., Thompson, R. H., et al.,
PNAS 101 (49); 17174-17179 (2004); Thompson, R. H. et al., Cancer Res. 66:3381-
3385 (2006); Gadiot, J., et al., Cancer 117:2192-2201 (2011); Taube, J. M. et al., Sci
Transl Med 4, 127ra37 (2012); and Toplian, S. L. et al., New Eng. J Med. 366 (26):
2443-2454 (2012).
One approach employs a simple binary end-point of positive or negative for PD-
L1 expression, with a positive result defined in terms of the percentage of tumor cells
that exhibit histologic evidence of cell-surface membrane staining. A tumor tissue
section is counted as positive for PD-L1 expression is at least 1%, and preferably 5%
of total tumor cells.
In another approach, PD-L1 expression in the tumor tissue section is quantified
in the tumor cells as well as in infiltrating immune cells, which predominantly comprise
lymphocytes. The percentage of tumor cells and infiltrating immune cells that exhibit
membrane staining are separately quantified as < 5%, 5 to 9%, and then in 10%
increments up to 100%. For tumor cells, PD-L1 expression is counted as negative if
the score is < 5% score and positive if the score is ≥ 5%. PD-L1 expression in the
immune infiltrate is reported as a semi-quantitative measurement called the adjusted
inflammation score (AIS), which is determined by multiplying the percent of membrane
staining cells by the intensity of the infiltrate, which is graded as none (0), mild (score
of 1, rare lymphocytes), moderate (score of 2, focal infiltration of tumor by
lymphohistiocytic aggregates), or severe (score of 3, diffuse infiltration). A tumor tissue
section is counted as positive for PD-L1 expression by immune infiltrates if the AIS is
≥ 5.
The level of PD-L1 mRNA expression may be compared to the mRNA
expression levels of one or more reference genes that are frequently used in
quantitative RT-PCR, such as ubiquitin C.
In some embodiments, a level of PD-L1 expression (protein and/or mRNA) by
malignant cells and/or by infiltrating immune cells within a tumor is determined to be
“overexpressed” or “elevated” based on comparison with the level of PD-L1 expression
(protein and/ or mRNA) by an appropriate control. For example, a control PD-L1 protein
or mRNA expression level may be the level quantified in nonmalignant cells of the
same type or in a section from a matched normal tissue.
“RECIST 1.1 Response Criteria” as used herein means the definitions set forth
in Eisenhauer et al., E.A. et al., Eur. J Cancer 45:228-247 (2009) for target lesions or
nontarget lesions, as appropriate based on the context in which response is being
measured.
“Sustained response” means a sustained therapeutic effect after cessation of
treatment with a therapeutic agent, or a combination therapy described herein. In some
embodiments, the sustained response has a duration that is at least the same as the
treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment
duration.
"Tissue Section" refers to a single part or piece of a tissue sample, e.g., a thin
slice of tissue cut from a sample of a normal tissue or of a tumor.
"Treat" or "treating" a cancer as used herein means to administer a combination
therapy of a PD-L1 antagonist and another therapeutic agent to a subject having a
cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect,
such as for example, reduced number of cancer cells, reduced tumor size, reduced
rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor
metastasis or tumor growth. Positive therapeutic effects in cancer can be measured in
a number of ways (See, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example,
with respect to tumor growth inhibition, according to National Cancer Institute (NCI)
standards, a T/C less than or equal to 42% is the minimum level of anti-tumor activity.
A T/C < 10% is considered a high anti-tumor activity level, with T/C (%) = Median tumor
volume of the treated/Median tumor volume of the control × 100. In some
embodiments, the treatment achieved by a combination of the invention is any of partial
response (PR), complete response (CR), overall response (OR), progression free
survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also
referred to as “Time to Tumor Progression” indicates the length of time during and after
treatment that the cancer does not grow, and includes the amount of time patients have
experienced a CR or PR, as well as the amount of time patients have experienced
stable disease (SD). DFS refers to the length of time during and after treatment that
the patient remains free of disease. OS refers to a prolongation in life expectancy as
compared to naive or untreated subjects or patients. In some embodiments, response
to a combination of the invention is any of PR, CR, PFS, DFS, OR, or OS that is
assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response
criteria. The treatment regimen for a combination of the invention that is effective to
treat a cancer patient may vary according to factors such as the disease state, age,
and weight of the patient, and the ability of the therapy to elicit an anti-cancer response
in the subject. While an embodiment of any of the aspects of the invention may not be
effective in achieving a positive therapeutic effect in every subject, it should do so in a
statistically significant number of subjects as determined by any statistical test known
in the art such as the Student’s t-test, the chi2-test, the U-test according to Mann and
Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-
test.
The terms “treatment regimen”, “dosing protocol” and dosing regimen are used
interchangeably to refer to the dose and timing of administration of each therapeutic
agent in a combination of the invention.
As used herein, “treatment” is an approach for obtaining beneficial or desired
clinical results. For purposes of this invention, beneficial or desired clinical results
include, but are not limited to, one or more of the following: reducing the proliferation
of (or destroying) neoplastic or cancerous cells, inhibiting metastasis of neoplastic
cells, shrinking or decreasing the size of tumor, remission of a PD-L1 associated
disease (e.g., cancer), decreasing symptoms resulting from a PD-L1 associated
disease (e.g., cancer), increasing the quality of life of those suffering from a PD-L1
associated disease (e.g., cancer), decreasing the dose of other medications required
to treat a PD-L1 associated disease (e.g., cancer), delaying the progression of a PD-
L1 associated disease (e.g., cancer), curing a PD-L1 associated disease (e.g., cancer),
and/or prolong survival of patients having a PD-L1 associated disease (e.g., cancer).
“Ameliorating” means a lessening or improvement of one or more symptoms as
compared to not administering a PD-L1 antibody. “Ameliorating” also includes
shortening or reduction in duration of a symptom.
As used herein, an “effective dosage” or “effective amount” of drug, compound,
or pharmaceutical composition is an amount sufficient to effect any one or more
beneficial or desired results. For prophylactic use, beneficial or desired results include
eliminating or reducing the risk, lessening the severity, or delaying the outset of the
disease, including biochemical, histological and/or behavioral symptoms of the
disease, its complications and intermediate pathological phenotypes presenting during
development of the disease. For therapeutic use, beneficial or desired results include
clinical results such as reducing incidence or amelioration of one or more symptoms of
various PD-L1 associated diseases or conditions (such as for example advanced
RCC), decreasing the dose of other medications required to treat the disease,
enhancing the effect of another medication, and/or delaying the progression of the PD-
L1 associated disease of patients. An effective dosage can be administered in one or
more administrations. For purposes of this invention, an effective dosage of drug,
compound, or pharmaceutical composition is an amount sufficient to accomplish
prophylactic or therapeutic treatment either directly or indirectly. As is understood in
the clinical context, an effective dosage of a drug, compound, or pharmaceutical
composition may or may not be achieved in conjunction with another drug, compound,
or pharmaceutical composition. Thus, an “effective dosage” may be considered in the
context of administering one or more therapeutic agents, and a single agent may be
considered to be given in an effective amount if, in conjunction with one or more other
agents, a desirable result may be or is achieved.
"Tumor" as it applies to a subject diagnosed with, or suspected of having, a
cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any
size, and includes primary tumors and secondary neoplasms. A solid tumor is an
abnormal growth or mass of tissue that usually does not contain cysts or liquid areas.
Different types of solid tumors are named for the type of cells that form them. Examples
of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of
the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of
Cancer Terms).
"Tumor burden" also referred to as "tumor load", refers to the total amount of
tumor material distributed throughout the body. Tumor burden refers to the total
number of cancer cells or the total size of tumor(s), throughout the body, including
lymph nodes and bone narrow. Tumor burden can be determined by a variety of
methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon
removal from the subject, e.g., using calipers, or while in the body using imaging
techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic
resonance imaging (MRI) scans.
The term "tumor size" refers to the total size of the tumor which can be
measured as the length and width of a tumor. Tumor size may be determined by a
variety of methods known in the art, such as, e.g. by measuring the dimensions of
tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using
imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
“Variable regions” or “V region” as used herein means the segment of IgG
chains which is variable in sequence between different antibodies. It extends to Kabat
residue 109 in the light chain and 113 in the heavy chain.
“VEGFR inhibitor” means a small molecule inhibitor of vascular endothelial
growth factor (VEGF) receptor or a monoclonal antibody against vascular endothelial
growth factor (VEGF). In an embodiment, a “VEGFR inhibitor” means a small molecule
inhibitor of vascular endothelial growth factor (VEGF) receptor. Specific VEGFR
inhibitors useful as the VEGFR inhibitor in the treatment method, medicaments and
uses of the present invention, include axitinib, sunitinib, sorafenib, tivozanib, and
bevacizumab. In an embodiment, specific VEGFR inhibitors useful as the VEGFR
inhibitor in the treatment method, medicaments and uses of the present invention,
include axitinib, sunitinib, sorafenib, and tivozanib.
In an embodiment of the treatment method, medicaments and uses of the
present invention, the VEGFR inhibitor is the compound, N-methyl[3-((E)pyridin-
2-yl-vinyl)-1H-indazolylsulfanyl]-benzamide or 6-[2-
(methylcarbamoyl)phenylsulfanyl]E-[2-(pyridinyl)ethenyl]indazole, of the
following structure:
which is known as axitinib or AG-013736.
Axitinib is a potent and selective inhibitor of vascular endothelial growth factor
(VEGF) receptors 1, 2 and 3. These receptors are implicated in pathologic
angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been
shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival (Hu-
Lowe, D.D., et al., Clin Cancer Res 14: 7272-7283 (2008); Solowiej, S., et al.,
Biochemistry 48: 7019-31 (2009)). Clinical trials are currently on-going or have been
conducted to study the use of axitinib for the treatment of various cancers, including
liver cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer,
renal cell carcinoma, soft tissue sarcomas and solid tumors. Inlyta® (axitinib) has been
approved in the United States, Europe, Japan and other jurisdictions for the treatment
of renal cell carcinoma.
Axitinib, as well as pharmaceutically acceptable salts thereof, is described in
U.S. Patent No. 6,534,524. Methods of making axitinib are described in U.S. Patent
Nos. 6,884,890 and 7,232,910, in U.S. Publication Nos. 2006-0091067 and 2007-
0203196 and in International Publication No. . Dosage forms of
axitinib are described in U.S. Publication No. 2004-0224988. Polymorphic forms and
pharmaceutical compositions of axitinib are also described in U.S. Publication Nos.
2006-0094763, 2008-0274192 and 2010-0179329 and International Publication No.
. The patents and patent applications listed above are incorporated
herein by reference.
Axitinib is understood to include reference to salts thereof, unless otherwise
indicated. Axitinib is basic in nature and capable of forming a wide variety of salts with
various inorganic and organic acids. The term "salt(s)", as employed herein, denotes
acidic salts formed with inorganic and/or organic acids. Pharmaceutically acceptable
salts of axitinib may be formed, for example, by reacting axitinib with an amount of
acid, such as an equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts of the compound of Formula I include acetates,
ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,
camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides,
hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates,
oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates,
thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally,
acids which are generally considered suitable for the formation of pharmaceutically
useful salts from basic pharmaceutical compounds are discussed, for example, by S.
Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,
International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of
Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their website). These disclosures
are incorporated herein by reference thereto.
All such acid salts are intended to be pharmaceutically acceptable salts within
the scope of axitinib, as used in the present invention and all acid salts are considered
equivalent to the free forms of the corresponding compound for purposes of the
invention.
Prodrugs of axitinib are also contemplated for use in the methods, medicaments
and uses of the present invention. The term "prodrug", as employed herein, denotes a
compound that is a drug precursor which, upon administration to a subject, undergoes
chemical conversion by metabolic or chemical processes to yield axitinib or a salt
thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as
Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American
Pharmaceutical Association and Pergamon Press, both of which are incorporated
herein by reference thereto.
The term “4-1BB antibody” as used herein means an antibody, as defined
herein, capable of binding to human 4-1BB receptor.
The terms "4-1BB” and “4-1BB receptor” are used interchangeably in the
present application, and refer to any form of 4-1BB receptor, as well as variants,
isoforms, and species homologs thereof that retain at least a part of the activity of4-
1BB receptor. Accordingly, a binding molecule, as defined and disclosed herein, may
also bind 4-1BB from species other than human. In other cases, a binding molecule
may be completely specific for the human 4-1BB and may not exhibit species or other
types of cross-reactivity. Unless indicated differently, such as by specific reference to
human4-1BB,4-1BB includes all mammalian species of native sequence4-1BB, e.g.,
human, canine, feline, equine and bovine. One exemplary human 4-1BB is a 255
amino acid protein (Accession No. NM_001561; NP_001552).
4-1BB comprises a signal sequence (amino acid residues 1-17), followed by an
extracellular domain (169 amino acids), a transmembrane region (27 amino acids),
and an intracellular domain (42 amino acids) (Cheuk ATC et al. 2004 Cancer Gene
Therapy 11: 215-226). The receptor is expressed on the cell surface in monomer and
dimer forms and likely trimerizes with 4-1BB ligand to signal.
“4-1BB agonist” as used herein means, any chemical compound or biological
molecule, as defined herein, which upon binding to 4-1BB, (1) stimulates or activates
4-1BB, (2) enhances, increases, promotes, induces, or prolongs an activity, function,
or presence of 4-1BB, or (3) enhances, increases, promotes, or induces the expression
of 4-1BB. 4-1BB agonists useful in the any of the treatment method, medicaments and
uses of the present invention include a monoclonal antibody (mAb), or antigen binding
fragment thereof, which specifically binds to 4-1BB. Alternative names or synonyms
for 4-1BB include CD137 and TNFRSF9. In any of the treatment method, medicaments
and uses of the present invention in which a human individual is being treated, the 4-
1BB agonists increase a 4-1BB-mediated response. In some embodiments of the
treatment method, medicaments and uses of the present invention, 4-1BB agonists
markedly enhance cytotoxic T-cell responses, resulting in anti-tumor activity in several
models.
Human 4-1BB comprises a signal sequence (amino acid residues 1-17),
followed by an extracellular domain (169 amino acids), a transmembrane region (27
amino acids), and an intracellular domain (42 amino acids) (Cheuk ATC et al. 2004
Cancer Gene Therapy 11: 215-226). The receptor is expressed on the cell surface in
monomer and dimer forms and likely trimerizes with 4-1BB ligand to signal.
Examples of mAbs that bind to human 4-1BB, and useful in the treatment
method, medicaments and uses of the present invention, are described in US
8,337,850 and US20130078240. In some embodiments an anti1BB antibody useful
in the treatment method, medicaments and uses disclosed herein is a fully humanized
IgG2 agonist monoclonal antibody comprising a heavy chain variable region and a light
chain variable region comprising the amino acid sequences shown in SEQ ID NO: 18
and SEQ ID NO: 19, respectively.
Table 3A below provides exemplary anti1BB antibody sequences for use in
the treatment method, medicaments and uses of the present invention.
Table 3A. EXEMPLARY ANTI-HUMAN 4-1BB MONOCLONAL ANTIBODY SEQUENCES
CDRH1 STYWIS (SEQ ID NO:12)
CDRH2 KIYPGDSYTNYSPSFQG (SEQ ID NO:13)
CDRH3 RGYGIFDY (SEQ ID NO:14)
CDRL1 SGDNIGDQYAH (SEQ ID NO:15)
CDRL2 QDKNRPS (SEQ ID NO:16)
CDRL3 ATYTGFGSLAV (SEQ ID NO:17)
EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGL
Heavy chain VR EWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDT
AMYYCARGYGIFDYWGQGTLVTVSS (SEQ ID NO: 18)
SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVL
Light chain VR VIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYT
GFGSLAVFGGGTKLTVL (SEQ ID NO: 19)
EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGL
EWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDT
AMYYCARGYGIFDYWGQGTLVTVSSastkgpsvfplapcsrstsestaalgclvk
dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvd
Heavy chain
ktverkccvecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyv
dgvevhnaktkpreeqfnstfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktkgqpr
epqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppmldsdgsfflys
kltvdksrwqqgnvfscsvmhealhnhytqkslslspgk (SEQ ID NO: 20)
SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVL
VIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYT
Light chain GFGSLAVFGGGTKLTVLgqpkaapsvtlfppsseelqankatlvclisdfypgavtva
wkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvapte
cs (SEQ ID NO: 21)
The term “M-CSF antibody” as used herein means an antibody, as defined
herein, capable of binding to human M-CSF receptor.
The terms "M-CSF” and “M-CSF receptor” are used interchangeably in the
present application, and refer to any form of M-CSF receptor, as well as variants,
isoforms, and species homologs thereof that retain at least a part of the activity of M-
CSF receptor. Accordingly, a binding molecule, as defined and disclosed herein, may
also bind M-CSF from species other than human. In other cases, a binding molecule
may be completely specific for the human M-CSF and may not exhibit species or other
types of cross-reactivity. Unless indicated differently, such as by specific reference to
human M-CSF, M-CSF includes all mammalian species of native sequence M-CSF,
e.g., human, canine, feline, equine and bovine. One exemplary human M-CSF is a 554
amino acid protein (UniProt Accession No. P09603).
“M-CSF antagonist antibody” as used herein means, any antibody, as defined
herein, which upon binding to M-CSF, inhibits the binding of a M-CSF to c-fms receptor
and blocks or prevents activation of c-fms. M-CSF antagonists useful in the any of the
treatment method, medicaments and uses of the present invention include a
monoclonal antibody (mAb) which specifically binds to M-CSF.
Examples of mAbs that bind to human M-CSF, and useful in the treatment
method, medicaments and uses of the present invention, are described in, for example,
U.S. Patent No. 7,326,414, PCT Patent Application Publication No. WO2014167088,
and U.S. Patent Application Publication No. 20140242071. In some embodiments an
anti-M-CSF antibody useful in the treatment method, medicaments and uses disclosed
herein is a fully human IgG2 antagonist monoclonal antibody comprising a heavy chain
variable region and a light chain variable region comprising the amino acid sequences
shown in SEQ ID NO: 30 and SEQ ID NO: 31, respectively.
Table 3B below provides exemplary anti-M-CSF antibody sequences for use in
the treatment method, medicaments and uses of the present invention.
Table 3B. EXEMPLARY ANTI-HUMAN M-CSF MONOCLONAL ANTIBODY SEQUENCES
CDRH1 SFSMT (SEQ ID NO: 24)
CDRH2 YISSRSSTISYADSVKG (SEQ ID NO: 25)
CDRH3 DPLLAGATFFDY (SEQ ID NO: 26)
CDRL1 RASQSVSSSYLA (SEQ ID NO: 27)
CDRL2 GASSRAT (SEQ ID NO: 28)
CDRL3 QQYGSSPLT (SEQ ID NO: 29)
MELGLCWVFLVAILEGVQCEVQLVESGGGLVQPGGSLRLSCAASG
FTFSSFSMTWVRQAPGKGLEWVSYISSRSSTISYADSVKGRFTISR
Heavy chain VR
DNAKNSLYLQMNSLRDEDTAVYYCARDPLLAGATFFDYWGQGTLV
TVSSA (SEQ ID NO: 30)
METPAQLLFLLLLWLPDTTGEFVLTQSPGTLSLSPGERATLSCRAS
QSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
Light chain VR
FTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK (SEQ ID NO:
MELGLCWVFLVAILEGVQCEVQLVESGGGLVQPGGSLRLSCAASG
FTFSSFSMTWVRQAPGKGLEWVSYISSRSSTISYADSVKGRFTISR
DNAKNSLYLQMNSLRDEDTAVYYCARDPLLAGATFFDYWGQGTLV
TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN
SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHK
Heavy chain PSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR
TPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTF
RVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP
QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY
TQKSLSLSPGK (SEQ ID NO: 22)
METPAQLLFLLLLWLPDTTGEFVLTQSPGTLSLSPGERATLSCRAS
QSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRTVAAPSVFIF
Light chain
PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV
TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC (SEQ ID NO: 23)
The term “OX40 antibody” as used herein means an antibody, as defined
herein, capable of binding to human OX40 receptor.
The terms "OX40” and “OX40 receptor” are used interchangeably in the present
application, and refer to any form of OX40 receptor, as well as variants, isoforms, and
species homologs thereof that retain at least a part of the activity of OX40 receptor.
Accordingly, a binding molecule, as defined and disclosed herein, may also bind OX40
from species other than human. In other cases, a binding molecule may be completely
specific for the human OX40 and may not exhibit species or other types of cross-
reactivity. Unless indicated differently, such as by specific reference to human OX40,
OX40 includes all mammalian species of native sequence OX40, e.g., human, canine,
feline, equine and bovine. One exemplary human OX40 is a 277 amino acid protein
(UniProt Accession No. P43489).
“OX40 agonist antibody” as used herein means, any antibody, as defined
herein, which upon binding to OX40, (1) stimulates or activates OX40, (2) enhances,
increases, promotes, induces, or prolongs an activity, function, or presence of OX40,
or (3) enhances, increases, promotes, or induces the expression of OX40. OX40
agonists useful in the any of the treatment method, medicaments and uses of the
present invention include a monoclonal antibody (mAb) which specifically binds to
OX40.
Examples of mAbs that bind to human OX40, and useful in the treatment
method, medicaments and uses of the present invention, are described in, for example,
U.S. Patent No. 7,960,515, PCT Patent Application Publication Nos. WO2013028231
and WO2013/119202, and U.S. Patent Application Publication No. 20150190506. In
some embodiments an anti-OX40 antibody useful in the treatment method,
medicaments and uses disclosed herein is a fully human agonist monoclonal antibody
comprising a heavy chain variable region and a light chain variable region comprising
the amino acid sequences shown in SEQ ID NO: 38 and SEQ ID NO: 39, respectively.
In some embodiments, the anti-OX40 antibody is a fully human IgG2 or IgG1 antibody.
Table 3C below provides exemplary anti-OX40 antibody sequences for use in
the treatment method, medicaments and uses of the present invention.
Table 3C. EXEMPLARY ANTI-HUMAN OX40 MONOCLONAL ANTIBODY SEQUENCES
CDRH1 SYSMN (SEQ ID NO: 32)
CDRH2 YISSSSSTIDYADSVKG (SEQ ID NO: 33)
CDRH3 ESGWYLFDY (SEQ ID NO: 34)
CDRL1 RASQGISSWLA (SEQ ID NO: 35)
CDRL2 AASSLQS (SEQ ID NO: 36)
CDRL3 QQYNSYPPT (SEQ ID NO: 37)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKG
Heavy chain VR LEWVSYISSSSSTIDYADSVKGRFTISRDNAKNSLYLQMNSLRDEDT
AVYYCARESGWYLFDYWGQGTLVTVSS (SEQ ID NO: 38)
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKS
Light chain VR LIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNS
YPPTFGGGTKVEIK (SEQ ID NO: 39)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKG
LEWVSYISSSSSTIDYADSVKGRFTISRDNAKNSLYLQMNSLRDEDT
Heavy chain
AVYYCARESGWYLFDYWGQGTLVTVSSastkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsnt
kvdktverkccvecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfn
wyvdgvevhnaktkpreeqfnstfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktk
gqprepqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppmldsdg
sfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk (SEQ ID NO: 40)
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKS
LIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNS
Light chain
YPPTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdna
lqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec
(SEQ ID NO: 41)
The “CD20” antigen is a ˜35 kDa, non-glycosylated phosphoprotein found on
the surface of greater than 90% of B cells from peripheral blood or lymphoid organs.
CD20 is expressed during early pre-B cell development and remains until plasma cell
differentiation. CD20 is present on both normal B cells as well as malignant B cells.
Other names for CD20 in the literature include “B-lymphocyte-restricted antigen” and
“Bp35”. The CD20 antigen is described in Clark et al. PNAS (USA) 82:1766 (1985), for
example.
Unless otherwise defined, 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 invention belongs. In case of conflict, the present specification, including
definitions, will control. Throughout this specification and claims, the word "comprise,"
or variations such as "comprises" or "comprising" will be understood to imply the
inclusion of a stated integer or group of integers but not the exclusion of any other
integer or group of integers. Unless otherwise required by context, singular terms shall
include pluralities and plural terms shall include the singular.
Exemplary methods and materials are described herein, although methods and
materials similar or equivalent to those described herein can also be used in the
practice or testing of the invention. The materials, methods, and examples are
illustrative only and not intended to be limiting.
II. METHODS, USES AND MEDICAMENTS
In one aspect of the invention, the invention provides a method for treating a
cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist and a VEGR inhibitor.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist and an anti1BB antibody.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist and an anti-M-CSF antibody.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist and an anti-OX40 antibody.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist, an anti1BB antibody, and an anti-M-CSF
antibody.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist, an anti1BB antibody, and an anti-OX40
antibody.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist, an anti1BB antibody, and a CD20 antagonist.
In some embodiments, the PD-L1 antagonist is avelumab, the anti1BB antibody is
PF-05082566, and the CD20 antagonist is rituximab. In some embodiments, the
method comprises a 28-day cycle wherein rituximab is administered on Day 1 of each
28-day cycle at a dose of 375 mg/m , PF-05082566 is administered on Day 1 or Day
2 at a fixed dose of 100 mg, and avelumab is administered at a dose of 10 mg/kg on
Day 2 and Day 15 or 16 of each 28-day cycle. In some embodiments on Day 2,
avelumab is administered at least 3 hours after administration of PF-05082566. In
some embodiments on Day 2, avelumab is administered about 30 minutes after
administration of PF-05082566. In some embodiments on Day 2, avelumab is
administered about 60 minutes after administration of PF-05082566.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist, an anti1BB antibody, and azacitidine. In some
embodiments, the PD-L1 antagonist is avelumab, and the anti1BB antibody is PF-
05082566. In some embodiments, the method comprises a 28-day cycle wherein
azacitidine is administered subcutaneously at a daily dose of 75 mg/m on Day 1 to
Day 7 consecutively of each 28-day cycle, PF-05082566 is administered intravenously
at a fixed dose of 100 mg on Day 1 or Day 2, and avelumab is administered at a dose
of 10 mg/kg on Day 2 and either Day 15 or Day 16 of each 28-day cycle. In some
embodiments on Day 2, avelumab is administered at least 3 hours after administration
of PF-05082566. In some embodiments on Day 2, avelumab is administered about 30
minutes after administration of PF-05082566. In some embodiments on Day 2,
avelumab is administered about 60 minutes after administration of PF-05082566. In
some embodiments on Day 2, avelumab is administered at least 3 hours after
administration of PF-05082566. In some embodiments on Day 2, avelumab is
administered about 30 minutes after administration of PF-05082566. In some
embodiments on Day 2, avelumab is administered about 60 minutes after
administration of PF-05082566. In some embodiments, azacitidine is administered at
least 3 hours prior to PF-05082566 when dosed on the same day.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist, bendamustine, and a CD20 antagonist. In some
embodiments, the PD-L1 antagonist is avelumab, and the CD20 antagonist is
rituximab. In some embodiments, the method comprises a 28-day cycle wherein
rituximab is administered on Day 1 of each 28-day cycle at a dose of 375 mg/m ,
bendamustine is administered intravenously at a dose of 90 mg/m on Day 2 and Day
3, and avelumab is administered at a dose of 10 mg/kg on Day 2 and Day 15 or 16 of
each 28-day cycle. In some embodiments, the method comprises a 28-day cycle
wherein rituximab is administered on Day 1 of each 28-day cycle at a dose of 375
mg/m , bendamustine is administered intravenously at a dose of 90 mg/m on Day 1
and Day 2, and avelumab is administered at a dose of 10 mg/kg on Day 2 and Day 15
or 16 of each 28-day cycle. In some embodiments on Day 2, avelumab is administered
at least 3 hours after administration of bendamustine. In some embodiments on Day
2, avelumab is administered about 30 minutes after administration of bendamustine.
In some embodiments on Day 2, avelumab is administered about 60 minutes after
administration of bendamustine.
In another aspect of the invention, the invention provides a method for treating
a cancer in a subject comprising administering to the subject a combination therapy
which comprises a PD-L1 antagonist and chemoradiotherapy.
The combination therapy may also comprise one or more additional therapeutic
agents. The additional therapeutic agent may be, e.g., a chemotherapeutic other than
a VEGR inhibitor, a biotherapeutic agent (including but not limited to antibodies to
VEGF, EGFR, Her2/neu, other growth factor receptors, CD40, CD-40L, CTLA-4, and
ICOS), an immunogenic agent (for example, attenuated cancerous cells, tumor
antigens, antigen presenting cells such as dendritic cells pulsed with tumor derived
antigen or nucleic acids, immune stimulating cytokines (for example, IL-2, IFNα2, GM-
CSF), a chimeric antigen receptior (CAR)-T cell, and cells transfected with genes
encoding immune stimulating cytokines such as but not limited to GM-CSF).
Examples of chemotherapeutic agents include alkylating agents such as
thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine;
acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the
synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly
cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic
analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,
cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine
oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine,
trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne
antibiotics (e.g. calicheamicin, especially calicheamicin gamma1I and calicheamicin
phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994); dynemicin, including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne antibiotic
chromomophores), aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins,
cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazooxo-L-norleucine, doxorubicin (including
morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such
as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,
tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and
-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate,
pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, 6-azauridine,
carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens
such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid
replenisher such as folinic acid; aceglatone; aldophosphamide glycoside;
aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone;
etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as
maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine;
pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide;
procarbazine; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid;
triaziquone; 2, 2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,
verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;
mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-
C”); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel and doxetaxel; chlorambucil;
gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as
carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone;
vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin;
xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and
pharmaceutically acceptable salts, acids or derivatives of any of the above. Also
included are anti-hormonal agents that act to regulate or inhibit hormone action on
tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs),
including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen,
trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); aromatase
inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in
the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide,
megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and
anastrozole; and anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives
of any of the above.
Each therapeutic agent in a combination therapy of the invention may be
administered either alone or in a medicament (also referred to herein as a
pharmaceutical composition) which comprises the therapeutic agent and one or more
pharmaceutically acceptable carriers, excipients and diluents, according to standard
pharmaceutical practice.
Each therapeutic agent in a combination therapy of the invention may be
administered simultaneously (i.e., in the same medicament), concurrently (i.e., in
separate medicaments administered one right after the other in any order) or
sequentially in any order. Sequential administration is particularly useful when the
therapeutic agents in the combination therapy are in different dosage forms (one agent
is a tablet or capsule and another agent is a sterile liquid) and/or are administered on
different dosing schedules, e.g., a chemotherapeutic that is administered at least daily
and a biotherapeutic that is administered less frequently, such as once weekly, once
every two weeks, or once every three weeks.
In some embodiments, the VEGFR inhibitor or anti1BB antibody is
administered before administration of the PD-L1 antagonist, while in other
embodiments, the VEGFR inhibitor or anti1BB antibody is administered after
administration of the PD-L1 antagonist.
In some embodiments, at least one of the therapeutic agents in the combination
therapy is administered using the same dosage regimen (dose, frequency and duration
of treatment) that is typically employed when the agent is used as monotherapy for
treating the same cancer. In other embodiments, the patient receives a lower total
amount of at least one of the therapeutic agents in the combination therapy than when
the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or
shorter treatment duration.
Each small molecule therapeutic agent in a combination therapy of the invention
can be administered orally or parenterally, including the intravenous, intramuscular,
intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration.
A combination therapy of the invention may be used prior to or following surgery
to remove a tumor and may be used prior to, during or after radiation therapy.
In some embodiments, a combination therapy of the invention is administered
to a patient who has not been previously treated with a biotherapeutic or
chemotherapeutic agent, i.e., is treatment-naïve. In other embodiments, the
combination therapy is administered to a patient who failed to achieve a sustained
response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is
treatment-experienced.
A combination therapy of the invention is typically used to treat a tumor that is
large enough to be found by palpation or by imaging techniques well known in the art,
such as MRI, ultrasound, or CAT scan. In some embodiments, a combination therapy
of the invention is used to treat an advanced stage tumor having dimensions of at least
3 3 3 3 3 3
about 200 mm , 300 mm , 400 mm , 500 mm , 750 mm , or up to 1000 mm .
In some embodiments, a combination therapy of the invention is administered
to a human patient who has a cancer that tests positive for PD-L1 expression. In some
embodiments, PD-L1 expression can be detected using a diagnostic anti-human PD-
L1 antibody, or antigen binding fragment thereof, in an IHC assay on an FFPE or frozen
tissue section of a tumor sample removed from the patient. Typically, the patient’s
physician would order a diagnostic test to determine PD-L1 expression in a tumor
tissue sample removed from the patient prior to initiation of treatment with the PD-L1
antagonist and VEGFR inhibitor, but it is envisioned that the physician could order the
first or subsequent diagnostic tests at any time after initiation of treatment, such as for
example after completion of a treatment cycle.
Selecting a dosage regimen (also referred to herein as an administration
regimen) for a combination therapy of the invention depends on several factors,
including the serum or tissue turnover rate of the entity, the level of symptoms, the
immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in
the subject being treated. Preferably, a dosage regimen maximizes the amount of each
therapeutic agent delivered to the patient consistent with an acceptable level of side
effects. Accordingly, the dose amount and dosing frequency of each biotherapeutic
and chemotherapeutic agent in the combination depends in part on the particular
therapeutic agent, the severity of the cancer being treated, and patient characteristics.
Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules
are available. See, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub.
Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and
Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and
Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert et al.
(2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med.
341:1966-1973; Slamon et al. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz
et al. (2000) New Engl. J. Med. 342:613-619; Ghosh et al. (2003) New Engl. J. Med.
348:24-32; Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602; Physicians' Desk
Reference 2003 (Physicians' Desk Reference, 57th Ed); Medical Economics
Company; ISBN: 1563634457; 57th edition (November 2002). Determination of the
appropriate dosage regimen may be made by the clinician, e.g., using parameters or
factors known or suspected in the art to affect treatment or predicted to affect
treatment, and will depend, for example, the patient's clinical history (e.g., previous
therapy), the type and stage of the cancer to be treated and biomarkers of response
to one or more of the therapeutic agents in the combination therapy.
Biotherapeutic agents in a combination therapy of the invention may be
administered by continuous infusion, or by doses at intervals of, e.g., daily, every other
day, three times per week, or one time each week, two weeks, three weeks, monthly,
bimonthly, etc. A total weekly dose is generally at least 0.05 μg/kg, 0.2 μg/kg, 0.5 μg/kg,
1 μg/kg, 10 μg/kg, 100 μg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg,
50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.
349:427-434; Herold et al. (2002) New Engl. J. Med. 346:1692-1698; Liu et al. (1999)
J. Neurol. Neurosurg. Psych. 67:451-456; Portielji et al. (20003) Cancer Immunol.
Immunother. 52:133-144.
In some embodiments that employ an anti-human PD-L1 mAb as the PD-L1
antagonist in the combination therapy, the dosing regimen will comprise administering
the anti-human PD-L1 mAb at a dose of about 1, 2, 3, 5 or 10 mg/kg at intervals of
about 14 days (± 2 days) or about 21 days (± 2 days) or about 30 days (± 2 days)
throughout the course of treatment.
In other embodiments that employ an anti-human PD-L1 mAb as the PD-L1
antagonist in the combination therapy, the dosing regimen will comprise administering
the anti-human PD-L1 mAb at a dose of from about 0.005 mg/kg to about 10 mg/kg,
with intra-patient dose escalation. In other escalating dose embodiments, the interval
between doses will be progressively shortened, e.g., about 30 days (± 2 days) between
the first and second dose, about 14 days (± 2 days) between the second and third
doses. In certain embodiments, the dosing interval will be about 14 days (± 2 days),
for doses subsequent to the second dose.
In certain embodiments, a subject will be administered an intravenous (IV)
infusion of a medicament comprising any of the PD-L1 antagonists described herein.
In some embodiments, the PD-L1 antagonist in the combination therapy is
avelumab, which is administered intravenously at a dose selected from the group
consisting of: about 1 mg/kg Q2W (Q2W = one dose every two weeks), about 2 mg/kg
Q2W, about 3 mg/kg Q2W, about 5 mg/kg Q2W, about 10 mg Q2W, about 1 mg/kg
Q3W (Q3W = one dose every three weeks), about 2 mg/kg Q3W, about 3 mg/kg Q3W,
about 5 mg/kg Q3W, and about 10 mg Q3W.
In some embodiments of the invention, the PD-L1 antagonist in the combination
therapy is avelumab, which is administered in a liquid medicament at a dose selected
from the group consisting of about 1 mg/kg Q2W, about 2 mg/kg Q2W, about 3 mg/kg
Q2W, about 5 mg/kg Q2W, about 10 mg Q2W, about 1 mg/kg Q3W, about 2 mg/kg
Q3W, about 3 mg/kg Q3W, about 5 mg/kg Q3W, and about 10 mg Q3W.
In some embodiments, a treatment cycle begins with the first day of combination
treatment and last for 2 weeks. In such embodiments, the combination therapy is
preferably administered for at least 12 weeks (6 cycles of treatment), more preferably
at least 24 weeks, and even more preferably at least 2 weeks after the patient achieves
a CR.
In some embodiments, the 4-1BB agonist in the combination therapy comprises
an anti1BB monoclonal antibody comprising heavy chain variable region and a light
chain variable region comprising the amino acid sequences shown in SEQ ID NO: 18
and SEQ ID NO: 19, respectively, and is administered in a liquid medicament at a dose
selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5
mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W,
and 10 mg Q3W. In some embodiments, the anti1BB monoclonal antibody is
administered as a liquid medicament, and the selected dose of the medicament is
administered by IV infusion over a time period of about 60 minutes.
In some embodiments, the anti1BB monoclonal antibody is administered at
a starting dose of about 0.6 mg/kg Q4W and avelumab is administered at a starting
dose of 10 mg/kg Q2W, and if the starting dose combination is not tolerated by the
patient, then the dose of avelumab is reduced to 5 mg/kg Q2W and/or the dose of the
anti1BB monoclonal antibody is reduced to 0.3 mg/kg Q4W.
In some embodiments, the patient is selected for treatment with the combination
therapy of the invention is the patient has been diagnosed with advanced RCC with
predominantly clear cell subtype, and the primary tumor has been resected. In some
embodiments, the patient has not received prior systemic therapy for advanced RCC.
The present invention also provides a medicament which comprises a PD-L1
antagonist as described above and a pharmaceutically acceptable excipient. When the
PD-L1 antagonist is a biotherapeutic agent, e.g., a mAb, the antagonist may be
produced in CHO cells using conventional cell culture and recovery/purification
technologies.
In some embodiments, a medicament comprising an anti-PD-L1 antibody as the
PD-L1 antagonist may be provided as a liquid formulation or prepared by reconstituting
a lyophilized powder with sterile water for injection prior to use.
The present invention also provides a medicament which comprises axitinib and
a pharmaceutically acceptable excipient.
The anti-PD-L1 and VEGFR inhibitor medicaments described herein may be
provided as a kit which comprises a first container and a second container and a
package insert. The first container contains at least one dose of a medicament
comprising an anti-PD-L1 antagonist, the second container contains at least one dose
of a medicament comprising a VEGFR inhibitor, and the package insert, or label, which
comprises instructions for treating a patient for cancer using the medicaments. The
first and second containers may be comprised of the same or different shape (e.g.,
vials, syringes and bottles) and/or material (e.g., plastic or glass). The kit may further
comprise other materials that may be useful in administering the medicaments, such
as diluents, filters, IV bags and lines, needles and syringes. In some embodiments of
the kit, the anti-PD-L1 antagonist is an anti-PD-L1 antibody and the instructions state
that the medicaments are intended for use in treating a patient having a cancer that
tests positive for PD-L1 expression by an IHC assay.
The anti-PD-L1 and anti1BB antibody medicaments described herein may be
provided as a kit which comprises a first container and a second container and a
package insert. The first container contains at least one dose of a medicament
comprising an anti-PD-L1 antagonist, the second container contains at least one dose
of a medicament comprising an anti1BB antibody, and the package insert, or label,
which comprises instructions for treating a patient for cancer using the medicaments.
The first and second containers may be comprised of the same or different shape (e.g.,
vials, syringes and bottles) and/or material (e.g., plastic or glass). The kit may further
comprise other materials that may be useful in administering the medicaments, such
as diluents, filters, IV bags and lines, needles and syringes. In some embodiments of
the kit, the anti-PD-L1 antagonist is an anti-PD-L1 antibody and the instructions state
that the medicaments are intended for use in treating a patient having a cancer that
tests positive for PD-L1 expression by an IHC assay.
The anti-PD-L1 antibody and CD20 antagonist medicaments described herein
may be provided as a kit which comprises a first container and a second container and
a package insert. The first container contains at least one dose of a medicament
comprising an anti-PD-L1 antagonist, the second container contains at least one dose
of a medicament comprising a CD20 antagonist, and the package insert, or label, which
comprises instructions for treating a patient for cancer using the medicaments. The
first and second containers may be comprised of the same or different shape (e.g.,
vials, syringes and bottles) and/or material (e.g., plastic or glass). The kit may further
comprise other materials that may be useful in administering the medicaments, such
as diluents, filters, IV bags and lines, needles and syringes. In some embodiments of
the kit, the anti-PD-L1 antagonist is an anti-PD-L1 antibody and the instructions state
that the medicaments are intended for use in treating a patient having a cancer that
tests positive for PD-L1 expression by an IHC assay.
These and other aspects of the invention, including the exemplary specific
embodiments listed below, will be apparent from the teachings contained herein.
III. GENERAL METHODS
Standard methods in molecular biology are described Sambrook, Fritsch and
Maniatis (1982 & 1989 2nd Edition, 2001 3rd Edition) Molecular Cloning, A Laboratory
Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and
Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold
Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San
Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols
in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which
describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in
mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3),
and bioinformatics (Vol. 4).
Methods for protein purification including immunoprecipitation,
chromatography, electrophoresis, centrifugation, and crystallization are described
(Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and
Sons, Inc., New York). Chemical analysis, chemical modification, post-translational
modification, production of fusion proteins, glycosylation of proteins are described
(see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John
Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular
Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-
Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89;
Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391).
Production, purification, and fragmentation of polyclonal and monoclonal antibodies
are described (Coligan, et al. (2001) Current Protcols in Immunology, Vol. 1, John
Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra).
Standard techniques for characterizing ligand/receptor interactions are available (see,
e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc.,
New York).
Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g.,
Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New
York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-
Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et
al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al.
(1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-
10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol.
224:487-499; U.S. Pat. No. 6,329,511).
An alternative to humanization is to use human antibody libraries displayed on
phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature
Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al.
(1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol.
Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996)
Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San
Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).
Purification of antigen is not necessary for the generation of antibodies. Animals
can be immunized with cells bearing the antigen of interest. Splenocytes can then be
isolated from the immunized animals, and the splenocytes can fused with a myeloma
cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290;
Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al.
(1999) J. Immunol. 163:5157-5164).
Antibodies can be conjugated, e.g., to small drug molecules, enzymes,
liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic,
diagnostic, kit or other purposes, and include antibodies coupled, e.g., to dyes,
radioisotopes, enzymes, or metals, e.g., colloidal gold (see, e.g., Le Doussal et al.
(1991) J. Immunol. 146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898;
Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J. Immunol.
168:883-889).
Methods for flow cytometry, including fluorescence activated cell sorting
(FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for
Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow
Cytometry, 2nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow
Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for
modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and
antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy
(2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003)
Catalogue, St. Louis, MO).
Standard methods of histology of the immune system are described (see, e.g.,
Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology,
Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott,
Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas,
McGraw-Hill, New York, NY).
Software packages and databases for determining, e.g., antigenic fragments,
leader sequences, protein folding, functional domains, glycosylation sites, and
sequence alignments, are available (see, e.g., GenBank, Vector NTI® Suite (Informax,
Inc, Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA);
DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000)
Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note
16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von
Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res.
14:4683-4690).
IV. Examples
Example 1: Combination Treatment with Avelumab and Axitinib
This example illustrates a clinical trial study to evaluate safety, efficacy,
pharmacokinetics, and pharmacodynamics of avelumab (MSB0010718C) in
combination with axitinib (AG-013736) in patients with previously untreated advanced
renal cell carcinoma (aRCC).
This study is an open-label, multi-center, multiple-dose trial designed to
estimate the maximum tolerated dose (MTD) and select the recommended phase 2
dose (RP2D) of avelumab (MSB0010718C) in combination with axitinib (AG-013736).
Once the MTD of avelumab administered in combination with axitinib is estimated
(dose finding portion), the dose expansion phase will be opened to further characterize
the combination in term of safety profile, anti-tumor activity, pharmacokinetics,
pharmacodynamics and biomarker modulation. Protocol design is set forth in Table 4.
The Dose Finding Phase will estimate the MTD and RP2D in patients with aRCC
with clear cell histology who did not receive prior systemic therapy for advanced
disease, using the modified toxicity probability interval (mTPI) method. Dose finding
will follow an “Up-and-Down” design, with up to 4 potential dose levels (DL) to be
tested, shown in Table 4.
The Dose Finding Phase will lead to the identification of an Expansion Test
Dose for avelumab in combination with axitinib in patients with aRCC who did not
receive prior systemic therapy for their advanced disease. The Expansion Test Dose
will either be the MTD (i.e., the highest dose of avelumab and axitinib associated with
the occurrence of DLTs in <33% of patients) or the RP2D, i.e., the highest tested dose
that is declared safe and tolerable by the investigators and sponsor. Once the
Expansion Test Dose is identified, the Dose Expansion Phase will be opened, and
avelumab in combination with axitinib will be evaluated in up to approximately 20-40
patients with previously untreated aRCC.
Table 4
Arms Assigned Interventions
Dose finding Group 1: avelumab 10 mg/kg IV Q2W; axitinib 5 mg oral
phase BID
Group 2: avelumab 5 mg/kg IV Q2W; axitinib 5 mg oral BID
Group 3: avelumab 10 mg/kg IV Q2W; axitinib 3 mg oral
Group 4: avelumab 5 mg/kg IV Q2W; axitinib 3 mg oral BID
Dose Group 1: avelumab 10 mg/kg IV Q2W; axitinib 5 mg oral
expansion BID
Group 2: avelumab 5 mg/kg IV Q2W; axitinib 5 mg oral BID
phase
Group 3: avelumab 10 mg/kg IV Q2W; axitinib 3 mg oral
Group 4: avelumab 5 mg/kg IV Q2W; axitinib 3 mg oral BID
Inclusion Criteria: Histologically or cytologically confirmed advanced RCC with
clear cell component. Primary tumor resected. Mandatory archival formalin fixed,
paraffin embedded (FFPE) tumor tissue block from primary tumor resection specimen
(all patients). For Extension Cohort only, mandatory de novo tumor biopsy from a
locally recurrent or metastatic lesion unless obtained from a procedure performed
within 6 months of study entry and if the patient has received no intervening systemic
anti-cancer treatment. At least one measureable lesion as defined by RECIST version
1.1. Age ≥18 years. Eastern Cooperative Oncology Group (ECOG) performance status
0 or 1. Adequate bone marrow function, renal and liver functions.
The number of patients to be enrolled in the Dose Finding Phase will depend
on the observed safety profile, and the number of tested dose levels. Up to
approximately 55 patients (including Dose Finding Phase and Dose Expansion Phase)
are projected to be enrolled in the study.
Study Treatment: Axitinib will be given orally (PO) twice daily (BID), with or
without food, on a continuous dosing schedule. Avelumab will be given as a 1-hour
intravenous infusion (IV) every two weeks (Q2W). In all patients, treatment with study
drugs may continue until confirmed disease progression, patient refusal, patient lost to
follow up, unacceptable toxicity, or the study is terminated by the sponsor, whichever
comes first.
In order to mitigate avelumab infusion-related reactions, a premedication
regimen of 25 to 50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral
equivalent acetaminophen/paracetamol (as per local practice) may be administered
approximately 30 to 60 minutes prior to each dose of avelumab. This may be modified
based on local treatment standards and guidelines, as appropriate.
Tumor Assessment: Anti-tumor activity will be assessed by radiological tumor
assessments at 6-week intervals, using RECIST version 1.1. Complete and partial
responses will be be confirmed on repeated imaging at least at 4 weeks after initial
documentation. After 1 year from enrollment in the study, tumor assessments should
be conducted less frequently, i.e., at 12-week intervals. In addition, radiological tumor
assessments will also be conducted whenever disease progression is suspected (e.g.,
symptomatic deterioration), and at the time of End of Treatment/Withdrawal (if not done
in the previous 6 weeks). If radiologic imaging shows progressive disease (PD), tumor
assessment should be repeated at least >4 weeks later in order to confirm PD.
Brain Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI)
scans are required at baseline and when there is a suspected brain metastasis. Bone
scan (bone scintigraphy) or 18fluorodeoxyglucose-positron emission
tomography/CT(18FDG-PET/CT) are required at baseline, then every 16 weeks only if
bone metastases are present at baseline. Otherwise, bone imaging is required only if
new bone metastases are suspected. Bone imaging is also required at the time of
confirmation of CR for patients who have bone metastases.
Pharmacokinetic/Immunogenicity Assessments: PK/immunogenicity sampling
will be collected. To understand the PK effects of avelumab on axitinib, a 7-day lead-
in period with single-agent axitinib will be included prior to Cycle 1 in all patients in the
Dose Finding Phase and in at least 8 patients in the Dose Expansion Phase of the
study. Since avelumab has a long half-life (3-5 days), it would not be feasible to run a
lead-in to study the PK of avelumab alone. Therefore, the effect of axitinib on avelumab
will be evaluated by comparing avelumab trough concentrations at steady state in the
presence of axitinib with those reported for avelumab alone in prior studies.
Biomarker Assessments: A key objective of the biomarker analyses that will be
performed in this study is to investigate biomarkers that are potentially predictive of
treatment benefit with the combination of avelumab and axitinib. In addition, biomarker
studies of tumor and blood biospecimens will be carried out to help further understand
the mechanism of action of the avelumab in combination with axitinib, as well as
potential mechanisms of resistance.
Tumor biospecimens from archived tissue samples and metastatic lesions will
be used to analyze candidate DNA, RNA, or protein markers, or a relevant signature
of markers, for their ability to identify those patients who are most likely to benefit from
treatment with the study drugs. Markers that may be analyzed include, but not be
limited to, PD-L1 expression tumor-infiltrating CD8+ T lymphocytes, and T-cell receptor
gene sequence quantitation. Optional tumor biopsies obtained upon disease
progression will be used to investigate acquired mechanisms of resistance. Only core
needle or excisional biopsies, or resection specimen are suitable.
Peripheral Blood: Specimens will be retained as whole blood, serum, and
plasma in a biobank for exploratory biomarker assessments, unless prohibited by local
regulation or by decision of the Institutional Review Board or Ethics Committee.
Samples may be used to identify or characterize cells, DNA, RNA, or protein markers
known or suspected to be of relevance to the mechanisms of action, or the
development of resistance to avelumab used in combination with axitinib. These
include biomarkers that may aid in the identification of those patients who might
preferentially benefit from treatment with avelumab in combination with axitinib,
including but not limited to biomarkers related to anti-tumor immune response or target
modulation, such as soluble VEGF-A, IL-8, IFNγ and/or tissue FoxP3, PD-1, PD-L2.
Biospecimens should be obtained pre-dose and at the same time as PK samples
whenever possible.
Example 2: Combination Treatment with Axitinib and Avelumab Versus Sunitinib
This example illustrates a clinical trial study to evaluate safety and efficacy of
avelumab (MSB0010718C) in combination with axitinib (AG-013736) and to
demonstrate the superiority of this combination versus standard-of-care sunitinib
monotherapy in the first-line treatment of patients with advanced RCC (aRCC).
Sunitinib malate (SUTENT®) is an oral multitargeted TKI of stem cell receptor factor
(KIT), platelet derived growth factor-receptors (PDGFRs), VEGFRs, glial cell-line
neurotrophic factor receptor (RET), and FMS-like tyrosine kinase 3 (FLT3), and colony
stimulating factor receptor Type 1 (CSR-1R) approved multinationally for the treatment
of aRCC, imatinib-resistant or intolerant gastrointestinal stromal tumor (GIST), and
unresectable, well-differentiated metastatic pancreatic neuroendocrine tumors (NET).
The study is a Phase 3, randomized, multination, multicenter, open-label,
parallel 2-arm study in which approximately 465 patients are planned to be randomized
to receive avelumab in combination with axitinib or sunitinib monotherapy: Arm A:
avelumab in combination with axitinib; Arm B: sunitinib. Patients will be stratified
according to ECOG performance status (0 versus 1) and LDH (>1.5 ULN vs. ≤1.5
ULN). In arm A (avelumab in combination with axitinib), avelumab will be given as a 1
hour intravenous infusion (IV) every 2 weeks in a 6-week cycle. Axitinib will be given
orally (PO) twice daily (BID), with or without food, on a continuous dosing schedule.
Treatment with study drugs may continue until confirmed disease progression,
patient refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated
by the sponsor, whichever comes first. Axitinib treatment may be adjusted by dosing
interruption with or without dose reduction. Intrapatient axitinib dose escalation may
occur if the intrapatient escalation criteria are met.
Study Treatment: Axitinib will be given orally twice daily PO on a continuous
daily dosing schedule. Avelumab will be given as a 1 hour intravenous infusion every
2 weeks in a 6-week cycle. Sunitinib will be given orally 50 mg taken once daily, on a
schedule 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). Patients who
develop disease progression on study treatment but are otherwise continuing to derive
clinical benefit from study treatment will be eligible to continue with avelumab
combined with axitinib, or single-agent avelumab, or single-agent axitinib, or single-
agent sunitinib provided that the treating physician has determined that the benefit/risk
for doing so is favorable.
Tumor Assessments: Anti-tumor activity will be assessed by radiological tumor
assessments and will be based on RECIST guidelines version 1.1 for primary and
secondary endpoints and on immune-related RECIST (irRECIST) guidelines for
exploratory endpoints. Tumor assessments will be performed every 6 weeks (Q6W)
up to 1 year from first dose therapy; thereafter, tumor assessments will be performed
every 2 cycles. In addition, radiological tumor assessments will also be conducted
whenever disease progression is suspected (e.g., symptomatic deterioration), at the
time of the End of Treatment/Withdrawal visit (if not done in the previous 6 weeks), and
during the Short term Follow-up period (at the 90-day visit only); subsequent tumor
assessments during the Long term Follow-up period can be collected in absence of
withdrawal of consent, regardless of initiation of subsequent anti-cancer therapies.
Tumor assessments will include all known or suspected disease sites. Imaging
may include chest, abdomen, and pelvis CT or MRI scans; brain CT or MRI scans
(required at baseline and when suspected brain metastasis) and bone scans or 18FDG
PET (required at baseline then every 16 weeks only if bone metastases are present at
baseline). Otherwise, bone imaging is required only if new bone metastasis are
suspected and at the time of confirmation of complete response for patients who have
bone metastases. The CT scans should be performed with contrast agents unless
contraindicated for medical reasons. The same imaging technique used to characterize
each identified and reported lesion at baseline will be employed in the following tumor
assessments. Antitumor activity will be assessed through radiological tumor
assessments conducted at baseline, at 6 weeks after the first dose of therapy, then
every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter,
(if not done in the previous 6 weeks), and during the Short term Follow-up period (at
the 90-day visit only); subsequent tumor assessments during the Long term Follow-up
period can be collected in absence of withdrawal of consent, regardless of initiation of
subsequent anti-cancer therapies. Further imaging assessments may be performed at
any time if clinically indicated (e.g., suspected PD, symptomatic deterioration, etc.).
Assessment of response will be made using RECIST version 1.1 and as per immune-
related response criteria (irRC) (Nishino 2013). All radiographic images will be
collected and may be objectively verified by a BICR independent third-party core
imaging laboratory.
Primary Endpoint: Progression-Free Survival (PFS) as assessed by Blinded
Independent Central Review (BICR) per RECIST v1.1. Secondary Endpoints: Overall
Survival (OS); objective tumor response rate (OR), as assessed by BICR per RECIST
version 1.1.; disease Control (DC), as assessed by BICR per RECIST version 1.1.;
time to event: time to response (TTR), Duration of Response (DR); adverse Events
(AEs) as characterized by type, frequency, severity (as graded by National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03),
timing, seriousness, and relationship to study therapy; Laboratory abnormalities as
characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), and
timing; PK parameters including trough concentrations (Ctrough) of avelumab and
trough concentrations (Ctrough) and maximum concentrations (Cmax) of axitinib;
tumor tissue biomarker status (i.e., positive or negative; based on for example, PD-L1
expression and/or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed
by immunohistochemistry); measures of clinical outcome (PFS, OS, OR, DCR, DR and
TTR) in biomarker-positive and biomarker-negative sub-groups; anti-drug antibodies
(ADAs; neutralizing antibodies) of avelumab when in combination with axitinib; patient-
Reported Outcomes (PRO): FACT-Kidney Symptom Index (FKSI-19), EuroQol 5
Dimension (EQ 5D).
Example 3: Combination Treatment with Anti1BB Antibody and Avelumab
This example illustrates the therapeutic activity of anti1BB antibody and
avelumab combination therapy in murine B16F10 melanoma and MC38 colon
carcinoma models.
Six (6)- to 8-week old female C57BL/6 mice were purchased from the Jackson
Laboratories. All animals were housed in a pathogen free vivarium facility at Rinat and
experiments were conducted according to the protocols in accordance with the
Institutional Animal Care and Use Committee (IACUC) guidelines.
The B16F10 melanoma cell line was purchased from American Type Culture
Collection (ATCC). The MC38 colon carcinoma cell line was kindly provided by Dr.
Antoni Ribas at University of California, Los Angeles, CA. Cells were cultured in
Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine
serum (FBS), 2 mM L-glutamine at 37°C in 5% carbon dioxide (CO2), and IMPACT-
tested for pathogens at Research Animal Diagnostic Laboratory (RADIL) (Columbia,
MO). Pathogen-free cells growing in an exponential growth phase were harvested and
used for tumor inoculation.
Antibodies used for cell surface or intracellular staining were purchased from
BD Biosciences or eBioscience. They were rat anti-mouse CD4-PerCP-Cy5.5 (clone
RM4-5, BD Biosciences), rat anti-mouse CD8a-APC-H7 (clone 53-6.7, BD
Biosciences), rat anti-mouse CD25-PE-Cy7 (clone PC61, BD Biosciences), rat anti-
mouse CD45-BV510 (clone 30-F11, BD Biosciences), rat anti-mouse CD90.2-FITC
(clone 53-2.1, BD Biosciences), rat anti-mouse Eomes-PE (clone: Dan11mag,
eBioscience), rat anti-mouse FoxP3-eFluor450 (clone FJK-16s, eBioscience), and rat
anti-mouse NKp46-BV421 or -AF647 (clone 29A1.4, BD Biosciences). Live cells were
separated from dead cells using LIVE/DEAD Fixable Blue Dead Cell Stain Kit
(Invitrogen).
Therapeutic mouse anti-mouse 4-1BB mAb (mouse immunoglobulin G1
[mIgG1]), derived from the parental clone MAB9371 (R&D Systems), was prepared in-
house. Avelumab was provided by Merck Serono. Isotype control mIgG1 (clone:
MOPC-21) was purchased from BioXcell. Human IgG1 was prepared in-house. Anti-
4-1BB and avelumab were diluted to concentrations of 0.1 mg/mL and 1 mg/mL,
respectively, in phosphate buffered saline (PBS) (Life Technologies), and dosed at 0.2
mL per mouse intraperitoneally (ip) for 3 doses 3 to 4 days apart.
C57BL/6 mice were inoculated subcutaneously at the right flank with 0.2 × 10
B16F10 or 0.5 × 10 MC38 cells in 0.1 mL of serum-free DMEM. When tumors reached
target size, mice were randomized into treatment groups. Treatment was started on
the same day as randomization. Tumor size was measured twice weekly in
2 dimensions using a caliper, and the volume was expressed in cubic millimeters using
the formula: V = 0.5 L × W where L is the longest diameter of the tumor and W is the
diameter perpendicular to L. Body weight was recorded weekly.
Tumors were disseminated into single cell suspension using gentle MACS and
Miltenyi Mouse Dissociation Kit (Miltenyi Biotec) according to manufacturer’s protocol
with modification. Ammonium-Chloride-Potassium (ACK) Lysing Buffer (Life
Technologies) was used to remove red blood cells. Cells were washed twice with
FACS staining buffer (PBS supplemented with 2% FBS and 0.9% sodium azide
[NaN3]), and finally resuspended in FACS staining buffer.
An aliquot of cells was pre-incubated with 10 µg/mL of mouse BD Fc Block
(BD Biosciences) for 10 minutes before phenotyping mAbs were added to specifically
stain immune cells. Cell surface antigens were labeled by incubating cells at 4°C for
minutes. After removing unbound mAbs, cells were washed twice with FACS
staining buffer, fixed in fixative buffer (PBS + 2% FBS + 1% paraformaldehyde), and
stored at 4°C in the dark until analyzed by flow cytometry. Intracellular staining was
carried out using Foxp3/Transcription Factor Staining Buffer set (eBioscience)
according to the manufacturer’s protocol. Flow cytometry data were acquired using
LSR Fortessa (BD Biosciences) and analyzed using FlowJo (TreeStar Inc.).
Results were expressed as mean SEM. Statistical analyses were performed
using GraphPad Prism 6.0. One-way or 2-way ANOVA was applied to compare the
statistical differences among multiple groups relative to the isotype control. P <0.05
was considered as significant difference.
Two murine models were used to evaluate the therapeutic efficacy of anti
1BB in combination with avelumab. In the B16F10 melanoma model, the average
starting tumor size was 67 to 78 mm (range 44 to 114 mm ; n = 7 animals per group)
(Table 5). By Day 26 post tumor inoculation, the tumors for isotype, anti1BB alone,
and avelumab alone groups reached an average of 1206 397 mm , 1979 425 mm ,
and 2112 429 mm , respectively (Table 5). By contrast, dramatic tumor suppression
(average of 341 146 mm ) was observed when animals were administered with anti-
4-1BB and avelumab concurrently (p <0.0001 vs single agent alone groups) (Table 5).
Table 5. Tumor Measurements (Mean SEM) of Subcutaneous B16F10
Melanoma over Time
Day Isotypes Anti1BB Avelumab Anti1BB /
s Avelumab
SEM N Mean SEM N Mean SEM N Mean SEM N
67 4 7 69 6 7 78 8 7 70 10 7
251 109 7 364 87 7 327 78 7 219 57 7
475 222 7 725 266 7 654 174 7 272 94 7
909 368 7 1511 417 7 1304 274 7 243 106 6
1206 397 7 1979 425 7 2112 429 7 341 146 6
Tumor volume is expressed in mm .
N = Number of animals within each group; SEM = Standard error of the mean.
In the MC38 colon carcinoma model, the average starting tumor size was
approximately 60 mm (range 41 - 92 mm ; n = 10 animals per group) (Table 6). At the
end of study (Day 23 post tumor implantation), the average tumor volumes of isotype,
anti1BB alone, avelumab alone, and anti1BB antibody/avelumab combination
3 3 3 3
groups were 1177 252 mm , 1093 183 mm , 901 206 mm , and 530 190 mm ,
respectively (Table 6). The reduction in tumor size by the combination treatment was
significant, compared to the isotype control (p <0.001) and 4-1BB alone groups (p
<0.01), but not to the avelumab group (p >0.05) (Table 6).
Table 6. Tumor Measurements (Mean SEM) of Subcutaneous MC38 Colon
Carcinoma over Time
Day Isotypes Anti1BB Avelumab Anti1BB /
s Avelumab
SEM N Mean SEM N Mean SEM N Mean SEM N
60 5 10 62 3 10 63 5 10 64 5 10
130 21 10 122 15 10 127 19 10 117 13 10
357 72 10 250 30 10 254 42 10 146 42 10
501 108 10 355 56 10 384 86 10 176 64 10
680 148 10 508 76 10 523 114 10 246 93 10
987 236 9 785 143 10 714 158 9 416 149 10
1177 252 9 1093 183 10 901 206 9 530 190 10
Tumor volume is expressed in mm .
N = Number of animals within each group; SEM = Standard error of the mean.
Tumor-infiltrating lymphocytes (TILs) were isolated from MC38 tumors after
treatment and analyzed for markers associated with anti-tumor immune response. The
combination treatment facilitated the infiltration of T cells into tumors with an average
of 53% of total CD45+ cells, while T-cell frequency (of CD45+ cells) was 25%, 31%,
and 36% in the isotype, anti-4 1BB antibody treatment alone, and avelumab alone
groups, respectively (Figure 1). The ratio of CD8+ T cells/ regulatory T cell (Treg) in
the isotype and avelumab groups was 1.2 and 2.5, respectively. This ratio increased
to 10 and 21 in anti1BB antibody treatment alone and in combination with avelumab,
respectively (Figure 2). Furthermore, the induction of Eomes, a marker associated with
T-cell effector/memory differentiation, was observed in the anti1BB antibody
treatment alone and anti1BB and avelumab combination groups (Figure 3).
These results demonstrate that treatment with anti1BB antibody in
combination with avelumab has a synergistic anti-tumor effect accompanied by the
enrichment of T cells in tumor, increased CD8 T cell/regulatory T cell (Treg) ratio, and
induction of eomesodermin (Eomes) expression. Furthermore, the combination
therapy elicited an anti-tumor immune response in the tumor microenvironment.
Example 4: Combination Treatment of Advanced Malignancies with Avelumab and
PF-05082566
This example illustrates a clinical trial study to evaluate safety, efficacy,
pharmacokinetics, and pharmacodynamics of avelumab (MSB0010718C) in
combination with PF-05082566, an anti1BB agonist IgG2 antibody, in patients with
with locally advanced or metastatic solid tumors (e.g., non-small cell lung cancer
(NSCLC), melanoma, and squamous cell carcinoma (SCCHN)). Protocol design is set
forth in Table 7.
Table 7
Arms Assigned Interventions
Cohort A1: NSCLC patients treated with Avelumab 10 mg/kg IV Q2W; PF-
mg/kg avelumab + 500 mg PF- 05082566 500 mg IV every 4 weeks.
05082566 Treatment with the combination of
avelumab with PF-05082566 will
continue until disease progression.
Cohort A2: NSCLC patients treated with Avelumab 10 mg/kg IV Q2W; PF-
mg/kg avelumab + 100 mg PF- 05082566 100 mg IV every 4 weeks.
05082566 Treatment with the combination of
avelumab with PF-05082566 will
continue until disease progression.
Arms Assigned Interventions
Cohort A3: NSCLC patients treated with Avelumab 10 mg/kg IV Q2W; PF-
mg/kg avelumab + 20 mg PF- 05082566 20 mg IV every 4 weeks.
05082566 Treatment with the combination of
avelumab with PF-05082566 will
continue until disease progression.
Cohort A4: Melanoma patients treated Avelumab 10 mg/kg IV Q2W; PF-
with 10 mg/kg avelumab + 100 mg PF- 05082566 100 mg IV every 4 weeks.
05082566 Treatment with the combination of
avelumab with PF-05082566 will
continue until disease progression.
Cohort A5: SCCHN patients treated with Avelumab 10 mg/kg IV Q2W; PF-
mg/kg avelumab + 100 mg PF- 05082566 100 mg IV every 4 weeks.
05082566 Treatment with the combination of
avelumab with PF-05082566 will
continue until disease progression.
Example 5: Combination Treatment of Cancer with Avelumab, Anti1BB antibody,
and Anti-M-CSF Antibody
This example illustrates the therapeutic activity of anti1BB antibody, anti-M-
CSF antibody, and the anti-PD-L1 antibody Avelumab triple combination therapy in
murine MC38 colon carcinoma models.
Six (6)- to 8-week old female C57BL/6 mice were purchased from the Jackson
Laboratories. All animals were housed in a pathogen free vivarium facility at Rinat and
experiments were conducted according to the protocols in accordance with the
Institutional Animal Care and Use Committee (IACUC) guidelines.
The MC38 colon carcinoma cell line was kindly provided by Dr. Antoni Ribas at
University of California, Los Angeles, CA. Cells were cultured in Dulbecco’s Modified
Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L
glutamine at 37°C in 5% carbon dioxide (CO2), and IMPACT-tested for pathogens at
Research Animal Diagnostic Laboratory (RADIL) (Columbia, MO). Pathogen-free cells
growing in an exponential growth phase were harvested and used for tumor
inoculation.
Therapeutic mouse anti-mouse 4-1BB mAb (mouse immunoglobulin G1
[mIgG1]), derived from the parental clone MAB9371 (R&D Systems), was prepared in-
house. Avelumab was provided by Merck Serono. Rat anti-mouse M-CSF (clone 5A1),
rat IgG1 (clone HRPN) and mIgG1 (clone: MOPC-21) isotype controls were purchased
from BioXcell. Human IgG1 isotype was prepared in-house. Anti1BB, avelumab and
anti-M-CSF mAbs were diluted to concentrations of 0.1 mg/mL and 1 mg/mL, and 1.5
mg/mL, respectively, in phosphate buffered saline (PBS) (Life Technologies), and
dosed at 0.2 mL per mouse intraperitoneally (ip) for 3 doses 3 to 4 days apart.
C57BL/6 mice were inoculated subcutaneously at the right flank with 0.5-1 x 10
MC38 cells in 0.1 mL of DMEM. When tumors reached an average of ~ 60 mm (range
41 – 93 mm ), mice were randomized into groups of 10 animals per group, and
treatment was started at the same day. Tumor size was measured in two dimensions
using a caliper, and the volume was expressed in mm using the formula: V = 0.5 L x
W2 where L and W are the long and short diameters of the tumor, respectively. Body
weight was recorded weekly.
Results were expressed as mean ± SEM (Table 8). Statistical analyses were
performed using GraphPad Prism 6.0. One-way or two-way ANOVA was applied to
compare the statistical differences among multiple groups relative to isotype controls.
P<0.05 was considered as significant difference.
Table 8
Group 1. Isotype control
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 60 5 10
130 21 10
14 357 72 10
16 501 108 10
18 680 148 10
21 987 236 9
23 1177 252 9
Group 2. Anti1BB antibody (1 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 62 3 10
122 15 10
14 250 30 10
16 355 56 10
18 508 76 10
21 785 143 10
23 1093 183 10
Group 3. Anti-M-CSF antibody (15 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 58 4 10
138 27 10
14 196 32 10
16 268 43 10
18 350 56 10
21 432 84 9
23 572 123 9
Group 4. Anti-PD-L1 antibody (Avelumab, 10 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 63 5 10
127 19 10
14 254 42 10
16 384 86 10
18 523 114 10
21 714 158 9
23 901 206 9
Group 5. Anti1BB antibody (1 mg/kg) + Anti-PD-L1 antibody (Avelumab, 10 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 64 5 10
117 13 10
14 146 42 10
16 176 64 10
18 246 93 10
21 416 149 10
23 530 190 10
Group 6. Anti-M-CSF antibody (15 mg/kg) + Anti-PD-L1 antibody (Avelumab, 10 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 62 4 10
106 10 10
14 182 29 10
16 211 32 9
18 297 65 9
21 436 112 9
23 499 145 9
Group 7. Anti1BB antibody (1 mg/kg) + Anti-M-CSFantibody (15 mg/kg) +
Anti-PD-L1 antibody (Avelumab, 10 mg/kg)
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
7 61 4 10
120 16 10
14 139 15 10
16 145 20 10
18 166 20 10
21 214 28 10
23 277 39 10
Treatment with the triple combination of anti1BB antibody, Avelumab, and
anti-M-CSF antibody delayed MC38 tumor growth compared to isotype control (Table
8). The triple antibody combination (Table 8, Group 7) was more efficacious than either
double combination of avelumab and anti1BB antibody (Table 8, Group 5) or
avelumab and anti-CSF-1 antibody (Table 8, Group 6). For example, at day 23 post-
tumor inoculation, tumors in animals treated with the triple combination of avelumab,
anti1BB antibody, and anti-CSF-1 antibody had a mean size of 277 mm . In
comparison, tumors in animals treated with either the double combination of avelumab
and anti1BB antibody or avelumab and anti-CSF-1 antibody had a mean size of 530
mm and 499 mm , respectively, at day 23. Tumors in animals given isotype control
had a mean size of 1177 mm at day 23. Tumors in animals given anti1BB antibody
had a mean size of 1093 mm at day 23. Tumors in animals given anti-CSF-1 antibody
had a mean size of 572 mm at day 23. Tumors in animals given anti-PD-L1 antibody
(Avelumab) had a mean size of 901 mm at day 23. These results demonstrate that
treatment with the triple combination of anti1BB antibody, Avelumab, and anti-M-
CSF-antibody is more efficacious in treating cancer than single antibody or double
antibody combination treatment.
Example 6: Combination Treatment of Colon Carcinoma with Avelumab, Anti1BB
antibody, and Anti-OX40 Antibody
This example illustrates the therapeutic activity of the anti-PD-L1 antibody
Avelumab, anti1BB antibody, and anti-OX40 antibody triple combination therapy in
murine cancer models.
Two murine models were used to evaluate the therapeutic efficacy of
combinatorial treatment of anti-OX40 antibody, anti1BB and Avelumab. Six (6)- to
8-week old female C57BL/6 mice or Balb/C mice were purchased from the Jackson
Laboratories. All animals were housed in a pathogen free vivarium facility at Rinat and
experiments were conducted according to the protocols in accordance with the
Institutional Animal Care and Use Committee (IACUC) guidelines.
The B16F10 melanoma cell line was purchased from American Type Culture
Collection (ATCC). The MC38 colon carcinoma cell line was kindly provided by Dr.
Antoni Ribas at University of California, Los Angeles, CA. Cells were cultured in
Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine
serum (FBS), 2 mM L-glutamine at 37°C in 5% carbon dioxide (CO2). Cells growing in
an exponential growth phase were harvested and used for tumor inoculation.
Therapeutic mouse anti-OX40 antibodies with either the mIgG1 or the mIgG2a
isotype (anti-OX40 mIgG1 and anti-OX40 mIgG2a, respectively) were derived from
parental clone OX86 in house. Therapeutic mouse anti-mouse 4-1BB antibody (mouse
immunoglobulin G1 [mIgG1]), derived from the parental clone MAB9371 (R&D
Systems), was prepared in-house. Avelumab was provided by Merck Serono. Isotype
control mIgG1 (clone: MOPC-21) and mIgG2a (C1.18.4) was purchased from BioXcell.
Human IgG1 was prepared in-house. Anti-OX40 antibody, anti1BB antibody, and
avelumab were dosed at 3 mg/kg, 1 mg/kg and 20 mg/kg in the B16F10 model and 1
mg/kg, 1 mg/kg and 10 mg/kg in the MC38 model, respectively, in phosphate buffered
saline (PBS) (Life Technologies), and dosed at 0.2 mL per mouse intraperitoneally (ip)
for 3 doses 3 to 4 days apart.
C57BL/6 mice were inoculated subcutaneously at the right flank with 0.3 × 10
B16F10 cells in 0.1 mL of PBS. Balb/C mice were inoculated subcutaneously at the
right flank with 0.5 × 10 MC38 cells in 0.1 mL of PBS. When tumors reached target
size, mice were randomized into treatment groups. Treatment was started on the same
day as randomization. Tumor size was measured twice weekly in 2 dimensions using
a caliper, and the volume was calculated in cubic millimeters using the formula: V =
0.5 L × W where L is the longest diameter of the tumor and W is the diameter
perpendicular to L. Body weight was recorded weekly.
Results are summarized in Table 9 (B16F10 melanoma) and Table 10 (MC38
colon carcinoma) below (mean tumor size SEM). Statistical analyses were performed
using GraphPad Prism 6.0. 2-way ANOVA was applied to compare the statistical
differences among multiple groups relative to the isotype control or other treatment
groups. P <0.05 was considered as significant difference. Tumor measurements are in
mm .
Table 9. Tumor Measurements of Subcutaneous B16F10 Melanoma over Time
Group 1. Isotype control
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
12 74 11 8
214 46 8
18 392 67 8
22 1015 204 8
1897 310 8
29 2233 249 8
32 2311 228 8
Group 2. Anti1BB antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
12 73 9 8
282 67 8
413 98 8
742 155 8
1392 278 8
29 2620 518 8
2759 493 8
Group 3. Anti-OX40 mIgG2a antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
71 7 9
198 51 9
18 370 105 9
22 783 293 9
1147 283 9
2046 433 9
32 2576 360 9
Group 4. Avelumab
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
12 77 15 5
236 71 5
396 137 5
750 134 5
1291 210 5
29 2159 326 5
2352 264 5
Group 5. Anti1BB antibody + Anti-OX40 mIgG2a antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
78 14 9
155 23 9
18 313 50 9
595 87 9
861 65 9
29 1453 137 9
32 2003 245 9
Group 6. Anti-OX40 mIgG1 antibody + Avelumab
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
76 15 8
228 77 8
18 336 80 8
22 648 149 8
1009 248 8
1381 228 8
32 1908 261 8
Group 7. Avelumab + Anti-OX40 mIgG2a antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
12 75 11 8
184 37 8
297 61 8
22 505 111 8
833 191 8
1731 392 8
2056 371 8
Group 8. Avelumab + Anti1BB antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
73 10 8
229 52 8
18 274 52 8
537 117 8
803 192 8
29 1435 305 8
32 1572 307 8
Group 9. Avelumab + Anti1BB antibody + Anti-OX40 mIgG1 antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
72 9 9
176 32 9
18 228 60 9
373 114 9
585 192 9
29 788 267 9
32 979 329 9
Group 10. Avelumab + Anti1BB antibody + Anti-OX40 mIgG2a antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
12 74 10 9
104 17 9
120 17 9
22 155 49 9
208 54 9
365 93 9
442 114 9
Table 10. Tumor Measurements of Subcutaneous MC38 Colon Carcinoma over Time
Group 1. Isotype control
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 7 9
13 162 23 9
16 305 41 9
21 696 66 9
24 1064 112 9
28 1830 214 9
Group 2. Anti-OX40 mIgG1 antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 6 9
13 160 15 9
16 280 28 9
21 751 79 9
24 1238 139 9
28 2223 270 9
Group 3. Anti-OX40 mIgG2a antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 7 9
13 154 11 9
16 247 18 9
21 455 64 9
24 648 102 9
28 1053 181 9
Group 4. Anti1BB antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
84 7 8
13 161 11 8
16 264 19 8
21 585 37 8
24 909 65 8
28 1494 129 8
Group 5. Anti-OX40 mIgG1 antibody + Anti1BB antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 7 9
13 171 11 9
16 246 20 9
21 492 27 9
24 737 62 9
28 1241 217 9
Group 6. Anti-OX40 mIgG2a antibody + Anti1BB antibody
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 7 8
13 175 15 8
16 248 29 8
21 387 74 8
24 567 119 8
28 854 163 8
Group 7. Anti1BB antibody + Avelumab
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 6 9
13 152 8 9
16 195 27 9
21 349 89 9
24 573 157 9
28 1026 255 9
Group 8. Anti-OX40 mIgG1 antibody + Anti1BB antibody + Avelumab
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 6 9
13 167 12 9
16 170 32 9
21 228 65 9
24 304 86 9
28 448 108 9
Group 9. Anti-OX40 mIgG2a antibody + Anti1BB antibody + Avelumab
Days Post-Tumor Mean Tumor Size SEM N
Inoculation (mm )
85 6 9
13 153 17 9
16 127 23 9
21 116 37 9
24 165 67 9
28 260 107 9
Two murine models were used to evaluate the therapeutic efficacy of triple
combinatorial treatment of anti-OX40 antibody, anti1BB antibody, and Avelumab. In
the B16F10 melanoma model, the average tumor size when treatment was started was
71-78 mm (Table 9). By day 32 post tumor innoculation, the tumors in animals treated
with isotype control, anti1BB antibody alone, avelumab alone, anti-OX40 mIgG2a
antibody alone and anti-OX40 mIgG1 antibody plus Avelumab groups were either very
3 3 3
close to or over 2000 mm ; they were 2311 228 mm , 2759 493 mm , 2352
3 3 3
264 mm , 2576 360 mm and 1908 261 mm , respectively. Treatment of animals
with anti1BB antibody plus anti-OX40 mIgG2a antibody, anti-OX40 mIgG2a
antibody plus Avelumab, or anti1BB antibody plus Avelumab had better treatment
efficacy by day 25 as comparing to isotype control treated animals; however the
difference in tumor size became insignificant on day 32. By contrast, dramatic tumor
suppression was observed when animals were administered Avelumab, anti1BB
antibody, and anti-OX40 mIgG1 antibody concurrently (Table 9, Group 9), or
Avelumab, anti1BB antibody, and anti-OX40 mIgG2a antibody concurrently (Table
9, Group 10). Tumors were 979 329 mm (Table 9, Group 9; p <0.001 vs isotype
control and single agent alone groups) and 442 114 mm (Table 9, Group 10; p
<0.00001 vs isotype control and single agent alone groups), respectively. In the case
of triple combination with anti1BB antibody, anti-OX40 mIgG2a antibody, and
Avelumab combination, it is also significantly better than the double combination
groups (p <0.01) (Table 9).
In the MC38 colon carcinoma model, the average tumor size when treatment
was started was 84-85 mm . By day 28 post tumor implantation, tumors in animals
treated with anti-OX40 mIgG2a antibody (Table 10, Group 3), anti-OX40 mIgG1
antibody plus anti1BB antibody (Table 10, Group 5), anti-OX40 mIgG2a plus anti
1BB antibody (Table 10, Group 6), or anti1BB antibody plus Avelumab (Table 10,
3 3 3
Group 7) had tumors sizes of 1053 181 mm , 1241 217 mm , 854 163 mm and
1026 255 mm , respectively, which is significantly lower than that of the isotype
control treated group (1830 214 mm ) (p <0.001) (Table 10, Group 1). Treatment with
anti-OX40 mIgG1 antibody alone (Table 10, Group 2) or anti1BB antibody alone
(Table 10, Group 4) did not inhibit tumor growth. By contrast, treatment with the triple
combination of anti1BB antibody and Avelumab with either anti-OX40 mIgG1
antibody (Table 10, Group 8) or anti-OX40 mIgG2a antibody (Table 10, Group 9)
significantly inhibited tumor growth with the tumor size averaging 448 108 mm and
260 107 mm , respectively. In both cases this is not only significant comparing to the
isotype control group (p <0.0001), both triple combinations were also significantly
better than any of the double combinations (p <0.001) (Table 10).
These results demonstrate that treatment with the triple combination of
anti1BB antibody, Avelumab, and anti-OX40 antibody is more efficacious in treating
cancer than single antibody or double antibody combination treatment.
Example 7: Combination Treatment of relapsed or refractory (R/R) Diffuse Large B-
cell Lymphoma (DLBCL) with Avelumab in Combination with Anti1BB Antibody,
Azacitidine, Anti-CD20 Antagonist Antibody, and/or Conventional Chemotherapy
(Bendamustine).
In this study example, three treatment regiments are illustrated:
• Avelumab in combination with rituximab and PF-05082566 for the treatment
of patients with relapsed or refractory DLBCL
• Avelumab in combination with azacitidine and PF-05082566 for the treatment
of patients with relapsed or refractory DLBCL
• Avelumab in combination with rituximab and bendamustine is indicated for the
treatment of patients with relapsed or refractory DLBCL
The target population for the study is patients with R/R DLBCL defined as
follows: (i) patients with R/R DLBCL following failure of at least 2 lines (and a maximum
of 4 lines) of prior rituximab/multi-agent chemotherapy and/or (ii) failure of ASCT, or
(iii) who are not candidates for ASCT (refusal or no available donor), or (iv) who are
not candidates for intensive second-line chemotherapy.
The current NCCN Guidelines (version 1.2016) for DLBCL recommend
treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
(R-CHOP) in patients with newly diagnosed disease in all stages of disease, or mini-
CHOP in patients >80 years with comorbidities. Approximately 60% of patients with
DLBCL are expected to be cured following treatment with R-CHOP. Thirty to 50% of
those with advanced disease will, however, have disease that is either primary
refractory (~15%) or resistant (~25%) to R-CHOP (NCCN Guidelines, 2016; Sehn &
Gascoyne, 2015; Vacirca et al, 2014).
High-dose chemotherapy followed by ASCT provides the best chance of a cure
in patients with R/R DLBCL in the second-line setting; however, due to advanced age
and/or comorbidities, only approximately 50% of patients for whom first-line R-CHOP
failures are fit for high-dose chemotherapy, and of these, only about ~50% have
chemosensitive disease in the second-line setting and are suitable for ASCT (Sehn &
Gascoyne, 2015). Even if eligible for high-dose chemotherapy, patients may refuse
ASCT, lack a good donor, or be ineligible due to a variety of comorbidities. Even in
patients treatmed with high-dose chemotherapy followed by ASCT, only a minority
(<10%) are cured.
The following rituximab-containing chemotherapy regimens are currently
recommended by the NCCN Guidelines (version 1.2016) for second-line salvage
therapy and beyond in patients who are not eligible for high-dose chemotherapy and
ASCT: bendamustine ± rituximab, brentuximab, cyclophosphamide/etoposide/
procarbazine/prednisone (CEPP), cyclophosphamide/etoposide/
vincristine/prednisone (CEOP), dose-adjusted etoposide, prednisone, vincristine,
cyclophosphamide and doxorubicin (DA-EPOCH) ± rituximab, gemcitabine,
dexamethasone and cisplatin (GDP) ± rituximab, gemcitabine/oxaliplatin ± rituximab,
lenalidomide ± rituximab, and rituximab (NCCN Guidelines, 2016).
The outcome of patients for whom treatment with R-CHOP failures, and who
are not eligible for high-dose chemotherapy or ASCT is dismal, with a median PFS of
3.6 months (Vacirca et al, 2014). The treatment options for these patients remain very
limited, and there is consequently a high unmet medical need in patients with R/R
DLBCL for the development of more effective salvage strategies that can prolong PFS
and overall survival (OS).
The proposed Study is a multicenter, international, parallel design, randomized,
open-label, 2-component (Phase 1b followed by Phase 3) study of avelumab in various
combinations for the treatment of R/R DLBCL. Agents that will be tested include:
(i) PF-05082566, a novel fully human IgG2 monoclonal antibody agonist of 4-
1BB,
(ii) Azacitidine, a DNA methyltransferase inhibitor (DNMTi) and epigenetic agent
which has been shown to have potential immune priming activity through various
mechanisms including the induction of PD-1 on tumor infiltrating lymphocytes (TILs)
and PD-L1 on tumor cells as well as the induction of tumor neo-antigen expression,
(iii) Rituximab, a CD20 antagonist antibody, and
(iv) Bendamustine, an alkylatingchemotherapy agent which is one of the
National Comprehensive Cancer Network (NCCN) recommended agents for the
salvage therapy of patients with DLBCL who are ineligible for high dose chemotherapy
and autologous stem cell transplant (ASCT).
The treatment regimens proposed in the study include avelumab combined with:
(i) Rituximab and PF-05082566
(ii) Azacitidine and PF-05082566, and
(iii) Rituximab and bendamustine
In Phase 3, patients will be randomized in a 1:1 ratio to the treatment regimen
selected in Phase 1b versus the Investigator’s Choice standard of care (SOC)
treatment to determine whether the selected treatment regimen is superior to the
Investigator’s Choice SOC treatment in prolonging progression-free survival (PFS).
The target study population of this Phase 1b/Phase 3 registrational study will
comprise patients with R/R DLBCL who have completed at least 2 (but not more than
4) lines of prior rituximab/multi-agent chemotherapy, or in whom ASCT has been a
failure , or who are not candidates for ASCT, or who are not eligible for intensive
chemotherapy. The study will assess the safety, efficacy, pharmacokinetics (PK),
immunogenicity, and patient reported outcomes.
The primary objective of the Phase 1b component is to make a preliminary
assessment of safety for each combination regimen. Each arm without a significant
safety signal among the first 6 patients will then be expanded to a total of 28 patients
per arm in order to select a treatment regimen to be advanced to the Phase 3
component of the study. This decision will be based upon the investigator observed
objective response rate (ORR) and safety profile of each combination regimen. The
combination regimens to be assessed in the Phase 1b component of the study in 28-
day cycles include:
Arm A: Avelumab/Rituximab/PF-05082566 (4-1BB)
(i) Rituximab 375 mg/m (IV) in the morning on Day 1 of each 28-day cycle.
Rituximab is administered for a maximum of 8 cycles.
Rituximab will be administered at least 3 hours prior to PF-05082566 when
dosed on the same day.
(ii) PF-05082566 100 mg fixed dose (IV) in the morning on Day 2 of Cycles 1
and 2 of each 28-day cycle. If PF-05082566 is well tolerated in Cycles 1 and 2,
administration of PF-05082566 may be on Day 1 in Cycle 3 (and all subsequent
cycles).
PF-05082566 will be administered at least 3 hours prior to avelumab in Cycle 1.
If PF-05082566 is well tolerated in Cycle 1, in Cycle 2 and all subsequent cycles the
window of dose administration between PF-05082566 and avelumab may be
decreased from at least 3 hours apart to 30-60 minutes apart.
(iii) Avelumab 10 mg/kg (IV) every 2-weeks Day 2 and Day 16 of each 28-day
cycle in Cycle 1 and Cycle 2. If avelumab is well tolerated in Cycle 1 and 2,
administration of avelumab may be on Day 1 and Day 15 in Cycle 3 (and all
subsequent cycles).
Avelumab will be administered at least 3 hours after PF-05082566 in Cycle 1
and Cycle 2. If avelumab is well tolerated in Cycle 1 Day 2, in Cycle 2 Day 2 and
subsequent cycles the window of dose administration between avelumab and PF-
05082566 may be decreased from at least 3 hours apart to 30-60 minutes apart.
Arm B: Avelumab/Azacitidine/PF-05082566 (4-1BB)
(i) Azacitidine 75 mg/m (SC) in the morning on Day 1 - Day 7 consecutively of
each 28-day cycle. Azacitidine is administered for a maximum of 6 cycles.
Azacitidine will be administered at least 3 hours prior to PF-05082566 when
dosed on the same day.
(ii) PF-05082566 100 mg fixed dose (IV) in the morning on Day 2 for Cycle 1
and Cycle 2, of each 28-day cycle. If PF-05082566 is well tolerated in Cycle 1 and 2,
PF-05082566 may be administered on Day 1 commencing with Cycle 3 (and
subsequent cycles).
PF-05082566 should be administered at least 3 hours prior to avelumab
administration. If PF-05082566 is well tolerated in Cycle 1, in Cycle 2 and all
subsequent cycles the window of dose administration between PF-05082566 and
avelumab may be decreased from at least 3 hours apart to 30-60 minutes apart.
(iii) Avelumab 10 mg/kg every 2-weeks (IV) Day 2 and Day 16 of each 28-day
cycle in Cycle 1 and Cycle 2. If avelumab is well tolerated in Cycle 1 and 2,
avelumab may be administered on Day 1 and Day 15 in Cycle 3 (and all subsequent
cycles).
Avelumab administration should be at least 3 hours after PF-05082566 in Cycle
1 and Cycle 2. If avelumab is well tolerated in Cycle 1 Day 2, in Cycle 2 Day 2 and
subsequent cycles the window of dose administration between avelumab and PF-
05082566 may be decreased from at least 3 hours apart to 30-60 minutes apart.
Arm C: Avelumab/Bendamustine/Rituximab
(i) Rituximab 375 mg/m (IV) in the morning on Day 1 of each 28-day cycle.
Rituximab is administered for a maximum of 8 cycles.
(ii) Bendamustine 90 mg/m (IV) on Day 2 and Day 3 of each 28-day cycle in
Cycle 1 and Cycle 2. If bendamustine is well tolerated in Cycle 1 and 2, bendamustine
may be administered on Day 1 and Day 2 in Cycle 3 (and all subsequent cycles).
Bendamustine is administered for a maximum of 6 cycles.
(iii) Avelumab 10 mg/kg every 2-weeks (IV) Day 2 and Day 16 of each 28-day
cycle in Cycle 1 and Cycle 2. If avelumab is well tolerated in Cycle 1 and 2,
avelumab may be administered on Day 1 and Day 15 in Cycle 3 (and all subsequent
cycles). Avelumab administration should be at least 3 hours after bendamustine.
In Phase 3 (N = 220), the primary objective is to demonstrate superiority in PFS
(as assessed by Blinded Independent Central Review [BICR]) of the combination
regimen identified in Phase 1b, over the control treatment, namely Investigator’s
Choice SOC chemotherapy (comprising rituximab/bendamustine or rituximab/
gemcitabine/ oxaliplatin).
The following treatment regimens will be assessed in the Phase 3 component
of the study, with all treatments being administered in 28-day cycles:
Arm D (N=110): Regimen Selected from Phase 1b
Arm D will be one of the treatment regimens assessed in Phase 1b, ie, Arm A,
B, or C, selected based on safety and efficacy assessments.
Cohort E (N=110): Investigator’s Choice Option Between the Following
Standard of Care Regimens:
(i) Rituximab/bendamustine
- Rituximab 375 mg/m IV Day 1
- Bendamustine 120 mg/m IV Day 1 and Day 2
(ii) Rituximab/gemcitabine/oxaliplatin
- Rituximab 375 mg/m IV Day 1
- Gemcitabine 1000 mg/m IV on Day 2 and Day 17
- Oxaliplatin 100 mg/m IV on Day 2 and Day 17
Example 8: Combination Treatment of Patients with Advanced Malignancies whose
Disease has Progressed on an Immune Checkpoint Inhibitor with Avelumab in
Combination with anti1BB antibody.
This example illustrates a Phase 2 study to assess safety and efficacy of
avelumab (MSB0010718C) in combination with anti1BB agonist antibody PF-
05082566 in patients with advanced NSCLC, RCC, or urothelial cancer (UC) whose
disease has progressed on prior therapy(ies), including a single-agent immune
checkpoint inhibitor.
The objective of this study is to evaluate the Objective Response Rate (ORR)
based on RECIST 1.1 of avelumab plus PF-05082566. Patients must have advanced
NSCLC, RCC, or urothelial cancer which was resistant (responded and then
progressed) or refractory (never responded) to prior therapy(ies), including a single-
agent immune checkpoint inhibitor (e.g.,anti- PD-1/anti-PD-L1 or anti-CTLA-4).
Avelumab will be given as a 1-hour intravenous infusion every 2 weeks at a
dose of 10 mg/kg in all three cohorts. PF-05082566 will be administered at 100 mg as
a 1-hour IV infusion once every 4 weeks on Day 1 of each cycle.
On days when both drugs are administered, PF 05082566 will be administered
first, followed by the avelumab infusion no more than 30 minutes after the end of the
PF-05082566 infusion.
Dosing will continue until disease progression is confirmed by the investigator,
patient refusal, unacceptable toxicity, patient is lost to follow-up, or until the study is
terminated by the Sponsor, whichever occurs first.
The combination of avelumab plus anti1BB antibody PF-05082566 and anti-
OX40 antibody PF-04518600 has been evaluated for cytokine release using the
standard human PBMC in vitro test. The cytokine release assay was completed for
PF-05082566 alone and in combination with avelumab and PF-04518600. Results for
the PF-05082566 antibody alone did not show a significant increase in cytokine
release. In addition, there was no additive effect on cytokine release when the three
monoclonal antibodies were combined.
ORR estimation will be the primary objective in any potential evaluation of
avelumab in combination with immunotherapy other that PF-05082566. In each case,
the ORR will be evaluated with the totality of the data for potential cohort expansion or
testing of multiple tumor types and/or other combination immunotherapeutic agents.
Example 9: Randomized, Phase 3 Study of Avelumab (MSB0010718C) in
Combination with Standard of Care Chemoradiotherapy (Cisplatin and Definitive
Radiation Therapy) Versus Standard-of-Care Chemoradiotherapy in the Front-line
Treatment of Patients with Locally Advanced Squamous Cell Carcinoma of the Head
and Neck
This example illustrates a Phase 3, multicenter, multinational, randomized,
placebo controlled study of avelumab (MSB0010718C) in combination with standard
of care (SOC) chemoradiotherapy (cisplatin and definitive radiation therapy) versus
SOC chemotherapy for front-line treatment of patients with locally-advanced
squamous cell carcinoma of the head and neck.
Approximately 640 patients who have received no prior therapy for their SCCHN
(oral cavity, oropharynx, larynx, or hypopharynx) HPV-: Stage III, IVa, or IVb or HPV+:
T4 or N3 who are eligible for definitive chemoradiotherapy with cisplatin will be
randomized 1:1 to treatment with avelumab + SOC chemoradiotherapy vs. placebo +
chemoradiotherapy followed by maintenance avelumab or placebo for up to 1 year.
Patients will be stratified based on:
Tumor (T) stage (<T4 vs T4);
Nodal (N) stage (N0 vs N1/N2a/N2b vs N2c/N3)
Tumor assessment will occur every 12 weeks following the completion of
definitive chemoradiotherapy for 2 years, and then every 16 weeks thereafter.
A blinded independent review committee (BICR) will review tumor assessments
in addition to investigator reviews.
When the study treatment is discontinued for reasons other than progressive
disease (PD), patient withdrawal of consent, or death, patients will be followed and
have tumor assessments performed every 12 weeks until: 1) PD, 2) death, 3) patient
withdrawal of consent from study, or 4) 2 years from completion of chemoradiotherapy
have passed after which tumor assessments can be every 16 weeks, whichever occurs
first.
Arm A: Avelumab (MSB0010718C) +SOC Chemoradiotherapy (CRT).
In this study, the lead-in phase is to start seven days prior to initiation of the CRT
phase. The maintenance phase will start after completion of the CRT phase (i.e., two
weeks following completion of CRT).
Cisplatin 100 mg/m Days 1, 22, 43. Administered in 500 ml normal saline over a
60-120 minute infusion with an additional 1 to 1.5 L of fluid given post-hydration.
Radiation therapy (RT) 70 Gy/33-35 fractions/day, 5 fractions/week intensity
modulated radiation therapy (IMRT)
Avelumab: 10 mg/kg administered on Day 1 of the lead-in phase and Days 8, 29,
39 of the CRT phase, and every 2 weeks (Q2W) thereafter for up to 12 months.
Arm B: SOC Chemoradiotherapy.
Cisplatin 100 mg/m Days 1, 22, 43
RT 70 Gy/33-35 fractions/day, 5 fractions/week IMRT
Placebo: Day 1 of the lead-in phase, Days 8, 29, 39 of the CRT phase and Q2W
thereafter for up to 12 months.
Avelumab and placebo will be administered as IV infusion.
Patients will receive study treatment until: 1) 12 months after start of
maintenance therapy (study intervention completion), 2) PD 3) death, 4) patient
withdrawal of consent, 5) patient is lost to follow-up, 6) unacceptable toxicity occurs,
or 7) the study is terminated by the Sponsor, whichever occurs first.
The dose of cisplatin may be modified on Days 22 and/or 43 for toxicity as
follows: starting dose level is 100 mg/m , dose level -1 is 75 mg/m , and dose level -
2 is 50 mg/m .
Peripheral blood and additional tumor tissue biomarkers consisting of the levels
of cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or proteins that may be
related to anti-tumor immune response and/or response to or disease progression on
avelumab, such as genes related to IFN-γ or transforming growth factor (TGF)-β.
Example 10: Phase 1b dose-finding study of avelumab (MSB0010718C; anti-PD-L1)
+ axitinib in treatment-naïve patients with advanced renal cell carcinoma
This example illustrates results from the study described in Example 1 above.
Eligible patients have histologically confirmed aRCC with a clear-cell component,
primary tumour resection, ≥1 measurable lesion, archival/fresh tumour biopsy, ECOG
PS ≤1, no preexisting uncontrolled hypertension, and no prior systemic therapy for
aRCC. To determine dose modifications for future cohorts, dose escalation/de-
escalation rules that follow the modified toxicity probability interval method were used.
Adverse events (AEs) were graded by NCI CTCAE v4. Objective response rates (ORR;
RECIST v1.1) were evaluated.
The starting dose of avelumab 10 mg/kg (1h IV infusion) Q2W + axitinib 5 mg
PO BID met MTD criteria. By 05 April 2016, 6 pts (median age 59.5 [range, 45-73])
have been treated with avelumab for a median of 17.0 wks (range, 11.9-21.7) and with
axitinib for 16.3 wks (range, 12.7-22.7). One DLT of grade 3 proteinuria occurred. The
most common treatment-related (TR) AEs of any grade were dysphonia (n=4),
hypertension (n=4), fatigue (n=3), and headache (n=3). Grade 3-4 TRAEs were
hypertension (n=2), hand-foot syndrome (n=1), elevated lipase (n=1), and proteinuria
(n=1). Confirmed ORR is 83.3% (95% CI: 35.9, 99.6) based on 5 PRs and stable
disease in 1 pt.
The MTD/RP2D for this expansion phase and further studies in aRCC has been
confirmed as avelumab 10 mg/kg IV Q2W + axitinib 5 mg PO BID continuously. The
regimen has shown preliminary antitumour activity in treatment-naïve pts with aRCC.
Enrollment is ongoing in the expansion cohort. These results demonstrate the efficacy
and safety of avelumab + axitinib vs current monotherapies for aRCC.
Although the disclosed teachings have been described with reference to various
applications, methods, kits, and compositions, it will be appreciated that various
changes and modifications can be made without departing from the teachings herein
and the claimed invention below. The foregoing examples are provided to better
illustrate the disclosed teachings and are not intended to limit the scope of the
teachings presented herein. While the present teachings have been described in terms
of these exemplary embodiments, the skilled artisan will readily understand that
numerous variations and modifications of these exemplary embodiments are possible
without undue experimentation. All such variations and modifications are within the
scope of the current teachings.
All references cited herein, including patents, patent applications, papers, text
books, and the like, and the references cited therein, to the extent that they are not
already, are hereby incorporated by reference in their entirety. In the event that one or
more of the incorporated literature and similar materials differs from or contradicts this
application, including but not limited to defined terms, term usage, described
techniques, or the like, this application controls.
The foregoing description and Examples detail certain specific embodiments of
the invention and describes the best mode contemplated by the inventors. It will be
appreciated, however, that no matter how detailed the foregoing may appear in text,
the invention may be practiced in many ways and the invention should be construed in
accordance with the appended claims and any equivalents thereof.
Claims (25)
1. The use of an antagonist of a Programmed Death Ligand 1 protein (PD-L1) in the manufacture of a medicament for treating a cancer in a subject, said treating comprising combination therapy with the antagonist of PD-L1 and a VEGFR inhibitor, wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising: three CDRs in the heavy chain variable region having amino acid sequences according to SEQ ID NO’s: 2, 3 and 4, and three CDRs in the light chain variable region having amino acid sequences according to SEQ ID NO’s: 5, 6 and 7, and wherein the VEGFR inhibitor is N-methyl[3-((E)pyridinyl-vinyl)-1H-indazol- 6-ylsulfanyl]-benzamide (axitinib) or a pharmaceutically acceptable salt thereof.
2. The use of a VEGFR inhibitor in the manufacture of a medicament for treating a cancer in a subject, said treating comprising combination therapy with the VEGFR inhibitor and a PD-L1 antagonist, wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising: three CDRs in the heavy chain variable region, having amino acid sequences according to SEQ ID NO’s 2, 3 and 4, and three CDRs in the light chain variable region, having amino acid sequences according to SEQ ID NO’s 5, 6, and 7, and wherein the VEGFR inhibitor is N-methyl[3-((E)pyridin- 2-yl-vinyl)-1H-indazolylsulfanyl]-benzamide (axitinib) or a pharmaceutically acceptable salt thereof.
3. The use of claims 1 or 2 in which both the VEGFR inhibitor and PD-L1 antagonist are used in the manufacture of the medicament.
4. The use of any one of claims 1 to 3, wherein the PD-L1 antagonist is avelumab.
5. The use of any one of claims 1 to 4, wherein the combination therapy comprises administering the PD-L1 antagonist as an initial dose of at least about 5 mg/kg, or about 10 mg/kg; and the VEGFR inhibitor as an initial dose of at least 3 mg/kg or 5 mg/kg.
6. The use of any one of claims 1 to 5, wherein the combination therapy comprises administering the PD-L1 antagonist once every two weeks; and the VEGFR inhibitor twice daily.
7. The use of claim 4, wherein the combination therapy comprises administering the avelumab as a 1-hour intravenous infusion, and the axitinib orally.
8. The use of claim 7, wherein the combination therapy comprises administering the axitinib with or without food.
9. The use of claim 7 or 8, wherein combination therapy comprises administering the axitinib on a continuous dosing schedule.
10. The use of any one of claims 1 to 9, wherein the axitinib is formulated as a 5 mg tablet.
11. The use of any one of claims 1 to 10, wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin’s lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), Squamous Cell Carcinoma of the Head and Neck (SCCHN), or small lymphocytic lymphoma (SLL).
12. The use of claim 11, wherein the cancer is renal cell carcinoma.
13. The use of claim 11 or 12, wherein the cancer is advanced renal cell carcinoma.
14. The use of claim 12 or 13, wherein the renal cell carcinoma is previously untreated advanced renal cell carcinoma.
15. The use of any one of claims 1 to 14, wherein the cancer tests positive for PD-L1 expression.
16. A kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising an antagonist of a Programmed Death 1 protein (PD-L1), the second container comprises at least one dose of a medicament comprising a VEGFR inhibitor, and the package insert comprises instructions for treating a subject for cancer using the medicaments, wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising three CDRs in the heavy chain variable region having the amino acid sequences according to SEQ ID NO’s: 2, 3 and 4 and three CDRs in the light chain variable region having the amino acid sequences shown in SEQ ID NO’s: 5, 6 and 7, and further wherein the VEGFR inhibitor is N-methyl- 2-[3-((E)pyridinyl-vinyl)-1H-indazolylsulfanyl]-benzamide (axitinib) or a pharmaceutically acceptable salt thereof.
17. The kit of claim 16, wherein the instructions state that the medicaments are intended for use in treating a subject having a cancer that tests positive for PD-L1 expression by an immunohistochemical (IHC) assay.
18. The kit of claims16 or 17, wherein the PD-L1 antagonist is avelumab formulated as a liquid medicament and the axitinib is formulated as a 1 mg tablet or a 5 mg tablet.
19. The kit of any one of claims 16 to 18, wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin’s lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), Squamous Cell Carcinoma of the Head and Neck (SCCHN), or small lymphocytic lymphoma (SLL).
20. The kit of claim 19, wherein the cancer is renal cell carcinoma.
21. The kit of claim 19 or 20, wherein the cancer is advanced renal cell carcinoma.
22. The kit of claim 20 or 21, wherein the renal cell carcinoma is previously untreated advanced renal cell carcinoma.
23. A use according to claim 1 substantially as herein described or exemplified.
24. A use according to claim 2 substantially as herein described or exemplified.
25. A kit according to claim 16 substantially as herein described or exemplified.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562180543P | 2015-06-16 | 2015-06-16 | |
US62/180,543 | 2015-06-16 | ||
US201562219995P | 2015-09-17 | 2015-09-17 | |
US62/219,995 | 2015-09-17 | ||
US201662286501P | 2016-01-25 | 2016-01-25 | |
US62/286,501 | 2016-01-25 | ||
US201662337489P | 2016-05-17 | 2016-05-17 | |
US62/337,489 | 2016-05-17 | ||
PCT/US2016/037498 WO2016205277A1 (en) | 2015-06-16 | 2016-06-15 | Pd-l1 antagonist combination treatments |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ737018A NZ737018A (en) | 2021-11-26 |
NZ737018B2 true NZ737018B2 (en) | 2022-03-01 |
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