Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:

OUTLINE: This is a multi-center study.

The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in
subjects with metastatic clear cell renal carcinoma after failure of at least one systemic
therapy for metastatic disease. The phase II trial will determine the activity of the
combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic
clear cell renal carcinoma.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 5mg on
day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate
intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 10mg on
day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate
intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of
therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in
dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be
enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation
beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b
cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease
progression, unacceptable toxicity, subject refusal, or subject death either from progression
of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the
study, have progressive disease, or unacceptable toxicities will be followed for a total of
24 months.

Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol
therapy.

Life Expectancy: 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for
protocol therapy:

Hematopoietic:

- Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L

- Platelets ≥ 100 × 10 9/L

- Hemoglobin (Hgb) ≥ 9.0 g/dL

Renal:

- Serum creatinine ≤ 1.5 × upper limit of normal (ULN)

- OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40
mL/min

Hepatic:

- Total serum bilirubin ≤ 1.5 × ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN

- OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying
malignancy

Coagulation:

- INR < 1.5 × ULN

- OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's
opinion, be clinically stable with no evidence of active bleeding while receiving
anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the
goal of anticoagulant therapy.

Inclusion Criteria:

- Male or female ≥ 18 years of age at time of consent.

- Phase Ib dose escalation cohort study: subjects with histologically assessed
metastatic clear cell RCC (defined as more than 50% clear cell component) after
failure of at least one systemic therapy for metastatic disease (including, but not
limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and
mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not
required.

- Phase II study: subjects with treatment-naïve histologically assessed metastatic clear
cell RCC (defined as more than 50% clear cell component) and who are candidates for
standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not
required.

- Measurable disease, defined as at least 1 tumor that fulfills the criteria for a
target lesion according to RECIST 1.1, and obtained by imaging within 28 days prior to
registration for protocol therapy.

- Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol
therapy.

- Life expectancy of 6 months or greater as determined by the treating physician.

- Adequate hepatic function within 28 days prior to registration for protocol therapy
defined as meeting all of the following criteria:

- total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
subjects with total bilirubin levels > 1.5 x ULN

- and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with
known hepatic metastases

- and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with
known hepatic metastases

- Adequate renal function within 28 days prior to registration for protocol therapy
defined by either of the following criteria:

- serum creatinine ≤ 3 mg/dL

- OR if serum creatinine > 3 mg/dL, estimated glomerular filtration rate (GFR) ≥ 20
mL/min

- Adequate hematologic function within 28 days prior to registration for protocol
therapy defined as meeting all of the following criteria:

- hemoglobin ≥ 9 g/dL

- and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

- and platelet count ≥ 100 × 10^9/L

- Adequate coagulation functioning within 28 days prior to registration for protocol
therapy defined by either of the following criteria:

- INR < 1.5 × ULN

- OR for subjects receiving warfarin or LMWH, the subjects must, in the
investigator's opinion, be clinically stable with no evidence of active bleeding
while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5
× ULN if that is the goal of anticoagulant therapy.

- Provided written informed consent and HIPAA authorization for release of personal
health information, approved by an Institutional Review Board/Independent Ethics
Committee (IRB/IEC).

- Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A
negative serum or urine pregnancy test is required within 72 hours of study
registration. If the urine test cannot be confirmed as negative, a serum pregnancy
test will be required.

- Women of childbearing potential (WOCP) must be willing to use two effective methods of
birth control such as an oral, implantable, injectable, or transdermal hormonal
contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,
sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total
abstinence for the course of the study until 120 days after the last dose of study
drug.

- Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
of contraception. Male subjects with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms from
the first dose of study drug through at least 120 days after the last dose of study
drug. Total abstinence for the same study period is an acceptable alternative.

- Availability of tissue if applicable (from the primary tumor or metastases) for
correlative studies.

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

Exclusion Criteria:

- Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4
weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline)
from adverse events of such agents administered more than 4 weeks earlier.

- Phase II: has had prior therapy for metastatic renal cell carcinoma.

- Surgery within 4 weeks prior to study treatment except for minor procedures: NOTES:
Hepatic biliary stent placement is allowed. Subject must have adequately recovered
from the toxicity and/or complications of major surgery prior to study registration,
as determined by the treating physician.

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with neurological symptoms must undergo a head CT scan or brain MRI to
exclude brain metastasis. Subjects with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging for
at least four weeks prior to the first dose of trial treatment and any neurologic
symptoms have returned to baseline), have no evidence of new or enlarging brain
metastases, and are not using steroids for at least 7 days prior to study
registration. This exception does not include carcinomatous meningitis, which is
excluded regardless of clinical stability.

- Previously received an organ or allogeneic progenitor/stem cell transplant.

- Received a live vaccine within 30 days prior to the first dose of trial treatment:
Examples of live vaccines include, but are not limited to: measles, mumps, rubella,
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are
not allowed.

- History of blood clots, pulmonary embolism, or deep vein thrombosis unless controlled
by anticoagulant treatment.

- Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].

- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to study registration.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs).

NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form
of systemic treatment.

- Received prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1
or at baseline) from adverse events from previously administered agents. NOTE:
Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and can still be
considered for the study.

- Any clinically significant infection defined as any acute viral, bacterial, or fungal
infection that requires specific treatment. NOTE: Anti-infective treatment must be
completed ≥ 7 days prior to study registration.

- Evidence of interstitial lung disease, history of (non-infectious) pneumonitis that
required steroids, or current pneumonitis.

- Known history of active tuberculosis.

- Any other severe, uncontrolled medical condition, including uncontrolled diabetes
mellitus or unstable congestive heart failure.

- Known allergy to pembrolizumab or any of its excipients.

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies.

- Any condition that, in the opinion of the treating physician, would exclude the
subject from receiving bevacizumab. Examples may include but are not limited to:

- Hemoptysis (defined as > ½ teaspoon of blood)

- Pre-existing bleeding diathesis, coagulopathy or hemorrhage

- Myocardial infarction or cerebrovascular accident within 6 months prior to study
registration

- Any drugs or supplements that interfere with blood clotting can raise the risk of
bleeding during treatment with bevacizumab. These drugs include vitamin E,
non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil,
Motrin), and naproxen (Aleve, Naprosyn), warfarin (Coumadin), ticlopidine
(Ticlid), and clopidogrel (Plavix).These agents should be used with caution.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for enrollment in this study.

- Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study
registration.

- Any condition that, in the opinion of the investigator, might jeopardize the safety of
the subject or interfere with protocol compliance.

- Any mental or medical condition that prevents the subject from giving informed consent
or participating in the trial.

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or
other cancer for which the subject has been disease-free for at least 5 years.

- Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

- Treatment with any investigational agent within 28 days prior to registration for
protocol therapy and the subject must have recovered from the acute toxic effects of
the regimen.