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

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.