An Enzyme Inhibitor (ESK981) and Nivolumab for the Treatment of Metastatic Kidney Cancer

Inclusion Criteria

• Histologic diagnosis of renal cell carcinoma (any histology except medullary carcinoma or collecting duct carcinoma is acceptable) with radiologic or histologic evidence of metastatic disease
• Prior treatment with up to one (and only one) anti-VEGF or VEGFR inhibitor (small molecule or antibody)
• Must have measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) criteria
• Ability to understand and the willingness to sign a written informed consent
• Karnofsky performance status >= 60
• Most recent systemic therapy or most recent radiation therapy >= 2 weeks of first study drug dose
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)4.03 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically non-significant and/or stable on supportive therapy
• Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to prior to registration. Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. All others are considered women of child bearing potential
• Absolute neutrophil count (ANC) >= 1.5 K/mm^3
• Hemoglobin (Hgb) >= 9 g/dL
• Platelets (Plt) >= 100,000/mm^3
• Calculated creatinine clearance serum creatinine =< 1.5 times the upper limit of normal OR creatinine clearance > 30 mL/min by Cockcroft-Gault formula
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) =< 2.5 x ULN (=< 3 x ULN with known hepatic metastases)
• Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 3 x ULN with known hepatic metastases)
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels =< 1.5 x ULN (If patient is receiving anticoagulation that is expected to alter these levels, should be in targeted therapeutic range for that agent)

Exclusion Criteria

• Prior treatment for metastatic disease with > 1 anti-VEGF/VEGFR inhibitor
• Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody or ESK981 (for Cohort A and Cohort B patients) * Prior mTOR inhibitors or glutaminase inhibitors are allowed
• Untreated brain metastases or spinal cord compression * Patients with suspected or known treated brain metastases at screening should have a magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) preferably with IV contrast of the brain prior to study entry. Patients whose brain metastases have been treated may be considered if they have completed their treatment for brain metastasi(e)s at least 4 weeks prior to study registration AND they show radiographic and clinical stability (by CT or MRI brain imaging, obtained after treatment to the brain metastases). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable without the use of steroids at daily doses greater than 10 mg prednisone or equivalent for at least 14 calendar days prior to the start of treatment
• Uncontrolled hypertension defined as blood pressure > 150/90 despite at least 2 anti-hypertensive medications as assessed by 2 blood pressure readings taken at least 1 hour apart during screening
• Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration (> 6 weeks prior to registration is permitted as long as they have fully recovered from any such procedure)
• History of another primary malignancy except for: malignancy treated with curative intent and no known active disease for >= 2 years, adequately treated non-melanoma skin cancer without current evidence of active disease, adequately treated carcinoma in situ without current evidence of active disease, Gleason =< 6 prostate cancer
• Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous angioplasty or coronary arterial bypass surgery within the past 3 months
• History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved (e.g. through surgical resection or repair)
• The patient has known hypersensitivity to gelatin or lactose monohydrate
• The patient has received any investigational drug within 28 days prior to registration or 5 half-lives of the investigational drug, whichever is shorter
• History of bleeding disorders (e.g. pulmonary hemorrhage, significant hemoptysis, menometrorrhagia not responding to hormonal treatment) =< 6 weeks before cycle 1 day 1
• The patient is on a chronic daily medication known to be a severe or moderate inhibitor or inducer by micromedex of CYP1A2, CYP2C8, or CYP3A4 at registration
• Systemic corticosteroids greater than the equivalent of 10 mg of prednisone or equivalent alternative steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents (such as cyclosporine or methotrexate) and any other medications that could potentially impact the efficacy or safety of the study as judged by the treating investigator are NOT permitted from time of registration to subjects completing protocol therapy unless clinically indicated to manage adverse events or life threatening or serious conditions as determined by the treating investigator
• Have any condition that, in the opinion of the investigator, would compromise the ability of the subject to meet or perform study requirements