The objective of the trial is to determine the clinical efficacy of ESK981 in combination
with nivolumab therapy in patients with metastatic renal cell carcinoma.
- Histologic diagnosis of renal cell carcinoma (any histology except medullary carcinoma
or collecting duct carcinoma is acceptable) with radiologic or histologic evidence of
- 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.
- Must be of age ≥ 18 years at time of informed consent.
- Ability to understand and the willingness to sign a written informed consent.
- Karnofsky Performance Status ≥60. (The Karnofsky Performance Status Scale is an
assessment tool for functional impairment. It can be used to compare effectiveness of
different therapies and to assess the prognosis in individual patients. In most
serious illnesses, the lower the Karnofsky score, the worse the likelihood of
- Most recent systemic therapy or most recent radiation therapy ≥ 2 weeks of first study
- Recovery to baseline or < Grade 1 CTCAE v.4.03 from toxicities related to any prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
- Women of childbearing potential must have a negative serum or urine pregnancy test
within 28 days prior to registration.
- Adequate organ and marrow function
- Prior treatment for metastatic disease with >1 anti-VEGF/VEGFR inhibitor.
- Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody (for Cohort B patients only) or
ESK981 (for Cohort A and Cohort B patients).
- Prior mTOR inhibitors or glutaminase inhibitors are allowed.
- Untreated brain metastases or spinal cord compression.
- Uncontrolled hypertension defined as blood pressure >150/90 despite at least 2
anti-hypertensive medication(s) 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 Day1.
- 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
- Have any condition that, in the opinion of the investigator, would compromise the
ability of the subject to meet or perform study requirements.