Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma

Phase 2

Terminated

Conditions: Renal Cell Carcinoma, Metastatic

Interventions: Drug: ESK981
Drug: Nivolumab

Registration Number: NCT03562507

Lead Sponsor: University of Michigan Rogel Cancer Center

Brief Summary: 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 (RCC).

Detailed Description: The study was terminated early due to changes in the RCC treatment landscape which limited the patient population. Due to this early termination no subjects were enrolled into Cohort B.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

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.
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 survival.)
Most recent systemic therapy or most recent radiation therapy ≥ 2 weeks of first study drug dose.
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 therapy.
Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to registration.
Adequate organ and marrow function

Exclusion Criteria

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 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ESK981 Monotherapy	ESK981	ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles
ESK981 and Nivolumab	ESK981	ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles Nivolumab: 480 mg/dose IV, Day 1 of each 28-day cycle
ESK981 and Nivolumab	Nivolumab	ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles Nivolumab: 480 mg/dose IV, Day 1 of each 28-day cycle

Primary Outcome Measures

Name	Time	Method
1. The Percentage of Patients That Respond to Treatment With the Combination of ESK981 Monotherapy and Nivolumab Therapy (Cohort B).	Up to 24 months after last dose of study treatment	The percentage of patients in Cohort B that achieve a complete response (CR) or partial response (PR). Response will be assessed by combined Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Immune-related (ir)RECIST.

Secondary Outcome Measures

Name	Time	Method
Duration of Response	Up to 24 months after last dose of study treatment	Measured from the time of complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Response will be assessed by RECIST v1.1 (Cohort A) and by combined RECIST v1.1/irRECIST (Cohort B).
The Percentage of Patients That Respond to Treatment With ESK981 Monotherapy (Cohort A).	Up to 24 months after last dose of study treatment, 5 month treatment duration on average, no CR or PR responses were recorded.	The percentage of patients in Cohort A that achieve a complete response (CR) or partial response (PR). Response will be assessed by RECIST v1.1.
Duration of Therapy	Up to approximately 24 months after treatment start	Measured from the first to the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy).
Median Overall Survival Time	Up to 24 months after last dose of study treatment	Overall survival time measured from start of treatment until up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy).
Progression Free Survival Time	Up to 24 months after last dose of study treatment	Measured from start of treatment to time of progression or death, or up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy). Disease progression will be assessed by RECIST v1.1 in Cohort A and by combined RECIST v1.1/irRECIST in Cohort B.