Study of Sitravatinib, Nivolumab and Ipilimumab in Advanced or Metastatic Clear-Cell Renal Cell Carcinoma or Other Solid Malignancies

Study Overview
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Brief Summary
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Study 516-008 is an open-label Phase 1 dose escalation/Phase 1b dose expansion study evaluating the safety and tolerability, clinical activity, and PK of sitravatinib in combination with nivolumab and ipilimumab for the treatment of ccRCC and potentially other solid tumor types.

Detailed Description
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Sitravatinib is a spectrum-selective receptor tyrosine kinase (RTK) inhibitor that inhibits several closely related RTKs including the TAM family (Tyro3/Axl/MERTK), VEGFR2, KIT, and MET. NIVO/IPI are monoclonal antibodies (mAbs) that inhibit the immune checkpoint proteins programmed death receptor-1 (PD-1) and cytotoxic T- lymphocyte antigen-4 (CTLA-4), respectively. The current study is designed to evaluate the triple combination of sitravatinib plus NIVO/IPI in patients with solid tumor malignancies that have shown favorable responses to NIVO/IPI combinations in previous clinical trials. Combining sitravatinib and NIVO/IPI is predicted to have complementary effects in triggering a tumor-directed immune response.

Official Title
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A Phase 1/1b Study of Sitravatinib in Combination With Nivolumab and Ipilimumab in Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma or Other Solid Malignancies

Conditions
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Clear-Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sitravatinib
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Clear-Cell Renal Cell Carcinoma (for initial cohorts under consideration) No prior treatment with systemic therapy (for initial cohorts under consideration) Adequate bone marrow and organ function Exclusion Criteria: Known or suspected presence of other cancer Brain metastases (for initial cohorts under consideration) Carcinomatous meningitis Immunocompromising conditions Impaired heart function Active or prior documented autoimmune disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Following the identification of the recommended dose of sitravatinib in combination with NIVO/IPI Phase 1 dose escalation, two Phase 1b dose expansion cohorts will enroll patients with ccRCC based on IMDC risk. All patients receive the same treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation<br>Patients with poor- or intermediate-risk RCC with clear cell component for first-line treatment. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: OPDIVO;Drug: Ipilimumab<br>* Ipilimumab is a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) blocking antibody<br>* Other names: YERVOY;|
| Experimental: Phase 1b Dose Escalation Cohort A<br>Patients with poor- or intermediate-risk RCC with clear cell component for first-line treatment | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: OPDIVO;Drug: Ipilimumab<br>* Ipilimumab is a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) blocking antibody<br>* Other names: YERVOY;|
| Experimental: Phase 1b Dose Escalation Cohort B<br>Patients with favorable-risk RCC with clear cell component for first-line treatment. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: OPDIVO;Drug: Ipilimumab<br>* Ipilimumab is a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) blocking antibody<br>* Other names: YERVOY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of patients experiencing treatment-emergent AEs | Characterization of AEs by incidence, severity, timing, seriousness & relationship to study treatment | Through study completion, an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) in accordance with RECIST v1.1 | Frequency of patients experiencing an objective response | Through duration of study, average of 10 months | 
| Duration of Response (DOR) | Time in months from date of the first documentation of objective tumor response (CR or PR) to the first documentation of objective PD or to death due to any cause in the absence of documented PD | Through duration of study, average of 10 months | 
| Progression-free Survival (PFS) | Time from date of first study treatment to first PD or death due to any cause in the absence of documented PD | Through duration of study, average of 10 months |