Neoadjuvant Sitravatinib in Combination With Nivolumab in Patients With Clear Cell Renal Cell Carcinoma

Study Overview
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Brief Summary
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The study will evaluate the clinical activity of sitravatinib in combination with nivolumab in patients with locally-advanced clear cell renal cell carcinoma (ccRCC) in the neoadjuvant setting prior to nephrectomy.

Detailed Description
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Sitravatinib is a receptor tyrosine kinase inhibitor (TKI) that targets multiple closely related receptor tyrosine kinase pathways including VEGFR, PDGFR, c-KIT, MET, and the TAM family of receptors (TYRO3, AXL, and MER). Nivolumab is a monoclonal antibody directed against PD-1 and blocks the interaction between PD-1 and its ligands, thereby releasing PD-1-mediated inhibition of T-cell proliferation (including cytotoxic CD8+ T-cells) and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment the efficacy of nivolumab.

Official Title
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A Phase 2 Study of Sitravatinib in Combination With Nivolumab in Patients Undergoing Nephrectomy for Locally-Advanced Clear Cell Renal Cell Carcinoma

Conditions
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Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sitravatinib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Imaging results consistent with locally-advanced RCC Candidate for partial or complete nephrectomy as part of treatment plan. Measurable disease per RECIST version 1.1. ECOG performance status 0 or 1. Adequate bone marrow and organ function. Exclusion Criteria: Prior systemic anti-tumor treatment for RCC. Patients who are receiving any other investigational agents. Clinical status indicating that immediate surgery (within 6 weeks) is warranted regardless of whether neoadjuvant therapy is to be administered, as assessed by the treating surgeon. Inability to undergo baseline tumor biopsy. Active or prior documented autoimmune or immunocompromising conditions. Uncontrolled hypertension.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitravatinib and nivolumab<br>Sitravatinib oral capsule administered daily 2 weeks alone then in combination with nivolumab administered as 240 mg IV every 2 weeks. Total treatment duration: 6-8 weeks prior to planned nephrectomy. | Drug: Sitravatinib<br>* Sitravatinib oral capsule administered daily for 6-8 weeks in segments 1 and 2.<br>Drug: Nivolumab<br>* Nivolumab administered as 240 mg IV every 2 weeks for 4-6 weeks in segment 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Point in Time Objective Response (Either Complete or Partial Response [CR or PR]) Prior to Surgery | Objective response is defined as the percent of participants documented by investigator assessment to have Complete Response (CR) or Partial Response (PR) in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR is defined as complete disappearance of all baseline target and non-target lesions with the exception of nodal disease; PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Point in Time Objective Response Prior to Surgery | Number and percentage of participants who experienced a response prior to surgery in accordance with RECIST 1.1. CR is defined as complete disappearance of all baseline target and non-target lesions with the exception of nodal disease; PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions; Stable Disease (SD) is concluded when the single point in time response does not qualify for CR, PR or Progressive Disease (PD); PD is defined as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing nontarget lesions. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | TEAEs occured after the first dose of any study treatment or any preexisting condition that increased in severity after the first dose of study treatment and prior to 28 days after last dose of study drug or surgery, whichever occurred last. TEAEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Day 1 until 28 days after last dose of study drug or surgery, whichever occurred last (up to a maximum of 13 weeks) | 
| Blood Plasma Concentrations of Sitravatinib | The blood plasma concentrations of sitravatinib were determined using blood samples. Blood samples for analysis of blood plasma concentrations of sitravatinib were taken after scheduled vital signs and triplicate electrocardiogram assessments. | Day 1 (pre-dose, and 30 minutes and 4 hours post-dose), Day 15 (pre-dose) and Day 43 (pre-dose) | 
| Time to Surgery | Time to surgery was defined as the number of calendar days between Day 1 and the planned nephrectomy. | Day 1 up to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Disease Free Survival (DFS) | DFS was defined as the time from date of surgery to disease recurrence or death whichever occurred first. | Up to 3 years after surgery (maximum time to surgery was approximately 13 weeks) | 
| Percentage Change From Baseline in Programmed Death Ligand 1 (PD-L1) Expression in the Tumor | Tumor tissue was collected from study biopsies and surgical samples. Tumor tissue was used to assess the mean PD-L1 expression in the tumor via immunohistochemistry and/or immunofluorescence. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline in Myeloid-derived Suppressor Cells (MDSCs) in the Tumor | Tumor tissue was collected from study biopsies and surgical samples, and was used to assess mean MDSCs using immunohistochemistry. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline in Regulatory T-cells (Tregs) in the Tumor | Tumor tissue was collected from study biopsies and surgical samples, and was used to assess mean Tregs using immunohistochemistry. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline in CD4+ T-cells in the Tumor | Tumor tissue was collected from study biopsies and surgical samples, and was used to assess mean CD4+ T-cells using immunohistochemistry. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline in CD8+ T-cells in the Tumor | Tumor tissue was collected from study biopsies and surgical samples, and was used to assess mean CD8+ T-cells using immunohistochemistry. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline in Ratio of Type 1 to Type 2 Tumor Associated Macrophages in the Tumor | Tumor tissue was collected from study biopsies and surgical samples, and was used to assess mean ratio of Type 1 to Type 2 tumor associated macrophages using immunohistochemistry. | Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) | 
| Change From Baseline of Selected Cytokines in Peripheral Blood | Cytokines measured in peripheral blood were soluble CD27 (sCD27), eotaxin, macrophage inflammatory protein 1b (MIP-1b), and soluble programmed cell death protein 1 (sPD-1). | Baseline to Day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MGCD516, ccRCC, Antineoplastic Agents, Immunologic factors, nivolumab, Tyrosine Kinase Inhibitor, VEGFR, TAM RTKs, PD-1, PD-L1