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

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

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.

Study Overview

• Status: Completed
• Conditions: Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Drug: Sitravatinib; Drug: Nivolumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Imaging results consistent with locally-advanced RCC
2. Candidate for partial or complete nephrectomy as part of treatment plan.
3. Measurable disease per RECIST version 1.1.
4. ECOG performance status 0 or 1.
5. Adequate bone marrow and organ function.

Exclusion Criteria:

1. Prior systemic anti-tumor treatment for RCC.
2. Patients who are receiving any other investigational agents.
3. 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.
4. Inability to undergo baseline tumor biopsy.
5. Active or prior documented autoimmune or immunocompromising conditions.
6. Uncontrolled hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitravatinib and nivolumab; 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; Sitravatinib oral capsule administered daily for 6-8 weeks in segments 1 and 2.; Drug: Nivolumab; Nivolumab administered as 240 mg IV every 2 weeks for 4-6 weeks in segment 2.

What is the study measuring?

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)
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)
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)
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

Collaborators and Investigators

• Sponsor: Mirati Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2018
• Primary Completion (Actual): April 27, 2020
• Study Completion (Actual): May 18, 2023

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: September 19, 2018
• First Posted (Actual): September 21, 2018

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: MGCD516; PD-1; PD-L1; nivolumab; Antineoplastic Agents; Immunologic factors; VEGFR; ccRCC; Tyrosine Kinase Inhibitor; TAM RTKs
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 516-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No