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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Sitravatinib oral capsule administered daily for 6-8 weeks in segments 1 and 2.
Nivolumab administered as 240 mg IV every 2 weeks for 4-6 weeks in segment 2.
MD Anderson Cancer Center
Houston, Texas, United States
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.
Time frame: 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.
Time frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks)
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.
Time frame: Day 1 until 28 days after last dose of study drug or surgery, whichever occurred last (up to a maximum of 13 weeks)
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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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: Baseline to Day 43