Assessments
diarrhoea, death, DLTs, fatigue, toxicity, toxicities, HTG, nausea, vomiting
BLOOD, DISEASE, RECURRENCE, PANCREATITIS
Baseline disease assessments were performed using computed tomography (CT), X-ray (radiography), or magnetic resonance imaging (MRI). Subsequent, on-study disease assessment included imaging of all known and suspected sites of disease identified in the preoperative setting (ie, CT or X-ray of the chest, CT, or MRI of the abdomen, and, if clinically indicated, whole body bone scan and CT with contrast or MRI of the brain and evaluation of any superficial lesions). The allowable window for imaging was 4 weeks prior to first study treatment for screening/baseline evaluation and within 1 week of planned surgery for on-study disease assessment. Imaging results were evaluated by the investigator to assess disease response per RECIST v1.1. Blood samples for PK evaluation were collected at specified timepoints prior to and following study treatment dosing. Safety assessments were conducted at the initiation of study treatment and at each clinic visit. Per protocol, patients would be followed for survival every 6 months from the last study visit for up to 3 years or more until death, disease recurrence, or loss to follow-up; disease recurrence will be based on imaging assessments performed off study per standard of care for patients post-nephrectomy.Dose-limiting toxicities (DLTs) were assessed to guide adjustment of the starting dose of sitravatinib after 3 weeks for the first six treated patients or earlier if ≥2 patients were suspected of experiencing DLTs. The dose of sitravatinib was to be decreased if >2 of the first six patients experienced DLTs. DLTs were defined as non-haematological grade 4 AEs; non-haematological grade 3 AEs except (a) manageable nausea, vomiting, and diarrhoea persisting <2 h, (b) uncomplicated electrolyte abnormalities resolved within 72 h, (c) fatigue persisting <8 days, and d) amylase or lipase elevation not associated with pancreatitis; any toxicity that delayed surgery by >2 weeks.Biomarker expression analyses were conducted on core needle biopsies taken at baseline (timepoint 1), during sitravatinib monotherapy at day 14 (timepoint 2), and on resected specimens at the time of surgery during sitravatinib plus nivolumab (timepoint 3). Blood samples for correlative studies were collected at screening, day 1, day 15, day 29, and day 43/surgery. Biomarker analyses included immunohistochemistry (IHC) for PD-L1 expression (using clone 28-8; cat# ab205921 [Abcam, Cambridge, UK] as used in the Agilent PharmDx system), multiplex immunofluorescence (IF) profiling, gene expression profiling using NanoString nCounter and HTG EdgeSeq technologies, and tissue and blood flow cytometry.