A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).

Abstract

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.