Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study

Abstract

Background: Resistance of pancreatic adenocarcinoma (PDA) to therapy remains a challenge. One factor of the barrier is the T-lymphocyte driven inflammatory response seen in PDA. The CTLA-4 T-cell receptor provides inhibitory signals to the T cells that serve to dampen antitumor immune responses. Abrogating CTLA-4 represents a novel strategy to induce tumor regression, stabilize disease, and prolong survival by manipulating the immune system. Blocking CTLA-4 may sustain activation and proliferation of tumor specific T-cells, or alter the phenotype of tumor specific Treg. Ipilimumab (IPI), a monoclonal antibody to the CTLA-4 receptor, downregulates T-cell responses. Objective: Determine MTD of IPI combined with gemcitabine (GEM) for PDA. Methods: Single institution study with dose escalation performed in a 3+3 fashion. Dose expansion was performed at the MTD. Therapy consisted of 12 weeks of induction with DLT determined after week 12. Maintenance therapy to continue indefinitely if clinical benefit is seen. Eligibility: No prior GEM for advanced disease was allowed. Results: 16 patients enrolled (13 in dose escalation + 3 at MTD). Of the 16, 63% females, 38% male. 31% had a PS of 0 and 69% with a PS 1. 13 out of 16 patients had adenocarcinoma, 1 adenosquamous & 2 patients with mucinous features. Cohort 1 (GEM 750mg/m2+IPI 3mg/kg) enrolled 19% of patients with no DLT. Cohort 2 (GEM 1000mg/m2+IPI 3mg/kg) enrolled 25% of patients with no DLTs. Cohort 3 (GEM 1000mg/m2 + IPI 6mg/kg): enrolled 38% of patients and had 2 DLTs (elevated AST and diarrhea). MTD established at cohort 2 dosing. 63% of patients received 10 cycles of treatment with only 6% not tolerating more than 1 cycle. 12 /16 patients came off study for PD with 2 patients still remaining on study. Response (PR+SD) by waterfall plot was seen in 43% of patients. 2 out of 16 with PR & 5 of 16 had SD. 38% had PD. Median PFS was 2.5 mths (95%CI 0.8-4.8mths) & Median OS 8.5mths (95%CI 2.2-10.3mths). Exploratory Immune Correlatives: CD8 cells universally decreased in the immune inhibitory molecule LAG3 after treatment with IPI. Post IPI treatment increase in FrI Treg & decrease in FrII Treg is seen. Conclusions: GEM/IPI is tolerable and viable treatment option warranting further evaluation.