Final toxicity results of a phase I dose-escalation trial of tremelimumab (CP-675206) in combination with gemcitabine in chemotherapy-naive patients (pts) with metastatic pancreatic cancer.

Abstract

4081 Background: Tremelimumab (CP-675206) is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA4) on T lymphocytes and T regulatory cells. It is thought to stimulate the immune system to attack tumor cells by blocking the CTLA4-negative regulatory signal. The primary objective of this phase I study was to determine the maximum tolerated dose and evaluate the safety of tremelimumab plus gemcitabine in pts with previously untreated metastatic pancreatic cancer. Methods: In Part A of the study, pts received gemcitabine only during a 1-mo lead-in period. Gemcitabine (1,000 mg/m2) was administered on days 1, 8, and 15 of a 4-wk cycle. Escalating doses of tremelimumab (6 mg/kg, 10 mg/kg, and 15 mg/kg) were then administered intravenously on day 1 of each 12-wk cycle. In Part B, tremelimumab at 2 dose levels (10 mg/kg and 15 mg/kg) was administered simultaneously with gemcitabine. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 wk after the first dose of tremelimumab. Results: A total of 34 pts (M/F = 22/12; median age 59; range 29-76) received at least 1 dose of tremelimumab. The median number of cycles was 1 (range, 1-5). No DLTs related to tremelimumab were observed at any dose level. Most frequent grade (G) 3-4 toxicities were neutropenia (n=8), fatigue (n=5), transaminases increase (n=4), nausea (n=3), and diarrhea (n=3). Two cases of G3 diarrhea, 1 case of G3 nausea, and 1 case of G3 transaminases increase were considered related to tremelimumab. Other toxicities related to tremelimumab were G2 diarrhea (n=6), G2 thrombocytopenia (n=1), G2 rash (n=1), and G2 vitiligo (n=1). Two of 25 evaluable pts had confirmed partial responses (PR), and 5 had stable disease (SD) at 7 wk (defined by measurements demonstrating neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease after the start of treatment). One pt with SD as best result remains progression free after 14 mo of therapy. Conclusions: Tremelimumab (up to 15 mg/kg every 12 wk) plus gemcitabine was well tolerated in pts with metastatic pancreatic cancer.