Authors:
G. L. Beatty, E. G. Chiorean, D. A. Torigian, U. R. Teitelbaum, W. Sun, K. D. Fly, R. D. Huhn, R. H. Vonderheide, & P. J. O'Dwyer
Summary:
Background - CP-870,893 is a fully human CD40 agonist monoclonal antibody that activates antigen presenting cells, triggers the release of inflammatory cytokines, and enhances antitumor cellular immunity. In preclinical models chemotherapy enhances the antitumor effect of anti-CD40 immunotherapy by facilitating tumor antigen release. A phase I study was conducted to investigate the safety of CP-870,893 administered in combination with gemcitabine for patients with chemotherapy-naïve pancreatic adenocarcinoma.
Methods - Patients with ECOG PS 0-1 were treated with gemcitabine (1000 mg/m2) i.v. on days 1, 8, and 15 of a 28-day cycle with escalating doses (0.1 or 0.2 mg/kg) of CP-870,893 given i.v. on day 3 of each cycle. Patients were monitored for toxicity, clinical response including FDG-PET/CT, and modulation of immune parameters.
Results - DLTs were observed in 0 of 3 pts at 0.1 mg/kg and 0 of 6 pts at 0.2 mg/kg. The MTD/RP2D was defined as 0.2 mg/kg. The most common AE was transient cytokine release syndrome (grade 1-2). In the MTD expansion cohort (n=6) at 0.2 mg/kg, there was 1 DLT (nonfatal CVA). Analysis of plasma cytokines demonstrated increased IL-6, IL-10, TNF-alpha, and IL-12 after treatment consistent with immune activation. Changes in CA19-9 were evaluable in 13 patients, with 6 patients (46%) demonstrating a >50% decrease from baseline. There were 2 PRs (14%), 8 SDs (57%), and 4 PDs (29%). One pt with a PR remains on study after 13 months of treatment. Three patients with SD were evaluated with FDG-PET/CT imaging. Decreases in SUVmax were observed in the primary pancreatic lesion (decrease of 28-78%) as well as target metastatic lesions (decrease of 11-28%) of each patient, suggesting the utility of PET imaging for evaluating disease response to chemoimmunotherapy.
Conclusions - Combined CP-870,893 and gemcitabine is well- tolerated and active in patients with pancreatic cancer. FDG-PET/CT identified metabolic responses both in the primary and in metastases in patients defined as having stable disease by RECIST. Further investigation of this combination in pancreatic cancer is warranted.
Source:
2010 American Society of Clinical Oncology Annual Meeting; 2539, 8:00AM-12:00PM (06/07/10)