Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody

Abstract

2507 Background: The cell-surface molecule CD40 plays a critical role in activating antigen presenting cells (APC) and mediates upregulation of costimulatory and MHC molecules, cytokine release, and enhancement of tumor immunity. CD40 is also expressed by 30%-70% of solid tumors, and engagement of CD40 on tumor cells results in apoptosis. CP-870,893 - a fully human and selective CD40 agonist monoclonal antibody - activates human APC in vitro and inhibits growth of human tumors in immune-deficient and immune-reconstituted SCID-beige mice. Methods: A phase 1, dose-escalation study of CP-870,893 was designed to characterize the safety and maximum tolerated dose (MTD) of single doses of CP-870,893 in patients (pts) with advanced solid tumors. CP-870,893 was administered i.v. on day 1 and pts were followed for 43 days. Results: Twenty-nine pts received CP-870,893 in doses ranging from 0.01 to 0.3 mg/kg. Dose limiting toxicity was observed in 2 of 7 pts at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). The MTD was defined as 0.2 mg/kg. The most common adverse event was dose-related cytokine release syndrome (grade 1 to 2). Abnormal lab findings included dose-related and transient elevations in liver transaminases (grade 1 to 2; one pt with grade 3). Modest elevations in serum D-dimer were observed in pts treated at the highest dose levels. Four pts with melanoma (14% of all pts and 27% of pts with melanoma) had objective partial responses (PR) at day 43 evaluation (one PR sustained at 7+ months and 3 unsustained on follow-up scans). Each pt with a PR received 0.2 or 0.3 mg/kg of antibody. To assess pharmacodynamic actions of CP-870,893, flow cytometry was performed on peripheral blood B cells, which uniformly express CD40. CP-870,893 infusion resulted in depletion of peripheral CD19+ B cells (>80% depletion at the highest dose levels). Among B cells remaining in blood, we found a marked, dose-related upregulation of costimulatory and MHC molecules after treatment. Conclusions: Clinical and laboratory findings demonstrate biological activity of CP-870,893. Antitumor activity was observed in 4 pts with melanoma. Further studies of repeated doses of CP-870,893, and CP-870,893 in combination with other antineoplastic agents, are warranted. [Table: see text]