title: Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors.
abstract: CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 (Schedule A) or day 8 (Schedule B), repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.
authors.affiliation: Abramson Cancer Center; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Burg
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Trosko
authors.forename: Dongguang
authors.initials: D
authors.lastname: Li
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
keywords: CD40; CP-870,893; T cells; chemotherapy; clinical trial; monoclonal antibody