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.

Trial registration: ClinicalTrials.gov NCT00607048.

Keywords: CD40; CP-870,893; T cells; chemotherapy; clinical trial; monoclonal antibody.

Figures

Figure 1. Best overall percentage change from baseline in target tumor lesion measurements. Percentage changes are shown as waterfall plots for 30 evaluable patients treated with CP-870,893 in combination with carboplatin and paclitaxel with two dose levels on two schedules. Data do not reflect new lesions.

Figure 2. Changes relative to baseline of hematological, chemical and coagulation parameters after the first infusion of CP-870,893. Data are grouped for all patients on a given schedule and dose level and reported as mean values. Schedule A: 0.1 mg/Kg (dashed red) and 0.2 mg/Kg (solid red); schedule B: 0.1 mg/Kg (dashed blue) and 0.2 mg/Kg (solid blue). Follow up (F/U) is at day 8 (5 d after infusion) for schedule A and day 15 (7 d after infusion) for schedule B. Detailed statistical analyses are provided in Table S1. ALC, absolute lymphocyte count; AMC, absolute monocyte count ANC, absolute neutrophil count.

Figure 3. Change relative to baseline of B-cell and T-cell immune parameters after the first infusion of CP-870,893. (A) B-cell parameters including absolute count and percentage of peripheral CD19+ B cells, percentages of CD86+ B cells among total CD19+ B cells and molecules of equivalent soluble fluorophore (MESF) of HLA-DR and CD54 on CD19+ B cells. Data are grouped for all patients on a given schedule and dose level and reported as mean values. Schedule A: 0.1 mg/Kg (dashed red) and 0.2 mg/Kg (solid red); schedule B: 0.1 mg/Kg (dashed blue) and 0.2 mg/Kg (solid blue). (B) Change in T-cell subsets at end of study relative to baseline shown as both percentage and absolute counts (Abs). The black bar represents mean value. Detailed statistical analyses are reported in Table S2.

Figure 4. Tetramer-based assessments of T-cell immune responses after therapy. (A and B) Cytoflurometric analyses of two HLA-A2+ patients with malignant melanoma on schedule B, 0.1 mg/Kg CP-870,893 (A), and schedule B, 0.2 mg/Kg CP-870,893 (B). The percentages of tetramer-positive CD8+ T cells are shown for each gate.