Phase 1 first-in-human dose escalation study of cp-751,871, a specific monoclonal antibody against the insulin like growth factor 1 receptor

Abstract

7609 Background: Multiple lines of evidence indicate that the Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in the progression of multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes survival to the cytotoxic effects of chemotherapy in animal models of MM and its blood levels has been shown to correlate with those of paraprotein in MM patients. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. Methods: Based on its mechanism of action and the potential relevance of IGF-1R in MM, a Phase 1 First-in-Human dose escalation study was initiated with the objective to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic properties of CP-751,871 in this patient population. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase and/or less than complete remission following autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 10 dose-escalation cohorts of patients received from 0.025 to 10 mg/kg of CP-751,871 by iv infusion on Day 1 of 4-week cycles. In patients with a suboptimal response to CP-751,871 alone, oral dexamethasone was added to the treatment regimen. Patients received up to 14 cycles of CP-751,871 therapy, alone or in combination with dexamethasone. No dose limiting toxicities have been identified to date. Plasma CP-751,871 exposure increases with dose, and the pharmacokinetic characteristics are consistent with target-mediated disposition. Pharmacodynamic measurements indicate complete target saturation by CP-751,871 for the complete length of the dosing period. One near CR and 2 PR in combination with dexamethasone have been reported. Conclusions: These data indicate that CP-751,871 is well tolerated and may constitute a therapeutic approach for patients with multiple myeloma. [Table: see text]