Abstract
Background: CP-751,871, a fully human IgG2 subtype monoclonal antibody, is a potent and specific inhibitor of the insulin- like growth factor type I receptor (IGF-IR). The IGF-IR regulates the growth, survival, adhesion and invasiveness of multiple myeloma cells. High IGF-IR expression is observed in poor-prognostic subtypes of multiple myeloma and its inhibition has been long proposed as a potential therapeutic approach for treatment of this disease.
Methods: A phase 1 dose escalation study was conducted to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic (granulocyte surface IGF-IR expression and serum IGF-I levels) properties of CP-751,871 in patients with multiple myeloma. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase including those less than complete remission to autologous stem cell transplant or tandem transplant.
Results: Following informed consent and screening, 47 patients were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/Kg. Median patient age was 60 years. Median number of previous regimens was 4 (range 1–8). CP-751,871 was given as an IV infusion on Day 1 of 4-week cycles. Patients with a suboptimal response to CP-751,871 alone were eligible to receive CP-751,871 in combination with either oral dexamethasone and/or rapamycin at the discretion of the investigator. Twenty-seven patients received CP-751, 871 in combination with dexamethasone, while four patients received rapamycin in combination with either CP-751,871 or CP-751,871 and dexamethasone. Median number of treatment cycles was 3 (range 1–16). Ten patients were dosed at the highest cohort of 20 mg/Kg. No CP-751,871 related dose limiting toxicities were identified. Grade 3 toxicities were all observed at the 20 mg/Kg cohort (1 hyperglycemia, 1 anemia, 1 AST increase, 1 accidental fall, 1 muscle weakness). Plasma CP-751,871 exposure increased with dose, and the pharmacokinetic characteristics were consistent with target-mediated disposition. Granulocyte IGF-IR expression was maximally down-regulated for the entire duration of the dosing period at doses ≥1.5 mg/kg, indicating a saturation of circulating targets. CP-751,871 also led to a dose-dependent increase in circulating IGF-I concentrations. Tumor response was assessed according to Blade criteria. Two remissions and 4 partial remissions were reported in patients treated with different doses of CP-751,871 in combination with dexamethasone. Interestingly, the 2 patients with remission were previously found to be refractory to dexamethasone treatment.
Conclusions: These data indicate that CP-751,871 is well tolerated either as a single agent or in combination with dexamethasone. Furthermore, CP-751,981 in combination with dexamethasone, may constitute a novel and effective therapeutic approach for patients with multiple myeloma.
Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma
