Originally published as JCO Early Release 10.1200/JCO.2007.15.9319 on May 12 2008

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Phase I, Pharmacokinetic and Pharmacodynamic Study of the Anti–Insulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma

Martha Q. Lacy, Melissa Alsina, Rafael Fonseca, M. Luisa Paccagnella, Carrie L. Melvin, Donghua Yin, Amarnath Sharma, M. Enriquez Sarano, Michael Pollak, Sundar Jagannath, Paul Richardson, Antonio Gualberto

From the Mayo Clinic, Divisions of Hematology and Cardiovascular Diseases, Rochester, MN; H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; Mayo Clinic, Division of Hematology, Scottsdale, AZ; Pfizer Global Research & Development, New London, CT; St Vincent's Comprehensive Cancer Center, New York, NY; Dana Farber Cancer Institute Boston, MA; and the McGill University and Lady Davis Research Institute, Montreal, Quebec, Canada

Corresponding author: Antonio Gualberto, MD, PhD, Pfizer Global Research & Development, 50 Pequot Ave, MS6025-A3266, New London, CT 06320; e-mail: antonio.gualberto{at}pfizer.com

Purpose: A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.

Patients and Methods: After informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.

Results: No CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.

Conclusion: These data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.

published online ahead of print at www.jco.org on May 12, 2008.

Supported in part by Pfizer Inc (M.Q.L., M.A., R.F., M.M.P., S.J., P.R.).

Presented at the 49th Annual Meeting of the American Society of Hematology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.