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Karp DD , Pollak MN , Cohen RB , Eisenberg PD , Haluska P , Yin DH , Lipton A , Demers L , Leitzel K , Hixon ML , Terstappen LW , Garland L , Paz-Ares LG , Cardenal F , Langer CJ , Gualberto A
Safety, Pharmacokinetics, and Pharmacodynamics of the Insulin-Like Growth Factor Type 1 Receptor Inhibitor Figitumumab (CP-751,871) in Combination with Paclitaxel and Carboplatin
Journal of Thoracic Oncology. 2009 Nov;4(11) :1397-1403
PMID: ISI:000271394000017    PMCID: PMC2941876   
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Abstract
Introduction: This phase I study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type I receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods: Patients received paclitaxel 200 mg/m(2), carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated. Results: Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts. Conclusions: F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
Notes
Karp, Daniel D. Pollak, Michael N. Cohen, Roger B. Eisenberg, Peter D. Haluska, Paul Yin, Donghua Lipton, Allan Demers, Laurence Leitzel, Kim Hixon, Mary L. Terstappen, Leon W. Garland, Linda Paz-Ares, Luis G. Cardenal, Felipe Langer, Corey J. Gualberto, Antonio Pfizer Inc. Supported by Pfizer Inc. 20 Lippincott williams & wilkins; 530 walnut st, philadelphia, pa 19106-3621 usa 514kt