Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin.
BACKGROUND
This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 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/m2, 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.
Karp
Daniel D
DD
The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Pollak
Michael N
MN
Cohen
Roger B
RB
Eisenberg
Peter D
PD
Haluska
Paul
P
Yin
Donghua
D
Lipton
Allan
A
Demers
Laurence
L
Leitzel
Kim
K
Hixon
Mary L
ML
Terstappen
Leon W
LW
Garland
Linda
L
Paz-Ares
Luis G
LG
Cardenal
Felipe
F
Langer
Corey J
CJ
Gualberto
Antonio
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D016190:Carboplatin; D017526:Receptor, IGF Type 1; D017239:Paclitaxel; C525021:figitumumab