Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin

Daniel D. Karp, Michael N. Pollak, Roger B. Cohen, Peter D. Eisenberg, Paul Haluska, Donghua Yin, Allan Lipton, Laurence Demers, Kim Leitzel, Mary L. Hixon, Leon W. Terstappen, Linda Garland, Luis G. Paz-Ares, Felipe Cardenal, Corey J. Langer, Antonio Gualberto

Research output: Contribution to journalArticle

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Abstract

Introduction: 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.

Original languageEnglish (US)
Pages (from-to)1397-1403
Number of pages7
JournalJournal of Thoracic Oncology
Volume4
Issue number11
DOIs
StatePublished - Nov 2009

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IGF Type 1 Receptor
Carboplatin
Paclitaxel
Pharmacokinetics
Safety
Insulin-Like Growth Factor I
Non-Small Cell Lung Carcinoma
Insulin-Like Growth Factor Binding Protein 3
Maximum Tolerated Dose
gamma-Glutamyltransferase
Hyperglycemia
Thrombocytopenia
Area Under Curve
Fatigue
Disease Progression
Diarrhea
figitumumab
Carcinoma
Neoplasms

Keywords

  • CP-751
  • Figitumumab
  • IGF-1R
  • NSCLC

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin. / 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.

In: Journal of Thoracic Oncology, Vol. 4, No. 11, 11.2009, p. 1397-1403.

Research output: Contribution to journalArticle

Karp, DD, Pollak, MN, Cohen, RB, Eisenberg, PD, Haluska, P, Yin, D, Lipton, A, Demers, L, Leitzel, K, Hixon, ML, Terstappen, LW, Garland, L, Paz-Ares, LG, Cardenal, F, Langer, CJ & Gualberto, A 2009, '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, vol. 4, no. 11, pp. 1397-1403. https://doi.org/10.1097/JTO.0b013e3181ba2f1d
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. / Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin. In: Journal of Thoracic Oncology. 2009 ; Vol. 4, No. 11. pp. 1397-1403.
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abstract = "Introduction: 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.",
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T1 - Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin

AU - Karp, Daniel D.

AU - Pollak, Michael N.

AU - Cohen, Roger B.

AU - Eisenberg, Peter D.

AU - Haluska, Paul

AU - Yin, Donghua

AU - Lipton, Allan

AU - Demers, Laurence

AU - Leitzel, Kim

AU - Hixon, Mary L.

AU - Terstappen, Leon W.

AU - Garland, Linda

AU - Paz-Ares, Luis G.

AU - Cardenal, Felipe

AU - Langer, Corey J.

AU - Gualberto, Antonio

PY - 2009/11

Y1 - 2009/11

N2 - Introduction: 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.

AB - Introduction: 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.

KW - CP-751

KW - Figitumumab

KW - IGF-1R

KW - NSCLC

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