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

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.

FIGURE 1

Mean (±SD) plasma concentration-time profiles of figitumumab (F) after cycles 1 and 3 of treatment.

FIGURE 2

Time profiles of circulating endothelial cell (CEC) counts in (A) all patients with providing samples for CEC enumeration (N = 22) and (B) according to figitumumab (F) treatment doses ≤6 mg/kg (N = 12) or 10 to 20 mg/kg (N = 10). Data are represented as box plots (minimum, 25 percentile, median, 75 percentile, maximum) and individual CEC counts. Values outside the box plots are considered outliers (smaller or larger than the minimum or maximum estimates).

FIGURE 3

Soluble insulin-like growth factor type 1 receptor (IGF-1R) extracellular domain (sIGF-1R), IGF binding protein-3 (IGFBP-3), and free IGF-1 (fIGF-1) levels by figitumumab (F) dose. Data are represented relative to baseline levels.

FIGURE 4

Analysis of insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), free IGF-1 (fIGF-1) levels, and fIGF-1/IGFBP-3 ratio in responders(R) and nonresponders (NR) to treatment, according to RECIST, at figitumumab (F) treatment doses ≤6 mg/kg (N = 18) or 10 to 20 mg/kg (N = 22).