Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors

摘要

Background: Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments. Patients: Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m2 (B) docetaxel, 1250 mg/m2 gemcitabine/100 mg erlotinib (C1), or 60 mg/m2 doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3. Results: Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m2 gemcitabine/75 mg erlotinib) and D2 (50 mg/m2 doxorubicin). Grade 3-4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ??12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ?? 25 ng/ml in patients discontinuing treatment 12 weeks, and fell by 55.5 ?? 21 ng/ml with disease control (P0.001). Conclusion: AVE1642 was tolerable with 75-100 mg/m2 docetaxel and 1000 mg/m2 gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response. ? The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.