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.

Abstract

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/m(2) (B) docetaxel, 1250 mg/m(2) gemcitabine/100 mg erlotinib (C1), or 60 mg/m(2) 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/m(2) gemcitabine/75 mg erlotinib) and D2 (50 mg/m(2) 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 (P < 0.001).

CONCLUSION:

AVE1642 was tolerable with 75-100 mg/m(2) docetaxel and 1000 mg/m(2) gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response.

• Authors: V M Macaulay, M R Middleton, A S Protheroe, A Tolcher, V Dieras, C Sessa, R Bahleda, J-Y Blay, P LoRusso, D Mery-Mignard, J-C Soria
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 24 Issue 3 Pg. 784-91 (Mar 2013) ISSN: 1569-8041 [Electronic] England
• PMID: 23104723 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Quinazolines
• Taxoids
• Deoxycytidine
• Docetaxel
• Doxorubicin
• Erlotinib Hydrochloride
• Receptor, IGF Type 1
• AVE1642
• Gemcitabine

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Diarrhea (chemically induced)
• Docetaxel
• Doxorubicin (administration & dosage)
• Erlotinib Hydrochloride
• Female
• Humans
• Leiomyosarcoma (drug therapy)
• Male
• Melanoma (drug therapy)
• Middle Aged
• Quinazolines (administration & dosage)
• Receptor, IGF Type 1 (immunology)
• Skin Neoplasms (drug therapy)
• Soft Tissue Neoplasms (drug therapy)
• Taxoids (administration & dosage)
• Treatment Outcome
• Gemcitabine