title: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.affiliation: Department of Oncology, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford OX3 7LE, UK. valentine.macaulay@oncology.ox.ac.uk
authors.forename: V M
authors.initials: VM
authors.lastname: Macaulay
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.forename: A S
authors.initials: AS
authors.lastname: Protheroe
authors.forename: A
authors.initials: A
authors.lastname: Tolcher
authors.forename: V
authors.initials: V
authors.lastname: Dieras
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.forename: R
authors.initials: R
authors.lastname: Bahleda
authors.forename: J-Y
authors.initials: JY
authors.lastname: Blay
authors.forename: P
authors.initials: P
authors.lastname: LoRusso
authors.forename: D
authors.initials: D
authors.lastname: Mery-Mignard
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride; D017526:Receptor, IGF Type 1; C545477:AVE1642; D000093542:Gemcitabine