title: Safety of repeated administrations of ixabepilone given as a 3-hour infusion every other week in combination with irinotecan in patients with advanced malignancies.
abstract: Epothilones are active tubulin-interacting agents that warrant combinations in clinical studies. This phase I combination study explored ixabepilone administered as a 3-h infusion followed by a 90-minute infusion irinotecan, on days 1 and 14 of every 28-day cycle. Forty-one patients received doses of ixabepilone and irinotecan ranging from 15-30 mg/m(2) and 120-180 mg/m(2) every 2 weeks for a total of 173 cycles, respectively. Dose limiting toxicities reported at doses 25 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan consisted of acute grade 3 diarrhoea and asthenia, eventually associated with neutropenia and sepsis, and/or delayed grade 3 peripheral neuropathy. Therefore, the recommended doses were 20 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan. At this dose level, acute side effects were neutropenia, anaemia, nausea-vomiting, diarrhoea, asthenia, and alopecia. Delayed neuropathy was mostly restricted to reversible grade I-II. Pharmacokinetic data suggested no drug-drug interaction. Five objective responses were observed in four patients with lung cancer and one unknown primary epidermoid carcinoma patient. In conclusion, toxicity including peripheral neuropathy was manageable at the recommended doses of 20 mg/m(2) ixabepilone combined with 180 mg/m(2) irinotecan on days 1 and 14 every 28 days. Promising antitumour activity was observed in patients with platinum-pretreated lung cancer.
authors.affiliation: Department of Medicine, Gustave-Roussy Institute, Villejuif, France. sandrine.faivre@bjn.aphp.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Catherine
authors.initials: C
authors.lastname: Delbaldo
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Fouad
authors.initials: F
authors.lastname: Namouni
authors.forename: Ronald
authors.initials: R
authors.lastname: Peck
authors.forename: Marvin
authors.initials: M
authors.lastname: Cohen
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001247:Asthenia / Q000139:chemically induced; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D010292:Paresthesia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: D034261:Epothilones; D000077146:Irinotecan; C430592:ixabepilone; D002166:Camptothecin