title: A phase I study of ixabepilone in combination with epirubicin in patients with metastatic breast cancer.
abstract: In this phase I trial, 42 women with metastatic breast cancer were treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). The maximum-tolerated dose of ixabepilone in combination with epirubicin was 30 mg/m2 (the recommended dose for phase II evaluation), and the dose-limiting toxicity dose was 35 mg/m2 with grade 4 neutropenia.
  
  
  OBJECTIVE
  The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer.
  
  
  METHODS
  Patients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m(2)) and escalating doses of ixabepilone (25, 30, and 35 mg/m(2)).
  
  
  RESULTS
  Forty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m(2) (n = 6) in combination with 75 mg/m(2) epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m(2) was 30 mg/m(2), and the DLT dose was 35 mg/m(2) with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels.
  
  
  CONCLUSIONS
  The combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m(2), followed by ixabepilone 30 mg/m(2) every 3 weeks.
authors.affiliation: Institut Claudius Regaud, Toulouse, France. roche.henri@claudiusregaud.fr
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Elena
authors.initials: E
authors.lastname: De Benedictis
authors.forename: Ewa
authors.initials: E
authors.lastname: Cottura
authors.forename: Silvia
authors.initials: S
authors.lastname: Govi
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Alberta
authors.initials: A
authors.lastname: Locatelli
authors.forename: Marion
authors.initials: M
authors.lastname: Deslandres
authors.forename: Milvia
authors.initials: M
authors.lastname: Zambetti
authors.forename: Laurence
authors.initials: L
authors.lastname: Gladieff
authors.forename: Marianne
authors.initials: M
authors.lastname: Messina
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome
chemical_list: D034261:Epothilones; D015251:Epirubicin; C430592:ixabepilone