title: Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.
abstract: The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
authors.affiliation: Department of Medical Oncology, Royal Melbourne Hospital, Grattan St, 2nd Floor, Parkville, Melbourne, VIC 3050, Australia. Richard.DeBoer@wh.org.au
authors.forename: Richard H
authors.initials: RH
authors.lastname: De Boer
authors.forename: Dusan
authors.initials: D
authors.lastname: Kotasek
authors.forename: Shane
authors.initials: S
authors.lastname: White
authors.forename: Bogda
authors.initials: B
authors.lastname: Koczwara
authors.forename: Paul
authors.initials: P
authors.lastname: Mainwaring
authors.forename: Arlene
authors.initials: A
authors.lastname: Chan
authors.forename: Rebeca
authors.initials: R
authors.lastname: Melara
authors.forename: Yining
authors.initials: Y
authors.lastname: Ye
authors.forename: Adeboye H
authors.initials: AH
authors.lastname: Adewoye
authors.forename: Robert
authors.initials: R
authors.lastname: Sikorski
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009841:Oligonucleotides; D017239:Paclitaxel / Q000008:administration & dosage*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000008:administration & dosage*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors
chemical_list: D007211:Indoles; D009841:Oligonucleotides; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C519562:imetelstat; D017239:Paclitaxel