title: A phase I, dose-finding study of sunitinib combined with cisplatin and 5-fluorouracil in patients with advanced gastric cancer.
abstract: Background This phase I, open-label, dose-escalation study examined the safety, maximum tolerated dose (MTD), and pharmacokinetics of sunitinib plus chemotherapy in patients with advanced gastric cancer. Patients and methods Sunitinib (25 or 37.5 mg/day, Schedule 2/1: 2 weeks on treatment/1 week off) plus chemotherapy (fixed starting doses of cisplatin 80 mg/m(2) and 5-fluorouracil [5-FU] 4,000 mg/m(2)) was administered to patients with advanced gastric cancer who had not received prior therapy for metastatic disease. Results Thirty-four patients were enrolled and received sunitinib 25 mg/day (n = 24) or 37.5 mg/day (n = 10) plus chemotherapy. No dose-limiting toxicity (DLT) was reported in the sunitinib 37.5 mg cohort. However, repeated patterns of myelosuppression beyond the first cycle led to investigation of sunitinib 25 mg/day. This was the MTD, and one DLT (grade 3 mucosal inflammation) was reported. The combination had an acceptable adverse event profile; generally of grade 1/2. There was no evidence of a pharmacokinetic drug-drug interaction between sunitinib and 5-FU. Six patients (26 %) receiving the MTD had a partial response and eight patients experienced stable disease ≥3 months. Conclusions Sunitinib plus cisplatin 80 mg/m(2) and 5-FU 4,000 mg/m(2) were combinable and adverse events were manageable. The MTD of sunitinib was established as 25 mg/day on Schedule 2/1.
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Centre (CNIO), Fuenlabrada University Hospital, Camino del Molino 2, 28950 Madrid, Spain. cgomezm@cnio.es
authors.forename: C
authors.initials: C
authors.lastname: Gómez-Martín
authors.forename: R
authors.initials: R
authors.lastname: Salazar
authors.forename: C
authors.initials: C
authors.lastname: Montagut
authors.forename: M
authors.initials: M
authors.lastname: Gil-Martín
authors.forename: J A
authors.initials: JA
authors.lastname: Núñez
authors.forename: M
authors.initials: M
authors.lastname: Puig
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: R
authors.initials: R
authors.lastname: Khosravan
authors.forename: J M
authors.initials: JM
authors.lastname: Tursi
authors.forename: M J
authors.initials: MJ
authors.lastname: Lechuga
authors.forename: J
authors.initials: J
authors.lastname: Bellmunt
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D011758:Pyrroles / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000077210:Sunitinib; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D007211:Indoles; D011758:Pyrroles; D002945:Cisplatin; D005472:Fluorouracil; D000077210:Sunitinib