title: Phase I. Trial of irinotecan plus carboplatin in two dose schedules.
abstract: A phase I study of carboplatin (Paraplatin) administered in two different dosing schedules (single dose every 4 weeks and weekly dosing) in combination with weekly irinotecan (CPT-11, Camptosar) was conducted in patients with relapsed or refractory advanced malignancies. Fifty-three patients with a variety of tumor types were randomly enrolled on the two different treatment regimens and have received a total of 163 cycles of treatment to date. Twenty-six patients received weekly irinotecan in combination with a single fixed dose of every-4-week carboplatin (arm 1). Initially, patients received irinotecan on days 1, 8, and 15, in combination with fixed-dose carboplatin at an area under the concentration-time curve (AUC) of 5.5 (Calvert formula) on day 1 every 28 days. Due to dose-limiting toxicities encountered at the first two dose levels, the protocol was amended to decrease the fixed dose of carboplatin to an AUC of 4.0 every 4 weeks. Dose-limiting toxicity was again encountered, so the day-15 dose of irinotecan was eliminated from the dosing regimen. The recommended phase II dose for heavily pretreated patients is irinotecan at 60 mg/m2 on days 1 and 8 in combination with carboplatin at AUC 4.0 on day 1 with cycles repeated every 28 days. Twenty-seven patients were treated with weekly irinotecan in combination with fixed-dose weekly carboplatin (arm 2). The initial dosing regimen consisted of irinotecan in combination with fixed-dose carboplatin at an AUC of 1.8 on days 1, 8, and 15, with treatment cycles repeated every 28 days. Due to the development of dose-limiting toxicities at the first two dose levels, the dosing regimen was subsequently amended to weekly irinotecan in combination with fixed-dose carboplatin at AUC 2.0 on days 1 and 8 only, and the dosing interval was shortened to every 21 days. With this amended regimen, the recommended phase II doses are irinotecan at 90 mg/m2 in combination with carboplatin at AUC 2.0 on days 1 and 8, with treatment cycles repeated every 21 days.
authors.affiliation: Sarah Cannon Cancer Center, Tennessee Oncology, PLLC Nashville, Tennessee, USA. sjones@tnonc.com
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.forename: Eric A
authors.initials: EA
authors.lastname: Raefsky
authors.forename: Fernando T
authors.initials: FT
authors.lastname: Miranda
authors.forename: Michel E
authors.initials: ME
authors.lastname: Kuzur
authors.forename: Noel T
authors.initials: NT
authors.lastname: Willcutt
authors.forename: Melissa B
authors.initials: MB
authors.lastname: White
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity; D016190:Carboplatin / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin