title: Optimal modeling for phase I design of a two drug combination-results of a phase I study of cisplatin with 9-nitrocamptothecin.
abstract: Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks. A new two arm crossing design was created: patients in arm 1 were treated with at the single agent recommended dose of cisplatin (50 mg/m(2)), and increasing doses of 9NC and in arm 2 with the single agent recommended dose of 9NC (1.5 mg/day) and increasing dose of cisplatin. Once a dose limiting toxicity was observed, the dose of the escalated drug was decreased by one level, and the fixed-dose drug was then escalated. A 3 + 3 design was used. Eligibility criteria were standard for a phase I trial. Pharmacokinetics was performed. Eighteen patients were treated on Arm 1, 3 at the crossing level, and 33 on Arm 2. Dose limiting toxicities were gastrointestinal at the crossing dose level. After crossing, prolonged grade 3 thrombocytopenia was the DLT in arm 1, and grade 4 neutropenia in Arm 2. Only one patient with ovarian cancer had a partial remission, and 12 patients had disease stabilization (24% of clinical benefit). A Bayesian optimal dose finding was tested post-facto. The recommended doses for phase II studies by the 3 + 3 design are cisplatin 60 mg/m(2) and 9NC 1.25 mg/day and cisplatin 40 mg/m(2) and 9NC 2.0 mg/day. The Bayesian optimal dose finding suggested a different solution, closest to that of the latter dosing which may be less toxic.
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Gounder
authors.forename: E H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Jong Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Zheming
authors.initials: Z
authors.lastname: Gu
authors.forename: A
authors.initials: A
authors.lastname: Thalasila
authors.forename: E
authors.initials: E
authors.lastname: Loyer
authors.forename: A P
authors.initials: AP
authors.lastname: Kudelka
authors.forename: C F
authors.initials: CF
authors.lastname: Verschraegen
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001499:Bayes Theorem; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002945:Cisplatin / Q000008:administration & dosage; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D012074:Remission Induction / Q000379:methods; D055815:Young Adult
chemical_list: C079905:rubitecan; D002945:Cisplatin; D002166:Camptothecin