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Investigational New Drugs

, Volume 26, Issue 6, pp 541–551 | Cite as

Optimal modeling for phase I design of a two drug combination—results of a phase I study of cisplatin with 9-nitrocamptothecin

  • S.-J. Lee
  • M. Gounder
  • E. H. Rubin
  • Jong Ming Li
  • Zheming Gu
  • A. Thalasila
  • E. Loyer
  • A. P. Kudelka
  • C. F. VerschraegenEmail author
PHASE I STUDIES

Summary

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/m2), 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/m2 and 9NC 1.25 mg/day and cisplatin 40 mg/m2 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.

Keywords

Camptothecin Phase I Pharmacokinetics Bayesian design Solid tumors 

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • S.-J. Lee
    • 1
  • M. Gounder
    • 2
  • E. H. Rubin
    • 2
  • Jong Ming Li
    • 2
  • Zheming Gu
    • 5
  • A. Thalasila
    • 2
  • E. Loyer
    • 3
  • A. P. Kudelka
    • 4
  • C. F. Verschraegen
    • 1
    Email author
  1. 1.Cancer Research and Treatment CenterUniversity of New MexicoAlbuquerqueUSA
  2. 2.The Cancer Institute of New JerseyUMDNJ-Robert Wood Johnson Medical SchoolNew BrunswickUSA
  3. 3.The University of TexasM. D. Anderson Cancer CenterHoustonUSA
  4. 4.Stony Brook UniversityStony BrookUSA
  5. 5.XenoBiotic Laboratories Inc.PlainsboroUSA

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