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Investigational New Drugs

, Volume 23, Issue 6, pp 555–562 | Cite as

A Phase I Clinical and Pharmacokinetic Study of Fenretinide Combined with Paclitaxel and Cisplatin for Refractory Solid Tumors

  • G. A. Otterson
  • J. Lavelle
  • M. A. Villalona-Calero
  • M. Shah
  • X. Wei
  • K. K Chan
  • B. Fischer
  • M. Grever
Article

Summary

Background: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy.

Patients and methods: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8.

Results: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1800 mg/m2 of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2–8 cycles at the recommended level of 60/135/1800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC.

Conclusions: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1800 mg/m2 respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.

Keywords

cisplatin fenretinide paclitaxel pharmacokinetics 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • G. A. Otterson
    • 1
  • J. Lavelle
    • 1
  • M. A. Villalona-Calero
    • 1
  • M. Shah
    • 1
  • X. Wei
    • 2
  • K. K Chan
    • 1
    • 2
  • B. Fischer
    • 1
  • M. Grever
    • 1
  1. 1.Experimental Therapeutics ProgramThe Ohio State University Comprehensive Cancer CenterColumbusUSA
  2. 2.College of PharmacyThe Ohio State UniversityColumbusUSA

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