Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian

Robert J. Morgan, Timothy W. Synold, David Gandara, Franco Muggia, Sidney Scudder, Eddie Reed, Kim Margolin, James Raschko, Lucille Leong, Stephen Shibata, Merry Tetef, Steven Vasilev, Kathryn McGonigle, Jeff Longmate, Yun Yen, Warren Chow, George Somlo, Mary Carroll, James H. Doroshow

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6 Citations (Scopus)

Abstract

Purpose: To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA. Experimental design: To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Results: Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean ± SD end-of-infusion CSA level (HPLC assay) was 1253 ± 400 μg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC. Conclusions: Steady-state levels of > 1 μg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics.

Original languageEnglish
Pages (from-to)283-289
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number4
DOIs
Publication statusPublished - Oct 1 2004
Externally publishedYes

Keywords

  • Chemomodulation
  • Chemotherapy
  • Phase II

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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    Morgan, R. J., Synold, T. W., Gandara, D., Muggia, F., Scudder, S., Reed, E., Margolin, K., Raschko, J., Leong, L., Shibata, S., Tetef, M., Vasilev, S., McGonigle, K., Longmate, J., Yen, Y., Chow, W., Somlo, G., Carroll, M., & Doroshow, J. H. (2004). Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian. Cancer Chemotherapy and Pharmacology, 54(4), 283-289. https://doi.org/10.1007/s00280-004-0818-x