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

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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.

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Acknowledgements

This work was supported by NCI Cancer Center Grants CA 33572, CA 63265, and CA 62505.

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Authors and Affiliations

  1. Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA

    Robert J. Morgan Jr., Timothy W. Synold, Kim Margolin, James Raschko, Lucille Leong, Stephen Shibata, Merry Tetef, Yun Yen, Warren Chow, George Somlo, Mary Carroll & James H. Doroshow

  2. Department of Medical Oncology, University of Southern California, Los Angeles, CA, USA

    Franco Muggia

  3. Department of Medical Oncology, University of California, Davis, Davis, CA, USA

    David Gandara

  4. Medicine Branch, National Cancer Institute, Bethesda, MD, USA

    Eddie Reed

  5. Department of Gynecologic Oncology, City of Hope, USA

    Steven Vasilev & Kathryn McGonigle

  6. Department of Biostatistics, City of Hope, USA

    Jeff Longmate

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  1. Robert J. Morgan Jr.
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  7. Kim Margolin
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  14. Jeff Longmate
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  15. Yun Yen
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  16. Warren Chow
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  17. George Somlo
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  18. Mary Carroll
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  19. James H. Doroshow
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Correspondence to Robert J. Morgan Jr..

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Morgan, R.J., Synold, T.W., Gandara, D. et al. Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer. Cancer Chemother Pharmacol 54, 283–289 (2004). https://doi.org/10.1007/s00280-004-0818-x

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  • DOI: https://doi.org/10.1007/s00280-004-0818-x

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