Phase I trial of carboplatin and infusional cyclosporine in advanced malignancy

Robert J. Morgan, Kim Margolin, James Raschko, Steven Akman, Lucille Leong, George Somlo, Kevin Scanlon, Chul Ahn, Mary Carroll, James H. Doroshow

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Purpose: To determine the maximal-tolerated dose (MTD) of infusional cyclosporine (CSA) with fixed-dose carboplatin (CBDCA). Patients and Methods: Clonogenic cytotoxicity assays were performed to assess the effect of CSA on reversal of resistance to CBDCA. The phase I study was performed in three phases. In phases 1 and 2, escalating-dose CSA (5, 7.5, 8.8, or 9.5 mg/kg/d) with fixed-dose CBDCA 300 or 250 mg/m2 were administered. Phase 3 required an initial cycle of CBDCA 250 mg/m2 alone, followed by combination therapy with CBDCA 250 mg/m2 and CSA (8.8, 9.5, or 10.0 mg/kg/d). Results: Preincubation of platinum-resistant A2780 human ovarian cancer cells with CSA 2 μg/mL significantly enhanced CBDCA cytotoxicity in clonogenic assays. Fifty-one patients received 130 courses of therapy. The phase 1 MTD was thrombocytopenia (CSA 7.5 mg/kg/d and CBDCA 300 mg/m2) attributable to the effects of CBDCA alone. The phase 2 MTD was reversible nephrotoxicity (serum creatinine elevations to 3.6 and 4.4 mg/dL) and neutropenia (CSA 9.5 mg/kg/d and CBDCA 250 mg/m2). In phase 3, headache was observed in five patients and hypertension in one patient at CSA 10 mg/kg/d. The expected change in platelet count predicted for CBDCA alone was compared with the actual change; no excessive thrombocytopenia was observed with addition of CSA. Steady- state CSA levels of 2 μg/mL capable of reversing platinum resistance in vitro were observed. Four objective responses were observed. Conclusion: CSA is effective in reversing CBDCA resistance in A2780 ovarian cancer cells. Short-term infusions of CSA ≤ 8.8 mg/kg/d in combination with CBDCA are well-tolerated for heavily pretreated patients and result in CSA levels known to reverse CBDCA resistance in vitro.

Original languageEnglish (US)
Pages (from-to)2238-2246
Number of pages9
JournalJournal of Clinical Oncology
Volume13
Issue number9
DOIs
StatePublished - Sep 1995

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Morgan, R. J., Margolin, K., Raschko, J., Akman, S., Leong, L., Somlo, G., Scanlon, K., Ahn, C., Carroll, M., & Doroshow, J. H. (1995). Phase I trial of carboplatin and infusional cyclosporine in advanced malignancy. Journal of Clinical Oncology, 13(9), 2238-2246. https://doi.org/10.1200/JCO.1995.13.9.2238