Phase I trial of carboplatin and infusional cyclosporin in advanced malignancy.

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 micrograms/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 micrograms/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 < or = 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.

• Authors: R J Morgan Jr, K Margolin, J Raschko, S Akman, L Leong, G Somlo, K Scanlon, C Ahn, M Carroll, J H Doroshow
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 13 Issue 9 Pg. 2238-46 (Sep 1995) ISSN: 0732-183X [Print] United States
• PMID: 7666081 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclosporine
• Carboplatin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• Carboplatin (administration & dosage, adverse effects)
• Cohort Studies
• Cyclosporine (administration & dosage, adverse effects, blood)
• Drug Resistance
• Feasibility Studies
• Female
• Humans
• Infusions, Intravenous
• Kidney Diseases (chemically induced)
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Ovarian Neoplasms (pathology)
• Thrombocytopenia (chemically induced)
• Tumor Cells, Cultured (drug effects)