Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine in refractory ovarian cancer patients.

Abstract

The feasibility and pharmacokinetics of cyclosporine (CsA) delivered intraperitoneally (IP) have not been previously explored. We performed a pharmacokinetic study of IP CsA followed by a phase I dose-escalation trial of the combination of IP CsA and carboplatin in refractory ovarian cancer patients. A pilot study was performed of three patients who received 1, 10, and 20 mg/kg IP CsA alone. Subsequently, a phase I trial of 35 patients was performed between April 1990 and April 1993. Whole-blood and IP fluid CsA concentrations were measured at serial time points. The highest dose delivered IP was 34.6 mg CsA/kg in combination with carboplatin (250 mg/m2 or 300 mg/m2, depending on creatinine clearance), which was not dose-escalated. The area under the concentration-time curve (AUC) for CsA and half-life (T1/2) were calculated. Objective and serologic responses were noted, and toxicity was graded using the National Cancer Institute common toxicity criteria. The feasibility of delivering IP CsA alone was established. We observed a 1,000:1 ratio between IP fluid and blood concentrations at 20 mg CsA/kg. Pharmacokinetic analysis confirmed that at 20 mg CsA/kg, there was an IP fluid-to-blood AUC ratio of 600:1 in favor of peritoneal exposure. At the highest dose delivered, 34.6 mg CsA/kg, the mean IP CsA levels of 1,110 micrograms/ mL were tolerated moderately well and the IP fluid-to-blood ratio of 1,000:1 was maintained. Blood and IP CsA concentrations were analyzed in the presence and absence of IP carboplatin. At 20 mg CsA/kg, there was no difference in either mean blood CsA levels (0.9 microgram/ mL) or mean IP CsA concentrations (1,000 micrograms/mL) obtained in the absence or presence of carboplatin. The most common toxicity in the phase I study was anemia, seen in 66% of patients. Common toxicities at the maximum CsA dose delivered (34.6 mg/kg) were anemia, leukopenia, thrombocytopenia, and hypertension. In this trial, three objective responses (two complete and one partial) were observed for a duration of 3 to 11 months. Control of platinum-resistant ascites was an important feature, noted in five of eight patients. We have established the feasibility of delivering IP CsA up to doses of 34.6 mg/kg in conjunction with carboplatin, and the sustaining of IP fluid to blood ratios of 1,000:1. The IP administration of CsA resulted in a favorable ratio of exposure for the peritoneal cavity compared with systemic exposure, indicating a therapeutic advantage of this approach with a significant decrease in systemic toxicity. We recommend that 34.6 mg/ kg of IP CsA be tested as a phase II dose in combination with carboplatin in refractory ovarian cancer patients. This report provides the groundwork for future studies using IP CsA, both as a chemomodulator of platinum and of multidrug resistance.