Journal of Clinical Oncology, Vol 15, 1945-1952, Copyright © 1997 by American Society of Clinical Oncology
Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine in refractory ovarian cancer patients
SK Chambers, JT Chambers, CA Davis, EI Kohorn, PE Schwartz, MI Lorber, RE Handschumacher and G Pizzorno
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
PURPOSE: 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. PATIENTS AND METHODS: 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.
RESULTS: 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. CONCLUSION: 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.
