Objectives: Paclimer is a biodegradable polymer microsphere formulation containing 10% (w/w) paclitaxel that is designed to provide a sustained-release form of paclitaxel after intraperitoneal (IP) administration. The goals of this phase I study were to determine the maximum tolerated dose (MTD) of IP paclitaxel microspheres and the pharmacology of paclitaxel after IP paclitaxel microsphere administration.
Methods: Twelve patients with recurrent or persistent ovarian or primary peritoneal carcinoma were treated. After placement of an IP catheter, patients were treated with escalating doses of IP paclitaxel microspheres administered with 2 l of normal saline following premedication. Treatment could be repeated once, 8 weeks after initial treatment. The starting dose was 60 mg/m2 and no intrapatient dose escalation was used.
Results: One dose-limiting toxicity consisting of abdominal pain, ileus and bowel obstruction was seen with the second cycle of therapy in one patient who received 900 mg/m2. Patients received up to 1200 mg/m2 without further evidence of dose-limiting toxicities (DLT). The study was discontinued before MTD was defined due to the manufacturer's decision to suspend further clinical development of paclitaxel microspheres. Pharmacokinetic analysis showed a trend toward a dose-dependent effect of IP paclitaxel microspheres on measured plasma paclitaxel levels. Sustained paclitaxel levels were maintained throughout all 8 weeks of therapy; however, paclitaxel concentrations were well below the plasma concentrations associated with toxicity. In one patient, laparoscopy revealed extensive adhesions, fat necrosis, foreign body giant cell reaction and detectable residual polymer filaments 7 months after completion of treatment with paclitaxel microspheres.
Conclusions: IP administration of paclitaxel microspheres is well tolerated up to 1200 mg/m2 without defining MTD. The low but persistent detection of plasma paclitaxel indicates that paclitaxel continues to be released for at least 8 weeks after IP paclitaxel microsphere treatment. The finding of significant peritoneal abnormalities, including the presence of residual polymer filaments, months after IP Paclimer treatment suggests that the polymer preparation used in Paclimer degrades slowly.