Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity: Dose-Limiting Toxicity and Pharmacokinetics

Purpose: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Experimental Design: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m² every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Results: Tumor types included gastric adenocarcinoma (n = 7), ovarian cancer (n = 4), other gastrointestinal primaries (n = 3), and other cancers (n = 7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m² dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m ² docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m² D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m ² i.p. docetaxel of 3.14 and 6.33 μM·h (ranges, 1.02-5.88 and 3.97-12.70 μM·h), respectively; the mean peritoneal AUCs were 315 and 1063 μM·h (ranges, 250-373 and 239-2222 μM·h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m ² i.p. docetaxel were 0.46 and 0.66 μM, and the mean peak peritoneal concentrations at those doses were 59 and 81 μM, respectively. The median and mean pharmacological advantage calculations (AUC _peritoneal/AUC_plasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 μM (range, 0.2-1.6 μM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 μM was 31.2 h (range, 27-36.5 h). Conclusions: i.p. docetaxel can be safely delivered at a dose of 100 mg/m² i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.