Phase I trial of weekly paclitaxel plus oral estramustine phosphate in patients with hormone-refractory prostate cancer.

OBJECTIVES: To exploit the favorable dose intensity and safety profile of weekly paclitaxel, we conducted a Phase I trial of paclitaxel by 3-hour infusion in combination with estramustine phosphate (EM) in men with hormone-refractory prostate cancer (HRPC). The antimicrotubule drug combination of paclitaxel by 96-hour infusion plus EM is active in HRPC. METHODS: Twenty-four patients with metastatic HRPC and progressive tumor after antiandrogen withdrawal were enrolled in this study. Oral EM was taken at a dose of 600 mg/m(2) daily for the initial 21 patients and on a reduced schedule of 280 mg twice daily for the final 3 patients. Paclitaxel was escalated from 60 to 118 mg/m(2). RESULTS: The major toxicities were gastrointestinal and thromboembolic complications related to daily oral dosing of EM. Of the first 21 patients, one third (n = 7) discontinued therapy within 4 weeks because of protracted nausea and/or thrombotic complications. Dose-limiting toxicities at 118 mg/m(2) paclitaxel were fatigue and hepatotoxicity. Of 13 patients with measurable soft-tissue lesions, 6 had objective partial regressions, and 9 (37.5%) of 24 patients (95% confidence interval 19.1% to 59.1%) with elevated prostate-specific antigen levels had a 50% or greater decline of at least 4 weeks' duration. CONCLUSIONS: Weekly paclitaxel at doses of 60 to 107 mg/m(2) were feasible in combination with oral EM, but daily oral EM produced unacceptable toxicity. On the basis of these results, a Phase II trial of weekly paclitaxel with the reduced dose and schedule of EM was initiated by the Eastern Cooperative Oncology Group to assess further the benefits and risks of this treatment in men with metastatic HRPC.

Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies.

Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor beta pathway and/or inhibition of p21ras signaling, leading to differentiation or apoptosis. In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 28-day cycle. The starting dose of POH was 1600 mg/m2/dose, with escalations to 2100 and 2800 mg/m2/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m2. Grade 1-2 hypokalemia was common at 2100 and 2800 mg/m2. Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentration versus time curve and peak plasma concentration (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. One patient treated at the 2800 mg/m2/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21ras, rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600-2100 mg/m2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.