Phase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma.

OBJECTIVES: In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. METHODS: Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. RESULTS: All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added. CONCLUSIONS: : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

A phase I and pharmacologic study of pyrazoloacridine and cisplatin in patients with advanced cancer.

Pyrazoloacridine (PZA, NSC366140, PD115934) is an acridine derivative currently undergoing clinical evaluation. In preclinical testing, PZA has shown selectivity for solid tumor cell lines, activity in hypoxic, noncycling, and multidrug-resistant cell lines, and synergy with cisplatin in a variety of lung cancer cell lines. In early phase I clinical studies PZA has shown modest activity in ovarian, cervical, and colon cancer. The purpose of the present study was threefold: to determine the maximally tolerated doses of the combination of PZA (3-h infusion) and cisplatin administered with and without Filgrastim (G-CSF) (Amgen, Thousand Oaks, CA) every 3 weeks in untreated or minimally pretreated patients, to describe and quantify the clinical toxicities of combination chemotherapy with PZA and cisplatin, and to evaluate the effects of drug sequencing on the toxicity profile and pharmacologic behavior of PZA. The starting doses in this dose-escalation trial were PZA 400 mg/m2 as a 3-h intravenous infusion and cisplatin 50 mg/m2 as a 1 mg/min intravenous infusion. The sequence of drugs was alternated with each successive course in each patient treated. Twenty-one patients with refractory solid tumors received 43 courses of therapy through four dose levels. Neutropenia was dose-limiting and defined the maximum tolerated dose of PZA 400 mg/m2 and cisplatin 50 mg/m2 without G-CSF support. With G-CSF support, nausea and vomiting were dose-limiting. The maximum tolerated and recommended doses for further study of this combination are PZA 600 mg/m2 over 3 h and cisplatin 50 mg/m2 followed by G-CSF support. Pharmacokinetic analysis showed that sequence does not impact on the pharmacokinetics of PZA when given in combination with cisplatin.