A phase I study of paclitaxel/doxorubicin/ thalidomide in patients with androgen- independent prostate cancer

The antiangiogenic and immunomodulatory effects of thalidomide induce responses in patients with androgen-independent prostate cancer (AIPC). Paclitaxel and doxorubicin also have significant antitumor activity. A phase I dose-escalation study was conducted to evaluate the use of these agents in combination to enhance the chemotherapeutic effects of treatment for refractory cancer.

Twelve men with AIPC (mean age, 64.5 years) and a median prostate-specific antigen (PSA) level of 30 ng/mL were enrolled. Patients received starting doses of weekly paclitaxel (100 mg/m(2)) as a 1-hour intravenous infusion, weekly doxorubicin (20 mg/m(2)) as a 24-hour intravenous infusion, and daily oral thalidomide at escalating dose levels of 200 mg (dose level 0), 300 mg (dose level +1), and 400 mg (dose level +2). Paclitaxel and doxorubicin were administered for 3 consecutive weeks of a 5-week cycle. Exposure to thalidomide was daily. Patients were evaluated weekly for dose-limiting toxicities to determine the maximum tolerated dose. In addition, PSA levels were measured before each cycle of treatment. Response to treatment was defined as a > or =50% decrease in baseline PSA levels associated with stable radiographic disease, improvement of bone scan results with plain radiograph correlation, or improvement in soft tissue disease.

Four patients were treated on dose level 0, 5 were treated on dose level +1, and 3 were treated on dose level +2. The thalidomide 400-mg dose level resulted in 3 of 3 patients experiencing grade 3 leukopenia. The maximum tolerated dose was 300 mg of thalidomide in combination with paclitaxel/doxorubicin. Nine of the 12 patients were evaluable for PSA response, with 88% exhibiting partial responses or stable disease. One patient (11%) had a significant response, with PSA levels decreasing > 90% from baseline values. Overall, PSA-level decreases ranged from 0.5 ng/mL to 39.5 ng/mL among the 9 evaluable patients. A maximum of 7 cycles of therapy were administered. Twelve patients were evaluable for toxicity: neutropenia (grade 3, 27%; grade 4, 54%), leukopenia (grade 3, 63%), constipation (grade 3, 27%), fatigue (grade 3, 27%), nausea (grade 3, 9%), and deep vein thrombosis (grade 3, 9%) were reported.

The combined dosing of paclitaxel (100 mg/m(2) weekly), doxorubicin (20 mg/m(2) weekly), and thalidomide (300 mg daily) is tolerated by men with AIPC and merits continued phase II study.