Phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC)

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14504 Background: Docetaxel is first-line standard treatment for metastatic HRPC. New combinations with targeted therapies may improve clinical responses. . Atrasentan is an endothelin receptor A (ETA) inhibitor with an IC50 in the pM range. Clinical studies suggest atrasentan delays time to disease progression, bone turnover markers and PSA kinetics. Methods: We conducted a Phase I/II trial of docetaxel and atrasentan to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and treatment response of this regimen. Patients were treated with docetaxel IV every 3 weeks at doses ranging from 60 to 75 mg/m2. Atrasentan was given orally at 10 mg daily starting on Day 3 and continuously thereafter. Initially, we defined DLT as grade IV neutropenia, but subsequently amended the protocol to redefine DLT as grade IV neutropenia lasting ≥ 7 days. Plasma PK evaluations were conducted for each drug when administered alone (Cycle 1 Day 1, 21) and together (Cycle 2 Day 1). Serial samples were evaluated by LC-MS and data were modeled using a standard, two-stage approach. Results: 18 patients were enrolled over 3 dose levels (9 at 60 mg/m2; 6 at 70 mg/m2 and 3 at 75 mg/m2) in the phase I portion and to date 9 more patients have been enrolled in a dose expansion cohort at a docetaxel dose of 70 mg/m2. Patient demographics include median age 69, PSA level 87.3 ng/ml, hemoglobin 12.7 g/dl, and KPS 90%. DLT, initially any grade IV neutropenia, was seen at every dose level, however no grade IV neutropenia has lasted ≥ 7 days and no MTD has been defined to date. Drug-related grade III/IV toxicities included only neutropenia (42%); grade I-II toxicities included fatigue, peripheral edema, and nausea. To date, 5 of 15 evaluable patients who have been treated with 70–75 mg/m2 of docetaxel and 10 mg of atrasentan demonstrate a sustained PSA response. Preliminary PK data in 11 patients show a mean docetaxel terminal half-life of 46 hr and systemic clearance of 55 L/hr. The median difference in systemic clearance between the cycles was 18% with values increasing in 67% of subjects. Conclusions: The combination of docetaxel and atrasentan appears to be well tolerated to date. The study is ongoing to more accurately determine safety, response and potential pharmacokinetic interactions. [Table: see text]