We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents.Following previous experiments demonstrating increased efficacy of microtubule-active drugs when combined with ketoconazole in vitro, when tested in multiple prostate cancer cell lines, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with androgen independent prostate cancer (AIPC). The primary objective of this study is to determine the side effect profile and MTD. In recognition of possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. The dosing regimen was modified to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 30 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing.A randomized Phase II trial of ketoconazole plus alendronate versus ketoconazole alone has been completed with 72 patients with progressive AIPC metastatic to bone. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.A Phase II study in AIPC has recently been completed with perifosine. Treatment with this agent was complicated by fatigue and gastrointestinal toxicity. No significant clinical activity against prostate cancer was observed. Perifosine does not merit further study in the setting of monotherapy in this population.A Phase II study of BAY 43-9006 (Sorafenib) has recently been initiated. is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase isoforms in vitro. In addition, this agent also inhibits p38, c-kit, VEGFR-2 and PDGFR-b affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf. At this time, over 500 patients have been treated with this drug at other institutions with tolerable side effects. The primary objective of this study is to determine if BAY 43-9006 is associated with a 50% 4 month probability of progression free survival in patients with metastatic AIPC as determined by clinical, radiographic, and PSA criteria. The secondary objectives will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible), and to determine the time to progression measured by clinical and radiographic criteria. Correlative studies will be conducted on serially obtained tissue biopsies, bone marrow biopsies, and white blood cell collections. These laboratory correlates will include elucidation of activation of components of the Raf-ERK-MEK and angiogenesis pathways using protein microarray technologies developed by the NCI/FDA clinical proteomics program. The combination of correlated clinical and laboratory endpoints with emphasis on molecular signaling will provide new information on the anti-tumor effects helping to characterize its role in the treatment of AIPC. Thirty patients have been enrolled on this ongoing study.
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