Development of Drugs That Target Prostate Cancer

Project Details


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 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. Dr. Dahut and myself recently completed the initial phase of a clinical trial with Sorafenib. We wanted to determine if sorafenib is associated with a 4 month probability of progression free survival which is consistent with 50%, as determined by clinical, radiographic, and prostate specific antigen (PSA) criteria in patients with metastatic androgen independent prostate cancer (AIPC). Patients with progressive metastatic AIPC were enrolled in an open-label, single arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were performed every cycle while radiographic measurements were carried out every 2 cycles. Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median (range) age of 63.9 years (50-77), Gleason score of 9 (4-9.5), and PSA concentration of 53.3 ng/mL (2-1905). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as demonstrated by bone scan, even though they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included: one grade 3 hypertension and hand-foot syndrome; grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in-vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0; 12) and maximum concentration (Cmax) were 9.76 hr*mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 hrs and 0.68 to 6.43 respectively. Sorafenib is relatively well tolerated in AIPC with two patients demonstrating evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based upon these observations, further investigation using only clinical and radiographic endpoints as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
Effective start/end date1/10/0630/09/08


  • National Cancer Institute: $291,303.00
  • National Cancer Institute: $171,486.00


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