This project is focused on translational clinical trials for the treatment of genitourinary malignancies (primarily prostate cancer). Phase I trials of novel agents, phase II efficacy trials and a small phase III trial are included in this project. Many of these trials involve antiangiogenic agents or novel vaccine strategies. Currently nine trials are involved in the active treatment of patients. Two of these trials have closed to accrual of new patients. 1. A Randomized Phase II Study of High Dose Ketoconazole plus Alendronate versus High Dose Ketoconazole in Patients with Androgen Independent Metastatic Prostate Cancer. This trial is designed to determine if the addition of alendronate to high dose ketoconazole produces acceptable disease responses as opposed to high dose ketoconazole alone. Translational end points are focused on the matrix metalloproteinase inhibition by alendronate. All seventy-two patients have enrolled on this study. Laboratory and clinical analysis is currently underway 2. A Randomized Phase II Trial of Weekly Docetaxel Plus Thalidomide versus Weekly Docetaxel in Metastatic Androgen Independent Prostate Cancer Thalidomide and docetaxel have both shown biologic activity against androgen independent prostate cancer (AIPC). This is a randomized phase II study designed to evaluate the efficacy of weekly docetaxel as compared to the combination of docetaxel and thalidomide in patients with AIPC. Each patient that has biopsiable lesions undergoes a pretreatment biopsy of their prostate (or other site of soft tissue disease). Molecular markers of apoptosis, angiogenesis as well as pharmacokinetics are evaluated in all patients. All seventy-one patients have enrolled in this study. Laboratory and clinical analysis is currently underway. 3. A Phase I Trial of High Dose Ketoconazole Plus Weekly Docetaxel in Metastatic Androgen Independent Prostate Cancer Others and we have demonstrated clinical activity of docetaxel and ketoconazole as single agents in patients with advanced androgen independent prostate cancer. Doug Figg and colleagues have previously demonstrated ketoconazole potentiated the antitumor effects of microtubal drugs (paclitaxel and vinblastine) in androgen independent prostate cancer cell lines. Not surprisingly, the authors found that ketoconazole alone decreased the cell number of hormone sensitive cell lines and hormone independent cell lines. In addition, ketoconazole blocked the recovery of prostate cancer cell lines after exposure to microtubal inhibitors. It appeared that this was independent of p53. Resistance was also not associated with BCL2 phosphorylation. More recently, Blagoskonny and Figg have shown synergy with the addition of docetaxel and ketoconazole using the DU145 prostate cancer cell line. Those data clearly show synergistic enhancement of cell kill with increasing concentrations of ketoconazole Docetaxel is predominately metabolized by the CYP 3A4 isozyme. In vitro data suggests ketoconazole has a 95% inhibition of docetaxel metabolism in human hepatocytes in primary culture and a 99% inhibition in human liver microsomes. This data suggests a significant interaction between these two agents. Protein binding and concomitant medications complicate the comparison of in vitro data to in vivo predictions. Thus it has been important to commence at a low dose of docetaxel and to escalate slowly. The eventual goal of this phase I trial is to determine the phase II dose of this combination. This would then serve as the foundation to add additional targeted therapies to this combination. In addition to pharmacokinetics, all patients will undergo bone marrow aspirates to measure the impact of this combination on circulating cells in the bone marrow. This trial opened in March 2002 and the first eight patients have been accrued. 4. A Double Blind Randomized Crossover Phase III Study of Oral Thalidomide versus Placebo in Patients with Stage D0 Androgen Dependent Prostate Cancer Following Limited Hormonal Ablation The use of Prostate Specific Antigen (PSA) has led to an earlier detection of prostate cancer. Nevertheless 30-40% of all patients will recur; most recurrence will be detected simply by a rise in PSA. The vast majority of patients will have no clinical symptoms or radiographic evidence of disease. Hormonal ablation has a clear role in metastatic patients, but the timing of its use in patients without metastatic disease remains controversial. Many patients do not enjoy the hot flashes, loss of libido and potential for bone thinning. Thalidomide is an agent that has had anti-tumor in patients with advanced prostate cancer, but may work best in patients with minimal disease. Thus we have initiated a multi-center placebo control trial in patients with stage D0 prostate cancer. The primary goal of the study is to determine if thalidomide can control prostate cancer (as measured by a rise in PSA) in patients with androgen dependent disease after the cessation of hormonal therapy and the subsequent rise of testosterone. Additional laboratory correlates are also being obtained from the serum of patients. The trial has accrued 125 patients (the majority at the Clinical Center) of the planned 280. 5. A Randomized Phase II Study of Either Immunotherapy w/ a Regimen of Recombinant Pox Viruses that Express PSA/B7.1 + Adjuvant GM-CSF & IL-2 or Hormone Tx w/ Nilutamide in Patients w/ Hormone Refractory Prostate Ca & No Radiographic Evidence of Disease. This study compares the effectiveness of the drug nilutamide with that of an experimental vaccine in controlling advanced prostate cancer. Nilutamide (Nilandron) is an anti-androgen approved for treating prostate cancer. The vaccine is composed of the following parts: A) rV-PSA vaccinia virus plus human DNA that produces PSA (prostate specific antigen); B).rV-B7.1 vaccinia virus plus human DNA that produces B7.1 (a protein that helps guide immune cells to their targets); C) rF-PSA fowlpox virus plus human DNA that produces PSA; and D) GM-CSF and IL-2 drugs that boost the immune system. Patients that are A-2 positive have blood obtained to determine their immunologic response using the ELISPOT assay. 6. A Randomized Phase II Study of a PSA-Based Vaccine in Patients with Localized Prostate Cancer Receiving Standard Radiotherapy We have been fortunate to have an excellent collaboration with the laboratory of Dr. Jeff Schlom and currently have three vaccine trials open in our program. I am the P.I on two of the trials. The first study will test the ability of an experimental vaccine to stimulate the immune system of localized prostate cancer patients during radiation therapy. The vaccine is intended to stimulate lymphocytes to target and attack cells containing a protein called prostate specific antigen, or PSA. The vaccine is composed of the following parts: A) rV-PSA vaccinia virus plus human DNA that produces PSA (prostate specific antigen); B).rV-B7.1 vaccinia virus plus human DNA that produces B7.1 (a protein that helps guide immune cells to their targets); C) rF-PSA fowlpox virus plus human DNA that produces PSA; and D) GM-CSF and IL-2 drugs that boost the immune system This regimen has proven to have acceptable tolerance. Twenty of the planned thirty patients have been enrolled. 7. A Pilot Trial of a Recombinant Pox Virus-PSA Vaccine Plus Weekly Docetaxel in Metastatic Androgen Independent Prostate Cancer Chemotherapy has been added to many new agents with the potential for improved efficacy. There has been reluctance to add chemotherapy to a vaccine regimen because of the concern that chemotherapy may suppress the immune response generated by the vaccine. Recently data published elsewhere indicated that in some cases low-doses of chemotherapy might enhance the immune response. This is a small-randomized phase II trial (14 patients per arm) designed to determine the impact of chemotherapy and a recombinant pox based vaccine on patients with prostate cancer. Patients are randomized to the vaccine regimen of A) rV-PSA vaccinia virus plus human DNA that produces PSA (prostrate specific antigen); B) rV-B7.1 vaccinia virus plus human DNA that produces B7.1 (a protein that helps guide immune cells to their targets); C) rF-PSA fowlpox virus plus human DNA that produces PSA D) GM-CSF plus weekly docetaxel or the vaccine regimen alone followed by chemotherapy at the time of progression. The primary endpoint of the trial is to determine the safety of this combination and to determine the impact on the immune system as measured by the ELISPOT assay. The trial opened in July 2002 and five patients have been accrued. 8. A Multidose Phase I Study of Oral CC5013, a Thalidomide Derivative, in Patients with Refractory Metastatic Cancer CC-5013, a-(3-aminophthalimido) glutarimide, is an analogue of thalidomide which is under clinical development for potential use in the treatment of human cancers. Thalidomide, the parent molecule of CC-5013, has antiangiogenic properties whose mechanisms have yet to be described in detail. However, thalidomide's antiangiogenic effects may occur via its inhibition of TNFa, bFGF, VEGF, COX-2, or the induction of IL-12 and IFNg, which are all effector molecules in the tumor microenvironment. This is a multidose phase I study proposal for the evaluation of CC-5013, an oral thalidomide derivative, in patients with refractory metastatic cancer. We will be defining the maximum tolerated dose, the toxicity profile, characterizing the pharmacokinetics, and evaluating the effect of CC-5013 on several biological endpoints (plasma VEGF, TNFa, bFGF). We have accrued nine patients (on three dose levels) since opening the trial in April 2002. 9. A Phase I Trial of 2-Methoxyestradiol (2ME2), (NSC-659853) an Angiogenesis Inhibitor, in Patients with Solid Tumors 2-Methoxyestradiol (2ME2) is an antiangiogenic and antiproliferative human metabolite of estradiol. 2ME2 inhibits endothelial cell proliferation and in vitro angiogenesis. In addition, 2ME2 has been shown to enhance tumor cell apoptosis and bind to tubulin. This is a dose-escalation phase I study of 2ME2, an oral angiogenesis inhibitor, in patients with solid tumors. The endpoints of this trial are to: 1) determine the maximum tolerated dose (MTD) of 2ME2, 2) characterize the toxicity profile of 2ME2, 3) characterize the pharmacokinetics of 2ME2. We will be looking at molecular/biological endpoints, in particular, the effect of 2ME2 on PET imaging (O15 and FDG), and the effect of 2ME2 on apoptosis (either endothelial cells or epithelial cells). All patients on this trial have been required to undergo biopsies as well as PET Scans. We have collaborated on this trial with Dr Doug Figg and Dr Elise Kohn.
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