I had previously shown that the combination of docetaxel and thalidomide is clinically promising in treating castrate-resistant prostate cancer (CRPC). I hypothesized that the addition of a second antiangiogenic agent with a different target could increase the activity of this combination. Thus a series of preclinical studies in support of this trial were conducted by Dr. William Figg (Medical Oncology Branch, CCR) to better delineate the antiangiogenic targets of thalidomide. In microarray experiments using thalidomide and thalidomide analogs, which are similar to the active metabolite of thalidomide, multiple angiogenesis factors (KIF5A, TTK, etc.) were downregulated, but not vascular endothelial growth factor (VEGF). VEGF expression was not altered in xenograft experiments using these analogs; however, platelet-derived growth factor was significantly reduced. Bevacizumab is a recombinant humanized anti-VEGF mAb composed of human IgG1 framework regions and antigen-binding complementary determining regions from a murine mAb which blocks the binding of human VEGF receptors. It has no known significant activity against other targets. My hypothesis was that by combining the anti-VEGF activity of bevacizumab with the antiangiogenic activity of thalidomide against multiple targets, but not VEGF, I could effectively suppress the most important angiogenic factors, leading to increased antitumor activity. The treatment regimen consists of docetaxel 75 mg/m2 plus bevacizumab 15 mg/kg on day 1 every 21 days, plus daily thalidomide 200 mg and prednisone 10 mg. All 60 patients have enrolled as planned. The median Gleason score is 8, on-study PSA 99 ng/mL (range, 6.0 to 4399), and prestudy PSA doubling time (PSADT) is 1.6 months (range, 0.3 to 18.2; 81% less than 3 months) all indicitive of a population with aggressive tumors. Ninety percent of patients have had PSA declines of ≥ 50%, with the median ≥ 50% PSA duration 11 cycles. Forty-one patients (71%) have had a ≥ 80% PSA decline. Thirty-two patients have measurable disease. There have been 2 complete remissions (CRs) and 18 partial remissions (PRs_, for a 63% overall response rate. The current estimated median progression-free survival (PFS) is 18.2 months. Large randomized trials of this combination (outside of the CCR) to demonstrate its clinical activity are in the planning stages. Although I had seen some evidence of activity with sorafenib (an oral anti-angiogenic agent), I felt it was important to study more potent and specific inhibitors of angiogenesis. Therefore, I am conducting a phase II study of cediranib, an oral small molecule inhibitor of VEGF receptor tyrosine kinases at a dose of 20 mg daily. All patients have prostate cancer resistant to docetaxel and hormonal therapy, with no limit on the number of prior chemotherapy regimens or radioisotopes. To date, 18 patients have been enrolled. Of the 11 patients with measurable disease, 2 have had PRs. Additional significant decreases in lymph node metastases and in lung, liver, and bone lesions have been documented. As with sorafenib, there has been no correlation with PSA declines and improvements on imaging studies. Adverse events have been similar to other VEGF receptor inhibitors, including hypertension, dysphonia, and fatigue. As part of the assessment of outcome in this protocol, dynamic enhanced-contrast magnetic resonance imaging (DCE-MRI) studies are obtained at baseline and at early time points after the administration of the agents to detect early changes in vascularity. The enhancement curves of the tumor are fit to the model, and the fitting parameters Ktrans and kep represent the rate constants of leak from the vascular space to the extracellular tumor space and the back reflux from the extracellular tumor space to the vascular space, respectively. Ktrans and kep color maps are generated from these parameters, allowing regional assessment of permeability. This study is unique in that bone metastases were accepted as lesions for follow-up to determine if angiogenic changes can be detected at bone sites. Although results of the DCE-MRI are still in the preliminary stage, there appears to be an early correlation between clinical response and DCE-MRI changes. Additional accrual is ongoing to characterize the response rate and discrepancy between PSA and imaging, and to establish clinical correlation for DCE-MRI. My research program has had a major interest in vaccines as an important treatment modality against prostate cancer. I began by studying the use of a single vector and in sequential studies have developed the prime and boost approach, added costimulatory molecules, and explored the use of cytokines. Concurrent trials demonstrated the safety and immunologic activity of vaccines combined with radiotherapy, hormonal therapy, chemotherapy, and an experimental monoclonal antibody. Several important findings from this work will be emphasized in the next several years. In particular, emphases will be placed on validating the improved survival (more than 18 months longer than expected) with PSA-TRICOM, confirming the sequence-dependent improved survival of vaccines administered with standard therapies, and exploring for the first time the ability of antiangiogenic inhibitors to modulate immune response and lead to improved clinical outcome. The identification of genes involved in the biosynthesis, activation, metabolism, and degradation of androgens is important in elucidating the molecular profiles of individual prostate cancer patients and the development of novel preventative and therapeutic strategies. In a collaborative project with Dr. Figg's laboratory, we have focused on genes coding for enzymes involved in androgen metabolism (CYP17, CYP1B1) and testosterone transport (SLCO1B3), or that may be important in the pharmacology of drugs important to treat prostate cancer (ABCB1). The source of the specimens is samples from CRPC patients enrolled on NCI prostate protocols (1300 CRPC samples from patients enrolled on NCI trials). The ultimate goal of my program is to improve the outcome of patients with prostate cancer. I have better defined measures of outcome and am now working to characterize genetic markers that may help us select appropriate therapy for patients. Ultimately, however, treatment for this disease needs to improve. I have designed and conducted a series of trials which are beginning to demonstrate meaningful activity, but need definitive testing in a cooperative group or similar setting. In order to move these findings forward, emphasis will be placed on vaccine therapy alone and in combination in an attempt to replicate the improved survival that I have demonstrated in smaller hypothesis-generating trials. In addition, my most active antiangiogenic combinations need confirmation in phase III studies. Finally, I plan to define the ideal schedule, patient population, and means of antitumor evaluation of more potent, targeted agents such as cediranib that will hopefully result in more effective treatment of metastatic docetaxel-resistant CRPC.
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