The Evaluation of Novel Therapeutics for Genitourinary Malignancies

Division Of Clinical Sciences - Nci

Investigators

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Abstract

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 consisted 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 enrolled as planned. The median Gleason score was 8, on-study PSA 99 ng/mL (range, 6.0 to 4399), and prestudy PSA doubling time (PSADT) was. 1.6 months. The PSA decline rate and time to progression (18 months) was the most of active of any published regimen. More recentley we have conducted a similar trial using lenalidomide instead of thalidomide as a means to decrease toxicity. To date 47 of 51 planned patients have enrolled. Among 45 pts who have completed at least 2 cycles, 39 (86.7%) and 30 (66.7%) of the pts had PSA declines of at least 50% and 75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). We are now planning a follow-one trial in which this regimen will be combined a the PROST-VAC vaccine . 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.