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 antiVEGF 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 antiVEGF 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 54 of the planned 62 pts have been enrolled. Median age was 65.5, median Gleason score 8, median on study PSA 85.2 ng/ml (0.15 to 3520), and median prestudy PSA doubling time 1.49 months (0.52 to 6.73). Median number of treatment Cs was 16 (3 to 38) . As of this analysis the PFS was 22 months and the probability of survival at 12 months was 90%. Forty six (85.2%) and 42 (77.8%) patients had PSA declines of greater than 50% and 75%, respectively. Of 30 pts with measurable disease there were 1 CR, 25 PR, and 4 SD (65% overall RR). 17/54 pts were taken off study for radiographic disease progression and 8/54 for other reasons. Grade 2 or greater toxicities included neutropenia (34/54), febrile neutropenia (8/54), anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts were on bisphosphonates, 2/12 had used bisphosphonates previously, and 3/12 had no history of bisphosphonate use. The incidence of ONJ was comparable to 18.3% reported by Ning, but lower than the incidence reported by a recent study of carboplatin plus weekly docetaxel. 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 TRC105 and AMG386 that will hopefully result in more effective treatment of metastatic CRPC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC010098-10
Application #
8554039
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2012
Total Cost
$492,502
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Madan, Ravi A; Gulley, James L; Dahut, William L (2016) Radium-223 in prostate cancer: emitting the right signals. Lancet Oncol 17:1186-7
Karzai, Fatima H; Madan, Ravi A; Dahut, William L (2016) Metabolic syndrome in prostate cancer: impact on risk and outcomes. Future Oncol 12:1947-55
Madan, Ravi A; Dahut, William L (2015) Prostate cancer: Charting a course in metastatic castration-sensitive prostate cancer. Nat Rev Urol 12:368-9
Madan, Ravi; Dahut, William L (2015) Abiraterone's efficacy confirmed; time to aim higher. Lancet Oncol 16:119-21
Turkbey, Baris; Agarwal, Harsh K; Shih, Joanna et al. (2015) A Phase I Dosing Study of Ferumoxytol for MR Lymphography at 3 T in Patients With Prostate Cancer. AJR Am J Roentgenol 205:64-9
Ojemuyiwa, Michelle A; Madan, Ravi A; Dahut, William L (2014) Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development. Expert Opin Emerg Drugs 19:459-70
Dahut, William L; Madan, Ravi A (2014) Real-world experience with abiraterone. Lancet Oncol 15:1188-90
Adesunloye, Bamidele A; Karzai, Fatima H; Dahut, William L (2014) Angiogenesis inhibitors in the treatment of prostate cancer. Chem Immunol Allergy 99:197-215
Gulley, James L; Heery, Christopher R; Madan, Ravi A et al. (2013) Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. Cancer Immunol Immunother 62:1521-31
Figg, William D; Chau, Cindy H; Madan, Ravi A et al. (2013) Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity. Clin Genitourin Cancer 11:229-37

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