Caffeinated energy shots significantly increased SBP and DBP over a 3-hour period compared with decaffeinated energy shots in healthy, nonhypertensive individuals.

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

89 Background: Single agent atorvastatin and celecoxib have been associated with reductions in the risk of PC. Our laboratories have demonstrated that low doses of the drug combination have synergistic effects inhibiting the progression of LNCaP tumors to androgen independence. We therefore sought to determine the effects of the combination in androgen-dependent PC on PSA kinetics and the plasma correlates of IL-6, C-reactive protein (CRP), PGE-2, and the pharmacokinetics of the drug combination to validate preclinical biomarker findings. Methods: Patients with rising PSA after primary therapy for PC were enrolled. Patient must have three rising PSA values, each obtained at least 1 month apart. No prior hormone-ablative therapy was allowed, except in the neoadjuvant setting or in the setting of salvage XRT completed 3 months prior to enrollment. Patients with any history of coronary artery disease or a previous myocardial infarction in the past 6 months were excluded. All patients were treated with atorvastatin 20 mg daily and celecoxib 200 mg twice a day for 6 months. Paired pre-treatment and on treatment PSA kinetics were compared using the Wilcoxon Signed Rank test. Results: We report on 14 patients that have completed therapy. Median pretreatment PSA slope was 0.14 log PSA/mo (median PSADT 4.98 mos), in contrast to the median on treatment slope of 0.09 log PSA/mo (median PSADT 7.37 mos); p=0.11. Eleven of the fourteen patients completed the 6 months of therapy, 1 patient withdrew and 2 patients therapy was stopped early due to lack of response. A declining PSA was observed in one patient. The combination was well tolerated, with no clinically significant therapy related toxicities ( > grade 1) reported in 76 months of therapy. Conclusions: In this ongoing phase II trial, the combination of low dose atorvastatin and celecoxib has been well tolerated and demonstrates a tendency of increasing PSA doubling time. Enrollment continues with analysis of IL-6, CRP, and PGE-2 to be correlated to individual clinical results.

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