Phase II study of maintenance therapy with temsirolimus (TEM) after response to first-line docetaxel (TAX) chemotherapy in castration-resistant prostate cancer (CRPC).

160 Background: TAX is the standard first-line chemotherapy for CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX, maintenance therapy with well-tolerated agents such as the mTOR inhibitor TEM could be one strategy to prolong treatment response and the chemotherapy-free interval, without significantly compromising quality of life. In fact, the mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-CRPC activity in preclinical testing. Methods: CRPC pts eligible for this single-arm, multicenter phase II trial must have received between 6 to 8 cycles of first-line TAX (75 mg/m2 q3wks) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. 30 pts will be enrolled and administered weekly TEM (25 mg iv × 4/cycle). The primary endpoint is time to treatment failure (TTF, by RECIST or symptomatic progression). Secondary endpoints include safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST), and overall survival. We will also study correlative endpoints using plasma and peripheral blood mononuclear cells (i.e., markers of mTOR inhibition, of antiangiogenic TEM effects and of intratumoral hypoxia/acidosis, the latter as potential predictive markers). Results: 10 pts have been enrolled to date: mean age 68 (range 52-80), prior definitive local therapy (7)—radiation (6), prostatectomy (1), mean PSA at entry 99.28 (2.3- 380.7), ECOG 0 (4) or 1 (6), prior cycles of TAX 6 (6) or 8 (4), sites of metastasis—bone (8), lymph nodes (4), visceral (3). 6 pts have been discontinued due to treatment failure after a mean of 5.3±1.9 cycles (range 3-8) - RECIST (1), symptomatic (2), combined (3). 4 pts are on cycle 1-2-8-9, respectively. TEM has been generally well tolerated without unexpected side-effects, but may have contributed to worsening lymphedema in 1 pt. Conclusions: TEM maintenance therapy in CRPC pts that have responded to first-line TAX is well tolerated and appears to result in meaningful TTF. No significant financial relationships to disclose.

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