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

Abstract

TPS246 Background: TAX chemotherapy is the standard of care for first-line cytotoxic therapy of CRPC. However, a number of questions remain regarding the optimal use of TAX following maximal response. Aside from intermittent TAX chemotherapy, maintenance therapy with well- tolerated cytotoxic or cytostatic agents could be one strategy used to prolong the treatment response and chemotherapy-free interval without significantly compromising quality of life. The mammalian target of rapamycin (mTOR) serine/threonine protein kinase is involved in many aspects of CRPC, and mTOR inhibitors have demonstrated significant anti-prostate cancer activity in preclinical testing. Methods: This nonrandomized, open-label, multicenter phase II trial studies maintenance therapy with the mTOR inhibitor temsirolimus (TEM) in patients that have responded to TAX chemotherapy. Eligible CRPC patients must have received between 6 to 8 cycles of first-line TAX chemotherapy (75 mg/m2 q3weeks plus prednisone 5 mg po bid) with documented treatment response by PSA (>50% decline from baseline) or RECIST criteria. They will be administered weekly TEM (25 mg iv) until treatment failure, i.e., objective (RECIST) or symptomatic disease progression. Assuming an increase in time to treatment failure (the primary endpoint of this trial) from 3 to 6 months by using TEM, a type I error rate of 0.05, a power of 80% and a 15% drop-off rate, 30 patients will be enrolled. Secondary clinical endpoints include safety (NCI-CTCAE v3.0) and quality of life (FACT-P and PPI) assessments, changes in PSA doubling time and time to PSA progression, objective tumor response rate (RECIST) and overall survival. Correlative studies on serum/plasma and peripheral blood mononuclear cell lysates will assess surrogate markers of mTOR inhibition (e.g., phospho-p70S6 kinase), cellular and molecular markers of the postulated antiangiogenic effects of TEM (e.g., circulating endothelial (progenitor) cells, vascular endothelial cell growth factor), and markers of intratumoral hypoxia/pH (e.g., osteopontin, carbonic anhydrase IX, as potential predictive markers of treatment benefit). No significant financial relationships to disclose.