Phase I safety and pharmacodynamic of XXXX , a novel VDR agonist with @entity1205 in metastatic castration-resistant @entity263 @entity1 .

@entity1 @entity137 @entity263 @entity7735 @entity2741 @entity3873 @entity229 @entity66287 @entity1205 @entity560
PURPOSE: We conducted a phase I multicenter trial in na  ve metastatic castrate-resistant @entity263 @entity1 with escalating @entity66287 dosages, combined with @entity1205 -based chemotherapy. @entity66287 is a novel @entity560 receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than @entity3873 . EXPERIMENTAL DESIGN: Safety and efficacy were evaluated in groups of three to six @entity1 receiving @entity66287 during a 21-day cycle in combination with @entity1205 (75 mg/m2 every 3 weeks) and oral @entity229 (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting @entity137 (DLT) defined as grade 3 @entity2741 within the first cycle. Efficacy endpoint was >= 30% @entity7735 decline within 3 months. RESULTS: Eight dose levels (40-8,000  g) were evaluated in 54 @entity1 . DLT occurred in two of four @entity1 receiving 8,000  g/day after one and two weeks of @entity66287 . Calcemia normalized a few days after interruption of @entity66287 . Two other @entity1 reached grade 2, and the dose level was reduced to 4,000  g. After dose reduction, calcemia remained within normal range and grade 1 @entity2741 . The maximum tolerated dose was 4,000  g daily. Respectively, 85% and 76% of the @entity1 had >= 30% @entity7735 decline within 3 months and >= 50% @entity7735 decline at any time during the study. Median time to @entity7735 progression was 169 days. CONCLUSION: High antiproliferative daily @entity66287 dose has been safely used in combination with @entity1205 and shows encouraging @entity7735 response (>= 30% @entity7735 response: 85%; >= 50% @entity7735 response: 76%). A randomized phase II study is planned.
