Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Paris Descartes University, Paris, France.
Groupe Hospital St. Joseph, Paris, France.
Clin Cancer Res. 2014 Sep 1;20(17):4471-7. doi: 10.1158/1078-0432.CCR-13-3247. Epub 2014 Jul 10.
We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol.
Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months.
Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days.
High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.
我们在初治转移性去势抵抗性前列腺癌患者中进行了一项 I 期多中心试验，这些患者接受递增剂量的伊奈钙醇，联合基于多西他赛的化疗。伊奈钙醇是一种新型维生素 D 受体激动剂，与骨化三醇相比，具有更高的抗增殖作用和 100 倍更低的高钙血症活性。
在 21 天的周期内，6 组患者（每组 3-6 人）接受伊奈钙醇联合多西他赛（每 3 周 75mg/m2）和口服泼尼松（5mg，每日两次）治疗，最多 6 个周期。主要终点是定义为第 1 周期内 3 级高钙血症的剂量限制毒性（DLT）。疗效终点是 3 个月内 PSA 下降≥30%。
在 54 名患者中评估了 8 个剂量水平（40-8000μg）。4 名接受 8000μg/天剂量的患者中有 2 名在伊奈钙醇治疗 1 周和 2 周后出现 DLT。中断伊奈钙醇治疗几天后血钙恢复正常。另外 2 名患者达到 2 级，剂量水平降低至 4000μg。降低剂量后，血钙仍在正常范围内，出现 1 级高钙血症。最大耐受剂量为每天 4000μg。分别有 85%和 76%的患者在 3 个月内 PSA 下降≥30%，在研究期间任何时候 PSA 下降≥50%。PSA 进展中位时间为 169 天。
高抗增殖的伊奈钙醇日剂量与多西他赛联合使用是安全的，并显示出令人鼓舞的 PSA 反应（PSA 反应≥30%：85%；PSA 反应≥50%：76%）。计划进行一项随机 II 期研究。
