Phase 2 Trial of Weekly Intravenous 1,25 Dihydroxy Cholecalciferol (Calcitriol) in Combination With Dexamethasone for Castration-Resistant Prostate Cancer
Phase 2 Trial of Weekly Intravenous 1,25 Dihydroxy Cholecalciferol (Calcitriol) in Combination With Dexamethasone for Castration-Resistant Prostate Cancer
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DOI：
10.1002/cncr.24973
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发表时间：
2010-05-01
期刊：
影响因子：
6.2
通讯作者：
Trump, Donald L.
中科院分区：
文献类型：
--
作者：
Chadha, Manpreet K.;Tian, Lili;Trump, Donald L.
背景：临床前数据表明骨化三醇和地塞米松之间具有显着的抗肿瘤活性和协同作用。根据这些数据，作者对去势抵抗性前列腺癌 (CRPC) 患者进行了一项 2 期试验，静脉注射 (iv) 骨化三醇每周 74 微克剂量（基于最近的 1 期试验）和地塞米松。方法：采用两阶段 Kepner-Chang 设计。 CRPC 患者在第 1 天和第 2 天每周口服 4 mg 地塞米松，第 2 天每周在地塞米松给药后 4 至 8 小时静脉注射骨化三醇（1 小时内 74 μg）。每周监测一次实验室数据，每 3 个月进行一次肾脏超声检查、计算机断层扫描和骨扫描。使用实体瘤反应评估标准 (RECIST) 和前列腺特异性抗原 (PSA) 反应的标准标准来评估疾病反应。骨化三醇的剂量是根据作者最近的一期试验确定的。结果：在 18 名可评估患者中，15 名患者是白人 (83%)。根据 RECIST 或 PSA 反应标准，没有患者获得完全或部分反应。 14 名患者病情进展，2 名患者拒绝继续治疗（64 天和 266 天后），2 名患者仍在试验中（306 天和 412 天）。疾病进展的中位时间为 106 天（95% 置信区间，80-182 天）。 7 名患者出现 14 次 3 级或 4 级毒性（高血糖、低钙血症、胸痛、呼吸困难、高钙血症、低磷血症、心律失常和疼痛）。只有 1 次 3/4 级毒性发作与骨化三醇（高钙血症）明确相关。没有发现与治疗相关的死亡。结论：每周 74 μg 的高剂量静脉注射骨化三醇与地塞米松联合用药耐受性良好，但未能在患有 CRPC 的男性中产生临床或 PSA 反应。癌症 2010；116：2132-9。 (C) 2010 美国癌症协会
BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 mu g weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 mu g over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days). The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 mu g weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC. Cancer 2010;116:2132-9. (C) 2010 American Cancer Society