A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.
A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.
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DOI：
10.1002/pros.23024
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发表时间：
2015-10
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影响因子：
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通讯作者：
Carducci MA
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作者：
Paller CJ;Rudek MA;Zhou XC;Wagner WD;Hudson TS;Anders N;Hammers HJ;Dowling D;King S;Antonarakis ES;Drake CG;Eisenberger MA;Denmeade SR;Rosner GL;Carducci MA
正在探索新疗法作为希望推迟雄激素剥夺治疗的生化复发性前列腺癌 (BRPC) 男性的治疗选择。 MPX 是磨碎的圆叶葡萄 (Vitis rotifundolia) 皮，含有鞣花酸、槲皮素和白藜芦醇，在体外表现出对抗前列腺癌细胞的临床前活性。在这项 I/II 期研究的 I 期部分中，非转移性 BRPC 患者被分配到 2 名患者的队列中增加 MPX 剂量（Muscadine Naturals Inc., Clemmons, NC），其中 6 名患者接受最高剂量，使用改良的连续重新评估方法。初始剂量选择基于临床前数据，显示相当于 500 至 4,000 毫克 MPX 在小鼠模型中是安全的。主要终点是推荐的 II 期给药方案。该队列（n=14，71% 白种人，29% 黑人）的中位随访时间为 19.2 (6.2 – 29.7) 个月，中位年龄 61 岁，格里森中位值为 7。4 名患者可能有相关胃肠道症状，包括 1 级胀气、1 级软便和 1 级嗳气。没有报告其他相关不良事件，一名患者报告慢性便秘有所改善。 14 名患者中的 6 名在中位暴露 15 个月后退出了疾病进展研究（5 名转移，1 名 PSA 上升）。一名患者因与治疗无关的重症肌无力而出院。七名患者仍在研究中。由于缺乏剂量限制性毒性，因此选择 4000 mg/d 作为进一步研究的最高剂量。患者内 PSADT 中位数增加了 5.3 个月（不显着，p = 0.17）。没有患者的血清 PSA 较基线持续下降。这些数据表明 4000 mg MPX 是安全的，对 PSADT 延长中位数 5.3 个月的探索性审查支持对 MPX 的进一步探索。低剂量（500 毫克）和高剂量（4,000 毫克）MPX 正在一项随机、多中心、安慰剂对照、剂量评估 II 期试验中进行进一步研究。
New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotifundolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. In the phase I portion of this phase I/II study non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals Inc., Clemmons, NC) in cohorts of 2 patients, with 6 patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary end point was the recommended phase II dosing regimen. The cohort (n=14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2 – 29.7) months, median age 61 years, and median Gleason of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (5 metastatic, 1 rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose limiting toxicities led to the selection of 4000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, p = 0.17). No patients experienced a maintained decline in serum PSA from baseline. These data suggest that 4000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low dose (500 mg) and high dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose evaluating phase II trial.