No approved medical therapies prevent progression of low-grade prostate cancer. Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with prostate cancer. Patients with Gleason ≤7 (3+4) disease (low and intermediate risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1, 0.5 mg/week; cohort 2, 1 mg/week; and cohort 3, 0.5 mg/day). Patients were treated for 3 months and followed for an additional 3 months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1, n = 3; cohort 2, n = 3; and cohort 3, n = 8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1–2 adverse events (AE) occurred that resulted in patient withdrawal. All AEs in cohorts 1 and 2 were grade 1. Peak serum rapamycin concentration was 7.1 ng/mL after a 1 mg dose. Stable trough levels (∼2 ng/mL) developed after 48–72 hours. Daily dosing mildly worsened QoL, although QoL recovered after treatment cessation in all categories, except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability. Prevention Relevance: There is an unmet medical need for a well-tolerated treatment capable of delaying progression of newly diagnosed low-grade prostate cancer. This treatment would potentially obviate the need for future surgical intervention and improve the perception of active surveillance as a more acceptable option among this patient population.

中文翻译：

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在积极监测的前列腺癌患者中进行胶囊化雷帕霉素预防进展的 I 期试验

没有批准的药物疗法可以防止低级别前列腺癌的进展。雷帕霉素抑制细胞增殖并增强免疫反应，产生抗肿瘤作用。封装的雷帕霉素 (eRapa) 将雷帕霉素结合到对 pH 敏感的聚合物中，确保剂量一致。在这里，我们展示了一项 I 期试验的结果，该试验评估了 eRapa 在前列腺癌患者中的安全性和耐受性。在主动监测下患有 Gleason ≤7 (3+4) 疾病（低风险和中风险）的患者参加了一项 3+3 研究，该研究有三个 eRapa 给药队列（队列 1，0.5 mg/周；队列 2，1 mg/周；队列 2，1 mg/周；和队列 3，0.5 mg/天）。患者接受了 3 个月的治疗，随后又进行了 3 个月的随访，以评估安全性、药代动力学、生活质量 (QoL)、免疫反应和疾病进展。14 名患者（队列 1，n = 3；队列 2，n = 3；和队列 3，n = 8) 被纳入。在队列 3 中，发生了一种剂量限制性毒性（DLT；中性粒细胞减少）和两种非 DLT 1-2 级不良事件（AE），导致患者退出。队列 1 和 2 中的所有 AE 均为 1 级。1 mg 剂量后的血清雷帕霉素峰值浓度为 7.1 ng/mL。48-72 小时后出现稳定的谷浓度（~2 ng/mL）。每日给药会使生活质量轻度恶化，尽管在所有类别的治疗停止后生活质量都恢复了，但疲劳除外。每周给药增加幼稚 T 细胞群。每日给药增加中央记忆细胞数量和衰竭标志物。未观察到疾病进展。总之，使用 eRapa 治疗是安全且耐受性良好的。每日给药会产生较高频率的低级毒性和 QoL 的短暂恶化，而每周给药会影响免疫反应。未来的研究将验证临床益处和长期耐受性。预防相关性：对于能够延缓新诊断的低级别前列腺癌进展的耐受性良好的治疗存在未满足的医疗需求。这种治疗可能会消除对未来手术干预的需要，并提高对主动监测作为该患者群体中更可接受的选择的看法。