HonorHealth Research Institute, Scottsdale, AZ, USA.
Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
Oncologist. 2024 Feb 2;29(2):132-141. doi: 10.1093/oncolo/oyad278.
Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D).
Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity.
Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients.
This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway.
米内利德是雷公藤内酯醇的水溶性前药。雷公藤内酯醇是一种通过多种机制靶向癌症耐药性的抗癌药物。米内利德在晚期胃肠道癌患者中进行了 I 期研究，以确定安全性、药效学、抗肿瘤活性和推荐的 II 期剂量（RP2D）。
符合条件的患者为患有难治性胃肠道癌且 CT 扫描有可测量疾病的患者。该研究采用了 3+3 剂量递增方案。由于中性粒细胞减少毒性，评估了两种给药方案以确定未来研究的 RP2D。使用 RECIST 1.1 和 Choi 标准评估反应。评估了米内利德和雷公藤内酯醇的 PK。没有剂量限制性毒性（DLT）的患者完成了第一个 28 天治疗周期后继续治疗，直到疾病进展或无法接受的毒性。
共纳入 45 例患者（23 例胰腺癌，10 例结直肠癌，其余 9 例为其他胃肠道肿瘤）；42 例患者接受了至少一剂米内利德。69%的患者发生了≥3 级毒性，最常见的是中性粒细胞减少（38%）。2 例小脑毒性严重的患者的雷公藤内酯醇浓度比其他参与者高 2 倍。客观缓解率（ORR）为 4%；疾病控制率（DCR）为 54%（15/28）。Choi 标准显示 57%（16/28）患者的平均肿瘤密度降低。
这是一项在难治性胃肠道癌患者中进行的首次人体 I 期临床研究，确定了米内利德的剂量和方案。主要毒性是血液学毒性。在该组患者中观察到米内利德治疗的疗效证据。14/28（50%）可评估患者的 DCR 范围为~2 至 6 个月。正在进行单药和联合治疗的研究。
