PAC-1 治疗晚期恶性肿瘤的 I 期研究。
Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies.
机构信息
Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Clinical Trials Office, University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
出版信息
Br J Cancer. 2023 Mar;128(5):783-792. doi: 10.1038/s41416-022-02089-7. Epub 2022 Dec 5.
BACKGROUND
Procaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics.
METHODS
Modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1-21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study.
RESULTS
Forty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1's t was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response.
CONCLUSIONS
PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation.
CLINICAL TRIAL REGISTRATION
Clinical Trials.gov: NCT02355535.
背景
Procaspase-3（PC-3）在多种肿瘤类型中过表达，而 procaspase 激活化合物 1（PAC-1）可直接激活 PC-3，并诱导癌细胞凋亡。本报告描述了 PAC-1 的首次人体、I 期研究，评估了最大耐受剂量、安全性和药代动力学。
方法
采用改良的 Fibonacci 剂量递增 3+3 设计。PAC-1 于 28 天周期的第 1-21 天口服给药，共 7 个剂量水平（DL）。在治疗的前两个周期评估剂量限制性毒性（DLT），并在第一个周期的第 1 和第 21 天进行药代动力学分析。整个研究过程中进行了神经和神经认知功能（NNCF）测试。
结果
共纳入 48 例患者，其中 33 例完成了≥2 个周期的治疗，可评估 DLT。DL 7（750mg/天）被确定为推荐的 II 期剂量，观察到 1 级和 2 级神经不良事件，而 NNCF 测试显示神经和认知评估稳定。PAC-1 多剂量后 t 为 28.5 小时，全身药物暴露达到预期的治疗浓度。在神经内分泌肿瘤（NET）患者中观察到 PAC-1 的临床活性，2/5 例患者获得持久的部分缓解。
结论
推荐 PAC-1 剂量为 750mg/天用于 II 期研究。PAC-1 在治疗抵抗性 NET 中的活性值得进一步研究。
临床试验注册
ClinicalTrials.gov：NCT02355535。
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