Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors
Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors
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DOI：
10.1007/s10637-015-0273-z
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发表时间：
2015-10-01
影响因子：
3.4
通讯作者：
Saltz, Leonard
中科院分区：
文献类型：
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作者：
Cercek, Andrea;Wheler, Jennifer;Saltz, Leonard
简介 这项 I 期、多中心、开放标签、单臂、剂量递增研究评估了 APTO-253（转录因子 KLF4 的诱导剂）在成人晚期实体瘤中的安全性、药代动力学和抗肿瘤活性。方法 APTO-253 在每个 28 天周期的第 1 天和第 2 天、第 15 天和第 16 天静脉注射；在 9 个队列中，剂量从 20 mg/m(2) 增加到 387 mg/m(2)，直至观察到 DLT。结果 本试验共有 32 名患者接受治疗（50% 为结肠癌，22% 为其他胃肠道恶性肿瘤，18% 为非小细胞肺癌）。疲劳是发生在 > 10% 患者中的唯一与药物相关的治疗相关不良事件。尽管进行了预防，但剂量限制性毒性（超敏反应和短暂性低血压）在 387 mg/m(2) 时仍发生，因此确定 298 mg/m(2) 为 MTD。只有 1 名患者在 229 mg/m(2) 或以下出现任何与药物相关的治疗相关 3 级不良事件。总共 21 名患者在 2 个周期后接受了至少 1 次重新分期； 11 名患者因不良事件 (9) 或疾病进展 (2) 在第 2 周期结束前停药。最好的总体反应是这 21 例中的 5 例（23.8%）疾病稳定（SD），持续时间从 3.6 到 8.4 个月不等。结论 APTO-253 在 2 期推荐剂量下具有良好的耐受性，并以疾病稳定的形式在晚期实体瘤患者中产生了抗肿瘤活性的证据。根据所达到的药物水平和治疗中出现的不良事件的较低频率，选择 229 mg/m(2) 作为推荐的 2 期剂量。总体而言，APTO-253 具有良好的耐受性并具有良好的药代动力学，21 名晚期实体瘤患者中有 5 名 (24%) 的治疗与病情稳定相关。
Introduction This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. Methods APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. Results Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in > 10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8%) with durations ranging from 3.6 to 8.4 months. Conclusion APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.