ADI-PEG 20 联合改良 FOLFOX6 方案治疗晚期肝细胞癌及其他胃肠道恶性肿瘤的Ⅰ期临床研究
A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.
机构信息
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Medical College, New York, NY, USA.
出版信息
Cancer Chemother Pharmacol. 2018 Sep;82(3):429-440. doi: 10.1007/s00280-018-3635-3. Epub 2018 Jul 3.
PURPOSE
Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.
METHODS
This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m (Cohort 2 and RP2D expansion).
RESULTS
Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response.
CONCLUSIONS
Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.
目的
精氨酸耗竭会干扰嘧啶代谢和 DNA 损伤修复途径。临床前数据表明，将聚乙二醇化精氨酸脱亚氨酶（ADI-PEG20）与氟嘧啶或铂类药物联合使用，可增强精氨酸营养缺陷型体外和体内的细胞毒性。
方法
这是一项单中心、开放标签、I 期临床试验，旨在评估 ADI-PEG20 联合改良 FOLFOX6（mFOLFOX6）治疗复发性肝细胞癌（HCC）和其他晚期胃肠道肿瘤的安全性、耐受性，并确定 ADI-PEG20 的推荐 II 期剂量（RP2D）。采用 3+3 剂量递增设计来评估安全性、耐受性，并确定 ADI-PEG20 的 II 期推荐剂量（RP2D）。对 HCC 患者进行了 RP2D 扩展队列研究，以确定客观缓解率（ORR）。次要目标是估计无进展生存期（PFS）、总生存期（OS），并探讨药效学和免疫原性。符合条件的患者接受标准剂量的 mFOLFOX6 静脉内每 2 周 1 次和 ADI-PEG-20 肌肉内每周 1 次 18（队列 1）或 36mg/m（队列 2 和 RP2D 扩展）。
结果
共入组 27 例患者，其中 23 例为晚期 HCC 患者，4 例为其他胃肠道肿瘤患者。在队列 1 或 2 中均未观察到剂量限制毒性。ADI-PEG20 的 RP2D 为每周 36mg/m 联合 mFOLFOX6。最常见的任何级别不良事件（AE）为血小板减少症、中性粒细胞减少症、白细胞减少症、贫血和疲劳。在 23 例 HCC 患者中，最常见的治疗相关≥3 级 AE 为中性粒细胞减少症（47.8%）、血小板减少症（34.7%）、白细胞减少症（21.7%）、贫血（21.7%）和淋巴细胞减少症（17.4%）。该组的客观缓解率为 21%（95%CI7.5-43.7）。中位 PFS 和 OS 分别为 7.3 个月和 14.5 个月。尽管出现了低水平的抗 ADI-PEG20 抗体，但治疗后精氨酸水平仍被耗尽。4 周和 8 周时的精氨酸耗竭以及存档的肿瘤精氨酸合成酶-1 水平与反应无相关性。
结论
与历史对照相比，每周 36mg/m 联合 mFOLFOX6 肌肉内应用 ADI-PEG-20 的安全性和疗效均令人满意。在晚期 HCC 患者中进一步评估该联合方案是合理的。
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