Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Medical College, New York, NY, USA.
Cancer Chemother Pharmacol. 2018 Sep;82(3):429-440. doi: 10.1007/s00280-018-3635-3. Epub 2018 Jul 3.
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.
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).
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.
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.
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。
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）。
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。
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。
