A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies
A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies
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DOI：
10.1007/s00280-018-3635-3
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发表时间：
2018-09-01
影响因子：
3
通讯作者：
Abou-Alfa, Ghassan K.
中科院分区：
文献类型：
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作者：
Harding, James J.;Do, Richard K.;Abou-Alfa, Ghassan K.
精氨酸耗竭干扰了嘧啶代谢和DNA损伤修复途径。临床前数据表明，聚乙二醇化精氨酸脱亚胺酶(ADI-PEG20)与氟嘧啶或铂配对可增强体内和体外对精氨酸缺乏症患者的细胞毒作用。这是一项单中心、开放标记的1期试验，ADI-PEG20和改良的FOLFOX6(MFOLFOX6)治疗难治性肝细胞癌(HCC)和其他晚期胃肠道肿瘤。采用3+3剂量递增设计评估ADI-PEG20的安全性和耐受性，并确定推荐的2期剂量(RP2D)。采用肝癌患者的RP2D扩展队列来确定客观有效率(ORR)。次要目标是估计无进展生存期(PFS)和总生存期(OS)，并探索药效学和免疫原性。符合条件的患者接受标准剂量的mFOLFOX6双周静脉注射和ADI-PEG-20每周肌肉注射，剂量分别为18(队列1)或36 mg/m(2)(队列2和RP2D扩展)。27例患者入选-23例晚期肝癌和4例其他胃肠道肿瘤。在队列1和队列2中没有观察到剂量限制性毒性。使用mFOLFOX6的ADI-PEG20的RP2D为每周36 mg/m(2)。最常见的不良反应是血小板减少、中性粒细胞减少、白细胞减少、贫血和疲劳。在23例肝癌患者中，与治疗相关的AE3级不良反应最常见的是白细胞减少症(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%)。本组ORR为21%(95%可信区间为7.5~43.7)。中位PFS为7.3个月，OS为14.5个月。尽管出现了低水平的抗ADI-PEG20抗体，但精氨酸水平随着治疗而耗尽。4周和8周的精氨酸耗竭和肿瘤组织的精氨酸琥珀酸合成酶-1水平与疗效无关。同时给予mFOLFOX6加ADI-PEG-20每周36 mg/m(2)肌肉注射，与历史对照相比，显示出可接受的安全性和良好的疗效。在晚期肝细胞癌患者中，有必要进一步评估这种联合治疗。
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(2) (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(2) 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 ae 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(2) weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.