Memorial Sloan Kettering Cancer Center, New York, New York.
Weill Cornell Medical College, New York, New York.
Cancer. 2017 Dec 1;123(23):4556-4565. doi: 10.1002/cncr.30897. Epub 2017 Aug 18.
ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1.
A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m ) and nab-paclitaxel (125 mg/m ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m weekly (cohort 1) or at 36 mg/m weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine.
Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached).
ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. © 2017 American Cancer Society.
ADI-PEG20 是一种精氨酸脱氨酶的聚乙二醇化形式。正常细胞利用酶精氨酸合成酶（ASS1）合成精氨酸；ADI-PEG20 选择性地针对缺乏 ASS1 的恶性细胞。
一项单臂、非随机、开放性、1/1B 期、标准 3+3 剂量递增，在推荐的 2 期剂量（RP2D）下扩展了 9 例患者的队列。纳入转移性胰腺癌患者，最多接受过 1 线治疗（剂量递增队列）或未接受过治疗（扩展队列），东部合作肿瘤学组的表现状态为 0 至 1。患者每 4 周接受 3 次 gemcitabine（1000mg/m2）和 nab-paclitaxel（125mg/m2），每周肌肉注射 ADI-PEG20 18mg/m2（队列 1）或 36mg/m2（队列 2 和扩展队列）。主要终点是确定 ADI-PEG20 联合 nab-paclitaxel 和 gemcitabine 的最大耐受剂量和 RP2D。
共纳入 18 例患者。队列 1 中未观察到剂量限制毒性（DLTs）；由于 1 例 DLT（胆红素、天冬氨酸转氨酶和丙氨酸转氨酶的 3 级升高）的发生，队列 2 扩展至 6 例患者。任何级别最常见的不良反应（AE）为中性粒细胞减少症、血小板减少症、白细胞减少症、贫血、周围神经病和疲劳；所有 18 例患者均发生 3/4 级 AE。无论与任何药物的关系如何，最常见的 3/4 级毒性包括中性粒细胞减少症（12 例患者或 67%）、白细胞减少症（10 例患者或 56%）、贫血症（8 例患者或 44%）和淋巴细胞减少症（6 例患者或 33%）。ADI-PEG20 的 RP2D 为每周 36mg/m2，联合标准剂量 gemcitabine 和 nab-paclitaxel。在一线治疗中，按 RP2D 治疗的患者的总缓解率为 45.5%（11 例患者中的 5 例）。这些患者的中位无进展生存期为 6.1 个月（95%置信区间，5.3-11.2 个月），中位总生存期为 11.3 个月（95%置信区间，6.7 个月至未达到）。
ADI-PEG20 与 gemcitabine 和 nab-paclitaxel 联合使用具有良好的耐受性。在先前接受过治疗和未接受过治疗的晚期胰腺癌患者以及 ASS1 缺乏和丰富的肿瘤患者中观察到了活性。癌症 2017；123:4556-4565。©2017 年美国癌症协会。
