Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies.
Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies.
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DOI：
10.1038/s41416-020-01230-8
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发表时间：
2021-04
影响因子：
8.8
通讯作者：
Fu S
中科院分区：
文献类型：
--
作者：
Yao S;Janku F;Subbiah V;Stewart J;Patel SP;Kaseb A;Westin SN;Naing A;Tsimberidou AM;Hong D;Piha-Paul SA;Shi N;Johnston A;Bomalaski J;Fu S
精氨酸耗尽干扰嘧啶代谢和DNA损伤修复途径，并与20，000分子量聚乙二醇（ADI-PEG 20）与铂配对精氨酸脱亚胺酶增强精氨酸营养缺陷型体外和体内细胞毒性。这项单中心I期试验采用3 + 3剂量递增进行，旨在评估安全性、耐受性并确定ADI-PEG 20的推荐II期剂量（RP 2D）。我们招募了99例转移性乙酰氨基琥珀酸合成酶1（ASS 1）缺陷型恶性肿瘤患者。我们没有观察到剂量限制性毒性作用或治疗相关死亡率。3%的患者因毒性而停止治疗。治疗后，5%（5/99）的患者部分缓解，41%的患者病情稳定。中位无进展生存期和总生存期分别为3.62和8.06个月。大部分患者的精氨酸消耗和瓜氨酸升高分别持续至第24周和第8周。肿瘤应答与第8周和第16周的抗ADI-PEG 20抗体水平相关（分别为p = 0.031和p = 0.0357）。同时给予ADI-PEG 20和顺铂具有可接受的安全性特征，并显示出对转移性ASS 1缺陷型实体瘤的抗肿瘤活性。需要对这种治疗组合进行进一步评价。
Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20. We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively). Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.
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影响因子：
8
作者：
Patil MD;Bhaumik J;Babykutty S;Banerjee UC;Fukumura D
通讯作者：
Fukumura D
DOI：
10.1073/pnas.1404171111
发表时间：
2014-09-30
影响因子：
11.1
作者：
Changou, Chun A.;Chen, Yun-Ru;Kung, Hsing-Jien
通讯作者：
Kung, Hsing-Jien
影响因子：
45.3
作者：
Ascierto, PA;Scala, S;Logan, TF
通讯作者：
Logan, TF
影响因子：
3
作者：
Harding, James J.;Do, Richard K.;Abou-Alfa, Ghassan K.
通讯作者：
Abou-Alfa, Ghassan K.
影响因子：
3.8
作者：
McAlpine JA;Lu HT;Wu KC;Knowles SK;Thomson JA
通讯作者：
Thomson JA