TY - JOUR
T1 - Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies
AU - Yao, Shuyang
AU - Janku, Filip
AU - Subbiah, Vivek
AU - Stewart, John
AU - Patel, Sapna Pradyuman
AU - Kaseb, Ahmed
AU - Westin, Shannon Neville
AU - Naing, Aung
AU - Tsimberidou, Apostolia Maria
AU - Hong, David
AU - Piha-Paul, Sarina Anne
AU - Shi, Nai
AU - Johnston, Amanda
AU - Bomalaski, John
AU - Fu, Siqing
N1 - Funding Information:
Funding information The trial was funded by Polaris Pharmaceuticals, Inc. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA016672. S.V.W. is supported by a NIH 1P50CA217685–01 SPORE in Ovarian Cancer and a GOG Foundation Scholar Investigator Award.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2021/4/27
Y1 - 2021/4/27
N2 - Background: 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. Methods: 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. Results: 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). Conclusion: 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.
AB - Background: 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. Methods: 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. Results: 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). Conclusion: 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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U2 - 10.1038/s41416-020-01230-8
DO - 10.1038/s41416-020-01230-8
M3 - Article
C2 - 33674736
AN - SCOPUS:85102041635
SN - 0007-0920
VL - 124
SP - 1533
EP - 1539
JO - British journal of cancer
JF - British journal of cancer
IS - 9
ER -