• Peter E Hall, Rachel Lewis, Nelofer Syed, Richard Shaffer, Jane Evanson, Stephen Ellis, Matthew Williams, Xiaoxing Feng, Amanda Johnston, Jim A Thomson, Fiona P Harris, Raj Jena, Tomasz Matys, Sarah Jefferies, Kate Smith, Bor-Wen Wu, John S Bomalaski, Timothy Crook, Kevin O'Neill, Dimitris Paraskevopoulos, Ramsay S Khadeir, Michael Sheaff, Simon Pacey, Piers N Plowman, and Peter W Szlosarek.
• Department of Oncology, Barts Health NHS Trust, London, United Kingdom.
• Clin Cancer Res. 2019 May 1; 25 (9): 2708-2716.

PurposePatients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.Patients And MethodsWe expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.ResultsTen ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7).ConclusionsIn this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.©2019 American Association for Cancer Research.

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