A Phase I study of pegylated arginine deiminase (pegargiminase), cisplatin and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma

Purpose: Patients with recurrent high-grade gliomas (HGGs) are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains very poor. Pre-clinically, 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. Experimental Design: We 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 three weeks for up to six cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pre-treated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being CTCAE 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 four weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% CI 2.5-20.8) and overall survival (OS) was 6.3 months (95% CI 1.8-9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

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