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Clin Cancer Res. 2019 May 1;25(9):2708-2716. doi: 10.1158/1078-0432.CCR-18-3729. Epub 2019 Feb 22.

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma.

Author information

1
Department of Oncology, Barts Health NHS Trust, London, United Kingdom.
2
Department of Medicine, Imperial College, London, United Kingdom.
3
St. Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, United Kingdom.
4
Department of Radiology, Barts Health NHS Trust, London, United Kingdom.
5
Department of Oncology, Imperial College Healthcare NHS Trust, London, United Kingdom.
6
Polaris Pharmaceuticals Inc., San Diego, California.
7
Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
8
Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
9
Department of Radiology, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
10
Department of Neurosurgery, Imperial College Healthcare NHS Trust, London, United Kingdom.
11
Department of Neurosurgery, Barts Health NHS Trust, London, United Kingdom.
12
Centre for Molecular Oncology, Queen Mary University of London, London, United Kingdom.
13
Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
14
Department of Oncology, Barts Health NHS Trust, London, United Kingdom. p.w.szlosarek@qmul.ac.uk.

Abstract

PURPOSE:

Patients 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 METHODS:

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 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.

RESULTS:

Ten 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).

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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