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

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


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Arginine / metabolism*
  • Argininosuccinate Synthase / deficiency*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / pathology
  • Cisplatin / administration & dosage
  • Female
  • Follow-Up Studies
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / pathology
  • Humans
  • Hydrolases / administration & dosage
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / enzymology
  • Neoplasm Recurrence, Local / pathology
  • Pemetrexed / administration & dosage
  • Polyethylene Glycols / administration & dosage
  • Retrospective Studies
  • Tissue Distribution
  • Treatment Outcome


  • Pemetrexed
  • Polyethylene Glycols
  • Arginine
  • Hydrolases
  • ADI PEG20
  • Argininosuccinate Synthase
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT02029690