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A PHASE I EXPANSION STUDY OF PEGARGIMINASE, CISPLATIN AND PEMETREXED IN ARGININOSUCCINATE SYNTHETASE 1-NEGATIVE RECURRENT HIGH GRADE GLIOMAS (HGGS)

ABSTRACT: Abstract BACKGROUND Patients (pts) with recurrent HGGs are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains poor with an overall survival (OS) of 7–9 months. Preclinically, we showed that HGGs are a target for arginine depletion with Pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-ve HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. METHODS We expanded a phase 1 trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS), which noted activity in aggressive thoracic cancers, to pts with relapsed HGGs (clinicaltrials.gov NCT02029690). Pts with ASS1-ve recurrent HGGs were enrolled (01/16 – 06/17) to receive ADI-PEG20 weekly at the maximum tolerated dose of 36 mg/m2 i.m. plus PEM 500 mg/m2 and CIS 75 mg/m2 i.v. every 3 weeks for up to 6 cycles. Pts with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of activity. Additional endpoints included pharmacodynamics, immunogenicity, OS, and ASS1/ASL epimutations. RESULTS 10/19 ASS1-ve heavily pre-treated pts were enrolled onto ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events (AEs) being CTCAE v4.03 grade 1–2; 7 pts (70%) had at least one grade 3 or 4 AE with neutropenia (40%) and thrombocytopenia (30%). The best response was stable disease by RECIST 1.1 and partial response (n=1; 10%) by RANO criteria. The median (95% CI) OS was 6.5 (1.8, 9.7) months. Two pts are alive and one continues 16 months on ADI-PEG20 as 3rd-line therapy for a de novo IDH-wildtype glioblastoma multiforme. Epimutations in ASS1 and/or ASL were detectable in pts’ tumours consistent with prior studies. CONCLUSIONS ADIPEMCIS was well tolerated and compares favourably to historical controls in recurrent HGG. A randomised, phase II trial comparing ADIPEMCIS with alkylating drugs at first relapse is planned (ATOMIC-G).

SUBMITTER: Hall P

PROVIDER: S-EPMC6168855 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:IntroductionPegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) cytotoxicity in argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore the mechanisms of resistance.MethodsA total of 32 patients with ASS1-deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and cisplatin (75 mg/m2) intravenously, every 3 weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore the mechanisms of resistance to pegargiminase.ResultsThe treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%-99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%-54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0-6.0) and 10.1 (95% CI: 6.1-11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; p = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1-an ADI-PEG 20 inducible gene-and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5).ConclusionsThe dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

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A PHASE I EXPANSION STUDY OF PEGARGIMINASE, CISPLATIN AND PEMETREXED IN ARGININOSUCCINATE SYNTHETASE 1-NEGATIVE RECURRENT HIGH GRADE GLIOMAS (HGGS)

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