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

Title: A phase I study of pegylated arginine deiminase ( Pegargiminase), cisplatin, and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma
Authors: Hall, PE
Lewis, R
Syed, N
Shaffer, R
Evanson, J
Ellis, S
Williams, M
Feng, X
Johnston, A
Thomson, JA
Harris, FP
Jena, R
Matys, T
Jefferies, S
Smith, K
Wu, B-W
Bomalaski, JS
Crook, T
O'Neill, K
Paraskevopoulos, D
Khadeir, RS
Sheaff, M
Pacey, S
Plowman, PN
Szlosarek, PW
Item Type: Journal Article
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.
Issue Date: 1-May-2019
Date of Acceptance: 12-Feb-2019
URI: http://hdl.handle.net/10044/1/82279
DOI: 10.1158/1078-0432.CCR-18-3729
ISSN: 1078-0432
Publisher: American Association for Cancer Research
Start Page: 2708
End Page: 2716
Journal / Book Title: Clinical Cancer Research
Volume: 25
Issue: 9
Copyright Statement: ©2019 American Association for Cancer Research.
Sponsor/Funder: Brain Tumour Research Campaign
Brain Tumour Research
Barrow Foundation UK
Funder's Grant Number: N/A
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
MALIGNANT PLEURAL MESOTHELIOMA
EXPRESSION
LOMUSTINE
DEPRIVATION
AUTOPHAGY
TUMORS
TRIAL
TEMOZOLOMIDE
COMBINATION
MELANOMA
Adult
Antineoplastic Combined Chemotherapy Protocols
Arginine
Argininosuccinate Synthase
Brain Neoplasms
Cisplatin
Female
Follow-Up Studies
Glioma
Humans
Hydrolases
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Grading
Neoplasm Recurrence, Local
Pemetrexed
Polyethylene Glycols
Retrospective Studies
Tissue Distribution
Treatment Outcome
Humans
Glioma
Brain Neoplasms
Neoplasm Recurrence, Local
Cisplatin
Polyethylene Glycols
Hydrolases
Argininosuccinate Synthase
Arginine
Antineoplastic Combined Chemotherapy Protocols
Treatment Outcome
Retrospective Studies
Follow-Up Studies
Maximum Tolerated Dose
Tissue Distribution
Adult
Middle Aged
Female
Male
Neoplasm Grading
Pemetrexed
Science & Technology
Life Sciences & Biomedicine
Oncology
MALIGNANT PLEURAL MESOTHELIOMA
EXPRESSION
LOMUSTINE
DEPRIVATION
AUTOPHAGY
TUMORS
TRIAL
TEMOZOLOMIDE
COMBINATION
MELANOMA
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-02-22
Appears in Collections:Department of Surgery and Cancer
Department of Brain Sciences