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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
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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. pdf.pdf | Accepted version | 3.26 MB | Adobe PDF | View/Open |
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 |