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@article{Hall:2019:10.1158/1078-0432.CCR-18-3729,
author = {Hall, PE and Lewis, R and Syed, N and Shaffer, R and Evanson, J and Ellis, S and Williams, M and Feng, X and Johnston, A and Thomson, JA and Harris, FP and Jena, R and Matys, T and Jefferies, S and Smith, K and Wu, B-W and Bomalaski, JS and Crook, T and O'Neill, K and Paraskevopoulos, D and Khadeir, RS and Sheaff, M and Pacey, S and Plowman, PN and Szlosarek, PW},
doi = {10.1158/1078-0432.CCR-18-3729},
journal = {Clinical Cancer Research},
pages = {2708--2716},
title = {A phase I study of pegylated arginine deiminase ( Pegargiminase), cisplatin, and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-18-3729},
volume = {25},
year = {2019}
}

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TY  - JOUR
AB  - 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.
AU  - Hall,PE
AU  - Lewis,R
AU  - Syed,N
AU  - Shaffer,R
AU  - Evanson,J
AU  - Ellis,S
AU  - Williams,M
AU  - Feng,X
AU  - Johnston,A
AU  - Thomson,JA
AU  - Harris,FP
AU  - Jena,R
AU  - Matys,T
AU  - Jefferies,S
AU  - Smith,K
AU  - Wu,B-W
AU  - Bomalaski,JS
AU  - Crook,T
AU  - O'Neill,K
AU  - Paraskevopoulos,D
AU  - Khadeir,RS
AU  - Sheaff,M
AU  - Pacey,S
AU  - Plowman,PN
AU  - Szlosarek,PW
DO  - 10.1158/1078-0432.CCR-18-3729
EP  - 2716
PY  - 2019///
SN  - 1078-0432
SP  - 2708
TI  - A phase I study of pegylated arginine deiminase ( Pegargiminase), cisplatin, and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma
T2  - Clinical Cancer Research
UR  - http://dx.doi.org/10.1158/1078-0432.CCR-18-3729
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000466767900006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://clincancerres.aacrjournals.org/content/25/9/2708
UR  - http://hdl.handle.net/10044/1/82279
VL  - 25
ER  -

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