| Autor: |
Peter W. Szlosarek, Piers N. Plowman, Simon Pacey, Michael Sheaff, Ramsay S. Khadeir, Dimitris Paraskevopoulos, Kevin O'Neill, Timothy Crook, John S. Bomalaski, Bor-Wen Wu, Kate Smith, Sarah Jefferies, Tomasz Matys, Raj Jena, Fiona P. Harris, Jim A. Thomson, Amanda Johnston, Xiaoxing Feng, Matthew Williams, Stephen Ellis, Jane Evanson, Richard Shaffer, Nelofer Syed, Rachel Lewis, Peter E. Hall |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6528723.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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