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Clinical Lung Cancer Nov 2020Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with...
BACKGROUND
Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC).
PATIENTS AND METHODS
Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m (36.8 mg/m), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity.
RESULTS
Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations.
CONCLUSION
Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.
Topics: Aged; Aged, 80 and over; Arginine; Case-Control Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Hydrolases; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Non-Randomized Controlled Trials as Topic; Polyethylene Glycols; Prognosis; Retrospective Studies; Salvage Therapy; Small Cell Lung Carcinoma
PubMed: 32859536
DOI: 10.1016/j.cllc.2020.07.012 -
Clinical Cancer Research : An Official... May 2019Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we...
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 () and/or argininosuccinate lyase (). 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/m intramuscularly plus pemetrexed 500 mg/m and cisplatin 75 mg/m 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.
Topics: 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
PubMed: 30796035
DOI: 10.1158/1078-0432.CCR-18-3729