Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers

Abstract

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m², 27 mg/m², or 36 mg/m², together with pemetrexed 500 mg/m² and cisplatin 75 mg/m² which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m² plus three-weekly cisplatin 75 mg/m² and pemetrexed 500 mg/m².

Fig 1

Patient screening and enrollment. ASS1, argininosuccinate synthetase 1; MPM, malignant pleural mesothelioma; NSCLC, non–small-cell lung cancer.

Fig 2

Pharmacodynamics of arginine and citrulline in patients treated with pegylated arginine deiminase combined with pemetrexed and cisplatin. Median serum concentrations of both arginine and citrulline are shown by week of treatment. Error bars shown are ±SEM.

Fig 3

Mean serum levels of anti–ADI-PEG 20 antibodies in all patients by week of treatment with ADI-PEG 20 combined with pemetrexed and cisplatin. Error bars shown are ± SEM. Ab, antibody, ADI-PEG 20, pegylated arginine deiminase.

Fig 4

(A) Sarcomatoid MPM displaying PR and SD responses (cohort 3). (B) Progression-free survival shown for ADIPemCis together with corresponding best tumor response (percentage change compared with baseline) for all patients. Dose cohort of each patient is indicated (1 to 3). ADIPemCis, pegylated arginine deiminase combined with pemetrexed and cisplatin; MPM, malignant pleural mesothelioma; NSCLC, non–small-cell lung cancer; PR, partial response; SD, stable disease (and resolution of pleural effusion).

Fig 4

(A) Sarcomatoid MPM displaying PR and SD responses (cohort 3). (B) Progression-free survival shown for ADIPemCis together with corresponding best tumor response (percentage change compared with baseline) for all patients. Dose cohort of each patient is indicated (1 to 3). ADIPemCis, pegylated arginine deiminase combined with pemetrexed and cisplatin; MPM, malignant pleural mesothelioma; NSCLC, non–small-cell lung cancer; PR, partial response; SD, stable disease (and resolution of pleural effusion).