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

Our plain-English summary of Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers, by E. Beddowes, J. Spicer, P.Y. Chan, et al (Journal of Clinical Oncology, 2017).

The study

• Authors: E. Beddowes, J. Spicer, P.Y. Chan, R. Khadeir, J.G. Corbacho, D. Repana, J.P. Steele, P. Schmid, T. Szyszko, G. Cook, M. Diaz, X. Feng, A. Johnston, J. Thomson, M. Sheaff, B.W. Wu, J. Bomalaski, S. Pacey, P.W. Szlosarek
• Journal: Journal of Clinical Oncology
• Published: 2017;35(16):1778-1785
• Cited by: 98 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This multicenter, open-label, phase 1 dose-escalation trial tested pegylated arginine deiminase (ADI-PEG 20) with the chemotherapy drugs cisplatin and pemetrexed. Patients' tumors had to show absent or weak staining for an enzyme called ASS1 in more than 50% of tumor cells. Of 38 patients screened, 17 had ASS1-negative tumors and nine were treated. Five had malignant pleural mesothelioma (one epithelioid, two biphasic, two sarcomatoid) and four had non-small-cell lung cancer. Three patients each received weekly ADI-PEG 20 at 18, 27 or 36 mg/m2. No dose-limiting toxicities were reported. Nine of 38 reported side effects were related to ADI-PEG 20, and all of those were grade 1 or 2. Blood arginine stayed at about 30% of baseline levels over 18 weeks. Seven of nine patients (78%; 95% confidence interval 39% to 97%) had a partial response, including two with biphasic and one with sarcomatoid mesothelioma. Median overall survival was 56.4 weeks for the mesothelioma patients. The authors noted the small number of patients. They recommended the 36 mg/m2 dose combined with cisplatin and pemetrexed for further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicenter, open-label, phase 1 dose-escalation clinical trial (3 + 3 + 3 design)
• Who was studied: Nine chemotherapy-naive adults whose tumors were ASS1-deficient, meaning absent (0) or weak (1+) ASS1 staining in more than 50% of tumor cells. Five had malignant pleural mesothelioma (one epithelioid, two biphasic, two sarcomatoid) and four had non-small-cell lung cancer (adenocarcinoma). They were selected from 38 patients screened, of whom 17 were ASS1-negative. Ages were 62 to 77; six were male and three female. The trial was approved by a UK (Leeds East) ethics board. The article does not give the study dates.
• Exposure: This is a drug treatment study and does not examine asbestos exposure. Patients received weekly intramuscular ADI-PEG 20 at 18, 27 or 36 mg/m2. They also received intravenous cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks, for up to six cycles. Patients with stable disease or better could continue ADI-PEG 20 alone.
• Main results:
  • There were no dose-limiting toxicities and no treatment-related deaths among the nine patients.
  • Of 38 reported adverse events, nine (all grade 1 or 2) were related to ADI-PEG 20.
  • Grade 3 neutropenia (a low white blood cell count) occurred in one of nine patients (11%).
  • In all patients, blood arginine fell quickly and stayed at about 30% of baseline throughout the 18 weeks of three-drug therapy.
  • Seven of nine patients (78%) had a partial response, seen at all dose levels (overall response rate 0.78; 95% CI, 0.39 to 0.97).
  • Two patients with biphasic mesothelioma and one with sarcomatoid mesothelioma had a partial response.
  • Among all nine patients, median overall survival was 55.7 weeks and median progression-free survival was 30.1 weeks.
  • Among the mesothelioma patients, median overall survival was 56.4 weeks and median progression-free survival was 30.7 weeks (range, 27.9 to 38.0 weeks).
  • Among the non-small-cell lung cancer patients, median overall survival was 55.5 weeks (range, 25.7 to 56.7 weeks). Median progression-free survival was 23.0 weeks (range, 12.7 to 41.0 weeks).
• The authors' conclusion: The authors concluded that the three-drug combination was well tolerated, achieved high response rates in this small trial, and warrants further study. They recommended a phase 2 dose of weekly ADI-PEG 20 at 36 mg/m2, plus cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every three weeks.
• Limitations the authors state:
  • The small sample size caused variability in the blood arginine and citrulline measurements.
  • With so few patients, no clear relationship between ADI-PEG 20 dose and side effects could be seen.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pemetrexed (Alimta), Pleural Mesothelioma, Lung Cancer, Chemotherapy, Disease Progression, Modified RECIST (mRECIST), Sarcomatoid.

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