Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia

Hui-Jen Tsai, Hui-Hua Hsiao, Ya-Ting Hsu, Yi-Chang Liu, Hsiao-Wen Kao, Ta-Chih Liu, Shih-Feng Cho, Xiaoxing Feng, Amanda Johnston, John S Bomalaski, Ming-Chung Kuo, Tsai-Yun Chen, Hui-Jen Tsai, Hui-Hua Hsiao, Ya-Ting Hsu, Yi-Chang Liu, Hsiao-Wen Kao, Ta-Chih Liu, Shih-Feng Cho, Xiaoxing Feng, Amanda Johnston, John S Bomalaski, Ming-Chung Kuo, Tsai-Yun Chen

Abstract

Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase-deficient. Pegylated arginine deiminase (ADI-PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI-PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor-risk AML patients. We conducted a phase I, dose-escalation study combining ADI-PEG20 and low-dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI-PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI-PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty-three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose-limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI-PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5-not reached) months. In seven treatment-naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI-PEG20 and LDC combination was well-tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI-PEG20 Plus Low-Dose Cytarabine in Older Patients With AML, NCT02875093).

Keywords: acute myeloid leukemia; arginine deprivation; low-dose cytarabine; pegylated arginine deiminase (ADI-PEG20); phase I.

Conflict of interest statement

This trial was sponsored by the Polaris Group. All authors declared no financial conflicts of interest, except for those who are Polaris Group employees Xiaoxing Feng, Amanda Johnston, and John S. Bomalaski are employees of the Polaris Group.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Flow diagram of the enrollment of patients in this study
FIGURE 2
FIGURE 2
Overall survival of the patients. (A) Intention‐to‐treat population (N = 23). (B) Evaluable population (N = 18)
FIGURE 3
FIGURE 3
Dynamic changes in arginine, citrulline, and anti‐ADI‐PEG20 antibody levels in the intention‐to‐treat patients. (A) Dynamic change in circulating arginine and citrulline levels. (B) Dynamic change in circulating arginine and anti‐ADI‐PEG20 antibody levels

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