A Phase 1A/B Combination Study of Pegargiminase (ADI-PEG 20), Venetoclax and Azacitidine in Patients with Acute Myeloid Leukemia

Background and Significance: Outcomes for adverse-risk acute myeloid leukemia (AML), especially in older and/or unfit patients and those with relapsed/refractory disease, remain poor despite several new drug approvals over the last decade. A promising area for drug development in AML resides in targeting tumor metabolism. The metabolism therapy of pegargiminase (ADI-PEG 20), an agent consisting of the arginine-degrading enzyme arginine deiminase combined with polyethylene glycol, has demonstrated preclinical and clinical efficacy as monotherapy and in combination in AML. ADI-PEG 20 has been shown to be most effective when tumors are deficient in argininosuccinate synthetase (ASS1), the rate limiting step in the urea cycle to form arginine. AML is one such cancer, which appears to be addicted to arginine, with about 90% of AML patient samples being deficient in ASS1 expression. The focus of this phase 1A/B study is to explore combination treatment with ADI-PEG 20 added to standard front-line venetoclax and azacitidine therapy in AML.

Study Design and Methods: This study (NCT05001828) is an open label, single arm, multicenter phase 1 trial for patients with newly diagnosed adverse-risk AML unfit for intensive chemotherapy or relapsed/refractory AML. Eligible patients must be ≥18 years old and are ineligible if determined favorable-risk by European LeukemiaNet (ELN) criteria. The primary objective is to determine the recommended phase 2 dose (RP2D) of ADI-PEG 20 administered by intramuscular injection weekly in combination with venetoclax and azacitidine. Secondary objectives include evaluating preliminary evidence of antitumor activity and determining the pharmacodynamics and immunogenicity of ADI-PEG 20 in combination with venetoclax and azacitidine. Patients receive ADI-PEG 20 via intramuscular injection on day -3 and then weekly along with the combination regimen of azacitidine 75 mg/m ² for 7 days and oral venetoclax on days 1-28 of the first cycle and days 1-21 for subsequent cycles. Subjects may remain on study treatment for a maximum of 24 cycles (96 weeks).

The study is designed with a lead-in group exploring 2 dose levels of ADI-PEG 20 and an RP2D expansion group with 18 subjects each in 2 cohorts: Cohort 1 including previously treated (relapsed/recurrent) or refractory AML and Cohort 2 including untreated AML with high-risk features and ineligible for intensive chemotherapy. In total, 48 to 60 subjects are planned across up to 5 centers in the United States. In the RP2D cohorts, the target response rates for the relapsed/refractory and untreated AML with high-risk features are 25% and 55%, respectively. Safety is assessed by comparing adverse events, laboratory results, and physical examination results. A greater than 20% clinically significant drug-related grade 3 or higher toxicity rate occurring in the first cycle is considered unacceptable. To assess efficacy, the number and percent of subjects' objective response rate, duration of response, and overall survival (OS) will be summarized. Pharmacodynamics using peripheral blood arginine and citrulline levels will be summarized for all subjects by time point for the observed value as well as for the change from baseline value and by duration of arginine depletion and citrulline increase. Immunogenicity, determined by antibodies to ADI-PEG 20, will be summarized for all subjects by time point for the observed value as well as for the change from baseline value. Semiquantitative assessment of ASS1 expression by immunoblots and/or immunohistochemistry or other appropriate means will be summarized descriptively. Demographics, clinical characteristics (including duration of response), and safety data of the patients will be summarized using descriptive statistics. For the efficacy analysis, we will estimate the response rate along with the 95% credible interval. The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate. The distribution of time-to-event endpoints, such as OS and others, will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. The trial is currently enrolling and presents a novel and promising therapeutic strategy for patients with high-risk newly diagnosed and relapsed/refractory AML.