Pegargiminase (ADI-PEG 20), Venetoclax and Azacitidine in Patients with Relapsed/Refractory Acute Myeloid Leukemia
Authors: Ragon Brittany Knick , Watts Justin M. , Bomalaski John , Johnston Amanda , Langlois Mirla , Chang Nicole DeFord , Borthakur Gautam 
Published: December 2024

Background: Outcomes for relapsed/refractory (R/R) acute myeloid leukemia (AML), especially in older and/or unfit patients (pts) remain poor despite progress in new drug approvals. Targeting tumor metabolism is a promising area for drug development. Pegargiminase (ADI-PEG 20), a metabolism therapeutic 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. Efficacy is most notable in tumors deficient in argininosuccinate synthetase (ASS1), the rate limiting step in the urea cycle to form arginine. AML has been shown to be addicted to arginine, with approximately 90% of AML patient samples deficient in ASS1 expression. We conducted a phase 1A/B trial to evaluate combination treatment with ADI-PEG 20 added to standard front-line azacitidine and venetoclax (AZA-VEN) therapy in AML.
Methods: This study was an open label, single arm, multicenter phase 1 trial for pts with R/R AML. Eligible pts were ≥18 years old with adequate organ function. Prior treatment with &gt;2 cycles of hypomethylating agent (HMA) with VEN was exclusionary. Pts received ADI-PEG 20 via intramuscular injection (dose level 0 was 36 mg/m2 with possible de-escalation to 27 mg/m2) on day -3 and then weekly along with AZA 75 mg/m2 for 7 days and oral VEN on days 1-28 of the first cycle and days 1-21 for subsequent cycles. Subjects could remain on study treatment up to 24 cycles (96 weeks). Primary study objective was to determine the recommended phase 2 dose (RP2D) of ADI-PEG 20 combined with AZA-VEN. Secondary objectives included assessment of efficacy, preliminary evidence of antitumor activity, and pharmacodynamics of ADI-PEG 20. To assess efficacy, the number and percent of subjects' objective response rate and overall survival (OS) were summarized. A minimum of 1 full course of triplet therapy was required for a subject to be evaluable for efficacy. Demographics, clinical characteristics, and safety data were summarized using descriptive statistics.
Results: Beginning 5/2022 to data cut off 7/2024, 13 pts were enrolled. Though study was closed early, no DLT was observed during the lead-in portion, and 36 mg/m2 was determined as the RP2D of ADI-PEG 20. Median age was 61 years, and 53.9% were female. Race was reported as White (N=12) and other (N=1), and ethnicity was reported as Hispanic or Latino (N=1) and Not Hispanic or Latino (N=12). Median time from initial AML diagnosis was 7 months. Forty-six percent of pts received 1 prior line of systemic therapy with remaining pts receiving between 2 to 5 prior lines of treatment. Prior VEN exposure was noted in 9 pts, with 6 of those having received HMA-VEN. Prior stem cell transplant was documented in 38.5% of pts. Cytogenetics were abnormal in 12 pts (1 unknown) and reported as poor/adverse in 6 pts (N=6 reported as other). TP53 mutation was identified in 5 pts. In the evaluable pts (N=11), objective overall response rate (CR+CRi+CRh) was 36.4% (95% CI 10.9%-69.2%). Responses were classified as CR 9.1%, CRi 27.3%, MLFS 18.2%, and no response 45.4%, with overall response rate including MLFS of 54.6% (95% CI 23.4%-83.3%). t(3q26) was observed in 2 pts, with best response of CR and CRi within 2 cycles. Of evaluable pts, TP53 mutation was identified in 4 pts, with best response in 2 cycles of CR (N=1), CRi (N=1), and no response (N=2). Additionally, a non-evaluable pt with post-transplant relapsed TP53-mutated AML achieved MLFS and eventual CR following 1 cycle of AZA-VEN with 3 doses of ADI-PEG (2 doses short of being evaluable). Median time to first response was 0.9 months (range, 0.8 to 1.1). Median OS for all enrolled subjects was 5.6 months with 3 pts still in follow-up and alive. Pharmacodynamic results show an expected decline in plasma levels of arginine and increase in citrulline.
Conclusions: ADI-PEG 20 with AZA-VEN in R/R and heavily pre-treated AML led to promising response rates. The regimen was well tolerated and demonstrated preliminary efficacy in notably adverse risk pts, including those with t(3q26) or mutations in TP53. With limited treatment options in these poor risk pts, inclusion of the novel metabolism therapeutic, ADI-PEG 20, may serve as a promising therapeutic strategy in select adverse risk groups. With these results in mind, we anticipate upcoming results of our ongoing trial cohort of ADI-PEG 20 with AZA-VEN in the frontline setting for pts with adverse risk AML.