Study of ADI-PEG 20, Venetoclax and Azacitidine in Acute Myeloid Leukemia

This is an open label, single arm, phase 1 trial with recommended phase 2 dose (RP2D) cohorts based on subject inclusion criteria.

Lead In: 6 patients will be enrolled to be treated with standard dose of azacitidine and venetoclax and the expected RP2D of ADI-PEG 20 (dose level 0). In case of DLT occurring in >1 patient in cycle 1, 6 additional patients will be accrued at dose level -1 of ADI-PEG 20 while keeping the doses of azacitidine and venetoclax unchanged (Dose level -1). Enrollment to cohort 1 and 2 will start after ≤1 patient out of 6 encounters DLT in cycle 1 at one of these dose levels. The 6 patients enrolled at that dose level will be counted for efficacy analysis. Cohort 1: Relapsed or refractory AML: target response 25%. Historical expectation for venetoclax and azacitidine is 15%.

Cohort 2: Newly diagnosed high risk AML: Target response 55%. Historical expectation for venetoclax and azacitidine is 40%.

Treatment may be continued for a maximum of 24 cycles or 104 doses of ADI-PEG 20 (study Week 103), whichever is reached first.

Inclusion criteria

• Cohort 1: Previously treated (relapsed/recurrent) or refractory AML based on the 2022 revision to the World Health Organization (WHO) criteria (Arber 2022)
• Cohort 2: Untreated AML per 2022 WHO (Arber 2022) criteria with high-risk features and not a candidate for intensive chemotherapy because of age 60 years or older, age-related comorbidities, cardiac disease, prior anthracycline use, high probability of treatment-related mortality, or otherwise would not benefit from intensive chemotherapy treatment.
• Age ≥ 18 years
• Life expectancy reasonably adequate for evaluating the treatment
• White blood cell (WBC) count of 10 × 109/L or less. (Use of hydroxyurea to control WBC is allowed till 48 hours prior to protocol treatment)
• Adequate renal function: Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (measured or calculated according to the Cockcroft-Gault formula)
• Adequate liver function

• Total bilirubin ≤ 1.5 x ULN
• ALT and AST both ≤ 2.5 x institutional ULN or ≤ 5 times the ULN for patients with leukemic involvement of liver

Exclusion criteria

• Prior treatments as follows:

• Cohort 1: >2 cycles of prior combination treatment with venetoclax+hypomethelating agent (i.e. azacitidine, decitabine) is exclusionary. All other prior treatment for antecedent hematological disorders and/or for AML is permitted.
• Cohort 2: Prior treatment for antecedent hematological disorders with venetoclax or chemotherapy or any prior treatment for their AML is exclusionary. However, treatment with other agents, including hydroxyurea or ≤2 cycles of hypomethylating agent (i.e. azacitidine, decitabine), for MDS or myeloproliferative neoplasm is permitted.
• Cohort 2: Favorable risk AML per European LeukemiaNet (ELN) 2022 criteria (Döhner 2022)
• Known active CNS involvement by leukemia