High-dose Ascorbate (HDA) in Combination With Azacitidine and Venetoclax (Aza/Ven) in Newly Diagnosed Acute Myeloid Leukemia (AML)
This is a randomized, open-label, Phase I clinical study with expansion. It will assess the safety and efficacy of high-dose ascorbate administered concomitantly with azacitidine and venetoclax in newly diagnosed AML.
• Adults aged ≥ 18 who are deemed unfit for intensive chemotherapy by meeting at least one of the following criteria:
‣ age ≥ 75
⁃ Eastern Cooperative Oncology Group (ECOG) performance of 2-3
⁃ Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)
⁃ Severe pulmonary disorder (e.g., DLCO ≤ 65% or FEV1 ≤ 65%)
⁃ Calculated Creatinine clearance 25 - 45 mL/min using the Cockcroft-Gault formula
⁃ Hepatic disorder with total bilirubin \> 1.5 times the upper limit of normal
⁃ Any other comorbidity that the investigators determine to be incompatible with intensive chemotherapy
• Newly diagnosed (non-APL) acute myeloid leukemia except those with cytogenetic/molecular abnormalities in the exclusion criteria
• Participants must have adequate organ function, defined as:
‣ Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN)
⁃ International normalized ratio (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) \< 1.5 x ULN (patient could be eligible if they respond appropriately to correction with FFP or cryoprecipitate)
• Patients with a history of antecedent myelodysplasia (MDS) are eligible if they have not had prior chemotherapy/hypomethylating agent (e.g., azacitidine or decitabine). Prior exposure to other investigational agents could be considered at PI's discretion
• Patients who have developed therapy-related AML after prior radiation or chemotherapy for other malignancy(ies) are eligible if they have not been exposed to hypomethylating agent (e.g., azacitidine or decitabine) and/or venetoclax
• Patients presenting with marked leukocytosis (WBC \> 25 k/mm3) should receive cytoreduction with hydroxyurea or cytarabine dose ≤ 1 g/m2 to mitigate the risk of tumor lysis syndrome before initiation of therapy with venetoclax
• For female participants of childbearing potential, a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening
• Ability to understand and the willingness to sign a written informed consent document.
• Both male and female participants of childbearing potential agree to use an adequate method of contraception from screening through 6 months after the last dose of study treatment.
• Patients with evidence of Central Nervous System (CNS) disease involvement or who are at high risk of developing CNS disease at baseline/screening (defined as: presenting WBC \> 200k/mm3, or monocytic differentiation or active CSN symptoms concerning CNS involvement per the treating physician) are eligible for this trial and may continue to receive or initiate intrathecal chemotherapy as treatment or prophylaxis, respectively, per institutional practice