A Phase 1B Investigator Initiated Study of Safety and Tolerability of Dexamethasone (D) in Combination With Venetoclax-based Low-Intensity Therapy (LIT) in Treatment-Naïve Acute Myeloid Leukemia (AML): DLIT-AML

Inclusion criteria

Age ≥ 18 years

ECOG performance status ≤2

Newly diagnosed AML morphologically confirmed in a bone marrow biopsy and aspiration done within 2 months of study enrollment, following the WHO 2022 morphologic classification for myeloid malignancies9

No prior AML treatment (treatment-naïve)

Ineligibility or unwillingness to undergo high-dose chemotherapy induction. Patient candidacy for high dose intensive chemotherapy or ineligibility due to older age or unfit medical status will be determined by the primary treating physician.

Adequate renal function including creatinine clearance > 30 ml/min based on the Cockcroft-Gault equation

Normal liver function with direct bilirubin ≤ 2xULN, ALT and AST ≤ 3xULN, unless deemed to be related to underlying leukemia

Women of child-bearing potential and men (except if previous vasectomy) must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Ability to understand and the willingness to sign a written informed consent.

Patients with known previous exposure to HMA or LDAC for treatment of a pre-leukemic condition including myelodysplastic syndromes or myeloproliferative neoplasms are eligible.

Exclusion

Acute promyelocytic leukemia diagnosis

Bone marrow transplant expected after first or second cycle of venetoclax-based LIT.

White Blood Cell (WBC) count >25K. If WBC is >25K in an otherwise eligible patient, the use of cytoreduction is allowed and patients can be included when WBC <25K. Hydroxyurea (at any dose) and/or one dose of cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy

The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions: 1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia, or 2) cytoreduction as point 3.2.3.

Uncontrollable infectious disease within 7 days of study enrollment defined as infection confirmed on laboratory tests or imaging and associated with systemic inflammatory response syndrome (SIRS), circulatory compromise or respiratory failure, where steroid treatment may be detrimental according to investigator. Clinically stable febrile neutropenia attributable to AML is not an exclusion criteria.

Patients with any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.

Baseline high-dose steroid treatment at dose preceding AML diagnosis for any cause, including concomitant autoimmune disease. The maximum acceptable daily steroid dose is the equivalent of 5 mg of prednisone.

Adrenal insufficiency

Active peptic ulcer disease (PUD), defined as actively having severe pain requiring intervention or bleeding. A simple history of PUD is not an exclusion criterion. If a patient with history of PUD is enrolled, proton pump inhibitor prophylaxis will be used.

Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known uncontrolled HIV infection. Patients with a history of treated HBV or HCV which has been previously treated, or those with controlled HIV on treatment are eligible.

Patients receiving any other investigational agents

Pregnant or nursing patients

Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications

Patients with uncontrolled diabetes, defined as hemoglobin A1C (HgbA1C) levels >9 and significant baseline hyperglycemia. Patients with controlled diabetes are eligible provided they continue with their treatments and HgbA1C is monitored every 3 months. HgbA1C levels are required only in diabetic patients riteria:

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