Study of Venetoclax in Combination With Azacytidine in AML Patients Selected Using Ex Vivo Drug Sensitivity Screening

Inclusion criteria

• Written informed consent
• Patients who present with one of the following (except acute promyelocytic leukemia):

• De novo or secondary AML patients who are non-fit for standard induction therapy (see below)
• Relapsed or refractory AML patients following at least 1 line of prior therapies (see below)
• Ex vivo sensitivity testing performed to assess venetoclax sensitivity

• Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.
• Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.
• Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age
• Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.
• Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
• Participant must have adequate liver function as demonstrated by

• alanine aminotransferase (ALT) ≤ 4.0 × ULN
• bilirubin ≤ 1.5 × ULN
• Specific inclusion criteria for participants non-fit for standard chemotherapy

Participant must be:

≥ 70 years of age OR ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the criteria following:

• Clinically significant comorbidities, reflected at least 1 of:

• Left ventricular ejection fraction (LVEF) < 50%.
• Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
• Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
• Chronic stable angina or congestive heart failure controlled with medication.
• Alanine aminotransferase (ALT) 3.0-4.0 × ULN
• Other contraindication(s) to anthracycline therapy (must be documented)
• Adverse risk karyotype associated with poor outcome with standard chemotherapy
• Patient's refusal from intensive chemotherapy
• Specific inclusion criteria for relapsed patients

Participant must be ≥ 55 years of age with non-CBF AML relapse OR ≥ 18 of age and meeting at least one of the criteria following:

• Not candidate for intensive chemotherapy (see the criteria 8.)
• The duration of remission < 12 months.
• Relapse after allogeneic transplantation.
• 2nd (or higher) relapse.
• Specific inclusion criteria for refractory patients The patients who fail to achieve a complete or partial remission after induction chemotherapy (two cycles of chemotherapy containing cytarabine or clofarabine, in compilation with topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone)

Exclusion criteria

• Participant has acute promyelocytic leukemia (APL)
• The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %
• ECOG >3 (see also inclusion criteria 4)
• Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)
• Participant with known HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with anti-viral medication.
• Participant has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which participants are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
• Evidence of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participation in this study (including but not limited to):

• Participant has a chronic respiratory disease that requires continuous oxygen use
• Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)
• Malabsorption syndrome or other condition that precludes enteral route of administration.
• Uncontrolled GVHD.
• Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.