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

Two-stage, Two-arm, Open-Label Phase II Study of Venetoclax in Combination With Azacytidine in Acute Myeloid Leukemia Patients Selected Using Ex Vivo Drug Sensitivity Screening

This is a multi center two-stage, two-arm, open label phase II study of venetoclax in combination with azacytidine in acute myeloid leukemia patients selected for therapy with ex vivo venetoclax sensitivity screening. This study will characterize the usability of ex vivo drug sensitivity testing for patient selection for selecting the responsive patients for venetoclax therapy. The exploratory study will aim to find novel combinations for overcoming resistance as well as finding/validating biomarkers for both sensitivity and resistance.

Inclusion Criteria:

1. Written informed consent

2. 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)

3. Ex vivo sensitivity testing performed to assess venetoclax sensitivity

   1. Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.
   2. Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.

4. Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age

5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.

6. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.

7. Participant must have adequate liver function as demonstrated by

   1. alanine aminotransferase (ALT) ≤ 4.0 × ULN
   2. bilirubin ≤ 1.5 × ULN

8. 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

9. 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.

10. 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:

1. Participant has acute promyelocytic leukemia (APL)

2. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %

3. ECOG >3 (see also inclusion criteria 4)

4. Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)

5. 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.

6. 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.

7. 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):

   1. Participant has a chronic respiratory disease that requires continuous oxygen use
   2. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)
   3. Malabsorption syndrome or other condition that precludes enteral route of administration.
   4. Uncontrolled GVHD.

8. Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.