A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
Condition: Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Placebo; Venetoclax; Cytarabine
Intervention description: tablet; tablet; Subcutaneous injection
Intervention MeSH terms: Cytarabine; Venetoclax
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 211.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia; Leukemia; Treatment naïve; Venetoclax; Cytarabine

Summary:

      The primary objective of this study is to evaluate if venetoclax when co administered with
      low-dose cytarabine (LDAC) improves overall survival (OS) versus LDAC and placebo, in
      treatment-naïve patients with acute myeloid leukemia (AML).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participant must have histological confirmation of acute myeloid leukemia (AML) by
             World Health Organization criteria, be ineligible for intensive induction chemotherapy
             and either be:

               -  ≥ 75 years of age OR

               -  ≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of
                  fitness for intensive induction chemotherapy:

                    -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 - 3

                    -  Cardiac history of congestive heart failure (CHF) requiring treatment or
                       ejection fraction ≤ 50% or chronic stable angina

                    -  Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced
                       expiratory volume in 1 second (FEV1) ≤ 65%

                    -  Creatinine clearance ≥ 30 mL/min to < 45 ml/min

                    -  Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × upper
                       limit of normal (ULN)

                    -  Other comorbidity that the physician judges to be incompatible with
                       conventional intensive chemotherapy which must be reviewed and approved by
                       the study medical monitor before study enrollment

          2. Participant must have an ECOG performance status:

               -  of 0 to 2 for subjects ≥ 75 years of age OR

               -  of 0 to 3 for subjects between 18 to 74 years of age

          3. Participant must have a projected life expectancy of at least 12 weeks.

          4. Participant must have adequate renal function as demonstrated by a creatinine
             clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by
             24-hour urine collection.

          5. Participant must have adequate liver function as demonstrated by:

               -  aspartate aminotransferase (AST) ≤ 3.0 × ULN*

               -  alanine aminotransferase (ALT) ≤ 3.0 × ULN*

               -  bilirubin ≤ 1.5 × ULN*

                    -  Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN

             (*Unless considered to be due to leukemic organ involvement.)

          6. Female participants must be either postmenopausal defined as:

               -  Age > 55 years with no menses for 12 or more months without an alternative
                  medical cause.

               -  Age ≤ 55 years with no menses for 12 or more months without an alternative
                  medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

             OR

               -  Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

             OR

               -  A woman of childbearing potential (WOCBP) practicing at least one protocol
                  specified method of birth control starting at Study Day 1 through at least 180
                  days after the last dose of study drug.

          7. Male participants who are sexually active, must agree, from Study Day 1 through at
             least 180 days after the last dose of study drug, to practice protocol specified
             methods of contraception. Male subjects must agree to refrain from sperm donation from
             initial study drug administration through at least 180 days after the last dose of
             study drug.

          8. Females of childbearing potential must have negative results for pregnancy test
             performed:

               -  At Screening with a serum sample obtained within 14 days prior to the first study
                  drug administration, and

               -  Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7
                  days since obtaining the serum pregnancy test results.

               -  Subjects with borderline pregnancy tests at Screening must have a serum pregnancy
                  test ≥ 3 days later to document continued lack of a positive result.

          9. Participant must voluntarily sign and date an informed consent form, approved by an
             Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the
             initiation of any screening or study-specific procedures.

        Exclusion Criteria:

          1. Participant has received any prior treatment for AML with the exception of
             hydroxyurea, allowed through the first cycle of study treatment. Note: Prior treatment
             for myelodysplastic syndrome is allowed except for use of cytarabine.

          2. Participant had an antecedent myeloproliferative neoplasm (MPN) including
             myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous
             leukemia (CML) with or without BCR-ABL 1 translocation and AML with BCR-ABL 1
             translocation.

          3. Participants that have acute promyelocytic leukemia (APL).

          4. Participant has known central nervous system (CNS) involvement with AML.

          5. Participant has known human immunodeficiency virus (HIV) infection (due to potential
             drug-drug interactions between antiretroviral medications and venetoclax). HIV testing
             will be performed at Screening, if required per local guidelines or institutional
             standards.

          6. Participant is known to be positive for hepatitis B virus (HBV), or hepatitis C virus
             (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on
             antivirals (non-exclusionary medications) are not excluded.

          7. Participant has received strong or moderate cytochrome P450 3A4 (CYP3A) inducers 7
             days prior to the initiation of study treatment.

               -  Chinese subjects are excluded from receiving strong and/or moderate CYP3A
                  inhibitors 7 days prior to the initiation of study treatment through the end of
                  intensive pharmacokinetic (PK) collection (24 hours post dose on Cycle 1 Day 10).

          8. Participant has consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or star fruit within 3 days prior to the
             initiation of study treatment.

          9. Participant has cardiovascular disability status of New York Heart Association Class >
             2. Class 2 is defined as cardiac disease which subjects are comfortable at rest but
             ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain.
             Class 3 is defined as cardiac disease which subjects are comfortable at rest but less
             than ordinary activity causes fatigue, palpitation, or dyspnea. Class 4 is defined as
             cardiac disease which subjects have an inability to carry on any physical activity
             without discomfort, symptoms of heart failure at rest, and if any physical activity is
             undertaken then discomfort increases.

         10. Participant has chronic respiratory disease that requires continuous oxygen, or
             significant history of renal, neurologic, psychiatric, endocrinologic, metabolic,
             immunologic, hepatic, cardiovascular disease, any other medical condition or known
             hypersensitivity to any of the study medications including excipients of LDAC that in
             the opinion of the investigator would adversely affect his/her participating in this
             study.

         11. Participant has a malabsorption syndrome or other condition that precludes enteral
             route of administration.

         12. Participant exhibits evidence of other clinically significant uncontrolled systemic
             infection requiring therapy (viral, bacterial or fungal).

         13. Participant has a history of other malignancies prior to study entry, with the
             exception of:

               -  Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
                  breast;

               -  Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
                  skin;

               -  Previous malignancy confined and surgically resected (or treated with other
                  modalities) with curative intent.

         14. Participant has a white blood cell count > 25 × 10^9/L. (Note: hydroxyurea
             administration or leukapheresis is permitted to meet this criterion).

         15. Previous treatment with venetoclax and/or current participation in any other research
             study with investigational products.