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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

NCT03069352

Description:

Acute Myeloid Leukaemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the patient has, and the age of the patient when diagnosed. Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to cytarabine works better than cytarabine on its own. This is a Phase 3, randomized, double-blind (treatment unknown to patients and doctors), placebo-controlled, multicenter study in patients with AML who are 18 or more years old and have not been treated before. Patients who take part in this study should not be suitable for intensive induction chemotherapy (usual starting treatment). Abbvie is funding this study which will take place at approximately 125 hospitals globally and enrol approximately 210 patients. In this study, 2/3 of patients will receive venetoclax every day with cytarabine and the remaining 1/3 will receive placebo (dummy) tablets with Cytarabine. Patients will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others. Additional blood tests will be completed for genetic factors and to see how long the drug remains in the body.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax Co-Administered With Low Dose Cytarabine Versus Low Dose Cytarabine in Treatment Naïve Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: M16-043
  • SECONDARY ID: 2016-003900-30
  • NCT ID: NCT03069352

Conditions

  • Acute Myeloid Leukemia (AML)

Interventions

DrugSynonymsArms
PlaceboPlacebo + LDAC
VenetoclaxABT-199, VenclextaVenetoclax + Low Dose Cytarabine (LDAC)
CytarabineCytosar-U, Ara-C, ArabinosylcytosineVenetoclax + Low Dose Cytarabine (LDAC)

Purpose

Acute Myeloid Leukaemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the patient has, and the age of the patient when diagnosed. Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to cytarabine works better than cytarabine on its own. This is a Phase 3, randomized, double-blind (treatment unknown to patients and doctors), placebo-controlled, multicenter study in patients with AML who are 18 or more years old and have not been treated before. Patients who take part in this study should not be suitable for intensive induction chemotherapy (usual starting treatment). Abbvie is funding this study which will take place at approximately 125 hospitals globally and enrol approximately 210 patients. In this study, 2/3 of patients will receive venetoclax every day with cytarabine and the remaining 1/3 will receive placebo (dummy) tablets with azacitidine. Patients will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others. Additional blood tests will be completed for genetic factors and to see how long the drug remains in the body.

Trial Arms

NameTypeDescriptionInterventions
Venetoclax + Low Dose Cytarabine (LDAC)ExperimentalVenetoclax 600 mg orally every day (QD) QD on Days 1 - 28 plus LDAC 20 mg/m^2 subcutaneously QD on Days 1 - 10 (28 day cycle)
  • Venetoclax
  • Cytarabine
Placebo + LDACPlacebo ComparatorMatching Placebo for Venetoclax 600 mg orally QD on Days 1 - 28 plus LDAC 20 mg/m^2 subcutaneous QD on Days 1 - 10 (28 day cycle)
  • Placebo
  • Cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Participant must have histological confirmation of Acute Myeloid Leukemia (AML) by
             World Health Organization criteria, be ineligible for intensive induction chemotherapy
             and either be:

             a. ≥ 75 years of age OR b. ≥ 18 to 74 years of age and fulfill at least one criteria
             associated with lack of fitness for intensive induction chemotherapy: i. Eastern
             Cooperative Oncology Group (ECOG) Performance status of 2 - 3; ii. Cardiac history of
             Congestive Heart Failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or
             chronic stable angina; iii. Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)
             ≤ 65% or Forced Expiratory Volume in 1 second(FEV1) ≤ 65%; iv. Creatinine clearance ≥
             30 mL/min to < 45 ml/min; v. Moderate hepatic impairment with total bilirubin > 1.5 to
             ≤ 3.0 × Upper Limit of Normal (ULN); vi. 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.

          -  Participant must have an ECOG Performance status:

               1. of 0 to 2 for participants ≥ 75 years of age or

               2. of 0 to 3 for participants between 18 to 74 years of age.

          -  Participant must have a projected life expectancy of at least 12 weeks.

          -  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-hours urine collection.

          -  Participant must have adequate liver function as demonstrated by:

               1. aspartate aminotransferase (AST) ≤ 3.0 × ULN*

               2. alanine aminotransferase (ALT) ≤ 3.0 × ULN*

               3. 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.

          -  Female participants must be either postmenopausal defined as:

               1. Age > 55 years with no menses for 12 or more months without an alternative
                  medical cause.

               2. Age ≤ 55 years with no menses for 12 or more months without an alternative
                  medical cause AND an FSH level > 40 IU/L; or

               3. Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy); or

               4. 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.

          -  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.

          -  Females of childbearing potential must have negative results for pregnancy test
             performed:

               1. At Screening with a serum sample obtained within 14 days prior to the first study
                  drug administration, and

               2. 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.

               3. Participants with borderline pregnancy tests at Screening must have a serum
                  pregnancy test ≥ 3 days later to document continued lack of a positive result.

          -  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:

          -  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.

          -  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.

          -  Participants that have acute promyelocytic leukemia (APL).

          -  Participant has known Central Nervous System (CNS) involvement with AML.

          -  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.

          -  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.

          -  Participant has received strong or moderate CYP3A inducers 7 days prior to the
             initiation of study treatment.

               -  Chinese participants are excluded from receiving strong and/or moderate CYP3A
                  inhibitors 7 days prior to the initiation of study treatment through the end of
                  intensive PK collection (24 hours post dose on Cycle 1 Day 10).

          -  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.

          -  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.

          -  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.

          -  Participant has a malabsorption syndrome or other condition that precludes enteral
             route of administration.

          -  Participant exhibits evidence of other clinically significant uncontrolled systemic
             infection requiring therapy (viral, bacterial or fungal).

          -  Participant has a history of other malignancies prior to study entry, with the
             exception of:

               1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
                  breast;

               2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
                  skin;

               3. Previous malignancy confined and surgically resected (or treated with other
                  modalities) with curative intent.

          -  Participant has a white blood cell count > 25 × 109/L. (Note: Hydroxyurea
             administration or leukapheresis is permitted to meet this criterion).

          -  Previous treatment with venetoclax and/or current participation in any other research
             study with investigational products.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Measured up to 2 years after the last participant is enrolled
Safety Issue:
Description:OS is defined as the number of days from the date of randomization to the date of death.

Secondary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:EFS will be defined as the number of days from randomization to the date of progressive disease, relapse from CR to CRi, treatment failure defined as failure to achieve CR, CRi, Partial Remission (PR), or Morphologic Leukemia Free State (MLFS), or death from any cause.
Measure:Composite Complete Remission Rate by Initiation of Cycle 2
Time Frame:Up to 6 months after the last participant is randomized
Safety Issue:
Description:This will be calculated based on the modified International Working Group (IWG) criteria. CR is defined as absolute neutrophil count greater than 10^3/ microliter (mcL), platelets greater than or equal to 10^5/mcL, red cell transfusion independence, bone marrow with less than 5% blasts, absence of circulating blasts and blasts with Auer rods and absence of extramedullary disease. All criteria as CR except for residual neutropenia < 10^3/microliter (mcL) (1,000/mcL) or thrombocytopenia < 10^5/microliter (mcL) (100,000/mcL) and no morphologic evidence of AML. If all criteria for CR are met except for RBC transfusion independence, this also fulfills CRi criteria by the initiation of Cycle 2.
Measure:Patient Reported Outcomes
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:Additional subscales and items from EORTC QLQ-C30 will be evaluated using a linear mixed effects regression model to test for differences between the two treatment arms.
Measure:Complete Remission Rate
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:The proportion of subjects with complete remission (CR) will be calculated based on the modified IWG criteria for AML.
Measure:Composite Complete Remission Rate
Time Frame:Up to 2 years after the last participant is randomized
Safety Issue:
Description:This will be calculated based on the modified International Working Group (IWG) criteria. CR is defined as absolute neutrophil count greater than 10^3/ microliter (mcL), platelets greater than or equal to 10^5/mcL, red cell transfusion independence, bone marrow with less than 5% blasts, absence of circulating blasts and blasts with Auer rods and absence of extramedullary disease. All criteria as CR except for residual neutropenia < 10^3/microliter (mcL) (1,000/mcL) or thrombocytopenia < 10^5/microliter (mcL) (100,000/mcL) and no morphologic evidence of AML. If all criteria for CR are met except for RBC transfusion independence, this also fulfills CRi criteria.
Measure:Patient Reported Outcomes
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:Exploratory research will be conducted on the subscales and items from the PROMIS and Fatigue SF 7a.
Measure:Patient Reported Outcomes
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:Exploratory research will be conducted on the subscales and items from EORTC QLQ-C30.
Measure:Patient Reported Outcomes
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:Exploratory research will be conducted on the subscales and items from EQ-5D-5L.
Measure:Complete Remission and Complete Remission With Partial Hematologic Recovery (CR + CRh)
Time Frame:Up to 2 years after the last participant is enrolled
Safety Issue:
Description:A response of CRh is achieved when the following criteria are met : Bone marrow with <5% blasts; Peripheral blood neutrophil count of >0.5*10^3/microliter (mcL); Peripheral blood platelet count of >0.5*10^5/microliter (mcL); A 1 week (>= 7 days) platelet transfusion-free period to the hematology lab collection.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • Acute Myeloid Leukemia
  • Leukemia
  • Treatment naïve
  • Venetoclax
  • Cytarabine

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