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Venetoclax With Combination Chemotherapy in Treating Patients With Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia

NCT03214562

Description:

This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia or acute myeloid leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, cytarabine, filgrastim and idarubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive Acute Myeloid Leukemia (AML) Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)
  • Official Title: A Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive Acute Myeloid Leukemia (AML) Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2016-0979
  • SECONDARY ID: 710467 30 120634 28
  • SECONDARY ID: NCI-2018-01119
  • NCT ID: NCT03214562

Conditions

  • Other Diseases of Blood and Blood-forming Organs
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
FludarabineFludarabine phosphate, FludaraVenetoclax + FLAG-IDA (Induction)
CytarabineAra-C, Cytosar, DepoCyt, Cytosine Arabinosine HydrochlorideVenetoclax + FLAG-IDA (Induction)
IdarubicinIdamycinVenetoclax + FLAG-IDA (Induction)
FilgrastimG-CSF, NeupogenVenetoclax + FLAG-IDA (Induction)
Pegylated FilgrastimNeulastaVenetoclax + FLAG-IDA (Induction)
VenetoclaxABT-199, GDC-0199Venetoclax + FLAG-IDA (Induction)

Purpose

The goal of this clinical research study is find the highest tolerable dose of venetoclax that can be given in combination with a type of chemotherapy called FLAG-IDA to patients with acute myeloid leukemia (AML). FLAG-IDA chemotherapy includes fludarabine, cytarabine, idarubicin, and filgrastim. The safety of this drug combination will also be studied. This is an investigational study. FLAG-IDA chemotherapy is FDA approved and commercially available for the treatment of AML. Venetoclax is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. It is considered investigational to use venetoclax to treat AML. The study doctor can explain how the study drugs are designed to work. Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to a study
      group based on when you join this study. Up to 3 dose levels of venetoclax will be tested: a
      high dose, a middle dose, and a low dose. About 3-6 participants will be enrolled in each
      dose level in Phase 1 of the study. Up to 25 participants who have not received treatment for
      AML and up to 25 patients who have previously received treatment for AML (up to 50
      participants total) will be enrolled in Phase 2.

      If you are enrolled in Phase 1, the dose of venetoclax you receive will depend on when you
      join this study. The first group of participants will receive the middle dose level of
      venetoclax. If there are no intolerable side effects at this dose, the next group of
      participants will be enrolled to receive the higher dose. If that dose is tolerable, Phase 1
      will close and Phase 2 will begin. If intolerable side effects are seen, a new group of
      participants will be enrolled to receive a lower dose of venetoclax than the group before it.
      This will continue until the highest tolerable dose of venetoclax is found. This is called
      dose escalation.

      If you are enrolled in Phase 2, you will receive venetoclax at the dose that was tolerated in
      Phase 1. This is called dose expansion.

      All participants will receive the standard dose of FLAG-IDA chemotherapy.

      Both you and the study doctor will know to which phase you will be assigned to.

      Study Drug Administration:

      Each study cycle is 28 days.

      FLAG-IDA chemotherapy is given in 2 phases: Induction and Consolidation. Induction may last
      1-2 cycles. Consolidation may last 4-5 cycles. During Induction, you will receive:

        -  Fludarabine by vein over about 30 minutes on Days 2-6 of each cycle.

        -  Cytarabine by vein over about 4 hours on Days 2-6 of each cycle. You will wait 4 hours
           after your dose of fludarabine before receiving cytarabine.

        -  Idarubicin by vein over about 15-30 minutes on Days 4 and 5 of each cycle.

        -  Filgrastim as an injection under the skin on Days 1-7 of each cycle. Instead of
           filgrastim, you may receive pegfilgrastim after Day 3, if the study doctor thinks it is
           in your best interest.

      During Consolidation, you will receive:

        -  Fludarabine by vein over about 30 minutes on Days 2-4 of each cycle.

        -  Cytarabine by vein over about 4 hours on Days 2-4 of each cycle.

        -  Filgrastim as an injection under the skin on Days 1-7 of each cycle. Instead of
           filgrastim, you may receive pegfilgrastim after Day 3, if the study doctor thinks it is
           in your best interest.

      If the doctor thinks it is needed, you may receive idarubicin by vein over about 15-30
      minutes during 1 of the consolidation cycles. The study doctor will discuss this with you.

      You will take venetoclax by mouth on Days 1-14 of each cycle during the induction phase and
      on Days 1-14 of each cycle during the consolidation phase. Each dose should be taken within
      30 minutes after eating a meal (preferably breakfast) with a cup (about 8 ounces) of water.

      Your dose of venetoclax will slowly increase over the first 3 days of Cycle 1. You will be
      hospitalized starting about 24 hours before your first dose of venetoclax until about 24
      hours after you receive the full dose of venetoclax. You may stay in the hospital for the
      first week while you receive chemotherapy, but this will depend on what the study doctor
      thinks is in your best interest.

      After you complete FLAG-IDA chemotherapy, you may receive a stem cell transplant as part of
      your standard care. If you are not eligible to receive a transplant, you may continue to
      receive venetoclax alone for an additional year. This is called maintenance therapy. During
      Maintenance Therapy, you will take venetoclax by mouth every day for up to 1 year.

      Length of Study:

      You may receive up to 5 cycles of FLAG-IDA chemotherapy and venetoclax, followed by up to 12
      months of venetoclax maintenance therapy (if you continue to receive it. You will no longer
      be able to take the study drugs if the disease gets worse, if intolerable side effects occur,
      or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      Study Visits:

      On Days 1-7 of Cycle 1, one (1) time every week during Induction, and Day 1 of each
      Consolidation cycle:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

        -  Blood for biomarker testing (about 1 tablespoons) will be drawn 1 time before treatment
           on Day 1 of Cycle 1. Biomarkers, which may include genetic biomarkers, are found in the
           blood and tissue and may be related to your reaction to the study drug.

      Between Day 21 of Cycle 1 and Day 1 of Cycle 2 and then every 3-4 months after that, you will
      have a bone marrow biopsy/aspirate to check the status of the disease and for cytogenetic
      testing. Biomarker testing on the bone marrow aspirate sample will be performed each time an
      aspirate is performed.

      On Day 28 of Cycle 1, blood (about 1 tablespoon) will be drawn for biomarker testing.

      On Day 1 of each Maintenance cycle (if you continue to receive venetoclax):

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

      If the disease appears to get better but then comes back, blood (about 2-3 tablespoons) will
      be drawn for biomarker testing.

      End-of-Study Visit:

      Within 30 days after your last dose of study drug(s):

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

        -  You will have a bone marrow aspirate/biopsy to check the status of the disease and for
           biomarker and cytogenetic testing.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax + FLAG-IDA (Induction)ExperimentalFludarabine by vein daily on days 2, 3, 4, 5, 6. Cytarabine by vein on days 2, 3, 4, 5, 6. Idarubicin by vein on days 4 and 5. Filgrastim given subcutaneously daily on days 1, 2, 3, 4, 5, 6, 7. Alternatively, a single injection of Pegylated Filgrastim can be administered subcutaneously after day 5 to replace remaining injections of Filgrastim. For patients not in remission after the first induction therapy cycle, a second re-induction can be administered using the same dosing as induction. Venetoclax starting dose of 100 mg by mouth on day 1, 200 mg on day 2, and 400 mg on day 3-14 of the first day cycle. At dose level -1, venetoclax administered at a dose of 100 mg on day 1, and 200 mg on day 2-14 of the first cycle. Phase Ib: The dose escalation portion (Part 1) includes a 3+3 design starting at dose level -1, with standard FLAG-IDA and Venetoclax at 200 mg orally daily. Study cycles are 28 days.
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Filgrastim
  • Pegylated Filgrastim
  • Venetoclax
Venetoclax + FLAG-IDA (Expansion) - Naive AMLExperimentalFludarabine by vein daily on days 2, 3, 4, 5, 6. Cytarabine by vein over about 4 hours on Days 2-4 of each cycle. Idarubicin by vein on days 4 and 5. Filgrastim given subcutaneously daily on days 1, 2, 3, 4, 5, 6, 7. Alternatively, a single injection of Pegylated Filgrastim can be administered subcutaneously after day 5 to replace remaining injections of Filgrastim. Venetoclax starting dose is MTD from Induction Phase taken by mouth Days 1-14 of each cycle during the consolidation phase.
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Filgrastim
  • Pegylated Filgrastim
  • Venetoclax
Venetoclax + FLAG-IDA (Expansion) - Relapsed/Refractory AMLExperimentalFludarabine by vein daily on days 2, 3, 4, 5, 6. Cytarabine by vein over about 4 hours on Days 2-4 of each cycle. Idarubicin by vein on days 4 and 5. Filgrastim given subcutaneously daily on days 1, 2, 3, 4, 5, 6, 7. Alternatively, a single injection of Pegylated Filgrastim can be administered subcutaneously after day 5 to replace remaining injections of Filgrastim. Venetoclax starting dose is MTD from Induction Phase taken by mouth Days 1-14 of each cycle during the consolidation phase.
  • Fludarabine
  • Cytarabine
  • Idarubicin
  • Filgrastim
  • Pegylated Filgrastim
  • Venetoclax
Venetoclax + FLAG-IDA (Maintenance)ExperimentalVenetoclax monotherapy maintenance at MTD continues for a period of one year after completion of induction/consolidation therapy, for those patients who do not proceed to stem cell transplantation.
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of AML by World Health Organization (WHO) criteria. Patients with high risk
             myelodysplastic syndrome (MDS) as defined by the presence of >/= 10% blasts are also
             eligible at the discretion of the Principal Investigator.

          2. Patients >/= 18 to </= 65 years. Patients older than 65 who are deemed fit to receive
             intensive chemotherapy by the treating physician will be eligible after discussion
             with the PI.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of </= 2

          4. Adequate renal function including creatinine clearance >/= 30 mL/min based on the
             Cockcroft-Gault equation.

          5. Adequate hepatic function including total bilirubin < 1.5x ULN unless increase is due
             to Gilbert's disease or leukemic involvement, and AST and/or ALT < 3x ULN unless
             considered due to leukemic involvement

          6. Ability to understand and provide signed informed consent

          7. Male subjects must agree to refrain from unprotected sex and sperm donation from
             initial study drug administration until 90 days after the last dose of study drug.

          8. Only patients who are relapsed, refractory, or intolerant of standard AML therapy will
             be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)

        Exclusion Criteria:

          1. Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (FAB
             class M3-AML)

          2. Patients having received any prior BCL2 inhibitor therapy

          3. Subject has known active central nervous system (CNS) involvement with AML.

          4. Patients with New York Heart Association (NYHA) Class III or IV congestive heart
             failure or LVEF < 40% by echocardiogram or multi-gated acquisition (MUGA) scan

          5. Patients with a history of myocardial infarction within the last 6 months or unstable
             / uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular
             arrhythmias

          6. Patients with known infection with human immunodeficiency virus (HIV) or active
             Hepatitis B or C

          7. Patients with known dysphagia, short-gut syndrome, or other conditions that would
             affect the ingestion or gastrointestinal absorption of drugs administered orally.

          8. Subject has any other significant medical or psychiatric history that in the opinion
             of the investigator would adversely affect participation in this study.

          9. Subject has a white blood cell count > 25 x 10{9}/L. (Note: Hydroxyurea is permitted
             to meet this criterion.)

         10. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy
             test, or women of childbearing potential who are not willing to maintain adequate
             contraception (a) Appropriate method(s) of contraception include oral or injectable
             hormonal birth control, IUD, and double barrier methods (for example a condom in
             combination with a spermicide).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML)
Time Frame:56 days
Safety Issue:
Description:MTD defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML)
Time Frame:56 days
Safety Issue:
Description:ORR determined by revised International Working Group (IWG) criteria.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Other diseases of blood and blood-forming organs
  • Acute Myeloid Leukemia
  • AML
  • Newly diagnosed
  • Relapsed/refractory
  • Fludarabine
  • Fludarabine phosphate
  • Fludara
  • Cytarabine
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine arabinosine hydrochloride
  • Idarubicin
  • Idamycin
  • Filgrastim
  • G-CSF
  • Neupogen
  • Pegylated filgrastim
  • Neulasta
  • Venetoclax
  • ABT-199
  • GDC-0199

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