Clinical Trials /

Venetoclax in Combination With Decitabine in r/r AML

NCT03404193

Description:

The goal of this clinical research study is to learn if venetoclax in combination with decitabine can help to control acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) in newly diagnosed elderly patients or in patients with disease that has relapsed (come back after treatment). The safety of this drug combination will also be studied. This is an investigational study. Venetoclax and decitabine are FDA approved and commercially available. Venetoclax is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. Decitabine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to use venetoclax in combination with decitabine to treat AML or HR-MDS. The study doctor can explain how the study drugs are designed to work. Up to 280 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-risk Myelodysplastic Syndrome
  • Official Title: A Phase II Study of Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-risk Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 2017-0912
  • SECONDARY ID: NCI-2018-00752
  • NCT ID: NCT03404193

Conditions

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

Interventions

DrugSynonymsArms
DecitabineDacogenDecitabine + Venetoclax
VenetoclaxABT-199, GDC-0199Decitabine + Venetoclax

Purpose

The goal of this clinical research study is to learn if venetoclax in combination with decitabine can help to control acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) in newly diagnosed elderly patients or in patients with disease that has relapsed (come back after treatment). The safety of this drug combination will also be studied. This is an investigational study. Venetoclax and decitabine are FDA approved and commercially available. Venetoclax is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. Decitabine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to use venetoclax in combination with decitabine to treat AML or HR-MDS. The study doctor can explain how the study drugs are designed to work. Up to 200 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      If you are found to be eligible to take part in this study, you will receive decitabine by
      vein over about 1 hour on Days 1-10 of each 28-day study cycle. Note that the start of future
      cycles may be delayed if you have side effects to the study drug.

      You will take venetoclax by mouth on Days 1-28 of the first cycle and Days 1-21 of all other
      cycles. Each dose should be taken within 30 minutes after eating a meal (preferably
      breakfast) with about a cup (8 ounces) of water. If the study doctor thinks it is needed
      based on any side effects you may be having (such as low blood cell counts and/or
      infections), your dose(s) of venetoclax may be delayed until it is thought to be safe for you
      to receive it.

      If venetoclax is not available at the start of treatment for any reason (insurance,
      financial, transportation, and so on), you can begin receiving decitabine and venetoclax can
      be added when it is available.

      During Cycle 1, you will be admitted into the hospital as an inpatient for at least the first
      3 days of combination therapy. During this time, you will also be given drugs to prevent
      tumor lysis syndrome (TLS). TLS happens when breakdown products of the cancer cells entering
      the blood stream, causing possible weakness, low blood pressure, muscle cramps, kidney
      damage, and/or other organ damage. You may be given fluids (either by mouth or by vein) and
      treatment with allopurinol or rasburicase. After Day 3, if there is If no evidence of TLS,
      you may be discharged. You will then receive the rest of the study drug doses as an
      outpatient.

      If the study doctor thinks it is in your best interest, you may be able to also receive
      standard of care therapies (such as sorafenib, midostaurin, imatinib, dasatinib, ponatinib,
      and so on) while you are on study. The study doctor will discuss these treatments with you,
      as well as their risks and benefits.

      If the study doctor thinks it is needed for your safety, you may also receive cytarabine to
      help prevent central nervous system side effects. Cytarabine will be given intrathecally
      (through a spinal tap) on either Day 21 of Cycle 1 or Day 14 of Cycle 2.

      Length of Study:

      You may continue taking the study drugs for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drug 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 Day 1 of each cycle (+/- 4 days), you will have a physical exam.

      One (1) time every week during Cycles 1, 2 and 3, and then on Day 1 of each cycle after that
      (+/- 4 days):

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

        -  You will have a bone marrow biopsy and aspirate to check the status of the disease, and
           for biomarker and cytogenetic testing (Day 21 [+/- 3 days]). If the study doctor thinks
           it is needed, this will be repeated on Day 28. Additionally, you will have a bone marrow
           biopsy and aspirate to check the status of the disease, for biomarker and for
           cytogenetic testing at the end of Cycles 2 and 4, then every 1-3 cycles after that, then
           at any time that the disease appears to get worse.

      Additional Research Tests:

      Blood (about 3 tablespoons) will be drawn for biomarker testing at the following time points
      (within 24 hours). Biomarkers, which may include genetic biomarkers, are found in the blood
      and tissue and may be related to your reaction to the study drug:

        -  Baseline (before the first decitabine dose), about Day 3 of Cycle 1, and between Days 21
           to 28 of Cycle 1

        -  At the end of Cycles 2 and 4

        -  At any point that the disease appears to get worse

      You will have a "cheek scrape" at the end of Cycle 1. These cells will be used to compare to
      cancer cells to look for effects of the study drug. For this test, a small sample of cells
      from the inside of your mouth will be collected by scraping a special brush against the
      inside of your cheek a few times, until enough cells are collected.

      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.

      Follow-up:

      If the disease responded to the study treatment, you will then be called every 3 to 6 months
      for up to 5 years and asked about how you are doing. Each call should last about 15-30
      minutes.
    

Trial Arms

NameTypeDescriptionInterventions
Decitabine + VenetoclaxExperimentalParticipants receive Decitabine by vein over about 1 hour on Days 1-10 of each 28-day study cycle. Participants take Venetoclax by mouth on Days 1-28 of the first cycle and Days 1-21 of all other cycles.
  • Decitabine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with AML, biphenotypic or bilineage leukemia (including a myeloid component)
             or mixed phenotype acute leukemia (MPAL) who have failed prior therapy. Patients with
             AML should have failed prior therapy or have relapsed after prior therapy. Patients
             with isolated extramedullary AML are eligible.

          2. Elderly (>60 year old) patients with newly diagnosed AML or mixed phenotype acute
             leukemia (MPAL) not eligible for intensive chemotherapy.

          3. AML patients with prior history of MDS or CMML who received any therapy or no therapy
             for the MDS or CMML and progressed to AML, are eligible at the time of diagnosis of
             AML regardless of any prior therapy for MDS. The WHO classification will be used for
             AML.

          4. Patients with high-risk MDS, and chronic myelomonocytic leukemia (CMML) with bone
             marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating
             agent (HMA) therapy, defined as prior receipt of 4 cycles of HMA therapy with failure
             to attain a response, or relapse after prior response to HMA therapy.

          5. Age >/= 18 years

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

          7. White blood cell count </= 10,000

          8. Adequate renal function including creatinine < 2 unless related to the disease.

          9. Adequate hepatic function including total bilirubin < 2x upper limit of normal (ULN)
             unless increase is due to Gilbert's disease or leukemic involvement, and ALT < 3 x ULN
             unless considered due to leukemic involvement

         10. Provision of written informed consent

         11. Oral hydroxyurea and/or one dose of cytarabine (up to 2 g/m2) for patients with
             rapidly proliferative disease is allowed before the start of study therapy and while
             the patient is on active study treatment through cycle 1, as needed, for clinical
             benefit and after discussion with the PI. Concurrent therapy for central nervous
             system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is
             permitted.

         12. Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
             at least 12 months) or if of childbearing potential, must have a negative serum or
             urine pregnancy test within 72 hours before the start of the treatment

         13. Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 3 months after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment.

        Exclusion Criteria:

          1. Patients having received any prior BCL2 inhibitor therapy.

          2. Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia
             (French-American-British [FAB] class M3-AML).

          3. Patients with symptomatic CNS leukemia or patients with poorly controlled CNS
             leukemia.

          4. Active and uncontrolled comorbidities including active uncontrolled infection,
             uncontrolled hypertension despite adequate medical therapy, active and uncontrolled
             congestive heart failure NYHA class III/IV, clinically significant and uncontrolled
             arrhythmia as judged by the treating physician.

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

          6. Any other medical, psychological, or social condition that may interfere with study
             participation or compliance, or compromise patient safety in the opinion of the
             investigator.

          7. Pregnant or breastfeeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) of venetoclax in combination with 10-day decitabine
Time Frame:3 months
Safety Issue:
Description:ORR defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with AML; and complete remission (CR), partial remission (PR) or marrow CR† (mCR) lasting at least 4 weeks for patients with MDS.

Secondary Outcome Measures

Measure:Duration of Response of patients with refractory/relapsed AML treated with this combination.
Time Frame:1 year
Safety Issue:
Description:
Measure:Disease-Free Survival (DFS) of patients with refractory/relapsed AML treated with this combination.
Time Frame:1 year
Safety Issue:
Description:
Measure:Overall Survival (OS) of patients with refractory/relapsed AML treated with this combination.
Time Frame:1 year
Safety Issue:
Description:
Measure:Determination of the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients who achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine.
Time Frame:1 year
Safety Issue:
Description:
Measure:Safety of venetoclax in combination with 10-day decitabine in patients with refractory/ relapsed AML.
Time Frame:Baseline up to 30 days after last dose of study drug
Safety Issue:
Description:The overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.
Measure:Determination of the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen.
Time Frame:3 months
Safety Issue:
Description:Response assessed based by Modified IWG Response Criteria for MDS (Cheson et al, 2006).

Details

Phase: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
  • Myelodysplastic Syndrome
  • MDS
  • Decitabine
  • Dacogen
  • Ventoclax
  • ABT-199
  • GDC-0199

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