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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)

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ClinicalTrials.gov Identifier: NCT03214562
Recruitment Status : Recruiting
First Posted : July 11, 2017
Last Update Posted : January 9, 2019
Sponsor:
Collaborator:
AbbVie
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE July 10, 2017
First Posted Date  ICMJE July 11, 2017
Last Update Posted Date January 9, 2019
Actual Study Start Date  ICMJE September 26, 2017
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2017)
  • Maximum Tolerated Dose of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML) [ Time Frame: 56 days ]
    MTD defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle.
  • Adverse Events of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML) [ Time Frame: 56 days ]
    Adverse events determined using Common Toxicity Criteria v 4.0.
Original Primary Outcome Measures  ICMJE
 (submitted: July 10, 2017)
  • Maximum Tolerated Dose of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML) [ Time Frame: 28 days ]
    MTD defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle.
  • Adverse Events of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML) [ Time Frame: 28 days ]
    Adverse events determined using Common Toxicity Criteria v 4.0.
Change History Complete list of historical versions of study NCT03214562 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2017)
Overall Response Rate (ORR) of FLAG-IDA + Venetoclax in Participants with Acute Myeloid Leukemia (AML) [ Time Frame: 56 days ]
ORR determined by revised International Working Group (IWG) criteria.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
Brief Summary

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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Other Diseases of Blood and Blood-forming Organs
  • Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Fludarabine

    Induction: 30 mg/m2 by vein over approximately 30 minutes daily on days 2, 3, 4, 5, 6.

    Consolidation: 30 mg/m2 by vein over about 30 minutes on Days 2-4 of each cycle.

    Other Names:
    • Fludarabine phosphate
    • Fludara
  • Drug: Cytarabine

    Induction: 2 g/m2 by vein over approximately 4 hours daily starting 4 hours (+/- 1 hour) after the completion of Fludarabine on days 2, 3, 4, 5, 6.

    Consolidation: 2 g/m2 by vein over about 4 hours on Days 2-4 of each cycle.

    Other Names:
    • Ara-C
    • Cytosar
    • DepoCyt
    • Cytosine Arabinosine Hydrochloride
  • Drug: Idarubicin
    6 mg/m2 by vein over approximately 15 to 30 minutes given following Fludarabine administration on days 4 and 5.
    Other Name: Idamycin
  • Drug: Filgrastim
    5 mcg/kg subcutaneously daily on days 1, 2, 3, 4, 5, 6, 7.
    Other Names:
    • G-CSF
    • Neupogen
  • Drug: Pegylated Filgrastim
    6 mg can be administered subcutaneously after day 5 as a single injection to replace remaining injections of Filgrastim.
    Other Name: Neulasta
  • Drug: Venetoclax

    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 28 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 Venetoclax at 200 mg orally daily.

    Consolidation Phase: Venetoclax starting dose is MTD from Induction Phase taken by mouth Days 1-14 of each cycle.

    Maintenance Phase: Arm: Venetoclax 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.

    Other Names:
    • ABT-199
    • GDC-0199
Study Arms  ICMJE
  • Experimental: Venetoclax + FLAG-IDA (Induction)

    Fludarabine 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.

    Interventions:
    • Drug: Fludarabine
    • Drug: Cytarabine
    • Drug: Idarubicin
    • Drug: Filgrastim
    • Drug: Pegylated Filgrastim
    • Drug: Venetoclax
  • Experimental: Venetoclax + FLAG-IDA (Expansion) - Naive AML

    Fludarabine 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.

    Interventions:
    • Drug: Fludarabine
    • Drug: Cytarabine
    • Drug: Idarubicin
    • Drug: Filgrastim
    • Drug: Pegylated Filgrastim
    • Drug: Venetoclax
  • Experimental: Venetoclax + FLAG-IDA (Expansion) - Relapsed/Refractory AML

    Fludarabine 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.

    Interventions:
    • Drug: Fludarabine
    • Drug: Cytarabine
    • Drug: Idarubicin
    • Drug: Filgrastim
    • Drug: Pegylated Filgrastim
    • Drug: Venetoclax
  • Experimental: Venetoclax + FLAG-IDA (Maintenance)
    Venetoclax 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.
    Intervention: Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 10, 2017)
56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2023
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Courtney DiNardo, MD 713-794-1141 cdinardo@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03214562
Other Study ID Numbers  ICMJE 2016-0979
710467 30 120634 28 ( Other Grant/Funding Number: HI-CRSP )
NCI-2018-01119 ( Registry Identifier: NCI CTRP )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE AbbVie
Investigators  ICMJE
Principal Investigator: Courtney DiNardo, MD M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP