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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

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.


Condition or disease Intervention/treatment Phase
Other Diseases of Blood and Blood-forming Organs Acute Myeloid Leukemia Drug: Fludarabine Drug: Cytarabine Drug: Idarubicin Drug: Filgrastim Drug: Pegylated Filgrastim Drug: Venetoclax Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 26, 2017
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
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.

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

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.

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

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.

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

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.
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




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03214562


Contacts
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Contact: Courtney DiNardo, MD 713-794-1141 cdinardo@mdanderson.org

Locations
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United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       cdinardo@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
AbbVie
Investigators
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Principal Investigator: Courtney DiNardo, MD M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03214562     History of Changes
Other Study ID Numbers: 2016-0979
710467 30 120634 28 ( Other Grant/Funding Number: HI-CRSP )
NCI-2018-01119 ( Registry Identifier: NCI CTRP )
First Posted: July 11, 2017    Key Record Dates
Last Update Posted: January 9, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
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

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Disease
Hematologic Diseases
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes
Fludarabine
Fludarabine phosphate
Cytarabine
Venetoclax
Idarubicin
Vidarabine
Lenograstim
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors