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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, cytarabine, filgrastim and idarubicin, 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: Venetoclax With Combination Chemotherapy in Treating Patients With Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive AML Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory AML

Clinical Trial IDs

  • ORG STUDY ID: 2016-0979
  • SECONDARY ID: NCI-2018-01119
  • SECONDARY ID: 2016-0979
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03214562

Conditions

  • High Risk Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (venetoclax, FLAG-IDA)
FilgrastimG-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (venetoclax, FLAG-IDA)
FludarabineFluradosaTreatment (venetoclax, FLAG-IDA)
Idarubicin4-Demethoxydaunomycin, 4-Demethoxydaunorubicin, 4-DMDRTreatment (venetoclax, FLAG-IDA)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSFTreatment (venetoclax, FLAG-IDA)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (venetoclax, FLAG-IDA)

Purpose

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, cytarabine, filgrastim and idarubicin, 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability and to determine the dose-limiting toxicity and
      the maximum tolerated dose MTD of the combination of fludarabine, cytarabine, filgrastim
      (GCSF), idarubicin (FLAG-IDA) + venetoclax for patients with acute myeloid leukemia (AML)
      (Phase 1b).

      II. To determine the overall activity of this combination in patients newly diagnosed or
      relapsed/refractory (AML) (Phase 2).

      SECONDARY OBJECTIVES:

      I. Determine the preliminary assessment of efficacy by response to revised International
      Working Group (IWG) criteria and time to response variables including overall survival (OS),
      event-free survival (EFS) and duration of response (DOR).

      II. Determine biomarkers that may be predictive of venetoclax activity.

      OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

      INDUCTION THERAPY: Patients receive venetoclax orally (PO) on days 1-14, fludarabine
      intravenously (IV) over 30 minutes on days 2-6, cytarabine IV over 4 hours on days 2-6,
      idarubicin IV over 15-30 minutes on days 4 and 5, filgrastim subcutaneously (SC) on days 1-7,
      or pegfilgrastim SC after day 5. Treatment repeats every 28 days for up to 2 cycles in the
      absence of disease progression or unacceptable toxicity.

      CONSOLIDATION THERAPY: Patients receive venetoclax PO on days 1-7, fludarabine IV over 30
      minutes on days 2-4, cytarabine IV over 4 hours on days 2-4, filgrastim SC on days 1-7, or
      pegfilgrastim SC after days 3. Treatment repeats every 28 days for up to 6 cycles in the
      absence of disease progression or unacceptable toxicity. Patients may also receive idarubicin
      as in Induction Therapy during 1 cycle of Consolidation Therapy per the treating physician.

      MAINTENANCE THERAPY: Patients receive venetoclax PO on days 1-28. Cycles repeat every 28 days
      for up to 1 year in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up within 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, FLAG-IDA)ExperimentalSee detailed description.
  • Cytarabine
  • Filgrastim
  • Fludarabine
  • Idarubicin
  • Pegfilgrastim
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Patients older than 65 who are deemed fit to receive intensive chemotherapy by the
             treating physician will be eligible after discussion with the principal investigator
             (PI).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

          -  Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation

          -  Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to
             Gilbert's disease or leukemic involvement

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN
             unless considered due to leukemic involvement

          -  Ability to understand and provide signed informed consent

          -  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

          -  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:

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

          -  Patients having received any prior BCL2 inhibitor therapy

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

          -  Patients with New York Heart Association (NYHA) class III or IV congestive heart
             failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram or
             multi-gated acquisition (MUGA) scan

          -  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

          -  Patients with known infection with human immunodeficiency virus (HIV) or active
             hepatitis B or C

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

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

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

          -  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, intrauterine device (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:Overall response rate (ORR)
Time Frame:Up to 6 years
Safety Issue:
Description:Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval.

Secondary Outcome Measures

Measure:Morphologic leukemia-free state
Time Frame:Up to 6 years
Safety Issue:
Description:Will be estimated along with the 95% credible interval.

Details

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

Last Updated

June 18, 2020