Clinical Trials /

Cladribine, Idarubicin, Cytarabine, and Quizartinib in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

NCT04047641

Description:

This phase II trial studies the side effects and how well cladribine, idarubicin, cytarabine, and quizartinib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Drugs used in chemotherapy, such as cladribine, idarubicin, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving quizartinib with cladribine, idarubicin, and cytarabine may help to control acute myeloid leukemia or high-risk myelodysplastic syndrome.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cladribine, Idarubicin, Cytarabine, and Quizartinib in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
  • Official Title: A Combination of Cladribine, Idarubicin, Cytarabine (CLIA) and Quizartinib for the Treatment of Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS))

Clinical Trial IDs

  • ORG STUDY ID: 2017-0153
  • SECONDARY ID: NCI-2019-04730
  • SECONDARY ID: 2017-0153
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04047641

Conditions

  • Acute Myeloid Leukemia
  • Blasts 20 Percent or More of Bone Marrow Nucleated Cells
  • High Risk Myelodysplastic Syndrome
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory High Risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (idarubicin, cladribine, cytarabine, quizartinib)
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 (idarubicin, cladribine, cytarabine, quizartinib)
Idarubicin4-Demethoxydaunomycin, 4-demethoxydaunorubicin, 4-DMDRTreatment (idarubicin, cladribine, cytarabine, quizartinib)
QuizartinibAC-220, AC010220, AC220Treatment (idarubicin, cladribine, cytarabine, quizartinib)

Purpose

This phase II trial studies the side effects and how well cladribine, idarubicin, cytarabine, and quizartinib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Drugs used in chemotherapy, such as cladribine, idarubicin, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving quizartinib with cladribine, idarubicin, and cytarabine may help to control acute myeloid leukemia or high-risk myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy (defined as event-free survival) of quizartinib (AC220) in
      combination with cladribine, idarubicin and cytarabine (ara-C) induction chemotherapy in
      newly diagnosed or relapsed/refractory patients with high-risk acute myeloid leukemia (AML)
      and high-risk myelodysplastic syndrome (MDS).

      II. To determine the safety of the combination.

      SECONDARY OBJECTIVES:

      I. To determine the overall survival and disease-free survival of patients treated with this
      combination.

      II. To investigate correlations of response to this combination with a 81-gene panel of gene
      mutations both in patients with and without FLT3 mutations.

      III. To identify individual treatment-resistant cell populations and their signaling state
      that may relate to clinical outcomes using CyTOF (cytometry by time of flight) and single
      cell sequencing.

      OUTLINE:

      INDUCTION: Patients receive idarubicin intravenously (IV) over 1 hours on days 1-3,
      cladribine IV over 1-2 hours on days 1-5, cytarabine IV over 3 hours on days 1-5 (or days 1-3
      for patients over age 60), and quizartinib orally (PO) once daily (QD) on days 6-19.
      Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      CONSOLIDATION: Patients who achieve complete response (CR) or CR with incomplete platelet
      recovery (CRp) after Induction receive idarubicin IV over 1 hours on days 1-2, cladribine IV
      over 1-2 hours on days 1-3, cytarabine IV over 3 hours on days 1-3, and quizartinib PO QD on
      days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE: Patients who achieve CR or CR with incomplete bone marrow recovery (CRi)/CR with
      partial hematologic recovery (CRh) after Consolidation receive quizartinib PO QD on days
      1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6-12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (idarubicin, cladribine, cytarabine, quizartinib)ExperimentalINDUCTION: Patients receive idarubicin Intravenous over 1 hours on days 1-3, cladribine intravenous over 1-2 hours on days 1-5, cytarabine Intravenous over 3 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib by mouth daily on days 6-19. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients who achieve CR or CRp after Induction receive idarubicin Intravenous over 1 hours on days 1-2, cladribine Intravenous over 1-2 hours on days 1-3, cytarabine Intravenous over 3 hours on days 1-3, and quizartinib by mouth daily on days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients who achieve CR or CRi/CRh after Consolidation receive quizartinib by mouth daily on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Cladribine
  • Cytarabine
  • Idarubicin
  • Quizartinib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of

               -  AML (World Health Organization [WHO] classification definition of >= 20% blasts,
                  excluding Acute promyelocytic leukemia),

               -  Acute biphenotypic leukemia or

               -  High-risk MDS (> 10% bone marrow blasts)

          -  Frontline cohort: Patients aged 18 to 65 years

          -  Relapse cohort: Patients aged >=18 years old

          -  Patients may be newly diagnosed (Frontline cohort) or with prior therapy (Relapsed
             cohort) as follows:

               -  For frontline cohort: Patients must be chemonaive, i.e., not have received any
                  chemotherapy (except hydroxyurea [Hydrea] [no dose limit], tretinoin [atra] [no
                  dose limit] or ara-C [one or two doses (max 2 gr/m^2 per dose)] for transient
                  control of hyperleukocytosis) for AML or MDS. They may have received
                  hypomethylating agents for prior MDS and transfusions, hematopoietic growth
                  factors or vitamins. Temporary prior measures such as apheresis or Hydrea are
                  allowed

               -  For relapsed cohort: Patients with previously treated, relapsed or refractory
                  AML, acute biphenotypic leukemia or high-risk MDS (> 10% bone marrow blasts)

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

          -  Creatinine < 1.5 mg/dl

          -  Total bilirubin < 1.5 mg/dL, unless increase is due to hemolysis or congenital
             disorder

          -  Transaminases (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of
             normal (ULN)

          -  Potassium, magnesium, and calcium (normalized for albumin) levels should be at least
             within institutional normal limits

          -  Ability to take oral medication

          -  Ability to understand and provide signed informed consent

          -  Baseline test of left ventricular ejection fraction >= 50%

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test within 7 days

          -  WOCBP must use appropriate method(s) of contraception such as oral contraceptive pills
             (OCP), birth control shots, intrauterine device (IUD) etc. WOCBP should use an
             adequate method to avoid pregnancy until 30 days after the last dose of
             investigational drug. Men must agree not to father a child and agree to use a condom
             if his partner is of child bearing potential. Women who are not of childbearing
             potential (ie, who are postmenopausal or surgically sterile) as well as men with known
             azoospermia do not require contraception

        Exclusion Criteria:

          -  Any coexisting medical condition that in the judgment of the treating physician is
             likely to interfere with study procedures or results

          -  Breastfeeding women

          -  Patients with current active malignancies or any remission for < 6 months, except
             patients with carcinoma in situ or with non-melanoma skin cancer who may be in
             remission for less than 6 months or have active disease

          -  Active clinically serious and uncontrolled infection. Patients with recent infections
             must have no temperature of >= 101 degrees Fahrenheit (F) for at least 48 hours (hrs)

          -  Patients with known significant impairment of gastrointestinal (GI) function or GI
             disease that may significantly alter the absorption of quizartinib

          -  Documented active central nervous system leukemia (patients with history of central
             nervous system [CNS] leukemia without active disease are allowed)

          -  Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV)
             infection or active viral hepatitis

          -  Patients who have had any major surgical procedure within 14 days of day 1

          -  Impaired cardiac function including any of the following:

               -  Screening electrocardiography (ECG) with a corrected QT (QTc) > 450 msec. The QTc
                  interval will be calculated by Fridericia's correction factor (QTcF) at screening
                  and prior to the first dose of quizartinib (on day 6 during induction and day 4
                  during consolidation). The QTcF will be derived from the average QTcF in
                  triplicate. If QTcF > 450 msec prior to the first dose, quizartinib will not be
                  given until corrected

               -  Patients with congenital long QT syndrome

               -  Sustained ventricular tachycardia requiring medical intervention

               -  Any history of clinically significant ventricular fibrillation or torsades de
                  pointes

               -  Known history of second or third degree heart block (may be eligible if the
                  patient currently has a pacemaker)

               -  Sustained heart rate of < 50/minute on pre-entry ECG

               -  Left bundle branch block

               -  Right bundle branch block + left anterior hemiblock (bifascicular block)

               -  Patients with myocardial infarction or unstable angina within 6 months prior to
                  starting study drug

               -  Congestive heart failure (CHF) New York (NY) Heart Association class III or IV

               -  Atrial fibrillation documented within 2 weeks prior to first dose of study drug

               -  Known family history of congenital long QT syndrome

               -  Patients who are actively taking a strong CYP3A4 inducing medication
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event free survival (EFS)
Time Frame:From the date of start of treatment until event (resistance or relapse) or death, whichever occurred first, assessed up to 12 months
Safety Issue:
Description:Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy EFS will be analyzed in the intent to treat (ITT) population per cohort.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 12 months
Safety Issue:
Description:Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy OS will be analyzed in the ITT population per cohort.
Measure:Disease free survival (DFS)
Time Frame:Up to 12 months
Safety Issue:
Description:Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy DFS will be analyzed in the ITT population per cohort.
Measure:Rate of response
Time Frame:Up to 12 months
Safety Issue:
Description:The rate of response will be estimated for each 28-gene panel of gene mutations for each patient cohort.
Measure:Change of FLT3 ligand level
Time Frame:Baseline up to 12 months
Safety Issue:
Description:Will also explore the change of FLT3 ligand level before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).
Measure:Change in the presence of other gene mutations
Time Frame:Baseline up to 12 months
Safety Issue:
Description:Will also explore the change in the presence of other gene mutations before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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