Clinical Trials /

Quizartinib With Azacitidine or Cytarabine in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT01892371

Description:

This phase I/II trial studies the side effects and best dose of quizartinib when given in combination with azacitidine or cytarabine in treating participants with acute myeloid leukemia or myelodysplastic syndrome that have come back or are not responding to treatment. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine 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. Giving quizartinib with azacitidine or cytarabine may work better in participants with acute myeloid leukemia or myelodysplastic syndrome.

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

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Quizartinib With Azacitidine or Cytarabine in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: Phase I/II Study of the Combination of Quizartinib (AC220) With 5-Azacytidine or Low-Dose Cytarabine for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: 2012-1047
  • SECONDARY ID: NCI-2018-01813
  • SECONDARY ID: 2012-1047
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: P50CA100632
  • NCT ID: NCT01892371

Conditions

  • FLT3 Gene Mutation
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaArm I (quizartinib, azacitidine)
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-28453Arm II (quizartinib, cytarabine)
QuizartinibAC-220, AC010220, AC220Arm I (quizartinib, azacitidine)

Purpose

This phase I/II trial studies the side effects and best dose of quizartinib when given in combination with azacitidine or cytarabine in treating participants with acute myeloid leukemia or myelodysplastic syndrome that have come back or are not responding to treatment. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine 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. Giving quizartinib with azacitidine or cytarabine may work better in participants with acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the
      combination of quizartinib (AC220) with either azacitidine (5-azacitidine [AZA]) or low-dose
      cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic
      syndrome (MDS). (Phase I) II. To determine the clinical activity of the combination of
      quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine the clinical activity of the combination of quizartinib with either AZA or
      LDAC in patients with AML or MDS. (Phase I) II. To determine the safety of the combination of
      quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II) III. To determine
      the induction of hypomethylation, deoxyribonucleic acid (DNA) damage and FLT3 signaling
      during therapy with this combination and its correlation with response. (Phase I and II) IV.
      To determine the effect of this combination therapy on plasma levels of FLT3-ligand. (Phase I
      and II) V. To determine the pharmacodynamics of this combination therapy in patients with AML
      or high-risk MDS. (Phase I and II)

      OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II
      study. Participants are assigned to 1 of 2 arms.

      ARM I: Participants receive quizartinib orally (PO) once daily (QD) on days 5-28 of course 1
      and on days 1-28 of subsequent courses and azacitidine subcutaneously (SC) or intravenously
      (IV) over 10-40 minutes on days 1-7. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Participants receive quizartinib PO QD on days 5-28 of course 1 and on days 1-28 of
      subsequent courses and cytarabine SC twice daily (BID) on days 1-10. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (quizartinib, azacitidine)ExperimentalParticipants receive quizartinib PO QD on days 5-28 of course 1 and on days 1-28 of subsequent courses and azacitidine SC or IV over 10-40 minutes on days 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Quizartinib
Arm II (quizartinib, cytarabine)ExperimentalParticipants receive quizartinib PO QD on days 5-28 of course 1 and on days 1-28 of subsequent courses and cytarabine SC BID on days 1-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Quizartinib

Eligibility Criteria

        Inclusion Criteria:

          -  PHASE I

          -  Refractory or relapsed disease defined as follows: patients with MDS or chronic
             myelomonocytic leukemia (CMML) should have failed prior therapy (e.g., with a
             hypomethylating agent, clofarabine, and/or with lenalidomide); patients with AML
             should have failed any prior induction therapy or have relapsed after prior therapy;
             patients (any age) with MDS or CMML who received therapy with a hypomethylating agent
             and progress to AML are eligible at the time of diagnosis of AML regardless any prior
             therapy for AML. The World Health Organization (WHO) classification will be used for
             AML; patients with any of the eligible diagnoses who have received no prior therapy
             are eligible if not candidates to receive standard intensive therapy (i.e., high-dose
             cytarabine-based chemotherapy).

          -  Patients are eligible regardless of their FLT3 mutation status.

          -  PHASE II

          -  Patients with MDS, CMML or AML who are either: age 60 years or older and newly
             diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C
             for the purpose of control of white blood cells (WBC) is acceptable.; age 18 years or
             older and with refractory or relapse disease who have received no more than one prior
             treatment regimen and will be receiving first salvage. For this purpose, a second
             induction cycle with the same drugs used during the first cycle, consolidation
             chemotherapy or stem cell transplant in complete remission (CR) (or complete response
             with incomplete platelet recovery [CRp] or complete response with incomplete bone
             marrow recovery [CRi]) will be considered part of the prior regimen. Prior therapy for
             MDS (or other malignancies) is not considered a prior regimen for AML in patients who
             progress from MDS (or other malignancies).

          -  Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent
             and progress to AML are eligible at the time of diagnosis of AML regardless any prior
             therapy for AML. The WHO classification will be used for AML.

          -  Patients must have evidence of FLT3 ITD in their most recent assessment.

          -  PHASE I AND II

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

          -  Bilirubin =< 2 x upper limit of normal (ULN).

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN.

               -  For patients with suspected liver infiltration from leukemia ALT should be =< 5
                  ULN.

          -  Creatinine =< 2 x ULN.

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

          -  Patients must provide written informed consent.

          -  Patients must have been off chemotherapy for 2 weeks prior to entering this study,
             unless there is evidence of rapidly progressive disease, and must have recovered from
             the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for patients
             with rapidly proliferative disease is allowed before the start of study therapy and
             for the first four weeks on therapy. The additional days of hydrea after 28 is
             permitted as clinically indicated, on case by case basis after discussion with the
             principal investigator (PI). Other agents given transiently with the intention to
             control rapid proliferation such as 1-2 doses of single agent ara-C or few doses of
             sorafenib are also allowed.

          -  Women of childbearing potential must practice contraception. Women considered not of
             childbearing potential include any of the following: no menses for at least 2 years or
             menses within 2 years but amenorrheic for at least 2 months and luteinizing hormone
             (LH) and follicular stimulating hormone (FSH) values within normal range (according to
             definition of postmenopausal for laboratory used) or bilateral oophorectomy or
             radiation castration and amenorrheic for at least 3 months. Females of childbearing
             potential should practice effective methods of contraception Effective methods of
             contraception include barrier methods (e.g., condoms, diaphragm), spermicidal jelly or
             foam, oral, depo provera, or injectable contraceptives, intrauterine devices, tubal
             ligation, and abstinence. Male patients with female partners who are of childbearing
             potential should also practice contraception.

          -  Negative urine or serum pregnancy test.

        Exclusion Criteria:

          -  Patients with known allergy or hypersensitivity to quizartinib, mannitol, AZA,
             cytarabine or any of their components.

          -  Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L.

          -  Serum magnesium above or below the institutional normal limit despite adequate
             management.

          -  Serum calcium (corrected for albumin levels) above or below institutional normal limit
             despite adequate management.

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

          -  Patients with any other known disease concurrent severe and/or uncontrolled medical
             condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive
             heart failure, myocardial infarction within 6 months and poorly controlled
             hypertension, chronic renal disease, or active uncontrolled infection) which could
             compromise participation in the study. 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 have active disease or be in remission for less than
             6 months.

          -  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.

          -  Patients with known malignant disease of the central nervous system.

          -  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 on day 5 prior
             to the first dose of AC220. The QTcF will be derived from the average QTcF in
             triplicate; if QTcF > 450 msec on day 5, AC220 will not be given; patients with
             congenital long QT syndrome; history or presence of 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; 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; patients who require treatment with concomitant drugs
             that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the
             exception of antibiotics, antifungals, and antivirals that are used as standard of
             care to prevent or treat infections and other such drugs that are considered
             absolutely essential for the care of the subject.

          -  Known family history of congenital long QT syndrome.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of quizartinib (Phase I)
Time Frame:At 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 12 months
Safety Issue:
Description:

Details

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

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