Clinical Trials /

Quizartinib and Decitabine in Treating Participants With Untreated or Relapsed FLT3-ITD Mutated Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT03661307

Description:

This phase I/II trial studies how well quizartinib and decitabine work in treating participants with FLT3-ITD mutated acute myeloid leukemia or myelodysplastic syndrome that is untreated or has come back. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 and decitabine may work better at treating acute myeloid leukemia and myelodysplastic syndrome.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Quizartinib and Decitabine in Treating Participants With Untreated or Relapsed FLT3-ITD Mutated Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: A Phase I/II Study of Quizartinib in Combination With Decitabine for the Treatment of Patients With FLT3-ITD Mutated Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0394
  • SECONDARY ID: NCI-2018-01789
  • SECONDARY ID: 2018-0394
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03661307

Conditions

  • Acute Myeloid Leukemia With FLT3/ITD Mutation
  • Blasts More Than 10 Percent of Bone Marrow Nucleated Cells
  • Blasts More Than 10 Percent of Peripheral Blood White Cells
  • Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, quizartinib)
QuizartinibAC-220, AC010220, AC220Treatment (decitabine, quizartinib)

Purpose

This phase I/II trial studies how well quizartinib and decitabine work in treating participants with FLT3-ITD mutated acute myeloid leukemia or myelodysplastic syndrome that is untreated or has come back. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 and decitabine may work better at treating acute myeloid leukemia and myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall response rate (ORR) including CR (complete remission) + CRp
      (complete remission with incomplete platelet recovery) + CRi (complete remission with
      incomplete count recovery) + partial remission (PR) within 3 months of treatment initiation
      of quizartinib and decitabine combination in patients with newly diagnosed or relapsed
      FLT3-ITD mutated acute myeloid leukemia (AML).

      II. To determine the safety and maximum tolerable dose (MTD) of this combination.

      SECONDARY OBJECTIVES:

      I. To determine the duration of response (DOR), event-free survival (EFS), overall survival
      (OS), and number of patients bridged to hematopoietic stem cell transplant (HSCT) and median
      duration to HSCT from the initiation of the combination.

      II. To investigate correlations of response to this combination with a pre-therapy,
      on-therapy, and progression 81-gene panel of gene mutations in AML and FLT3-ITD allele burden
      by reverse transcription polymerase chain reaction (RT-PCR).

      III. To determine the effect of this combination therapy on in-vivo FLT3 inhibition.

      EXPLORATORY OBJECTIVES:

      I. Quantitative changes of FLT3-ITD allelic burden and longitudinal evaluation to identify
      emergence of FLT3 non-ITD mutations with time in patients treated with the combination.

      II. To evaluate the extent of pharmacodynamics biomarker (such as p-FLT3, p-p70S6K, pERK,
      BCL-2, MCL1) inhibition and the induction of apoptosis in the bone marrow and peripheral
      blasts following treatment with the combination.

      III. To investigate possible relationships between response and non-response to the
      combination with pretherapy, on-therapy, and progression gene expression signatures.

      IV. To store and/or analyze surplus blood or tissue including bone marrow, if available, for
      potential future exploratory research into factors that may influence development of AML
      and/or response to the combination (where response is defined broadly to include efficacy,
      tolerability or safety).

      OUTLINE: This is a phase I, dose escalation study followed by a phase I study.

      Participants receive decitabine intravenously (IV) over 1 hour on days 1-10 and quizartinib
      orally (PO) every day beginning on day 5 of course 1. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3-6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, quizartinib)ExperimentalParticipants receive decitabine IV over 1 hour on days 1-10 and quizartinib PO every day beginning on day 5 of course 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Quizartinib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of 1) AML (World Health Organization [WHO] classification definition of >=
             20% blasts), or 2) myelodysplastic syndrome (MDS) with > 10% blasts (defined by the
             International Prognostic Scoring System [IPSS] classification).

          -  For frontline Cohort: Patients aged >= 60 years old.

          -  For relapsed cohort: Patients aged >= 18 years old.

          -  For frontline cohort: Patients must be chemonaive, i.e. not have received any
             chemotherapy (except hydrea or 1-2 doses of ara-C for transient control of
             hyperleukocytosis) for AML or MDS. They may have received transfusions, hematopoietic
             growth factors or vitamins for an antecedent hematological disorder (AHD) or for AML.
             Temporary prior measures such as apheresis, all-trans-retinoic acid (ATRA), steroids
             or hydrea while diagnostic work-up is being performed are allowed and not counted as a
             prior salvage.

          -  For relapsed cohort: Patients who have received at least one prior therapy for AML or
             for MDS with > 10% blasts will be eligible. Patients may have received up to 3 prior
             regimens for AML and/or MDS (defined by the IPSS classification). Prior therapy for
             AML or MDS will be counted as a prior salvage.

          -  In the absence of rapidly progressing disease, the interval from prior treatment to
             time of initiation of protocol therapy will be at least 2 weeks for cytotoxic agents
             or at least 5 half-lives for cytotoxic/noncytotoxic agents. The half-life for the
             therapy in question will be based on published pharmacokinetic literature and will be
             documented in the protocol eligibility document.

          -  The use of chemotherapeutic or anti-leukemic agents is not permitted during the study
             with the following exceptions: (1) intrathecal (IT) therapy for patients with
             controlled central nervous system (CNS) leukemia at the discretion of the PI and with
             the agreement of the Sponsor. Controlled CNS leukemia is defined by the absence of
             active clinical signs of CNS disease and no evidence of CNS leukemia on the most
             recent 2 simultaneous cerebrospinal fluid (CSF) evaluations (2) Use of one dose of
             cytarabine (up to 2 g/m^2) or hydroxyurea for patients with rapidly proliferative
             disease is allowed before the start of study therapy and for the first four weeks on
             therapy. These medications will be recorded in the case-report form.

          -  Detection of FLT3-ITD mutation or FLT3-ITD/TKD co-mutations in bone marrow and/or
             peripheral blood samples within 30 days prior to study enrollment.

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

          -  Serum biochemical values with the following limits unless considered due to leukemia,
             hemolysis or congenital disorder (creatinine < 1.8 mg/dl, total bilirubin < 1.8 mg/dL,
             [serum glutamate pyruvate transaminase (SGPT)] < 2.5 x upper limit of normal).

          -  Ability to take oral medication.

          -  Ability to understand and provide signed informed consent.

          -  Baseline left ventricular ejection fraction by echocardiogram (ECHO) or multigated
             acquisition (MUGA) >= 50%.

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test within 7 days. Men must agree not to father a child and agree to use a condom if
             his partner is of child bearing potential.

          -  WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate
             method to avoid pregnancy until at least 3 months after the last dose of
             investigational drug. Women who are not of childbearing potential (ie, who are
             postmenopausal or surgically sterile) as well as men with azoospermia do not require
             contraception.

          -  Negative urine or serum pregnancy test.

        Exclusion Criteria:

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

          -  Patients with electrolyte abnormalities at study entry defined as follows: 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 concurrent severe and/or uncontrolled medical condition
             including but not limited to diabetes, cardiovascular disease including hypertension,
             renal disease, or active uncontrolled infection, which could compromise participation
             in the study. Patients on active antineoplastic or radiation therapy for a concurrent
             malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid
             therapy for well-controlled malignancy is allowed.

          -  Patients with a known human immunodeficiency virus (HIV) infection.

          -  Patients with known positive hepatitis B or C infection by serology, with the
             exception of those with an undetectable viral load within 3 months. (Hepatitis B or C
             testing is not required prior to study entry). Subjects with serologic evidence of
             prior vaccination to HBV [i.e., hepatitis B surface antigen [HBs Ag]-, and anti-HBs+]
             may participate.

          -  Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Starfruit within 3 days prior to the
             initiation of study treatment.

          -  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 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). complete left bundle branch 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
             are actively taking a strong CYP3A4 inducing medication.

          -  Patients who require treatment with concomitant drugs that prolong QT/QTc interval or
             strong CYP3A4 inhibitors 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 or if
             the Investigator believes that beginning therapy with a potentially QTc-prolonging
             medication (such as anti-emetic) is vital to an individual subject's care while on
             study.

          -  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 the combination drugs (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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