Clinical Trials /

Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations

NCT04493138

Description:

This phase I/II trial studies the side effects and best dose of quizartinib when given with azacitidine and to see how well they work in treating patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy drugs, such as azacitidine, 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 azacitidine and quizartinib may help to control myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations
  • Official Title: Phase I/II Study of Azacitidine in Combination With Quizartinib for Patients With Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms With FLT3 or CBL Mutations

Clinical Trial IDs

  • ORG STUDY ID: 2019-1178
  • SECONDARY ID: NCI-2020-05261
  • SECONDARY ID: 2019-1178
  • NCT ID: NCT04493138

Conditions

  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Recurrent Myeloproliferative Neoplasm

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, quizartinib)
QuizartinibAC-220, AC010220, AC220Treatment (azacitidine, quizartinib)

Purpose

This phase I/II trial studies the side effects and best dose of quizartinib when given with azacitidine and to see how well they work in treating patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy drugs, such as azacitidine, 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 azacitidine and quizartinib may help to control myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib in
      combination with azacytidine.

      II. To assess overall response (ORR) rate to quizartinib in combination with azacitidine.

      SECONDARY OBJECTIVES:

      I. To assess overall survival (OS), duration of response, leukemia-free survival (LFS),
      relapse-free survival (RFS) and safety profile.

      II. Correlative studies.

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

      Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over about 30 minutes
      on days 1-5 and quizartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, quizartinib)ExperimentalPatients receive azacitidine SC or IV over about 30 minutes on days 1-5 and quizartinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Quizartinib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN)
             including chronic myelomonocytic leukemia (CMML) according to World Health
             Organization (WHO)

          -  For hypomethylating agent naive patients: int-2 or higher by International Prognostic
             Scoring System (IPSS) or > 5% bone marrow blasts if MDS or dysplastic CMML (white
             blood cell [WBC] < 13 x 10^9/L). Patients with proliferative (WBC >= 13 x 10^9/L) CMML
             or MDS/MPN, or those with dysplastic CMML with high-risk molecular features (mutations
             in ASXL1, TP53 or more than 3 mutations) are also eligible independently of IPSS risk
             score or bone marrow blast percentage

          -  For patients with prior hypomethylating agent therapy: no response after 6 cycles of
             azacitidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any
             number of cycles

          -  Detectable FLT3-ITD mutation in bone marrow and/or peripheral blood, or presence of
             CBL exon 8 or 9 deletions or point mutations

          -  Serum creatinine =< 2 x upper limit of normal (ULN)

          -  Total bilirubin < 2 x ULN (will allow less than 5 x ULN if Gilbert's at investigator's
             discretion)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x ULN

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Patient (or patient's legally authorized representative) must have signed an informed
             consent document indicating that the patient understands the purpose of and procedures
             required for the study and is willing to participate in the study

          -  Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors
             (eg, granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage
             colony-stimulating factor [GM-CSF], procrit, aranesp, thrombopoietins) is allowed at
             any time prior to or during study if considered to be in the best interest of the
             patient

        Exclusion Criteria:

          -  Uncontrolled infection not adequately responding to appropriate antibiotics

          -  Screening electrocardiogram (ECG) with a corrected QT interval by Fridericia's formula
             (QTcF) > 450 msec. The QTcF interval will be calculated by Fridericia's correction
             factor (QTcF). The QTcF will be derived from the average QTcF in triplicate. Patients
             are excluded if they have QTcF > 450. Subjects with prolonged QTcF interval in the
             setting of RBBB (right bundle branch block) may participate upon review and approval
             by the principal investigator and following evaluation by cardiology consult

          -  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 screening ECG

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

          -  Complete left bundle branch block

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

          -  New York Heart Association (NYHA) class III or IV congestive heart failure or left
             ventricular ejection fraction (LVEF) < 50 by echocardiogram or multigated acquisition
             (MUGA) scan

          -  History of myocardial infarction within the last 6 months or unstable/uncontrolled
             angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias

          -  Patients who are actively taking a strong CYP3A4 inducing medication

          -  Patients who require treatment with concomitant drugs that prolong QT/corrected 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, antiemetics (such as ondansetron) 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

          -  Female patients who are pregnant or lactating

          -  Patients with reproductive potential who are unwilling to following contraception
             requirements (including condom use for males with sexual partners, and for females:
             prescription oral contraceptives [birth control pills], contraceptive injections,
             intrauterine devices [IUD], double-barrier method [spermidical jelly or foam with
             condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the
             study

          -  Female patients with reproductive potential who do not have a negative urine or blood
             beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening

          -  Patients receiving any other concurrent investigational agent or chemotherapy,
             radiotherapy, or immunotherapy

          -  Patients known to be positive for hepatitis B surface antigen expression or with
             active hepatitis C infection (positive by polymerase chain reaction or on antiviral
             therapy for hepatitis C within the last 6 months). Patients with history of human
             immunodeficiency virus (HIV) disease are also excluded from the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:At least 4 cycles of therapy in the absence of progression (1 cycle = 28 days)
Safety Issue:
Description:Will be defined as complete remission, partial remission, complete remission with incomplete count recovery, marrow compete remission or hematological improvement. Will be estimated for all patients 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

July 27, 2020