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

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ClinicalTrials.gov Identifier: NCT04493138
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : August 25, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE July 27, 2020
First Posted Date  ICMJE July 30, 2020
Last Update Posted Date August 25, 2020
Actual Study Start Date  ICMJE July 21, 2020
Estimated Primary Completion Date February 3, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 27, 2020)
  • Overall response rate [ Time Frame: At least 4 cycles of therapy in the absence of progression (1 cycle = 28 days) ]
    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.
  • Overall survival [ Time Frame: Time from treatment start till death or last follow-up, assessed up to 2 years ]
    Will be listed and summarized by the Kaplan-Meier estimator.
  • Duration of response [ Time Frame: Duration from the first documented onset of partial response or complete response to the date of progressive disease/relapse, assessed up to 2 years ]
    Will be listed and summarized by the Kaplan-Meier estimator.
  • Relapse-free survival [ Time Frame: Time from start of response to the date of event defined as the first documented progressive disease/relapse or death, whichever comes first, assessed up to 2 years ]
    Will be listed and summarized by the Kaplan-Meier estimator.
  • Leukemia free survival [ Time Frame: Time from treatment start to the time of progression to leukemia or death, assessed up to 2 years ]
    Will be listed and summarized by the Kaplan-Meier estimator.
  • Incidence of adverse events (AEs) [ Time Frame: Up to 2 years ]
    The severity of the toxicities will be graded according to the latest version of National Cancer Institute Common Terminology Criteria for Adverse Events. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/Part. All reported AEs that occur after signing informed consent will be included in the analysis of all reported AEs. Exposure to study drug and reasons for discontinuation of study drug will be tabulated.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations
Official Title  ICMJE Phase I/II Study of Azacitidine in Combination With Quizartinib for Patients With Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms With FLT3 or CBL Mutations
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Recurrent Myeloproliferative Neoplasm
Intervention  ICMJE
  • Drug: Azacitidine
    Given SC or IV
    Other Names:
    • 5 AZC
    • 5-AC
    • 5-Azacytidine
    • 5-AZC
    • Azacytidine
    • Azacytidine, 5-
    • Ladakamycin
    • Mylosar
    • U-18496
    • Vidaza
  • Drug: Quizartinib
    Given PO
    Other Names:
    • AC-220
    • AC010220
    • AC220
Study Arms  ICMJE Experimental: Treatment (azacitidine, quizartinib)
Patients 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.
Interventions:
  • Drug: Azacitidine
  • Drug: Quizartinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 27, 2020)
58
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 3, 2022
Estimated Primary Completion Date February 3, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Guillermo M. Bravo 713-794-3604 ggarciam@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04493138
Other Study ID Numbers  ICMJE 2019-1178
NCI-2020-05261 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2019-1178 ( Other Identifier: M D Anderson Cancer Center )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Guillermo M Bravo M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP