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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04493138

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

29.3

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Myeloproliferative Neoplasm Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic Syndrome Recurrent Myeloproliferative Neoplasm	Drug: Azacitidine Drug: Quizartinib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib in combination with azacytidine.
To assess overall response (ORR) rate to quizartinib in combination with azacitidine.

SECONDARY OBJECTIVES:

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

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 21, 2020

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	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

Arm

Intervention/Treatment

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.

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

Outcome Measures

Primary Outcome Measures

Overall response rate [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 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 [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 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 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) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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