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.
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
Drug | Synonyms | Arms |
---|
Azacitidine | 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza | Treatment (azacitidine, quizartinib) |
Quizartinib | AC-220, AC010220, AC220 | Treatment (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
Name | Type | Description | Interventions |
---|
Treatment (azacitidine, quizartinib) | Experimental | 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. | |
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
August 25, 2020