Phase I/II Study of Azacitidine in Combination With Quizartinib for Patients With Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms With FLT3 or CBL Mutations
Overview
- Phase
- Phase 1
- Intervention
- Azacitidine
- Conditions
- Chronic Myelomonocytic Leukemia
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 58
- Locations
- 1
- Primary Endpoint
- Overall response rate
- Status
- Recruiting
- Last Updated
- 16 days ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years as MDS is a very rare disease in the pediatric setting.
- •Diagnosis of MDS or MDS/MPN including CMML according to WHO.
- •For hypomethylating agent naïve patients: int-2 or higher by IPSS or \>5% bone marrow blasts if MDS or dysplastic CMML (WBC \<13x109/L). Patients with proliferative (WBC \>/= 13x109/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 \</= 2xULN.
- •Adequate hepatic function with total bilirubin \<2x ULN (will allow less than 5xULN if Gilbert's at investigator's discretion), AST or ALT \</=3xULN.
- •ECOG Performance Status 0-
- •Patient 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, G-CSF, 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 ECG with a 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 \>
- •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. The heart rate will be derived from the average heart rate in triplicate.
- •Right bundle branch block + left anterior hemiblock (bifascicular block).
- •Complete left bundle branch block.
Arms & Interventions
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.
Intervention: Azacitidine
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.
Intervention: Quizartinib
Outcomes
Primary Outcomes
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.
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.
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.
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.