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

NCT04493138 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2019-1178NCI-2020-05261
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (6)

• Overall response rate

  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.

  At least 4 cycles of therapy in the absence of progression (1 cycle = 28 days)

• Overall survival

  Will be listed and summarized by the Kaplan-Meier estimator.

  Time from treatment start till death or last follow-up, assessed up to 2 years

• Duration of response

  Will be listed and summarized by the Kaplan-Meier estimator.

  Duration from the first documented onset of partial response or complete response to the date of progressive disease/relapse, assessed up to 2 years

• Relapse-free survival

  Will be listed and summarized by the Kaplan-Meier estimator.

  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

• Leukemia free survival

  Will be listed and summarized by the Kaplan-Meier estimator.

  Time from treatment start to the time of progression to leukemia or death, assessed up to 2 years

• Incidence of adverse events (AEs)

  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.

  Up to 2 years

Study Arms (1)

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.

Drug: Azacitidine; Drug: Quizartinib

Interventions

Azacitidine DRUG

Given SC or IV

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment (azacitidine, quizartinib)

Quizartinib DRUG

Given PO

Also known as: AC-220, AC010220, AC220

Treatment (azacitidine, quizartinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 0-2.
• 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.

You may not qualify if:

• 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 \>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. 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.
• 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 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/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.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Montalban-Bravo G, Jabbour E, Chien K, Hammond D, Short N, Ravandi F, Konopleva M, Borthakur G, Daver N, Kanagal-Shammana R, Loghavi S, Qiao W, Huang X, Schneider H, Meyer M, Kantarjian H, Garcia-Manero G. Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN. Leuk Res. 2024 Jul;142:107518. doi: 10.1016/j.leukres.2024.107518. Epub 2024 May 11.

  PMID: 38744144 DERIVED

Related Links

• http://www.mdanderson.org

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Myeloproliferative Disorders

Interventions

Azacitidine; quizartinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Guillermo M Bravo

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2020
• First Posted: July 30, 2020
• Study Start: July 21, 2020
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 4, 2026

Record last verified: 2026-05

Locations

US (1)