Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm

A Phase I/II Study of Azacitidine, Venetoclax, and Gilteritinib for Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome With an Activating FLT3 Mutation

This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, 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. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Acute Myeloid Leukemia; Recurrent Chronic Myelomonocytic Leukemia; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Recurrent Myelodysplastic/Myeloproliferative Neoplasm; Refractory Myelodysplastic/Myeloproliferative Neoplasm
• Intervention / Treatment: Drug: Venetoclax; Drug: Gilteritinib; Drug: Azacitidine

Detailed Description

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of the combination of azacitidine, venetoclax and gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML) or high-risk myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). (Phase I) II. To determine the complete remission/complete remission with incomplete count recovery (CR/CRi) rate of the regimen in patients with newly diagnosed or relapsed/refractory fms-like tyrosine kinase 3 (FLT3)-mutated AML or CMML or high-risk MDS/MPN. (Phase II)

SECONDARY OBJECTIVES:

I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, overall survival).

II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).

III. To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.

II. To determine the impact of baseline FLT3 allelic ratio on response and survival.

III. To evaluate clonal evolution from diagnosis to relapse using single-cell sequencing.

OUTLINE: This is phase I, dose-escalation study of gilteritinib followed by a phase II study.

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib 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 and then every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Estimated): 97
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Nicholas Short; Phone Number: 713-563-4485; Email: nshort@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Nicholas Short; Phone Number: 713-563-4485; Email: nshort@mdanderson.org
      • Principal Investigator: Nicholas Short

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis:

  • Phase I cohort: Adults ≥ 18 years with relapsed/refractory FLT3-mutated AML or CMML or other MDS/MPN that is intermediate-2 or high-risk by the International Prognostic Scoring System
  • Phase II cohort A: Adults ≥ 18 years with newly diagnosed FLT3-mutated AML
  • Phase II cohort B: Adults ≥ 18 years with relapsed/refractory FLT3-mutated AML or CMML or other MDS/MPN that is intermediate-2 or high-risk by the International Prognostic Scoring System
  • For all cohorts, patients with either FLT3-internal tandem duplication (FLT3-ITD) or FLT3 D835 mutations will be eligible
• Performance status ≤ 3 (Eastern Cooperative Oncology Group [ECOG] scale)
• Total serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the principal investigator (PI)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 x ULN, unless due to the underlying leukemia approved by the PI
• Creatinine clearance ≥ 30 mL/min
• Ability to swallow
• Signed informed consent

Exclusion Criteria:

• Prior therapies:

  • Phase I cohort: No restriction based on prior therapies
  • Phase II cohort A: Patients with prior therapy for AML are not eligible. Prior therapy for antecedent hematologic disorder is allowed. Prior hydroxyurea or cytarabine given for purposes of cytoreduction is also allowed. Prior all trans-retinoic acid given for presumed acute promyelocytic leukemia is also allowed
  • Phase II cohort B: No restriction on number of prior therapies
• Patients suitable for and willing to receive intensive induction chemotherapy (for Phase II cohort A only)
• Congenital long QT syndrome or corrected QT interval by Fridericia (QTcF) > 450 msec. Repeat electrocardiograms (EKGs) after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria. In cases where QTcF > 450 msec is considered to be falsely increased due to inaccurate automated reading and not clinically significant (e.g. due to bundle branch block), patients are still eligible if cardiologist reviews and documents that QTcF is ≤ 450 msec when manually measured
• Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
• Active grade III-V cardiac failure as defined by the New York Heart Association criteria
• Active central nervous system leukemia
• Known human immunodeficiency virus (HIV) seropositive

• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

  • Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
• Consumed strong inducer of cytochrome P450, family 3, subfamily A (CYP3A) or p-glycoprotein within 3 days of study enrollment. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wort
• Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) permitted
• Pregnant women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception throughout the study period and for at least 6 months after the last dose of study drugs. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control throughout the study period and for at least 4 months after the last dose of study drugs. Lactating women (or those planning to breastfeed) should not breastfeed during treatment of gilteritinib and for at least 2 months after the last dose of gilteritinib

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (azacitidine, venetoclax, gilteritinib); Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Gilteritinib; Given PO; Other Names: ASP2215; ASP-2215; Drug: Azacitidine; Given IV; Other Names: 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; Onureg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum-tolerated dose (MTD) of gilteritinib (Phase I)	The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.	Up to 28 days
Overall response rate (OR) (Phase II)	Will be defined as the complete remission/complete remission with incomplete count recovery (CR/CRi) rate. Will estimate the OR for the combination treatment along with the 95% credible interval.	Up to 56 days (2 cycles)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate	Will be estimated along with 95% credible interval.	Up to 3 years
Minimal residual disease negativity	Will be assessed by flow cytometry and estimated along with 95% credible interval.	Up to 3 years
Relapse-free survival	Will be estimated using the method of Kaplan and Meier.	The number of days from the date of response to the date of documented relapses from CR or death from any cause, whichever occurs first, assessed up to 3 years
Overall survival	Will be estimated using the method of Kaplan and Meier.	From the start of treatment until death or last follow-up, assessed for up to 3 years
Proportion of patients proceeding to hematopoietic stem cell transplantation	Will be estimated along with 95% credible interval.	Up to 3 years
Incidence of adverse events	Will be summarized using descriptive statistics such as mean, standard deviation, median and range.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of genomic alterations	The impact of genomic alterations on response and the survival of the combination regimen will be assessed. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.	Baseline
Impact of FLT3 allelic ratio	The impact of FLT3 allelic ratio on response and the survival will be assessed. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.	Baseline
Minimal residual disease negativity rates	Will be assessed by digital droplet polymerase chain reaction. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.	At time of remission
Evaluation of leukemia stem cell populations	Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.	Up to 3 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Nicholas Short, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Short NJ, Daver N, Dinardo CD, Kadia T, Nasr LF, Macaron W, Yilmaz M, Borthakur G, Montalban-Bravo G, Garcia-Manero G, Issa GC, Chien KS, Jabbour E, Nasnas C, Huang X, Qiao W, Matthews J, Stojanik CJ, Patel KP, Abramova R, Thankachan J, Konopleva M, Kantarjian H, Ravandi F. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. J Clin Oncol. 2024 May 1;42(13):1499-1508. doi: 10.1200/JCO.23.01911. Epub 2024 Jan 26.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2019
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: August 19, 2019
• First Submitted That Met QC Criteria: October 24, 2019
• First Posted (Actual): October 28, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic-Myeloproliferative Diseases; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; gilteritinib
• Other Study ID Numbers: 2019-0366 (Other Identifier: M D Anderson Cancer Center); NCI-2019-04959 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No