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

NCT04140487 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2019-0366NCI-2019-04959
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Chronic Myelomonocytic Leukemia; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic/Myeloproliferative Neoplasm; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Refractory Myelodysplastic/Myeloproliferative Neoplasm

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Complete response rate

  Up to 3 years

• Minimal residual disease negativity

  Up to 3 years

• Relapse-free survival

  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

  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

  Up to 3 years

Other Outcomes (4)

• Impact of genomic alterations

  Baseline

• Impact of FLT3 allelic ratio

  Baseline

• Minimal residual disease negativity rates

  At time of remission

Study Arms (1)

Treatment (azacitidine, venetoclax, gilteritinib)

EXPERIMENTAL

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: Azacitidine; Drug: Gilteritinib; Drug: Venetoclax

Interventions

Azacitidine DRUG

Given IV

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

Treatment (azacitidine, venetoclax, gilteritinib)

Gilteritinib DRUG

Given PO

Also known as: ASP-2215, ASP2215

Treatment (azacitidine, venetoclax, gilteritinib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (azacitidine, venetoclax, gilteritinib)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Related Publications (1)

• 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.

  PMID: 38277619 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic-Myeloproliferative Diseases

Interventions

Azacitidine; gilteritinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow 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

• Nicholas Short

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nicholas Short

CONTACT

713-563-4485; nshort@mdanderson.org

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: August 19, 2019
• First Posted: October 28, 2019
• Study Start: December 17, 2019
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: April 16, 2026

Record last verified: 2026-04

Locations

US (1)