Gilteritinib-Azacitidine-Venetoclax Combination Therapy in Patients With Relapsed/Refractory Leukemia (GAVE001)

A Phase 2 Trial of Gilteritinib in Combination With Azacitidine and Venetoclax to Overcome Venetoclax Resistance in Patients With Relapsed/Refractory FLT3-wild Type Acute Myeloid Leukemia

The goal of this clinical trial is to learn if gilteritinib-azacitidine-venetoclax combination drug therapy works to treat adults with FLT3-wt acute myeloid leukemia (AML). It will also learn about the safety and efficacy of this treatment. The main question this clinical trial aims to answer are:

• Will adding gilteritinib to standard-of-care therapy azacitidine-venetoclax show be more effective in treating AML FLT3-wt patients who have previously been treated with azacitidine and/or venetoclax for their disease and have had their cancer come back (relapsed) or have stopped responding to treatment (refractory)?

All participants in this trial will receive the combination therapy. Participants will be on repeated 28-day cycles, for a minimum of 2 cycles, while on the study

Participants will:

• Take the gilteritinib once daily, every day
• Take azacitidine and venetoclax on days 1-7 of each cycle
• Keep a daily dose diary of the days and times they have taken their treatments
• Visit the clinic every 4 weeks for checkups and tests

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; AML With FLT3 Mutation
• Intervention / Treatment: Combination product: gilteritinib-azacitidine-venetoclax

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet all the following inclusion criteria to be eligible for participation in this trial.

1. Age ≥ 18 years old at the time of informed consent.
2. Pathologically confirmed diagnosis of AML previously treated with azacitidine and venetoclax that are azacitidine and venetoclax-refractory, defined as:

2a. Primary refractory: Defined as no complete remission (CR) or CR with incomplete recovery (CRi) following at least 2 cycles of azacitidine and venetoclax with AML blasts ≥5% in the bone marrow, or 2b. Relapsed: Defined as recurrence of AML blasts ≥5% in the bone marrow after a previous CR or CRi to azacitidine and venetoclax 3. Confirmed to be negative for FLT3- internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations on repeat clinical testing following their last line of therapy 4. Adequate functional status (ECOG ≤ 2) 5. Participant is willing to provide informed consent and comply with trial procedures 6. Participants of either biological sex must be able and willing to use Health-Canada approved effective contraception methods starting 2-weeks prior to trial treatment, throughout the trial, and for 6 months following the last dose of trial drugs 7. For participants of child-bearing potential (menstruation within <2 years): negative serum pregnancy test within 14-days prior to enrollment.

8. Not currently breastfeeding and will not breastfeed while on the trial and for at least 2 months following the last trial dose.

Waivers to the inclusion criteria will NOT be allowed.

Exclusion Criteria:

Participants are excluded from the trial if any of the following criteria apply:

1. Diagnosis of acute promyelocytic leukemia (APL), BCR-ABL positivity, or favorable risk AML 2. Currently considered as eligible for intensive chemotherapy treatment in the opinion of the Investigator 3. Inadequate organ function, defined as: 3a. Liver function: Serum aspartate aminotransferase and alanine aminotransferase ≥ 2.5 x upper limit of normal (ULN) and total bilirubin ≥ 1.5 x ULN 3b. Renal function: estimated glomerular filtration rate of < 30 mL/min as calculated by the Modification of Diet in Renal Disease equation.

3c. Cardiac function: New York Heart Association (NYHA) class 3 or 4 heart failure or known history of left ventricular ejection fraction ≤ 40% or known history of prolonged QTc syndrome 4. Corrected QTc of > 450ms that is not corrected on repeat electrocardiogram (ECG) testing 5. Active and untreated CNS leukemia 6. Active solid organ malignancy requiring treatment in the last 24 months, with the exception of: 6a. Treated nonmelanoma skin cancer 6b. Completely treated breast carcinoma that is considered cured 6c. Completely treated cervical carcinoma that is considered cured 6d. Localized breast or prostate cancer receiving androgen deprivation therapy 6e. A previously treated malignancy that is considered cured with minimal risk of recurrence 7. Extramedullary disease without concomitant marrow based disease (blasts ≤5%) 8. Uncontrolled, active infection or untreated hepatitis B, C, or HIV 9. Known allergy or intolerance to azacitidine, venetoclax, or gilteritinib 10. Any comorbidity that the investigator believes would be incompatible with safe receipt or therapy 11. Inability to comply with requirements of the trial protocol 12. Pregnancy or breastfeeding 13. Unable or unwilling to use Health Canada-approved highly effective methods of contraception (i.e., hormonal contraceptives, vasectomy, tubal ligation, or double-barrier method), or abstinence while on the trial and for at least 6 months following the last dose of trial drugs.

Waivers to the exclusion criteria will NOT be allowed.

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: All Participants; administration of combination therapy gilteritinib-azacitidine-venetoclax on repeated 28-day cycles for a minimum of 2 cycles. Gilteritinib will be taken daily and azacitidine-venetoclax on days 1-7 of each cycle.	Combination product: gilteritinib-azacitidine-venetoclax; administration of combination therapy gilteritinib-azacitidine-venetoclax on repeated 28-day cycles for a minimum of 2 cycles. Gilteritinib will be taken daily and azacitidine-venetoclax on days 1-7 of each cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of triplet regimen on AML FLT3-wt participants	the ORR up to two cycles of triplet therapy. ORR is defined as the proportion of participants who achieve a CR, CRi, or MLFS after completing two cycles of the combination therapy	From enrollment to the end of treatment at week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety of triplet regimen based on toxicity findings	Safety and toxicity events defined as the frequency of grade > 3 non-hematologic adverse events while receiving triplet-therapy, as per National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 6.0	from enrollment to one month after end of treatment at 12 weeks
Impact of triplet regimen on measurable residual disease (MRD) in participants achieving a response	Rate of MRD negativity amongst participants achieving a response. MRD negativity is defined as the presence of leukemia cells below the threshold of detection by flow cytometry or PCR assay, as defined by ELN 2022 response criteria	from enrollment to one month after the end of treatment at 12 weeks
Impact of study treatment on event-free survival (EFS)	EFS, defined as the time from start of therapy until disease persistence after ≥ 2 cycles of triplet therapy, disease relapse of progression while on therapy, or death. EFS is defined as the time from start of treatment until disease progression after > 2 cycles of triplet therapy, disease relapse of progression while on triplet therapy, or death from any cause.	from enrollment to end of study closeout at 36 months
Impact of study treatment on relapse-free survival (RFS)	Relapse-free survival (RFS), defined as the time from start of therapy until disease progression or death for participants who achieve a response. RFS is defined as the time from start of treatment until disease progression or death from AML	from enrollment to end of study closeout at 36 months
Impact of study treatment on overall survival (OS) in AML FLT3-wt patients	Overall survival (OS), defined as the time from start of therapy until death from any cause.	from enrollment to end of study closeout at 36 months

Collaborators and Investigators

• Sponsor: Florian Kuchenbauer

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: August 5, 2026
• First Submitted That Met QC Criteria: August 5, 2026
• First Posted (Actual): August 10, 2026

Study Record Updates

• Last Update Posted (Actual): August 10, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute
• Other Study ID Numbers: GAVE001

Drug and device information, study documents

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