University of Kansas Medical Center

Condition

• Acute Myeloid Leukemia

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Patient must be ≥ 60 years of age or adults ˂ 60 who in the opinion of the treating
physician are better served by azanucleoside-based therapy rather than intensive,
cytarabine-based induction based on clinical status (i.e., performance status, age >
75 years), organ dysfunction, or disease biology

- Patient must have a morphologically confirmed diagnosis of AML according to the
World Health Organization (WHO) 2016 classification excluding acute promyelocytic
leukemia (APL) with PML-RARA, AML with RUNX1-RUNX1T1, or AML with CBFB-MYH11

- Patient must have no prior therapy for AML with the exception of hydroxyurea and
all-trans retinoic acid (ATRA), or leukapheresis. Patients with cytarabine-based
emergency therapy prior to the start of therapy on this trial are eligible

- Patient must have no prior therapy with hypomethylating agents or FLT3 inhibitors

- Patient must have the FLT3-ITD or D835 mutation based on MyeloMATCH Master Screening
and Reassessment Protocol (MSRP)

- Patient must be assigned to this protocol by the myeloMATCH MSRP

- Patient must not be pregnant or breast-feeding due to the potential harm to an
unborn fetus and possible risk for adverse events in nursing infants with the
treatment regimens being used.

- All patients of childbearing potential must have a blood test or urine study
within 14 days prior to registration to rule out pregnancy.

- A patient of childbearing potential is defined as anyone, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has achieved menarche at some point, 2) has not
undergone a hysterectomy or bilateral oophorectomy; or 3) has not been
naturally postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months)

- Patient of childbearing potential and/or sexually active patients must not expect to
conceive or father children by using an accepted and effective method(s) of
contraception or by abstaining from sexual intercourse for the duration of their
participation in the study. Contraception measures must continue for 30 days after
the last dose of venetoclax for all patients and for 6 months after the last dose of
gilteritinib for patients of childbearing potential and for 4 months after the last
dose of gilteritinib for male patients with partners of childbearing potential.
Patient must not breastfeed during treatment and for 2 months after treatment ends

- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC)
who have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible

- Total bilirubin 2X ≤ institutional upper limit of normal (ULN) (unless thought to be
elevated due to disease involvement or Gilbert's syndrome)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 3.0 x institutional ULN

- Either measured or estimated by Cockcroft-Gault equation

- Creatinine clearance of ≥ 30 mL/min/1.73m^2

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of registration/randomization
are eligible for this trial

- Patients must not have a baseline corrected QT interval ≥ 480 msec using Fredericia
correction (QTcF).

NOTE: Since older patients are at risk for prolonged QTc and many will require supportive
care with agents that affect the QTc, an ECG is recommended if clinically indicated. If
the QTc is prolonged, they should be treated on tier advancement process (TAP) instead of
EA02

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load

- Patient must not have the medical necessity for ongoing treatment with a strong
CYP3A4 inducing drug

- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial

- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better

- Patients must not have an active or uncontrolled infection

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To compare the achievement rate of measured residual disease negative (MRDneg) complete remission (CR) of either triplet regimen to azacitidine and venetoclax alone within 4 cycles of therapy. SECONDARY OBJECTIVES: I. To compare the achievement rate of MRDneg CR/complete remission with incomplete count recovery (CRi)/complete remission with partial hematologic recovery (CRh) of either triplet regimen to azacitidine and venetoclax alone within 4 cycles of therapy. II. To determine the safety and tolerability of the combination of gilteritinib, azacitidine, and venetoclax, if both of the triplet regimens show superiority to the azacitidine plus venetoclax regimen. III. To determine the optimal sequence and duration of gilteritinib, when added to azacitidine and venetoclax if both of the triplet regimens show superiority to the azacitidine plus venetoclax regimen. IV. To estimate the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), and complete remission with partial hematologic recovery (CRh), morphologic leukemia-free state (MLFS), event-free survival (EFS), and overall survival (OS) of the combination of gilteritinib, azacitidine, and venetoclax versus azacitidine and venetoclax alone. EXPLORATORY OBJECTIVES: I. To establish the degree reduction in FLT3- internal tandem duplication (ITD) mutation burden after 2 and 4 cycles of therapy using a highly sensitive next-generation sequencing (NGS) MRD assay and compare the median reduction in the investigational regimens among patients with CR/CRi/CRh to that of control regimen. II. To determine if the degree of FLT3 ITD reduction is associated with the duration of remission. III. To monitor which mutations are present at the time of relapse. IV. To monitor which co-mutations at presentation are associated with lack of response to these regimens. V. To determine if the FLT3 AR /variant allele frequency (VAF) is associated with response to the regimens. OUTLINE: Patients are randomized to 1 of 3 regimens. REGIMEN 1: INDUCTION: Patients receive azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7 of each cycle and venetoclax orally (PO) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 2: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 3: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. All patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial. After completion of study treatment, patients are followed up every 3 months if patient is < 2 years from first registration, and every 6 months if patient is 2-5 years from first registration. All patients, including those who discontinue protocol therapy early, are followed for response until progression, even if non-protocol therapy is initiated, and for survival for 10 years from the date of randomization.