MM1OA-EA02, A Randomized Phase II Study of Venetoclax and HMA-based Therapies for the Treatment of Older and Unfit Adults with Newly Diagnosed FLT3-mutated Acute Myeloid Leukemia (AML): A MyeloMATCH Treatment Trial

This phase II MyeloMATCH treatment trial compares the usual treatment of azacitidine and
venetoclax to the combination treatment of azacitidine, venetoclax and gilteritinib in
treating older and unfit patients with acute myeloid leukemia and FLT3 mutations.
Azacitidine is a drug that is absorbed into DNA and leads to the activation of cancer
suppressor genes, which are genes that help control cell growth. Venetoclax is in a class
of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of
cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib
is in a class of medications called kinase inhibitors. It works by blocking the action of
a certain naturally occurring substance that may be needed to help cancer cells multiply.
This study may help doctors find out if these different approaches are better than the
usual approaches. To decide if they are better, the study doctors are looking to see if
the study drugs lead to a higher percentage of patients achieving a deeper remission
compared to the usual approach.

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