UAMS - Translational Research Institute

Condition

• Acute Myeloid Leukemia

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Participants must have been registered to the MYELOMATCH Master Screening and
Reassessment Protocol prior to consenting to this study. Participants must have
disease with a detectable IDH2 mutation based on central testing through the
MYELOMATCH and be assigned to this clinical trial via MATCHBox prior to registration
to this study

- Note: Pre-enrollment/diagnosis labs must have already been performed under
MYELOMATCH

- Participants must have newly diagnosed, untreated acute myeloid leukemia (AML)
defined by having ≥ 20% blasts in the bone marrow and/or peripheral blood, or with
an AML defining genetic abnormality as described by the World Health Organization
(WHO) classification of AML, excluding acute promyelocytic leukemia (APL) with
PML-RARA

- Participants must not be receiving or planning to receive any other investigational
agents while on protocol therapy

- Participants must not have received prior therapy for AML, myelodysplastic syndrome
(MDS) or myeloproliferative neoplasm (MPN) with the exception of hydroxyurea,
all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor,
colony-stimulating factors, erythropoiesis-stimulating agents, thrombopoietin
receptor agonist, lenalidomide, luspatercept, immunosuppressive therapy, intrathecal
chemotherapy, cytarabine (up to 1 g/m^2 for the purpose of cytoreduction for
hyperleukocytosis/trial eligibility), and/or leukapheresis, with a maximum limit of
1 month of exposure.

- Note: White blood cell (WBC) must be < 25 x 10^9/L prior to start of treatment.
Hydroxyurea, leukapheresis, and cytarabine ≤ 1g/m^2 are permitted to control
the WBC prior to enrollment and initiation of protocol-defined therapy but must
be stopped prior to initiation of protocol therapy.

- Participants must be ≥ 60 years old; OR must be ≥ 18 years old and considered not
eligible for cytarabine-based induction therapy

- Participants must have Zubrod Performance Status of 0-3 as determined by a history
and physical (H&P) exam completed within 14 days prior to registration

- Participants must have a complete medical history and physical exam within 14 days
prior to registration

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless history of
Gilbert's syndrome. Participants with history of Gilbert's syndrome must have total
bilirubin ≤ 3 x institutional ULN (within 14 days prior to registration)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])
≤ 3 × institutional ULN, unless considered to be elevated due to disease involvement
(within 14 days prior to registration)

- Participants must have adequate kidney function as evidenced by creatinine clearance
≥ 30mL/min (by Cockcroft Gault) within 14 days prior to registration

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

- NOTE: Since older participants are at risk for prolonged QTc and may require
supportive care with agents that affect QTc, an electrocardiogram (ECG) is
recommended if clinically indicated. If the QTc is prolonged, they should be
treated on MYELOMATCH TAP instead of MM1OA-S03

- Participants must have adequate cardiac function in the assessment of their treating
physician. Participants with known history or current symptoms of cardiac disease,
or history of treatment with cardiotoxic agents, must have a clinical risk
assessment of cardiac function using the New York Heart Association Functional
Classification. To be eligible for this trial, participants must be class 2 or
better

- Participants with known human immunodeficiency virus (HIV)-infection must be on
effective anti-retroviral therapy at registration and have undetectable viral load
test on the most recent test results obtained within 6 months prior to registration

- Participants with a known history of chronic hepatitis B virus (HBV) infection must
have undetectable HBV viral load while on suppressive therapy on the most recent
test results obtained within 6 months prior to registration, if indicated

- Participants with a known history of hepatitis C virus (HCV) infection must have
been treated and cured. Participants currently being treated for HCV infection must
have undetectable HCV viral load test on the most recent test results obtained
within 6 months prior to registration, if indicated

- Participants must not have a prior or concurrent malignancy whose natural history or
treatment (in the opinion of the treating physician) has the potential to interfere
with the safety or efficacy assessment of the investigational regimen

- Participants must not be pregnant or nursing (nursing includes breast milk fed to an
infant by any means, including from the breast, milk expressed by hand, or pumped).
Individuals who are of reproductive potential must have agreed to use an effective
contraceptive method with details provided as a part of the consent process. A
person who has had menses at any time in the preceding 12 consecutive months or who
has semen likely to contain sperm is considered to be of "reproductive potential."
In addition to routine contraceptive methods, "effective contraception" also
includes refraining from sexual activity that might result in pregnancy and surgery
intended to prevent pregnancy (or with a side-effect of pregnancy prevention)
including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion,
and vasectomy with testing showing no sperm in the semen

- Participants must be able to swallow and retain oral medications and have no known
gastrointestinal disorders likely to interfere with absorption of oral medications

- Participants with central nervous system (CNS) involvement are eligible if follow-up
CNS evaluation shows no evidence of progression, or if the treating physician
determines that immediate CNS specific treatment is not required and is unlikely to
be required during the first cycle of therapy

- Participants must have agreed to have specimens submitted for translational medicine
for MRD under MYELOMATCH and specimens must be submitted

- Enrollment to this treatment study requires prior enrollment into the
myeloMATCH Master Protocol (MYELOMATCH). Participants enrolled in MYELOMATCH
will submit bone marrow samples, peripheral blood samples, and buccal swabs to
the Molecular Diagnostics Network (MDNet), the Clinical Laboratory Improvement
Act (CLIA) laboratory network for myeloMATCH

- In addition to the MYELOMATCH specimens, there will be specimens obtained on
treatment for this substudy. These specimens will be derived from procedures
performed as part of standard assessments in the clinical care and management
of AML with material being sent to the MDNet laboratories as specified.
Therefore, participants must be asked for their consent for the biobanking of
specimens for future unspecified research. Participants may refuse this, but it
is mandatory for sites to ask participants

- Participants must be offered the opportunity to participate in specimen banking

- NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration
process the treating institution's identity is provided in order to ensure that the
current (within 365 days) date of institutional review board approval for this study
has been entered in the system

- Participants must be informed of the investigational nature of this study and
must sign and give informed consent in accordance with institutional and
federal guidelines. For participants with impaired decision-making
capabilities, legally authorized representatives may sign and give informed
consent on behalf of study participants in accordance with applicable federal,
local, and Central Institutional Review Board (CIRB) regulations

Detailed Description

PRIMARY OBJECTIVES: I. To evaluate the safety of decitabine and cedazuridine (ASTX727) + venetoclax + enasidenib (Arm 2) before initiating randomization. II. To compare the rate of measurable residual disease (MRD) negative complete remission with or without partial hematologic recovery (complete remission [CR] or complete remission with partial hematologic recovery [CRh]) based on multiparameter flow cytometry (MFC) after two cycles of treatment in older adults (or unfit adults age 18 or older) with IDH2 mutated acute myeloid leukemia (AML) who receive ASTX727, venetoclax, and enasidenib versus ASTX727 and venetoclax alone. III. If the rate of measurable residual disease (MRD) negative CR+CRh is significantly higher on the ASTX727, venetoclax, and enasidenib arm compared to the ASTX727 and venetoclax arm, to hierarchically evaluate whether the measurable residual disease (MRD) negative CR rate is different between the randomized arms. SECONDARY OBJECTIVES: I. To estimate the rate of composite remission (CR + complete remission with incomplete count recovery [CRi] + complete remission with partial hematologic recovery [CRh]), relapse-free survival (RFS), event-free survival (EFS), duration of response (DOR), and overall survival (OS) of participants by treatment arm. II. To estimate IDH2 mutated variant allele frequency, flow cytometry MRD, and molecular MRD after two cycles of therapy in participants' bone marrow aspirates and blood by treatment arm. III. To estimate remission rates (CR with and without MRD [MFC and molecular MRD], CRh and CRi), and to estimate the rates of hematologic improvement by treatment arm. IV. To estimate the frequency and severity of adverse events by treatment arm. V. To evaluate the association between MFC and molecular MRD after two cycles of protocol treatment with the outcomes RFS and OS (landmarked by date of MRD measurement) by treatment arm. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. All patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. After completion of study treatment, patients are followed up every month for the first year, every 2 months for the second year, every 3 months for the third year, and every 6 months until 5 years after registration or death.