University of Kansas Medical Center

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, 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 or myelodysplastic
syndrome (MDS) and/or myeloproliferative neoplasm (MPN) with the exception of
hydroxyurea, all-trans retinoic acid (ATRA), colony-stimulating factors,
erythropoiesis-stimulating agents, immunosuppressive therapy, intrathecal
chemotherapy, a single dose of cytarabine for cytoreduction, and/or leukapheresis

- Participants must not be currently receiving any cytarabine-containing therapy other
than up to 1 g/m^2 of cytarabine, which is allowed for urgent cytoreduction. The use
of prior hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine
kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist
and lenalidomide are allowed. Participants may receive hydroxyurea prior to
treatment assignment on this substudy for cytoreduction but must agree to
discontinue hydroxyurea prior to beginning treatment on this substudy

- White blood cell (WBC) must be < 25 x 10^9/L. Hydroxyurea, leukapheresis, and
cytarabine < 1 g/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 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. After
performing the required tests on the specimens, the MDNet laboratories will
send the residual material for biobanking and future research. 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

Recruiting Locations

Study Contact

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 (CR) 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. SECONDARY OBJECTIVES: I. To estimate the composite remission rate (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.