Comparing New Treatments for People With Newly Diagnosed Acute Myeloid Leukemia That Has an IDH2 Gene Change (A MyeloMATCH Treatment Trial)
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow AspirationProcedure: Bone Marrow Biopsy
- Registration Number
- NCT06672146
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase II MyeloMATCH treatment trial studies how well ASTX727 and venetoclax plus enasidenib works compared to ASTX727 and venetoclax alone for the treatment of older patients with newly diagnosed acute myeloid leukemia (AML) or younger patients who are considered unfit for standard treatment, and who have an abnormal change (mutation) in the IDH2 gene. This gene mutation can cause AML to grow and spread. This trial is being done to see if adding enasidenib to the usual treatment can help more patients with the IDH2 gene get rid of AML. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. 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. Enasidenib works by stopping the growth and spread of tumor cells that have the IDH2 mutation. Giving ASTX727 and venetoclax plus enasidenib may work better in treating AML patients with the IDH2 mutation.
- Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the safety of 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 OBJECTIVES:
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 93
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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
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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
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Participants must not be receiving or planning to receive any other investigational agents while on protocol therapy
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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
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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
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Participants must be ≥ 60 years old; OR must be ≥ 18 years old and considered not eligible for cytarabine-based induction therapy
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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
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Participants must have a complete medical history and physical exam within 14 days prior to registration
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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)
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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)
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Participants must have adequate kidney function as evidenced by creatinine clearance ≥ 30mL/min (by Cockcroft Gault) within 14 days prior to registration
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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
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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
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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
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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
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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
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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
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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
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Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications
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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
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Participants must be offered the opportunity to participate in specimen banking
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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
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1 (ASTX727 + venetoclax) Decitabine and Cedazuridine Patients receive ASTX727 PO 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Decitabine and Cedazuridine 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 1 (ASTX727 + venetoclax) Biospecimen Collection Patients receive ASTX727 PO 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 1 (ASTX727 + venetoclax) Bone Marrow Aspiration Patients receive ASTX727 PO 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 1 (ASTX727 + venetoclax) Bone Marrow Biopsy Patients receive ASTX727 PO 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 1 (ASTX727 + venetoclax) Venetoclax Patients receive ASTX727 PO 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Biospecimen Collection 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Bone Marrow Aspiration 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Bone Marrow Biopsy 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Enasidenib 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. Arm 2 (ASTX727 + venetoclax + enasidenib) Venetoclax 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. Patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial.
- Primary Outcome Measures
Name Time Method Minimal residual disease negative (MRDneg) complete remission (CR) rate Baseline to 5 years A randomized design will be used to compare binary endpoints in two arms with a single interim futility analysis. For the final analysis, a 2-sample proportion z-test will be used to compare the MRDneg-CR rates between arms with a two-sided alpha of 20%.
- Secondary Outcome Measures
Name Time Method Relapse-free survival (RFS) Baseline to 5 years Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kapan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Landmark Kaplan-Meier plots will be used describe marker associations with overall survival (OS) and RFS. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
Event-free survival Baseline to 5 years Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kapan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Molecular and flow MRD rates in the peripheral blood will be tabulated and summarized by arm. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
Duration of response Baseline to 5 years Response and toxicity rates will be tabulated. Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kapan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
OS Baseline to 5 years Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kapan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Molecular and flow MRD rates in the peripheral blood will be tabulated and summarized by arm. Landmark Kaplan-Meier plots will be used describe marker associations with OS and RFS. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
Trial Locations
- Locations (32)
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Kootenai Health - Coeur d'Alene
🇺🇸Coeur d'Alene, Idaho, United States
Saint Luke's Cancer Institute - Fruitland
🇺🇸Fruitland, Idaho, United States
Saint Luke's Cancer Institute - Meridian
🇺🇸Meridian, Idaho, United States
Saint Luke's Cancer Institute - Nampa
🇺🇸Nampa, Idaho, United States
Kootenai Clinic Cancer Services - Post Falls
🇺🇸Post Falls, Idaho, United States
Kootenai Clinic Cancer Services - Sandpoint
🇺🇸Sandpoint, Idaho, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
🇺🇸Brighton, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Canton
🇺🇸Canton, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
OSF Saint Francis Hospital and Medical Group
🇺🇸Escanaba, Michigan, United States
Cancer Hematology Centers - Flint
🇺🇸Flint, Michigan, United States
Genesee Hematology Oncology PC
🇺🇸Flint, Michigan, United States
Genesys Hurley Cancer Institute
🇺🇸Flint, Michigan, United States
Trinity Health Saint Mary Mercy Livonia Hospital
🇺🇸Livonia, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
🇺🇸Ypsilanti, Michigan, United States
Billings Clinic Cancer Center
🇺🇸Billings, Montana, United States
Community Medical Center
🇺🇸Missoula, Montana, United States
Swedish Cancer Institute-Edmonds
🇺🇸Edmonds, Washington, United States
Swedish Cancer Institute-Issaquah
🇺🇸Issaquah, Washington, United States
Swedish Medical Center-First Hill
🇺🇸Seattle, Washington, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Saint Mary's
🇺🇸Green Bay, Wisconsin, United States
Gundersen Lutheran Medical Center
🇺🇸La Crosse, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Oconto Falls
🇺🇸Oconto Falls, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sheboygan
🇺🇸Sheboygan, Wisconsin, United States
Sheboygan Physicians Group
🇺🇸Sheboygan, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sturgeon Bay
🇺🇸Sturgeon Bay, Wisconsin, United States
Centro Comprensivo de Cancer de UPR
🇵🇷San Juan, Puerto Rico
San Juan City Hospital
🇵🇷San Juan, Puerto Rico