Testing the Addition of an IDH2 Inhibitor, Enasidenib, to Usual Treatment (Cedazuridine-Decitabine) for Higher-Risk Myelodysplastic Syndrome (MDS) With IDH2 Mutation (A MyeloMATCH Treatment Trial)
- Conditions
- Myelodysplastic Syndrome
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow AspirationProcedure: Bone Marrow Biopsy
- Registration Number
- NCT06577441
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase II MyeloMATCH treatment trial compares the usual treatment of cedazuridine-decitabine (ASTX727) to the combination treatment of ASTX727 and enasidenib in treating patients with higher-risk, IDH2-mutated myelodysplastic syndrome (MDS). ASTX727 is a combination of two drugs, decitabine and cedazuridine. 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. Enasidenib is an enzyme inhibitor that may stop the growth of cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with enasidenib may be effective in treating patients with higher-risk IDH2-mutated MDS.
- Detailed Description
PRIMARY OBJECTIVE:
I. To compare the complete remission (CR) rate of enasidenib + decitabine and cedazuridine (ASTX727) and ASTX727 monotherapy in patients with higher-risk IDH2-mutated MDS using International Working Group 2023 (IWG2023) response criteria.
SECONDARY OBJECTIVES:
I. To estimate the median event-free survival (EFS) at designated time point(s) 18 months for each treatment arm.
II. To estimate the median overall survival (OS) at designated time point(s) 18 months for each treatment arm.
III. To estimate the frequency and severity of toxicities with each regimen in this patient population.
IV. To estimate the median time to response for each treatment arm. V. To estimate the median duration of response for each treatment arm. VI. To estimate the IDH2 variant allele frequency (VAF) reduction for each treatment arm.
VII. To estimate the rate of allogeneic hematopoietic cell transplantation for each treatment arm.
VIII. To compare rates of partial response (PR), CR with limited count recovery (CRL), CR with partial count recovery (CRh), and hematologic improvement (HI) using IWG 2023 response criteria between treatment arms.
IX. To compare the measurable residual disease (MRD) kinetics by flow cytometry and next generation sequencing (NGS) at designated time point(s) at the end of cycle 4 \& 6 and to assess any correlation with clinical outcomes (e.g. CR, EFS, OS).
EXPLORATORY OBJECTIVES:
I. To estimate CR rate, median EFS, and median OS in patients treated with ASTX727 monotherapy that crossover to the treatment arm with ASTX727 + enasidenib after 6 cycles if CR is not achieved.
II. To estimate CR rate, median EFS, and median OS for patients based on Molecular International Prognostic Scoring System (IPSS-M) prognostic risk score at diagnosis, stratified for score level.
III. To estimate concordance between centrally-performed molecular studies and cytogenetics to those done locally.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or stable disease (SD) any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to Tier Advancement Pathway (TAP). Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.
ARM B: Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.
After completion of study treatment, patients are followed up every 6 months for up to 5 years after registration.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 54
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GENERAL MYLEOMATCH MSRP REGISTRATION CRITERIA:
-
Patients must be registered to the Master Screening and Reassessment Protocol (MSRP) and assigned to this protocol by the MATCHBox Treatment Verification Team.
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Participants must not have received prior anti-cancer therapy for AML or MDS.
- Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
- Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy for the purposes of eligibility.
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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 is allowed.
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REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
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Patients must have a morphologically-confirmed diagnosis of MDS with a Revised International Prognostic Scoring System (IPSS-R) score ≥ 4.
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Patients must have a detectable pathogenic IDH2 mutation based on the National Cancer Institute (NCI) Myeloid Panel.
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No prior treatment with deoxyribonucleic acid (DNA) methyltransferase inhibitors (ASTX727, azacitidine, or decitabine).
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Prior treatment with growth factors (ESA, granulocyte colony-stimulating factor [g-CSF], TPO agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.
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Age ≥ 18 years
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Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
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Total bilirubin ≤ 2.0 x upper limit of normal (ULN)
- Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT[) ≤ 3.0 x upper limit of normal (ULN)
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Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m^2
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Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.
- Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.
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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.
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HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.
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For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
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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.
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RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
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Patients on the ASTX727 monotherapy arm (Arm A) that do not achieve a CR (complete response), CRL (CR with limited count recovery), or CRh (CR with partial count recovery) after completing 6 cycles of study treatment.
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ECOG performance status ≤ 2
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Total bilirubin ≤ 2.0 x upper limit of normal (ULN).
- Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
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AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)
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GFR ≥ 30 mL/min/1.73m^2
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Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B (ASTX727, enasidenib) Decitabine and Cedazuridine Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm A (ASTX727) Biospecimen Collection Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm A (ASTX727) Bone Marrow Aspiration Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm A (ASTX727) Bone Marrow Biopsy Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm A (ASTX727) Decitabine and Cedazuridine Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm B (ASTX727, enasidenib) Biospecimen Collection Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm B (ASTX727, enasidenib) Bone Marrow Aspiration Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm B (ASTX727, enasidenib) Bone Marrow Biopsy Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. Arm B (ASTX727, enasidenib) Enasidenib Patients receive ASTX727 PO QD on days 1-5 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 who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.
- Primary Outcome Measures
Name Time Method Complete response (CR) rate Up to 4 cycles of treatment Will be assessed using the International Working Group 2023 (IWG2023) criteria. Will compare the CR rate between the two treatment arms to determine if patients treated with enasidenib + ASTX727 have a statistically significantly higher CR rate than patients treated with the ASTX727 monotherapy.
- Secondary Outcome Measures
Name Time Method Time to response Time from randomization to documented response, assessed up to 5 years Will be assessed only among patients who achieve a response (CR, CRL, or CRh).
Duration of response From patient first achieves a response until either progression or death, assessed up to 5 years Will be assessed only among patients who achieve a response (CR, CRL, or CRh). Will use the methods of Kaplan-Meier as well as Cox regression models.
Incidence of adverse events Up to 4 weeks after completion of study treatment Will be determined using the Common Terminology Criteria for Adverse Events version 5 criteria. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The incidence of severe (grade 3+) adverse events or toxicities will be described for each treatment arm, but will also be compared between the arms. Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest and will graphically assess differences in maximum grades observed for toxicities.
Change in IDH2 variant allele frequency (VAF) Baseline to end of cycle 4 and 6 Will report the percent change of VAF along with a 95% confidence interval.
Allogeneic stem cell transplantation rate Up to 5 years Will report along with a 95% confidence interval for each treatment arm.
Overall survival Time from randomization to death due to any cause, assessed up to 18 months Will use the methods of Kaplan-Meier as well as Cox regression models.
Event-free survival Time from randomization to either a failure to achieve a CR, CR with limited count recovery (CRL), or CR with partial count recovery (CRh) after four cycles of treatment, relapse, or death due to any cause, assessed up to 18 months Sensitivity analyses will be conducted. Will use the methods of Kaplan-Meier as well as Cox regression models.
Measurable residual disease rate At the end of cycle 4 and 6 Will be measured by flow cytometry and next generation sequencing (NGS). Will be compared and used to determine association with clinical outcomes such as CR, EFS, or OS.
Cytogenetic and molecular features Up to 5 years Cytogenetic and molecular classifications including Molecular International Prognostic Scoring System (IPSS-M) will be compared and used to determined association with clinical outcomes such as CR, EFS, and OS.
Trial Locations
- Locations (42)
Kootenai Health - Coeur d'Alene
🇺🇸Coeur d'Alene, Idaho, United States
Kootenai Clinic Cancer Services - Post Falls
🇺🇸Post Falls, Idaho, United States
Kootenai Clinic Cancer Services - Sandpoint
🇺🇸Sandpoint, Idaho, United States
Illinois CancerCare-Bloomington
🇺🇸Bloomington, Illinois, United States
Illinois CancerCare-Canton
🇺🇸Canton, Illinois, United States
Illinois CancerCare-Carthage
🇺🇸Carthage, Illinois, United States
Cancer Care Specialists of Illinois - Decatur
🇺🇸Decatur, Illinois, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Illinois CancerCare-Dixon
🇺🇸Dixon, Illinois, United States
Crossroads Cancer Center
🇺🇸Effingham, Illinois, United States
Illinois CancerCare-Eureka
🇺🇸Eureka, Illinois, United States
Illinois CancerCare-Galesburg
🇺🇸Galesburg, Illinois, United States
Illinois CancerCare-Kewanee Clinic
🇺🇸Kewanee, Illinois, United States
Illinois CancerCare-Macomb
🇺🇸Macomb, Illinois, United States
Illinois CancerCare-Ottawa Clinic
🇺🇸Ottawa, Illinois, United States
Illinois CancerCare-Pekin
🇺🇸Pekin, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸Peoria, Illinois, United States
Illinois CancerCare-Peru
🇺🇸Peru, Illinois, United States
Illinois CancerCare-Princeton
🇺🇸Princeton, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Springfield Clinic
🇺🇸Springfield, Illinois, United States
Springfield Memorial Hospital
🇺🇸Springfield, Illinois, United States
Illinois CancerCare - Washington
🇺🇸Washington, Illinois, 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
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
Parkland Health Center - Farmington
🇺🇸Farmington, Missouri, United States
Missouri Baptist Medical Center
🇺🇸Saint Louis, Missouri, United States
Sainte Genevieve County Memorial Hospital
🇺🇸Sainte Genevieve, Missouri, United States
Missouri Baptist Sullivan Hospital
🇺🇸Sullivan, Missouri, United States
BJC Outpatient Center at Sunset Hills
🇺🇸Sunset Hills, Missouri, United States
Billings Clinic Cancer Center
🇺🇸Billings, Montana, United States
Community Medical Center
🇺🇸Missoula, Montana, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Gundersen Lutheran Medical Center
🇺🇸La Crosse, Wisconsin, United States
Centro Comprensivo de Cancer de UPR
🇵🇷San Juan, Puerto Rico
San Juan City Hospital
🇵🇷San Juan, Puerto Rico