Clinical trial NCT06577441: 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)
Official title: A Randomized Phase II Trial of Enasidenib-Based Therapies Versus Cedazuridine-Decitabine in Higher-Risk IDH2-Mutated Myelodysplastic Syndrome: A MyeloMATCH Treatment Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Myelodysplastic Syndrome
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2024-08-29
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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.
  * 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.
  * 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.
* REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
* Patients must have a morphologically-confirmed diagnosis of MDS with a Revised International Prognostic Scoring System (IPSS-R) score ≥ 4.
* Patients must have a detectable pathogenic IDH2 mutation based on the National Cancer Institute (NCI) Myeloid Panel.
* No prior treatment with deoxyribonucleic acid (DNA) methyltransferase inhibitors (ASTX727, azacitidine, or decitabine).
* 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.
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* 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.
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\[) ≤ 3.0 x upper limit of normal (ULN)
* Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m\^2
* 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.
* 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.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.
* 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.
* RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
* 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.
* ECOG performance status ≤ 2
* 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.
* AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)
* GFR ≥ 30 mL/min/1.73m\^2
* Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.

Primary outcomes:
measure: Complete response (CR) rate
timeFrame: Up to 4 cycles of treatment
Secondary outcomes:
measure: Event-free survival
timeFrame: 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
measure: Overall survival
timeFrame: Time from randomization to death due to any cause, assessed up to 18 months
measure: Time to response
timeFrame: Time from randomization to documented response, assessed up to 5 years
measure: Duration of response
timeFrame: From patient first achieves a response until either progression or death, assessed up to 5 years
measure: Incidence of adverse events
timeFrame: Up to 4 weeks after completion of study treatment
measure: Change in IDH2 variant allele frequency (VAF)
timeFrame: Baseline to end of cycle 4 and 6
measure: Allogeneic stem cell transplantation rate
timeFrame: Up to 5 years
measure: Measurable residual disease rate
timeFrame: At the end of cycle 4 and 6
measure: Cytogenetic and molecular features
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center-Herrick Campus
state: California
city: Coeur d'Alene
country: United States
facility: Kootenai Health - Coeur d'Alene
state: Idaho
city: Post Falls
country: United States
facility: Kootenai Clinic Cancer Services - Post Falls
state: Idaho
city: Sandpoint
country: United States
facility: Kootenai Clinic Cancer Services - Sandpoint
state: Idaho
city: Bloomington
country: United States
facility: Illinois CancerCare-Bloomington
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare-Canton
state: Illinois
city: Carthage
country: United States
facility: Illinois CancerCare-Carthage
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Danville
country: United States
facility: Carle at The Riverfront
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: DeKalb
country: United States
facility: Northwestern Medicine Cancer Center Kishwaukee
state: Illinois
city: Dixon
country: United States
facility: Illinois CancerCare-Dixon
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Eureka
country: United States
facility: Illinois CancerCare-Eureka
state: Illinois
city: Galesburg
country: United States
facility: Illinois CancerCare-Galesburg
state: Illinois
city: Geneva
country: United States
facility: Northwestern Medicine Cancer Center Delnor
state: Illinois
city: Glenview
country: United States
facility: Northwestern Medicine Glenview Outpatient Center
state: Illinois
city: Grayslake
country: United States
facility: Northwestern Medicine Grayslake Outpatient Center
state: Illinois
city: Kewanee
country: United States
facility: Illinois CancerCare-Kewanee Clinic
state: Illinois
city: Lake Forest
country: United States
facility: Northwestern Medicine Lake Forest Hospital
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare-Macomb
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: New Lenox
country: United States
facility: UC Comprehensive Cancer Center at Silver Cross
state: Illinois
city: O'Fallon
country: United States
facility: Cancer Care Center of O'Fallon
state: Illinois
city: O'Fallon
country: United States
facility: HSHS Saint Elizabeth's Hospital
state: Illinois
city: Orland Park
country: United States
facility: Northwestern Medicine Orland Park
state: Illinois
city: Orland Park
country: United States
facility: University of Chicago Medicine-Orland Park
state: Illinois
city: Ottawa
country: United States
facility: Illinois CancerCare-Ottawa Clinic
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare-Pekin
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Peru
country: United States
facility: Illinois CancerCare-Peru
state: Illinois
city: Princeton
country: United States
facility: Illinois CancerCare-Princeton
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Springfield Memorial Hospital
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Washington
country: United States
facility: Illinois CancerCare - Washington
state: Illinois
city: Crown Point
country: United States
facility: UChicago Medicine Northwest Indiana
state: Indiana
city: Brighton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Brighton
state: Michigan
city: Canton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Canton
state: Michigan
city: Chelsea
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
state: Michigan
city: Flint
country: United States
facility: Cancer Hematology Centers - Flint
state: Michigan
city: Flint
country: United States
facility: Genesee Hematology Oncology PC
state: Michigan
city: Flint
country: United States
facility: Genesys Hurley Cancer Institute
state: Michigan
city: Livonia
country: United States
facility: Trinity Health Saint Mary Mercy Livonia Hospital
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
state: Michigan
city: Deer River
country: United States
facility: Essentia Health - Deer River Clinic
state: Minnesota
city: Duluth
country: United States
facility: Essentia Health Cancer Center
state: Minnesota
city: Hibbing
country: United States
facility: Essentia Health Hibbing Clinic
state: Minnesota
city: Sandstone
country: United States
facility: Essentia Health Sandstone
state: Minnesota
city: Virginia
country: United States
facility: Essentia Health Virginia Clinic
state: Minnesota
city: Farmington
country: United States
facility: Parkland Health Center - Farmington
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Sainte Genevieve
country: United States
facility: Sainte Genevieve County Memorial Hospital
state: Missouri
city: Sullivan
country: United States
facility: Missouri Baptist Sullivan Hospital
state: Missouri
city: Sunset Hills
country: United States
facility: BJC Outpatient Center at Sunset Hills
state: Missouri
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Boiling Springs
country: United States
facility: Prisma Health Cancer Institute - Spartanburg
state: South Carolina
city: Easley
country: United States
facility: Prisma Health Cancer Institute - Easley
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Butternut
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Faris
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Eastside
state: South Carolina
city: Greer
country: United States
facility: Prisma Health Cancer Institute - Greer
state: South Carolina
city: Seneca
country: United States
facility: Prisma Health Cancer Institute - Seneca
state: South Carolina
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Edmonds
country: United States
facility: Swedish Cancer Institute-Edmonds
state: Washington
city: Issaquah
country: United States
facility: Swedish Cancer Institute-Issaquah
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Ashland
country: United States
facility: Duluth Clinic Ashland
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: William S Middleton VA Medical Center
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: Centro Comprensivo de Cancer de UPR
city: San Juan
country: Puerto Rico
facility: San Juan City Hospital
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Anand A Patel
role: PRINCIPAL_INVESTIGATOR
References: