Trial Title:
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)
NCT ID:
NCT06577441
Condition:
Myelodysplastic Syndrome
Conditions: Official terms:
Preleukemia
Myelodysplastic Syndromes
Syndrome
Decitabine
Decitabine and cedazuridine drug combination
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo buccal swab and blood sample collection
Arm group label:
Arm A (ASTX727)
Arm group label:
Arm B (ASTX727, enasidenib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration
Arm group label:
Arm A (ASTX727)
Arm group label:
Arm B (ASTX727, enasidenib)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow biopsy
Arm group label:
Arm A (ASTX727)
Arm group label:
Arm B (ASTX727, enasidenib)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Drug
Intervention name:
Decitabine and Cedazuridine
Description:
Given PO
Arm group label:
Arm A (ASTX727)
Arm group label:
Arm B (ASTX727, enasidenib)
Other name:
ASTX 727
Other name:
ASTX-727
Other name:
ASTX727
Other name:
C-DEC
Other name:
CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Tablet
Other name:
DEC-C
Other name:
Inaqovi
Other name:
Inqovi
Intervention type:
Drug
Intervention name:
Enasidenib
Description:
Given PO
Arm group label:
Arm B (ASTX727, enasidenib)
Other name:
AG 221
Other name:
AG-221
Other name:
AG221
Other name:
CC-90007 Free Base
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.
Criteria for 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
January 17, 2025
Completion date:
March 1, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06577441
