Accelerated Phase Myeloproliferative NeoplasmPhase 2NCT06661915
A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)
A Phase 2 study testing Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy in people with Accelerated Phase Myeloproliferative Neoplasm and Blast Phase Myeloproliferative Neoplasm, run by National Cancer Institute (NCI) at 31 sites in United States.
Trial summary
This phase II trial compares the effect of ASTX727 in combination with iadademstat to ASTX727 alone in treating patients with accelerated or blast phase Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). ASTX727 is a combination of two drugs, cedazuridine and decitabine. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Accelerated Phase Myeloproliferative Neoplasm, Blast Phase Myeloproliferative Neoplasm, Essential Thrombocythemia
- What is being tested?
- Biospecimen Collection, Bone Marrow Aspiration and Bone Marrow Biopsy
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 31 sitesUnited States
- Study dates
- 14 Aug 2025to 31 Dec 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have morphologically confirmed diagnosis of Philadelphia-chromosome negative MPN in accelerated-phase (10-19% myeloid blasts) or blast-phase (≥ 20% myeloid blasts) arising from polycythemia vera, essential thrombocythemia, primary myelofibrosis, secondary myelofibrosis, or MPN not otherwise specified, as per the World Health Organization (WHO) 2016 classification OR myelodysplastic syndrome (MDS)/MPN overlap syndromes (e.g., chronic myelomonocytic leukemia [CMML]) with ≥ 10% blasts
- Patients must not have received prior DNMTi. Previous use of janus kinase (JAK) inhibition, hydroxyurea, and interferon is allowed. There is no required washout period for JAK inhibition and interferon
- Age ≥ 18 years
- Because no dosing or adverse event data are currently available on the use of ASTX727 (35 mg decitabine + 100 mg cedazuridine) in combination with iadademstat in patients < 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (Karnofsky ≥ 30)
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (unless elevated due to Gilbert's syndrome, thought to be related to MPN-AP/BP, or due to extrasvascular hemolysis. In these cases conjugated bilirubin should be ≤ 2.0 x ULN)
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- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN
- Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 by Modification of Diet in Renal Disease (MDRD)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months 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
- 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
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
- The effects of ASTX727 (35 mg decitabine + 100 mg cedazuridine) and/or iadademstat on the developing human fetus are unknown. For this reason and because DNMT inhibitor and LSD1 inhibitor agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and 6 months after completion of ASTX727 (35 mg decitabine + 100 mg cedazuridine) and/or iadademstat administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and 6 months after completion of ASTX727 (35 mg decitabine + 100 mg cedazuridine) and/or iadademstat administration
- Women of child-bearing potential must agree not to donate or freeze egg(s) during the course of this study or within 180 days after receiving their last dose of study drug. Male patients must agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug
- Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
- Patient is able to swallow oral medications
- Patients must have a body weight of at least 50 kg due to the use of flat doses. If a patient is on continued treatment and is receiving benefit, but falls below 50 kg, they may stay on the study per investigator discretion. Otherwise, they will have to come off the study
- Peripheral white blood cell (WBC) count < 25 x 10^9/L on day 1 prior to treatment initiation. Hydroxyurea is allowed for cytoreduction until 24 hours prior to study treatment. Hydroxyurea may be resumed during cycle 1 if WBC count rises above 25 x 10^9/L. Use of hydroxyurea beyond cycle 1 should be discussed with study chair
Who cannot join
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents or had received any investigational products within 3 weeks or 5 half-lives (whichever is shorter) prior to first dose of study treatment
- Patients with a Fridericia's corrected QT interval (QTcF) > 450 ms
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ASTX727 (35 mg decitabine + 100 mg cedazuridine) or iadademstat
- Patients medicated with anti-depressants reported to have KDM1A/LSD1 inhibitory activity: tranylcypromine or phenelzine
- Patients with IDH1-mutated MPN blast phase (≥ 20% blasts). Patients with an IDH1-mutation with MPN-AP (10-19%) blasts are eligible for this study
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- Iadademstat concomitant medication considerations: Patients are not allowed to receive prophylactic hematopoietic colony stimulating factors, any complementary or alternative medicine [any of various systems of healing or treating disease (as non-prescription supplements, herbal medicine and homeopathy)]. Of note, patients may receive granulocyte colony-stimulating factor for management of febrile neutropenia or for prolonged neutropenia
- Patients may not receive administration of live or live-attenuated vaccines. Administration of non-live vaccines included ribonucleic acid (RNA)-based vaccines is allowed and is recommended for pneumococcal, coronavirus, and influenza vaccines
- Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant women are excluded from this study because iadademstat is an LSD1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with iadademstat, breastfeeding should be discontinued if the mother is treated with iadademstat. These potential risks also apply to the ASTX727 (35 mg decitabine + 100 mg cedazuridine) used in this study
- Patients who require treatment while on study with concomitant drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline) except for drugs that are considered absolutely essential for the care of the patient and with appropriate treatment monitoring
Trial locations and contacts
31 sites in 1 country. Contact the study team or a site near you to ask about taking part.
31 sites in 1 country
United States31 sites, 31 recruiting
- Recruiting
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, 28203
Site Public Contact, 800-804-9376
Brittany K. Ragon
- Recruiting
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Site Public Contact, 773-702-8222, cancerclinicaltrials@bsd.uchicago.edu
Anand A. Patel
- Recruiting
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Site Public Contact, 800-293-5066, Jamesline@osumc.edu
Andrew Srisuwananukorn
- Recruiting
Atrium Health Cabarrus/LCI-Concord
Concord, North Carolina, 28025
Site Public Contact, 800-804-9376
Brittany K. Ragon
- Recruiting
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
UM Sylvester Comprehensive Cancer Center at Coral Springs
Coral Springs, Florida, 33065
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
UChicago Medicine Northwest Indiana
Crown Point, Indiana, 46307
Site Public Contact, 855-702-8222, cancerclinicaltrials@bsd.uchicago.edu
Anand A. Patel
- Recruiting
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
UM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, 33166
Site Public Contact, kginnity@med.miami.edu
Terrence J. Bradley
- Recruiting
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Abdulraheem M. Yacoub
- Recruiting
UM Sylvester Comprehensive Cancer Center at Hollywood
Hollywood, Florida, 33021
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Kiran Naqvi
- Recruiting
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Abdulraheem M. Yacoub
- Recruiting
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
Site Public Contact, 800-811-8480
Ashwin Kishtagari
- Recruiting
UC Comprehensive Cancer Center at Silver Cross
New Lenox, Illinois, 60451
Site Public Contact, 773-702-8222, cancerclinicaltrials@bsd.uchicago.edu
Anand A. Patel
- Recruiting
NYP/Weill Cornell Medical Center
New York, New York, 10065
Site Public Contact, 212-746-1848
Ghaith Abu Zeinah
- Recruiting
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, 33181
Site Public Contact, kginnity@med.miami.edu
Terrence J. Bradley
- Recruiting
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Site Public Contact, 405-271-8777, ou-clinical-trials@ouhsc.edu
Zimu Gong
- Recruiting
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Kiran Naqvi
- Recruiting
University of Chicago Medicine-Orland Park
Orland Park, Illinois, 60462
Site Public Contact, 773-702-8222, cancerclinicaltrials@bsd.uchicago.edu
Anand A. Patel
- Recruiting
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Abdulraheem M. Yacoub
- Recruiting
Stanford Cancer Institute Palo Alto
Palo Alto, California, 94304
Site Public Contact, 650-498-7061, cancertrialsinfo@stanford.edu
Gabriel N. Mannis
- Recruiting
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Site Public Contact, 305-243-2647
Terrence J. Bradley
- Recruiting
Oregon Health and Science University
Portland, Oregon, 97239
Site Public Contact, 503-494-1080, trials@ohsu.edu
Jessica M. Stempel
- Recruiting
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Site Public Contact, 804-628-6430, CTOclinops@vcu.edu
Thuy Ho
- Recruiting
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Site Public Contact, 916-734-3089
Francisco A. Socola
- Recruiting
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
Site Public Contact, 888-424-2100, cancerinfo@hci.utah.edu
Ami Patel
- Recruiting
Moffitt Cancer Center
Tampa, Florida, 33612
Site Public Contact, 800-679-0775, ClinicalTrials@moffitt.org
Andrew T. Kuykendall
- Recruiting
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Abdulraheem M. Yacoub
About this study
Official title: A Randomized Phase 2 Trial of ASTX727 +/- Iadademstat in Accelerated/Blast-Phase Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs)
This phase II trial compares the effect of ASTX727 in combination with iadademstat to ASTX727 alone in treating patients with accelerated or blast phase Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). ASTX727 is a combination of two drugs, cedazuridine and decitabine. 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. Iadademstat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with iadademstat may be more effective than ASTX727 alone in treating patients with accelerated or blast phase Philadelphia chromosome negative MPNs.
Read the detailed description
PRIMARY OBJECTIVE:
- To compare the acute leukemia response-complete (ALR-C) rate of iadademstat + ASTX727 (35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg decitabine + 100 mg cedazuridine) monotherapy within 4 cycles of therapy in patients with accelerated/blast-phase myeloproliferative neoplasms (MPN-AP/BP) previously untreated with deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi).
SECONDARY OBJECTIVE:
- To compare event-free survival (EFS), overall survival (OS), and percentage of patients going onto allogeneic hematopoietic stem cell transplant (allo-HCT) of iadademstat + ASTX727 (35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg decitabine + 100 mg cedazuridine) monotherapy in patients with MPN-AP/BP previously untreated with DNMTi.
EXPLORATORY OBJECTIVES:
- To compare iadademstat target engagement between patients treated with iadademstat + ASTX727 (35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg decitabine + 100 mg cedazuridine) monotherapy by evaluating transcriptional changes in proliferative pathways implicated in MPN-AP/BP development and/or progression.
II. To elucidate the common molecular pathways of resistance/progression in patients with MPN-AP/BP receiving DNMTi-based therapy.
III. To measure response using the European LeukemiaNet 2022 Acute Myeloid Leukemia (AML) criteria (Döhner et al., 2022) and compare with the 2012 MPN-BP criteria that is being utilized for primary objective assessment.
OUTLINE: This is a dose escalation study of ASTX727 and iadademstat followed by a randomized study. Patients are randomized to 1 of 2 arms.
ARM I: 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. Additionally, patients undergo buccal swab sample collection at baseline and blood sample collection and bone marrow aspiration and biopsy throughout the study.
ARM II: Patients receive ASTX727 PO QD on days 1-5 and iadademstat PO QD on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo buccal swab sample collection at baseline and blood sample collection and bone marrow aspiration and biopsy throughout the study.
After completion of study treatment, patients who stop the study for reasons other than disease progression are followed up every 3 months. Patients who stop the study due to disease progression, are followed up every 6 months.
- Conditions
- Accelerated Phase Myeloproliferative Neoplasm, Blast Phase Myeloproliferative Neoplasm, Essential Thrombocythemia, Myelodysplastic/Myeloproliferative Neoplasm, Myeloproliferative Neoplasm, Not Otherwise Specified, Polycythemia Vera
- Being tested
- Biospecimen Collection, Bone Marrow Aspiration, Bone Marrow Biopsy, Decitabine and Cedazuridine, Iadademstat
- Medical subject headings
- Thrombocythemia, Essential, Myelodysplastic-Myeloproliferative Diseases, Myeloproliferative Disorders, Polycythemia Vera, Primary Myelofibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo buccal swab and blood sample collection
Bone Marrow AspirationProcedure or surgery
Undergo bone marrow aspiration and biopsy
Bone Marrow BiopsyProcedure or surgery
Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow
Undergo bone marrow aspiration and biopsy
Decitabine and CedazuridineDrug
Also called ASTX 727, ASTX-727, ASTX727, C-DEC
Given PO
IadademstatDrug
Also called ORY 1001, ORY-1001, RG 6016, RG6016
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Arm I (ASTX727) | Experimental | 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. Additionally, patients undergo buccal swab sample collection at baseline and blood sample collection and bone marrow aspiration and biopsy throughout the study. Receives: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Decitabine and Cedazuridine |
| Arm II (ASTX727, iadademstat) | Experimental | Patients receive ASTX727 PO QD on days 1-5 and iadademstat PO QD on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo buccal swab sample collection at baseline and blood sample collection and bone marrow aspiration and biopsy throughout the study. Receives: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Decitabine and Cedazuridine; Drug: Iadademstat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Acute leukemia response-complete (ALR-C) rate
ALR-C rates will be compared between the two treatment arms using Fisher's exact test at the one-sided, alpha = 0.15 significance level.
Measured: Within 4 cycles (cycle length = 28 days)
Secondary outcomes (3)
Event-free survival
Treatment failure is defined as not achieving ALR-C by four cycles of therapy. Hematological relapse is defined as ≥ 5% blasts in bone marrow or peripheral blood or development of myeloid sarcoma after achievement of ALR-C or better. Kaplan-Meier curves will be generated and the two treatment arms will be compared using a stratified log rank test. Cox regression modeling, including treatment arm and dichotomized blast percentage as covariates, will also be performed to estimate the hazard ratio, along with a 90% confidence interval.
Measured: From day 1 of randomization to the date of treatment failure, hematological relapse from ALR-C, or death from any cause up to 2 years
Overall survival (OS)
Kaplan-Meier curves will be generated, and the two treatment arms will be compared using a stratified log rank test. Cox regression modeling including treatment arm and dichotomized blast percentage as covariates, will also be performed to estimate the hazard ratio, along with a 90% confidence interval.
Measured: From randomization to the time of death due to any cause up to 2 years
Percentage of allogeneic hematopoietic stem cell transplantation (allo-HCT)
Descriptive statistics will be utilized for analysis and will be broken down by which treatment arm to which a patient is assigned. The number receiving allo-HCT will be compared between the two treatment arms using Fisher's exact test.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 2024
- Study start14 Aug 2025
- Primary completion31 Dec 2027 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Accelerated Phase Myeloproliferative NeoplasmStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 78 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Anand A Patel, Principal investigator, City of Hope Comprehensive Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06661915
- Sponsor's protocol ID
- NCI-2024-08860
- Other IDs
- NCI-2024-08860, PHII-243, 10675, 10675, UM1CA186717
- Status last verified
- Aug 2026
- First submitted
- 25 Oct 2024
- Last updated
- 30 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.