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A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)

ConditionsAccelerated Phase Myeloproliferative NeoplasmBlast Phase Myeloproliferative NeoplasmEssential ThrombocythemiaMyelodysplastic/Myeloproliferative NeoplasmMyeloproliferative Neoplasm, Not Otherwise SpecifiedPolycythemia VeraPrimary MyelofibrosisSecondary Myelofibrosis
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

  • Biospecimen Collection

    Procedure/Surgery

    Undergo buccal swab and blood sample collection

  • Bone Marrow Aspiration

    Procedure/Surgery

    Undergo bone marrow aspiration and biopsy

  • Bone Marrow Biopsy

    Procedure/Surgery

    Undergo bone marrow aspiration and biopsy

  • Decitabine and Cedazuridine

    Drug

    Given PO

  • Iadademstat

    Drug

    Given PO

Treatment groups

78 Participants
are divided into 2 treatment groups
Group A: Arm I (ASTX727)Experimental treatment 4 interventions
Group B: Arm II (ASTX727, iadademstat)Experimental treatment 5 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Within 4 cycles (cycle length = 28 days)

Secondary outcomes

1

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.

Time frame
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
2

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.

Time frame
From randomization to the time of death due to any cause up to 2 years
3

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.

Time frame
Up to 2 years

Other outcomes

1

Gene expression levels

Will be compared between the two treatment groups using two-sample t-tests following log2 transformation.

Time frame
After one cycle of therapy (cycle length = 28 days)
2

Transcriptional changes in proliferative pathways and molecular pathways associated with resistance/disease progression

Will be summarized descriptively.

Time frame
Up to 2 years
3

Correspondence between responses

Correspondence between responses as determined by the European LeukemiaNet 2022 acute myeloid leukemia criteria versus the 2012 blast phase myeloproliferative neoplasm criteria will be assessed using McNemar's test.

Time frame
Up to 2 years
4

Incidence of adverse events (AEs)

AEs will be described and graded using National Cancer Institute Common Terminology Criteria for Adverse Events. AEs will be summarized by type, severity grade, and attribution to treatment. Comparisons between treatment arms will be performed using Fisher's exact test.

Time frame
Up to 30 days after last dose of study treatment

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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