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Myelodysplastic SyndromesPhase 1CELESTIAL-MDSNCT05636514

Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS

A Phase 1 study testing Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET and Defactinib in people with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia, run by Clinical Hub for Interventional Research (CHOIR) at 5 sites in Australia.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

The goal of this project is to see if two new potential treatments (defactinib and the combination tablet of decitabine/cedazuridine) can safely be combined to improve outcomes in people with high-risk myelodysplastic syndrome (MDS), certain forms of Acute Myeloid Leukaemia (AML), and Chronic Myelomonocytic Leukaemia… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET and Defactinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
5 sitesAustralia
Study dates
14 Dec 2022to 30 Dec 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

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

  • Participants must meet all of the following criteria at the time of screening:
  • Age ≥ 18 years
  • Documented diagnosis of:
  • Myelodysplastic syndrome (MDS) classified as intermediate-2 or high risk according to the International Prognostic Scoring System (IPSS), or
  • Acute Myeloid Leukaemia (AML) with 20-30% marrow blasts and multilineage dysplasia, according to WHO classification, or
  • Chronic myelomonocytic leukemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder according to World Health Organisation (WHO) classification. This confirmation will be from either the Bone marrow aspirate (BMA) performed at screening or a standard of care BMA if performed up to 6 weeks before cycle 1 day 1.
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  • Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1
  • Unsuitable for allogeneic stem cell transplantation
  • For participants who were born female who are of childbearing potential (FCBP) the following criteria apply:
  • Agreement to use at least two highly effective (per Clinical Trial Facilitation Group) contraceptive methods throughout the study, and for 6 months following the last dose of study drug:
  • Oral/intravaginal/transdermal combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
  • Oral/injectable/implantable progestogen-only hormonal contraception associated with inhibition of ovulation
  • Intrauterine device (IUD)
  • Intrauterine hormone-releasing system (IUS)
  • Bilateral tubal occlusion
  • Vasectomised partner
  • Sexual abstinence and
  • Confirmation of a negative serum pregnancy test at screening.
  • Male participants with a partner who was born female and is of childbearing potential must agree to use at least two highly effective (per Clinical Trial Facilitation Group) contraceptive methods throughout the course of the study and for 6 months following the last dose of study drug, and refrain from donating sperm during the same period
  • Provision of signed written informed consent document prior to any study related assessments or procedures being carried out.

Who cannot join

  • Participants who meet any of the following criteria at the time of screening/enrolment (up to 28 days prior to Cycle 1 Day 1) will be ineligible for entry into the study:
  • Acute myeloid leukemia (AML) with ≥ 30% blasts in bone marrow according to WHO classification.
  • Prior allogeneic or autologous stem cell transplant.
  • Prior receipt of >1 cycle of a hypomethylating agent.
  • Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
  • Use of any of the following within 28 days prior to cycle 1 day 1:
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  • thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, Interleukin-11)
  • ESAs (Erythropoiesis stimulating agent) and other RBC (Red blood cell) hematopoietic growth factors (eg, interleukin-3)
  • Any other investigational medicinal product from another clinical trial.
  • Exposure to any medication, supplement, traditional/herbal medicine, or food with potential for drug-drug interactions with defactinib during the course of the study. This includes:
  • strong CYP3A4 inhibitors or inducers
  • strong CYP2C9 inhibitors or inducers
  • P-glycoprotein (P-gp) inhibitors or inducers
  • Treatment with warfarin. Patients on warfarin can be converted to low molecular-weight heparin or direct oral anticoagulants (DOACs). Participants unwilling or unable to convert to an alternative are not eligible.
  • Use of hydrea for more than 7 days prior to cycle 1 day 1. Use within that time period is permissible.
  • Concurrent use of corticosteroids unless the participant is on a dose of ≤10mg prednisolone or equivalent for medical conditions other than MDS.
  • Active inflammatory bowel disease, or any other gastrointestinal disorder or defect that would interfere with the ingestion, absorption, distribution, metabolism or excretion of the investigational products and/or predispose the participant to an increased risk of gastrointestinal toxicity.
  • Prior history of malignancies, other than MDS unless the participant has been free of the disease for ≥ 12 months. However, participants with the following history/concurrent conditions are allowed:
  • Basal or squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix
  • Carcinoma in situ of the breast
  • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
  • Significant active cardiac disease within the previous 6 months, including:
  • New York Heart Association (NYHA) class III or IV congestive heart failure;
  • Unstable angina or angina requiring surgical or medical intervention; and/or
  • Myocardial infarction
  • Baseline Qt interval greater than 440 milliseconds (males) or 450 milliseconds (females)
  • Active systemic infection:
  • Infection with ongoing signs/symptoms related to the infection without improvement despite appropriate anti- infectives
  • Active Hepatitis B (HBV) infection (defined as HBsAg positive, or HBcAb positive and measurable HBV DNA; participants who are HBcAb positive must have HBV DNA assayed during screening)
  • Participants with Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection will be considered individually by the coordinating principal investigator:
  • Those with HIV will generally be eligible if receiving antiretroviral therapy, HIV viral load (VL) is suppressed <50 copies/mL , and CD4≥350 cells/mm3.
  • Those with HCV will generally be eligible if there is no evidence of clinical hepatic dysfunction or other systemic manifestations of HCV disease and the hepatic parameters below are met. Consideration should be given to curative HCV therapy prior to enrollment in consultation with HCV clinician, if possible.
  • Any of the following laboratory abnormalities:
  • Serum AST/SGOT (Aspartate transaminase / Serum glutamic oxaloacetic transaminase) or ALT/SGPT (Alanine aminotransaminase / Serum glutamic pyruvate transaminase) > 2.5 x ULN (upper limit of normal)
  • Serum total bilirubin > 1.5 x ULN. Patients with Gilbert syndrome may enroll if total bilirubin < 51 umol/L upon discussion with the coordinating investigator
  • Evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive direct anti-globulin test (DAT) or over 50% of indirect bilirubin
  • Creatinine clearance <50 ml/minute as calculated by the CockcroftGault formula or serum creatinine of ≥ 1.5 x ULN.
  • Absolute WBC (white blood cell count) ≥ 20 x 109/L f ) Participants with isolated individual lab abnormalities considered to be disease related will be considered individually in consultation with the Coordinating Principal Investigator.
  • Known or suspected hypersensitivity to study drugs or their constituents.
  • Pregnant or breast-feeding.
  • Any condition not already outlined above which, in the opinion of the clinical investigator, would place the participant at risk if they participated or would jeopardise adherence or follow up or confound the ability to interpret study data.

Trial locations and contacts

5 sites in 1 country. Contact the study team or a site near you to ask about taking part.

John Pimanda, Professor contact

1234567

celestial.jcsmr@anu.edu.au

Mark Polizzotto, Professor contact

celestial.jcsmr@anu.edu.au

5 sites in 1 country

Australia5 sites, 5 recruiting

  • Prince of Wales Hospital

    Sydney, New South Wales, 2031

    Mark Hertzberg, Dr

    Recruiting

  • Royal Prince Alfred Hospital

    Sydney, New South Wales, 2050

    Stephen Larsen Dr

    Recruiting

  • Concord Repatriation and General Hospital

    Sydney, New South Wales, 2139

    Robin Gasiorowski Dr

    Recruiting

  • Nepean Hospital

    Sydney, New South Wales, 2747

    Stephen Fuller Dr

    Recruiting

  • Westmead Hospital

    Westmead, New South Wales, 2145

    Lachlin Vaughan DR

    Recruiting

Other trials in Australia

About this study

Official title: A Phase I Study of Oral Decitabine and Cedazuridine (ASTX727) In Combination With Defactinib (VS-6063) as Therapy of Myelodysplastic Syndromes and Low-blast Acute Myeloid Leukaemia

The goal of this project is to see if two new potential treatments (defactinib and the combination tablet of decitabine/cedazuridine) can safely be combined to improve outcomes in people with high-risk myelodysplastic syndrome (MDS), certain forms of Acute Myeloid Leukaemia (AML), and Chronic Myelomonocytic Leukaemia (CMML). Decitabine/cedazuridine is approved for use by the Australian Therapeutics Goods Administration (TGA) as treatment for MDS. Defactinib is an experimental treatment. This means it is not an approved treatment for MDS in Australia. So far it has been given to over 625 patients in studies across the world.

All study participants will receive active treatment, there is no placebo. Participants will take the decitabine/cedazuridine treatment once a day for 5 days in a row (day 1 to day 5) on its own for the first month (cycle). From month 2 participants will take the decitabine/cedazuridine treatment and will also take the defactinib treatment, both for 5 days in a row on days 1 to day 5 each month (cycle). Defactinib is taken twice a day.

Read the detailed description

The primary objective of this study is to establish the maximum tolerated dose of the combination of ASTX727 (decitabine/cedazuridine) and defactinib administered for 5 days of a 28-day cycle in participants with high-risk MDS, low-blast Acute Myeloid Leukaemia (AML), or Chronic Myelomonocytic Leukaemia (CMML). The secondary objectives are to gather in vivo evidence that adjuvant focal adhesion kinase (FAK) inhibition promotes HSPC mobilisation and proliferation, increased decitabine (DAC) incorporation and DNA hypomethylation in bone marrow and peripheral blood mononuclear cells (MNCs) and increased hematopoietic output from haematopoietic stem and progenitor cells (HSPCs) {colony forming unit-cells [CFU-Cs]}) when used in combination with ASTX727. DAC incorporation and global DNA hypomethylation in peripheral blood and bone marrow MNCs will be assayed longitudinally using a mass spectrometry method (AZA-MS) and cell cycle changes in bone marrow MNCs using a flow cytometry method, which were both developed by these investigators.

Data from previous studies conducted by these Investigators, has shown that hypomethylating agents (HMA) do not alter the clonal architecture of mutant HSPCs but increase their hematopoietic output by epigenetic means. To demonstrate that adjuvant decitabine promotes HMA induced changes in mutant HSPCs, the investigators will use a method adapted from Rand and Molloy, and improved by this research group, for use in single cells in combination with simultaneous assessment of mutations and gene expression. Given the known impact of FAK inhibition on stromal and immune cells in the tumor microenvironment, the investigators will also assess longitudinal changes in these components using single cell transcriptomics and mass cytometry. Along with clinical efficacy data, the investigators will assess pre- and post-treatment density of mutant clones by sequencing a panel of genes associated with myeloid malignancies.

This study's overarching aim is to assess whether defactinib can be safely combined with ASTX727 to improve clinical outcomes in patients with high-risk MDS, low blast AML and CMML. This study will also provide correlative data to support the underlying hypothesis for use of this combination to optimise future HMA therapy.

Treatment of participants will occur in three phases: an initial 'prephase' cycle of monotherapy with ASTX727 (decitabine/cedazuridine) day 1 to 5 of a 28 day cycle (Cycle 1); a combination phase of up to 5 28 day cycles of ASTX727 (decitabine/cedazuridine) in combination with defactinib (VS-6063) (Cycles 2 through 6); and a continuation phase of monotherapy with ASTX727 decitabine/cedazuridine in participants continuing to derive benefit. Participants may continue therapy in continuation phase until progressive disease or the development of unacceptable toxicity.

Adverse events during the first combination cycle (Cycle 2) will be assessed to determine the maximum tolerated dose (MTD) for combination ASTX727 (decitabine/cedazuridine) with defactinib (VS-6063).

Being tested
Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET, Defactinib
Keywords
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, MDS, AML, CMML
Medical subject headings
Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLETDrug

    Also called ASTX727, INQOVI

    Fixed dose treatment cycles 1 to 6. Cycle 1 is monotherapy, cycles 2 to 6 combination therapy with defactinib.

  • DefactinibDrug

    Also called VS-6063

    Defactinib treatment will commence with at the starting dose (dose level 1) from cycle 2 to 6.

    Dose escalation/de-escalation will proceed based on the MTD determination.

    Dose Level 1: 200mg Defactinib twice daily (starting dose level)

    Dose Level 2: 400mg defactinib twice daily

    Dose Level -1: 200mg Defactinib daily

Study groups in NCT05636514
Study groupRoleWhat they receive
Decitabine/cedazuridine + defactinibExperimentalDecitabine/cedazuridine taken days 1-5 of each 28 day treatment cycle, cycle 1 to 6 Defactinib taken on days 1-5 of each 28 treatment day cycle from cycle 2 to cycle 6.
Receives: Drug: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET; Drug: Defactinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose

    Maximum dose at which no more than 1 of 6 participants experience a dose limiting toxicity (DLT)

    Measured: Once 3 participants have completed 2 cycles, assessed at approximately 2 months (each cycle is 28 days)

Secondary outcomes (9)

  1. Number of Grade 3 or 4 adverse events

    Number of participants experiencing Grade 3 or 4 adverse events or serious adverse events (SAEs) during cycles 1-6, along with description of events

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  2. Proportion of Grade 3 or 4 adverse events

    Proportion of participants experiencing Grade 3 or 4 adverse events or serious adverse events (SAEs) during cycles 1-6, along with description of events

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  3. Number of participants completing planned therapy

    Number of participants completing the planned six cycles of therapy, along with description of cycle delays

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  4. Proportion of participants completing planned therapy

    Proportion of participants completing the planned six cycles of therapy, along with description of cycle delays

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  5. Disease response rate

    Objective disease response rate determined using International Working Group criteria

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  6. Decitabine (DAC) incorporation in DNA as AUC

    Decitabine (DAC) incorporation in DNA of peripheral blood mononuclear cells as measured by mass spectrometry (AZA-MS) and computed as the area under the curve (AUC) per treatment cycle

    Measured: End of cycle 6 (24weeks, each cycle is 28 days)

  7. Global DNA methylation

    Mean methylcytosine/cytosine ratio in DNA of peripheral blood mononuclear cells within a treatment cycle as measured by mass spectrometry (AZA-MS)

    Measured: End of cycle 6 (24weeks, each cycle is 28 days)

  8. Percentage of Bone Marrow haematopoietic progenitors (HPCs) progressing through the cell cycle

    Percentage of Bone Marrow haematopoietic progenitors (HPCs) progressing through the cell cycle as determined by flow cytometry

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

  9. Percentage of cluster of differentiation 34 (CD34)+ cluster of differentiation 45 (CD45) dimLin- Haematopoietic progenitor cells (HPCs)/ Mononuclear cells (MNCs) per microlitre (uL) of peripheral blood as measured by flow cytometry

    Percentage of CD34+CD45dimLin- HPCs /MNCs/uL of peripheral blood as measured by flow cytometry

    Measured: End of cycle 6 (24 weeks, each cycle is 28 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Dec 2022
  2. Study start14 Dec 2022
  3. Primary completion30 Aug 2026 (estimated)
  4. Study completion30 Dec 2027 (estimated)

Resources

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 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
A phase 1, open-label, 3+3 dose escalation, multicentre study. All participants will receive a fixed dose of ASTX727, with escalation and de-escalation of the dose of defactinib. Enrolled participants will receive one cycle of ASTX727 alone (pre-phase) followed by five cycles of ASTX727 in combination with defactinib (combination phase). Participants with stable or responding disease by IWG criteria will be eligible to proceed to a continuation phase of monotherapy with ASTX727.
Masking
None (open label)
Enrolment
12 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05636514
Sponsor's protocol ID
22-M-002
Acronym
CELESTIAL-MDS
Status last verified
Mar 2026
First submitted
1 Nov 2022
Last updated
18 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET and Defactinib in people with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia, run by Clinical Hub for Interventional Research (CHOIR) at 5 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 18 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact John Pimanda, Professor (1234567, celestial.jcsmr@anu.edu.au), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (time frame: Once 3 participants have completed 2 cycles, assessed at approximately 2 months (each cycle is 28 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05636514.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2026.

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