Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS

NCT05636514 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 22-M-002
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 5

Brief 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 (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.

Conditions

Chronic Myelomonocytic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Acute Myeloid Leukemia; MDS; AML; CMML

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose

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

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

Secondary Outcomes (9)

• Number of Grade 3 or 4 adverse events

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

• Proportion of Grade 3 or 4 adverse events

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

• Number of participants completing planned therapy

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

• Proportion of participants completing planned therapy

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

• Disease response rate

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

Study Arms (1)

Decitabine/cedazuridine + defactinib

EXPERIMENTAL

Decitabine/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.

Drug: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET; Drug: Defactinib

Interventions

Defactinib DRUG

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

Also known as: VS-6063

Decitabine/cedazuridine + defactinib

Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET DRUG

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

Also known as: ASTX727, INQOVI

Decitabine/cedazuridine + defactinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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:
• 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.

Sponsors & Collaborators

• The University of New South Wales: collaborator
• Australian National University: collaborator
• Clinical Hub for Interventional Research (CHOIR): lead

Study Sites (5)

Prince of Wales Hospital

Sydney, New South Wales, 2031, Australia

RECRUITING

Royal Prince Alfred Hospital

Sydney, New South Wales, 2050, Australia

RECRUITING

Concord Repatriation and General Hospital

Sydney, New South Wales, 2139, Australia

RECRUITING

Nepean Hospital

Sydney, New South Wales, 2747, Australia

RECRUITING

Westmead Hospital

Westmead, New South Wales, 2145, Australia

RECRUITING

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute

Interventions

Decitabine; cedazuridine; decitabine and cedazuridine drug combination; defactinib

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• John Pimanda, Professor

  University of New South Wales

  PRINCIPAL INVESTIGATOR

Central Study Contacts

John Pimanda, Professor

CONTACT

1234567; celestial.jcsmr@anu.edu.au

Mark Polizzotto, Professor

CONTACT

celestial.jcsmr@anu.edu.au

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 1, 2022
• First Posted: December 5, 2022
• Study Start: December 14, 2022
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): December 30, 2027
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5)