Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS
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.
Study details:
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).
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Age ≥ 18 years
- Documented diagnosis of: Myelodysplastic syndrome (MDS) classified as intermediate-2 or high risk, or Acute Myeloid Leukaemia (AML) with 20-30% marrow blasts and multilineage dysplasia, or Chronic myelomonocytic leukemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder
- Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1
- Unsuitable for allogeneic stem cell transplantation
- For female participants of childbearing potential: Agreement to use at least two highly effective contraceptive methods throughout the study and for 6 months following the last dose of study drug, 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 contraceptive methods throughout the study and refrain from donating sperm during the same period
- Provision of signed written informed consent document prior to any study related assessments or procedures
Exclusion criteria
- 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, ESAs and other RBC hematopoietic growth factors, 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.
- Treatment with warfarin. Patients 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.
- Concurrent use of corticosteroids unless 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.
- Prior history of malignancies, other than MDS unless free of the disease for ≥ 12 months.
- Significant active cardiac disease within the previous 6 months.
- Baseline Qt interval greater than 440 milliseconds (males) or 450 milliseconds (females).
- Active systemic infection.
- Any of the following laboratory abnormalities: Serum AST/SGOT or ALT/SGPT > 2.5 x ULN, Serum total bilirubin > 1.5 x ULN, Evidence of autoimmune hemolytic anemia, Creatinine clearance <50 ml/minute or serum creatinine of ≥ 1.5 x ULN, Absolute WBC ≥ 20 x 109/L.
- Known or suspected hypersensitivity to study drugs or their constituents.
- Pregnant or breast-feeding.
- Any condition not already outlined which would place the participant at risk or jeopardise adherence or follow up.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE1
Study ID
NCT05636514
Intervention or treatment
DRUG: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET
DRUG: Defactinib
Conditions
- Myelodysplastic Syndromes
- Chronic Myelomonocytic Leukemia
- Acute Myeloid Leukemia
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Research sites nearby
Closest Location:
Prince of Wales Hospital
Select from list below to view details:
Prince of Wales Hospital
Sydney, New South Wales, Australia
Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
Concord Repatriation and General Hospital
Sydney, New South Wales, Australia
Nepean Hospital
Sydney, New South Wales, Australia
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Who is running the clinical trial?
Clinical Hub for Interventional Research (CHOIR)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Decitabine/cedazuridine + defactinib
| Drug: Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET, Drug: Defactinib |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| 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 Outcome
| Measure | Description | Time Frame |
|---|---|---|
| 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 | End of cycle 6 (24 weeks, each cycle is 28 days) |
| 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 | End of cycle 6 (24 weeks, each cycle is 28 days) |
| Number of participants completing planned therapy | Number of participants completing the planned six cycles of therapy, along with description of cycle delays | End of cycle 6 (24 weeks, each cycle is 28 days) |
| Proportion of participants completing planned therapy | Proportion of participants completing the planned six cycles of therapy, along with description of cycle delays | End of cycle 6 (24 weeks, each cycle is 28 days) |
| Disease response rate | Objective disease response rate determined using International Working Group criteria | End of cycle 6 (24 weeks, each cycle is 28 days) |
| 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 | End of cycle 6 (24weeks, each cycle is 28 days) |
| 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) | End of cycle 6 (24weeks, each cycle is 28 days) |
| 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 | End of cycle 6 (24 weeks, each cycle is 28 days) |
| 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 | End of cycle 6 (24 weeks, each cycle is 28 days) |
References
Clinical Trials Gov: Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDSOther trials to consider
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