NCT05636514

Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS

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

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (estimated)
• Sponsor: Clinical Hub for Interventional Research (CHOIR) · Other Government
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

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).

Conditions

• Myelodysplastic Syndromes
• Chronic Myelomonocytic Leukemia
• Acute Myeloid Leukemia

Interventions

Type	Name	Description
DRUG	Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET	Fixed dose treatment cycles 1 to 6. Cycle 1 is monotherapy, cycles 2 to 6 combination therapy with defactinib.
DRUG	Defactinib	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

Timeline

• Start date: 2022-12-14
• Primary completion: 2026-08-30
• Completion: 2027-12-30
• First posted: 2022-12-05
• Last updated: 2026-03-18

Locations

5 sites across 1 country: Australia

Regulatory

• FDA-regulated drug study