Trial Title:
Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS
NCT ID:
NCT05636514
Condition:
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Syndrome
Decitabine
Conditions: Keywords:
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
MDS
AML
CMML
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention 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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Decitabine/Cedazuridine 35 Mg-100 Mg ORAL TABLET
Description:
Fixed dose treatment cycles 1 to 6. Cycle 1 is monotherapy, cycles 2 to 6 combination
therapy with defactinib.
Arm group label:
Decitabine/cedazuridine + defactinib
Other name:
ASTX727
Other name:
INQOVI
Intervention type:
Drug
Intervention name:
Defactinib
Description:
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
Arm group label:
Decitabine/cedazuridine + defactinib
Other name:
VS-6063
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).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Participants must meet all of the following criteria at the time of screening:
1. Age ≥ 18 years
2. Documented diagnosis of:
1. Myelodysplastic syndrome (MDS) classified as intermediate-2 or high risk
according to the International Prognostic Scoring System (IPSS), or
2. Acute Myeloid Leukaemia (AML) with 20-30% marrow blasts and multilineage
dysplasia, according to WHO classification, or
3. 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.
3. Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1
4. Unsuitable for allogeneic stem cell transplantation
5. For participants who were born female who are of childbearing potential (FCBP) the
following criteria apply:
1. 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
2. Confirmation of a negative serum pregnancy test at screening.
6. 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
7. Provision of signed written informed consent document prior to any study related
assessments or procedures being carried out.
Exclusion Criteria:
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:
1. Acute myeloid leukemia (AML) with ≥ 30% blasts in bone marrow according to WHO
classification.
2. Prior allogeneic or autologous stem cell transplant.
3. Prior receipt of >1 cycle of a hypomethylating agent.
4. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis,
disseminated intravascular coagulation, or CNS leukemia.
5. Use of any of the following within 28 days prior to cycle 1 day 1:
1. thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag,
Interleukin-11)
2. ESAs (Erythropoiesis stimulating agent) and other RBC (Red blood cell)
hematopoietic growth factors (eg, interleukin-3)
3. Any other investigational medicinal product from another clinical trial.
6. 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:
1. strong CYP3A4 inhibitors or inducers
2. strong CYP2C9 inhibitors or inducers
3. P-glycoprotein (P-gp) inhibitors or inducers
7. 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.
8. Use of hydrea for more than 7 days prior to cycle 1 day 1. Use within that time
period is permissible.
9. Concurrent use of corticosteroids unless the participant is on a dose of ≤10mg
prednisolone or equivalent for medical conditions other than MDS.
10. 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.
11. 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:
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix
3. Carcinoma in situ of the breast
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
nodes, metastasis [TNM] clinical staging system)
12. Significant active cardiac disease within the previous 6 months, including:
1. New York Heart Association (NYHA) class III or IV congestive heart failure;
2. Unstable angina or angina requiring surgical or medical intervention; and/or
3. Myocardial infarction
13. Baseline Qt interval greater than 440 milliseconds (males) or 450 milliseconds
(females)
14. Active systemic infection:
1. Infection with ongoing signs/symptoms related to the infection without
improvement despite appropriate anti- infectives
2. 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)
3. 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.
15. Any of the following laboratory abnormalities:
1. 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)
2. 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
3. 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
4. Creatinine clearance <50 ml/minute as calculated by the CockcroftGault formula
or serum creatinine of ≥ 1.5 x ULN.
5. 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.
16. Known or suspected hypersensitivity to study drugs or their constituents.
17. Pregnant or breast-feeding.
18. 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Prince of Wales Hospital
Address:
City:
Sydney
Zip:
2031
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Mark Hertzberg, Dr
Facility:
Name:
Royal Prince Alfred Hospital
Address:
City:
Sydney
Zip:
2050
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Stephen Larsen Dr
Facility:
Name:
Concord Repatriation and General Hospital
Address:
City:
Sydney
Zip:
2139
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Robin Gasiorowski Dr
Facility:
Name:
Nepean Hospital
Address:
City:
Sydney
Zip:
2747
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Stephen Fuller Dr
Facility:
Name:
Westmead Hospital
Address:
City:
Westmead
Zip:
2145
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Lachlin Vaughan DR
Start date:
December 14, 2022
Completion date:
December 5, 2025
Lead sponsor:
Agency:
Clinical Hub for Interventional Research (CHOIR)
Agency class:
Other
Collaborator:
Agency:
The University of New South Wales
Agency class:
Other
Collaborator:
Agency:
Australian National University
Agency class:
Other
Source:
Clinical Hub for Interventional Research (CHOIR)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05636514
