Trial Title:
A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)
NCT ID:
NCT06661915
Condition:
Accelerated Phase Myeloproliferative Neoplasm
Blast Phase Myeloproliferative Neoplasm
Essential Thrombocythemia
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm, Not Otherwise Specified
Polycythemia Vera
Primary Myelofibrosis
Secondary Myelofibrosis
Conditions: Official terms:
Neoplasms
Polycythemia Vera
Blast Crisis
Primary Myelofibrosis
Myeloproliferative Disorders
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myelodysplastic-Myeloproliferative Diseases
Decitabine
Decitabine and cedazuridine drug combination
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo buccal swab and blood sample collection
Arm group label:
Arm I (ASTX727)
Arm group label:
Arm II (ASTX727, iadademstat)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Arm I (ASTX727)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Arm I (ASTX727)
Arm group label:
Arm II (ASTX727, iadademstat)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Drug
Intervention name:
Decitabine and Cedazuridine
Description:
Given PO
Arm group label:
Arm I (ASTX727)
Arm group label:
Arm II (ASTX727, iadademstat)
Other name:
ASTX 727
Other name:
ASTX-727
Other name:
ASTX727
Other name:
C-DEC
Other name:
CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Tablet
Other name:
DEC-C
Other name:
Inaqovi
Other name:
Inqovi
Intervention type:
Drug
Intervention name:
Iadademstat
Description:
Given PO
Arm group label:
Arm II (ASTX727, iadademstat)
Other name:
ORY 1001
Other name:
ORY-1001
Other name:
RG 6016
Other name:
RG6016
Other name:
RO 7051790
Other name:
RO7051790
Other name:
trans-N1-((1R,2S)-2-Phenylcyclopropyl)-1,4-cyclohexanediamine
Summary:
This phase II trial compares the effect of ASTX727 in combination with iadademstat to
ASTX727 alone in treating patients with accelerated or blast phase Philadelphia
chromosome negative myeloproliferative neoplasms (MPNs). ASTX727 is a combination of two
drugs, cedazuridine and decitabine. Cedazuridine is in a class of medications called
cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more
available in the body so that decitabine will have a greater effect. Decitabine is in a
class of medications called hypomethylation agents. It works by helping the bone marrow
produce normal blood cells and by killing abnormal cells in the bone marrow. Iadademstat
may stop the growth of tumor cells by blocking some of the enzymes needed for cell
growth. Giving ASTX727 in combination with iadademstat may be more effective than ASTX727
alone in treating patients with accelerated or blast phase Philadelphia chromosome
negative MPNs.
Detailed description:
PRIMARY OBJECTIVE:
I. To compare the acute leukemia response-complete (ALR-C) rate of iadademstat + ASTX727
(35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg decitabine + 100 mg
cedazuridine) monotherapy within 4 cycles of therapy in patients with
accelerated/blast-phase myeloproliferative neoplasms (MPN-AP/BP) previously untreated
with deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi).
SECONDARY OBJECTIVE:
I. To compare event-free survival (EFS), overall survival (OS), and percentage of
patients going onto allogeneic hematopoietic stem cell transplant (allo-HCT) of
iadademstat + ASTX727 (35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg
decitabine + 100 mg cedazuridine) monotherapy in patients with MPN-AP/BP previously
untreated with DNMTi.
EXPLORATORY OBJECTIVES:
I. To compare iadademstat target engagement between patients treated with iadademstat +
ASTX727 (35 mg decitabine + 100 mg cedazuridine) and ASTX727 (35 mg decitabine + 100 mg
cedazuridine) monotherapy by evaluating transcriptional changes in proliferative pathways
implicated in MPN-AP/BP development and/or progression.
II. To elucidate the common molecular pathways of resistance/progression in patients with
MPN-AP/BP receiving DNMTi-based therapy.
III. To measure response using the European LeukemiaNet 2022 Acute Myeloid Leukemia (AML)
criteria (Döhner et al., 2022) and compare with the 2012 MPN-BP criteria that is being
utilized for primary objective assessment.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 of each cycle.
Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Additionally, patients undergo buccal swab sample collection at cycle 1 day 0
and blood sample collection and bone marrow aspiration and biopsy throughout the study.
ARM II: Patients receive ASTX727 PO QD on days 1-5 and iadademstat PO QD on days 1-5,
8-12, and 15-19 of each cycle. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity. Additionally, patients undergo buccal swab sample
collection at cycle 1 day 0 and blood sample collection and bone marrow aspiration and
biopsy throughout the study.
After completion of study treatment, patients who stop the study for reasons other than
disease progression are followed up every 3 months. Patients who stop the study due to
disease progression, are followed up every 6 months.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have morphologically confirmed diagnosis of Philadelphia-chromosome
negative MPN in accelerated-phase (10-19% myeloid blasts) or blast-phase (≥ 20%
myeloid blasts) arising from polycythemia vera, essential thrombocythemia, primary
myelofibrosis, secondary myelofibrosis, or MPN not otherwise specified, as per the
World Health Organization (WHO) 2016 classification OR myelodysplastic syndrome
(MDS)/MPN overlap syndromes (e.g., chronic myelomonocytic leukemia [CMML]) with ≥
10% blasts
- Patients must not have received prior DNMTi. Previous use of janus kinase (JAK)
inhibition, hydroxyurea, and interferon is allowed. There is no required washout
period
- Age ≥ 18 years
- Because no dosing or adverse event data are currently available on the use of
ASTX727 (35 mg decitabine + 100 mg cedazuridine) in combination with
iadademstat in patients < 18 years of age, children are excluded from this
study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (Karnofsky ≥ 30)
- Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN) (unless elevated
due to Gilbert's syndrome, thought to be related to MPN-AP/BP, or due to
extrasvascular hemolysis. In these cases conjugated bilirubin should be ≤ 2.0 x ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])
≤ 3 x institutional ULN
- Creatinine ≤ 1.5 x institutional ULN OR glomerular filtration rate (GFR) ≥ 30
mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class II or better
- The effects of ASTX727 (35 mg decitabine + 100 mg cedazuridine) and/or iadademstat
on the developing human fetus are unknown. For this reason and because DNMT
inhibitor and LSD1 inhibitor agents are known to be teratogenic, women of
child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) for the duration of study participation
and 6 months after completion of ASTX727 (35 mg decitabine + 100 mg cedazuridine)
and/or iadademstat administration. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must
also agree to use adequate contraception for the duration of study participation and
6 months after completion of ASTX727 (35 mg decitabine + 100 mg cedazuridine) and/or
iadademstat administration
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
- Patient is able to swallow oral medications
- Patient must have a body weight of at least 50 kg
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to ASTX727 (35 mg decitabine + 100 mg cedazuridine) or
iadademstat
- Patients medicated with anti-depressants reported to have KDM1A/LSD1 inhibitory
activity: tranylcypromine or phenelzine
- Iadademstat concomitant medication considerations: Patients are not allowed to
receive prophylactic hematopoietic colony stimulating factors, any complementary or
alternative medicine [any of various systems of healing or treating disease (as
non-prescription supplements, herbal medicine and homeopathy)]. Of note, patients
may receive granulocyte colony-stimulating factor for management of febrile
neutropenia or for prolonged neutropenia
- Patients may not receive administration of live or live-attenuated vaccines.
Administration of non-live vaccines included ribonucleic acid (RNA)-based vaccines
is allowed and is recommended for pneumococcal, coronavirus, and influenza vaccines
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant women are excluded from this study because iadademstat is an LSD1 inhibitor
agent with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with iadademstat, breastfeeding should be discontinued if
the mother is treated with iadademstat. These potential risks also apply to the
ASTX727 (35 mg decitabine + 100 mg cedazuridine) used in this study
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
January 31, 2025
Completion date:
June 1, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06661915
