Trial Title:
Iadademstat in Combination With Azacitidine and Venetoclax in Treating Newly Diagnosed Acute Myeloid Leukemia
NCT ID:
NCT06357182
Condition:
Acute Myeloid Leukemia
Myelodysplastic Syndrome/Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Azacitidine
Venetoclax
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
The treatment plan starts with a 7 day monotherapy lead-in (Cycle 0 [C0]) and then
proceeds to combination therapy in 28 day cycles. Disease will be assessed pre-treatment
(Screening/Baseline), at the end of monotherapy, in C1 (and C2, if response is not
observed in C1), and at the end of alternating cycles, thereafter. A disease assessment
will also be conducted within 30 days of the last dose of IADA. Participants that do not
achieve response after up to 2 cycles of the triplet regimen will be taken off treatment.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
Given SC
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
5 AZC
Other name:
5-AC
Other name:
5-Azacitidine
Other name:
5-Azacytidine
Other name:
5-AZC
Other name:
Azacytidine
Other name:
Azacytidine, 5-
Other name:
Ladakamycin
Other name:
Mylosar
Other name:
U-18496
Other name:
Vidaza
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow biopsy
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
EC
Intervention type:
Drug
Intervention name:
Iadademstat
Description:
Given PO
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
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
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Other
Intervention name:
Questionnaire Administration
Description:
Ancillary study
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level -2(iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)
Arm group label:
Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)
Other name:
ABT-0199
Other name:
ABT-199
Other name:
ABT199
Other name:
GDC-0199
Other name:
RG7601
Other name:
Venclexta
Other name:
Venclyxto
Summary:
This phase I trial tests the safety, side effects, and best dose of iadademstat when
given together with azacitidine and venetoclax in treating patients with newly diagnosed
acute myeloid leukemia (AML). Iadademstat inhibits the LSD1 protein and may lead to
inhibition of cell growth in LSD1-overexpressing cancer cells. Chemotherapy drugs, such
as azacitidine, work in different ways to stop the growth of cancer cells, either by
killing the cells, by stopping them from dividing, or by stopping them from spreading.
Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It
may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell
survival. Giving iadademstat with azacitidine and venetoclax may be safe, tolerable
and/or effective in treating patients with newly diagnosed AML who cannot undergo
intensive chemotherapy.
Detailed description:
PRIMARY OBJECTIVE:
I. Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of
iadademstat (IADA) when administered as part of the investigational combination (i.e.,
iadademstat + azacitidine + venetoclax [IADA+AZA+VEN]).
SECONDARY OBJECTIVES:
I. Assess the preliminary efficacy of the investigational regimen based on disease
remission.
II. Assess the preliminary efficacy of the investigational regimen based on clinical
response.
III. Assess the safety of the investigational regimen.
EXPLORATORY OBJECTIVES:
I. Assess survival in the absence of treatment failure, hematologic relapse, or
progressive disease.
II. Assess overall survival.
III. Assess duration of response, based on morphological assessments.
IV. Identify mechanisms of transcriptional reprogramming and cell death.
V. Identify predictive biomarkers of response to LSD1 inhibition.
VI. Assess participant quality of life using Patient-Reported Outcomes Common Terminology
Criteria for Adverse Events (PRO-CTCAE).
OUTLINE: This is a dose-escalation study of iadademstat in combination with azacitidine
and venetoclax.
Patients receive iadademstat orally (PO) once daily (QD) on days 1-5 of cycle 0 and then
days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 or 1-28 and
azacitidine subcutaneously (SC) QD days 1-7. Patients with complete remission (CR), CR
with partial hematologic recovery (CRh), CR with incomplete blood count recovery, (CRi),
or morphologic leukemia-free state (MLFS) after cycle 1 continue to receive IADA PO QD on
days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 or
1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during
screening as clinically indicated on study. Patients under bone marrow biopsy throughout
the trial. Additionally, patients undergo blood sample collection during screening and on
the trial.
After completion of study treatment, patients are followed up every 3 months for 2 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients at least 18 years of age will be considered for inclusion without bias
against gender identity, race, or ethnicity
- Ability to comprehend the investigational nature of the study and provide written
informed consent
- Patients with previously untreated, morphologically documented AML based on World
Health Organization (WHO) 2008 definitions who are ineligible for standard of care
(SOC) intensive chemotherapy induction and also meet the following criteria:
- Documented intermediate- or adverse-risk AML based on European Leukemia Network
(ELN) 2022 criteria
- Note: Cases of AML/myelodysplastic syndrome (MDS) overlap with 10-19% bone
marrow (BM) or peripheral blood (PB) blasts will be considered
- Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1
fusions will be excluded
- Eastern Cooperative Oncology Group (ECOG) performance ≤ 2 (Patients aged ≥ 75 years,
at the time of consent)
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients aged ≥ 75 years, at
the time of consent)
- High total bilirubin values may require indirect and direct bilirubin testing.
Individuals with known Gilbert's syndrome may be considered for enrollment
despite high indirect (and total) bilirubin
- Creatinine clearance (CrCl) of ≥ 60 mL/min (estimated using the Cockcroft Gault
formula or measured by 24 hours urine collection) (Patients aged ≥ 75 years, at the
time of consent)
- Patients aged ≥ 18 to 74 years (ECOG performance status [PS] ≤ 3 is accepted) at
consent must meet ≥ 1 of the following criteria defining a co morbidity:
- ECOG PS of 2 or 3 (Note: Patients ≥ 18 to 74 years of age with PS of 0-1 must
meet criteria of one of the following comorbidities.)
- Cardiac history of congestive heart failure (CHF) requiring treatment or
ejection fraction ≤ 50% or chronic stable angina
- Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced
expiratory volume in 1 second (FEV1) ≤ 65%
- CrCl ≥ 30 mL/min to < 45 ml/min
- Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN;
- High total bilirubin values may require indirect and direct bilirubin
testing. Individuals with known Gilbert's syndrome may be considered for
enrollment despite high indirect (and total) bilirubin
- Other comorbidities that the physician judges to be incompatible with intensive
chemotherapy (IC). In these cases, the comorbidity must be reviewed and
approved by the principal investigator (PI) before study enrollment
- Ability to swallow oral medications
- No ongoing anticoagulation or antiplatelet therapy within 14 days of start of
treatment with IADA (i.e., cycle 0 day 1 [C0D1])
- No history of severe bleeding disorder such as hemophilia A, hemophilia B, von
Willebrand disease, or history of spontaneous bleeding requiring blood transfusion
or other medical intervention
- No history of stroke or intracranial hemorrhage within 180 days of start of IADA
- No major bleeding event, as defined by the International Society of Thrombosis and
Hemostasis (ISTH), within 12 weeks of start of IADA
- Uncorrected international normalized ratio (INR) or activated partial thromboplastin
time (aPTT) of < 1.5 x ULN.
- If INR or aPTT > 1.5 x ULN has been corrected (prior to enrollment), then
history of disseminated intravascular coagulation (DIC) must be absent
- White blood cell (WBC) < 20 x 10^9/L prior to study start. Cytoreduction prior to
study treatment is allowed with
- Hydroxyurea for up to 14 days and until 24 hours prior to start of IADA; or
- Leukapheresis for up to 14 days prior to start of IADA
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0
x institutional ULN
- Lower hepatic function may be considered if liver enzyme abnormalities are
determined by the treating MD and principal investigator (PI) to be due to
leukemic infiltration
- Willing and able to
- Adhere to study schedule of activities and life style restrictions while on
treatment;
- Provide bone marrow (BM) aspirate and core biopsy samples; and
- Accept supportive and prophylactic care for hematologic toxicities, infection,
and immediate sequelae, including transfusions
- Negative pregnancy test within 72 hours of start of IADA for persons of childbearing
potential (PCBP)
- Willingness to comply with study requirements for contraception, as follows: PCBP
and sperm-producing participants who are sexually active with a PCBP must use study
approved contraception from start of investigational product (first dose of IADA)
until 6 months after the last dose of IADA. Pregnancy is exclusionary because the
agents used in this study have the potential for teratogenic or abortifacient
effects
Exclusion Criteria:
- Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or any
excipients in the formulations
- Body weight < 50 kg
- Investigational therapy within 5 half-lives or, if unknown, within 28 days prior to
start of IADA
- Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patients
with proliferative disease must meet the criteria listed in inclusion criteria
- Radiotherapy less than 14 days prior to start of IADA
- Recent and significant medical interventions, such as major surgery within 28 days
prior to the start of IADA, or stem cell transplant within 100 days prior to the
start of IADA. Patients with active treatment for graft-versus-host disease (GVHD)
are excluded
- Another active malignancy within 5 years prior to the start of IADA, or at the
investigator's discretion
- Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to the
start of IADA
- Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions that
limit the ingestion or gastrointestinal absorption of drugs administered orally
- Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment is
not finalized at least 3 weeks prior to the start of IADA
- Active central nervous system involvement with AML
- Uncontrolled infection. Participants with controlled infection must be afebrile and
hemodynamically stable for at least 72 hours prior to start of IADA and must be
amenable to alternate treatment if current treatment will interact with
investigational regimen
- Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV,
respectively) status, except in cases of undetectable HBV/HCV viral load for at
least 3 months prior to the start of IADA. (Hepatitis B or C testing is not required
for eligibility assessment.)
- Individuals serology positive for human immunodeficiency virus (HIV) and under
active treatment with highly active antiretroviral therapy (HAART) (or another
therapy that may interfere with metabolism of study agents). Otherwise, enrollment
may be considered in cases of HIV that is controlled with another treatment type or
in cases that that acceptable modification of the patient's HIV treatment exists
- Use a P-gp inhibitor within 23 days prior to treatment with venetoclax
- Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half
lives whichever is longer, prior to start of treatment with venetoclax
- Unwillingness to stop breastfeeding. Because there is a potential risk for adverse
events in nursing infants secondary to treatment of the mother with the chemotherapy
agents, breastfeeding should also be avoided throughout the study and until at least
60 days after last dose of IADA
- Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic
blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension
before C1D1 is allowed
- Patients with poorly controlled diabetes. Poorly controlled diabetes mellitus
defined as glycosylated hemoglobin (HbA1c) ≥ 8%; patients with a history of
transient glucose intolerance due to corticosteroid administration may be enrolled
in this study if all other inclusion/exclusion criteria are met
- Patients with mean of triplicate corrected QT interval (Fridericia's correction
formula [QTcF]) > 450 ms at Screening based on central reading
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
uncontrolled infection, unstable cardiac or pulmonary function or acute
insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia), or psychiatric illness or social situation that could limit
compliance with study requirements, at the discretion of the investigator
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
OHSU Knight Cancer Institute
Address:
City:
Portland
Zip:
97239
Country:
United States
Status:
Recruiting
Contact:
Last name:
Curtis A. Lachowiez
Phone:
503-494-5058
Email:
lachowie@ohsu.edu
Investigator:
Last name:
Curtis A. Lachowiez
Email:
Principal Investigator
Start date:
September 16, 2024
Completion date:
May 29, 2026
Lead sponsor:
Agency:
OHSU Knight Cancer Institute
Agency class:
Other
Collaborator:
Agency:
Oregon Health and Science University
Agency class:
Other
Collaborator:
Agency:
Oryzon Genomics S.A.
Agency class:
Industry
Source:
OHSU Knight Cancer Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06357182
