Iadademstat in Combination With Azacitidine and Venetoclax in Treating Newly Diagnosed Acute Myeloid Leukemia

NCT06357182 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY00026136NCI-2024-01262
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome/Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Incidence of dose-limiting toxicities (DLTs) within specific iadademstat (IADA) dose levels

  Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).

  Start of IADA (cycle 1 of combination therapy) to end of cycle 1 (each cycle is 28 days)

Secondary Outcomes (3)

• Percentage of efficacy-evaluable participants achieving composite complete remission (cCR)

  Start of IADA (cycle 1 of combination therapy) to end of investigational study treatment, average of 1 year

• Percentage of efficacy-evaluable participants achieving an overall response (ORR)

  Start of IADA (cycle 1 of combination therapy) to end of investigational study treatment, average of 1 year

• Incidence of treatment-emergent grade ≥ 3 adverse events (AEs)

  Start of IADA (cycle 1 of combination therapy) to end of investigational study treatment, average of 1 year

Study Arms (4)

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax)

EXPERIMENTAL

Iadademstat (75 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-14), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO 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 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or 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 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or 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.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test; Drug: Iadademstat; Procedure: Multigated Acquisition Scan; Other: Questionnaire Administration; Drug: Venetoclax

Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax)

EXPERIMENTAL

Iadademstat (75 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-7), Azacitidine (50 mg/m2, day 1-7). Patients receive iadademstat PO 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 azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or 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 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or 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.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test; Drug: Iadademstat; Procedure: Multigated Acquisition Scan; Other: Questionnaire Administration; Drug: Venetoclax

Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax)

EXPERIMENTAL

Iadademstat (100 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-21), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO 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 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or 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 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or 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.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test; Drug: Iadademstat; Procedure: Multigated Acquisition Scan; Other: Questionnaire Administration; Drug: Venetoclax

Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

EXPERIMENTAL

Iadademstat (150 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-21), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO 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 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or 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 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or 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.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test; Drug: Iadademstat; Procedure: Multigated Acquisition Scan; Other: Questionnaire Administration; Drug: Venetoclax

Interventions

Azacitidine DRUG

Given SC

Also known as: 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC, Echocardiography

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Iadademstat DRUG

Given PO

Also known as: ORY 1001, ORY-1001, RG 6016, RG6016, RO 7051790, RO7051790, trans-N1-((1R,2S)-2-Phenylcyclopropyl)-1,4-cyclohexanediamine

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Questionnaire Administration OTHER

Ancillary study

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Venetoclax DRUG

Given PO

Also known as: ABT 199, ABT-0199, ABT-199, ABT199, GDC 0199, GDC-0199, GDC0199, RG7601, Venclexta, Venclyxto

Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax); Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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. If altered, CrCl is determined to be related to concomitant medication that alters renal function
• 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;

You may not qualify if:

• 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
• 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 21 days or 3 half-lives whichever is longer 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

Sponsors & Collaborators

• OHSU Knight Cancer Institute: lead
• Oregon Health and Science University: collaborator
• Oryzon Genomics S.A.: collaborator

Study Sites (1)

OHSU Knight Cancer Institute

Portland, Oregon, 97239, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; GATA2 Deficiency

Interventions

Azacitidine; Specimen Handling; Biopsy; iadademstat; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Curtis A Lachowiez

  OHSU Knight Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: February 29, 2024
• First Posted: April 10, 2024
• Study Start: August 22, 2024
• Primary Completion: March 8, 2026
• Study Completion (Estimated): May 29, 2026
• Last Updated: August 12, 2025

Record last verified: 2025-08

Locations

US (1)