Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML

NCT06514261 | Recruiting Phase 1 FDA Drug

• 4 other identifiers: NCI-2024-0461624-11510630UM1CA186690
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I trial tests safety, side effects and best dose of iadademstat with azacitidine and venetoclax for the treatment of patients with acute myeloid leukemia (AML) who have not received treatment (treatment naive). Chemotherapy drugs, such as iadademstat and 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 and tolerable in treating patients with treatment naive AML.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Incidence of dose limiting toxicity (DLT)

  DLT will be defined as any of the following adverse events (AEs) that cannot be considered primarily related to the underlying acute myeloid leukemia or a comorbid condition and evaluated during the first cycle of treatment. Will utilize National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for toxicity grading and reporting.

  Up to completion of cycle 1

• Incidence of AEs

  Will utilize NCI-CTCAE v5.0 for AE grading and reporting.

  Up to completion of therapy

Secondary Outcomes (7)

• Objective response rate

  Up to 4 years

• Morphologic leukemia free state

  Up to 4 years

• Minimal residual disease (MRD)-negative composite complete remission (cCR)

  After completion of 2 cycles

• Event free survival

  From study enrollment to disease progression, treatment failure (failure to achieve CR or < 5% bone marrow blasts) confirmed relapse or death, up to 4 years

• Overall survival

  Up to 4 years

Other Outcomes (11)

• MRD-negative cCR and molecular/cytogenetic risk group status

  After cycles 1, 3 and 6

• Percentage LSD1 target engagement by chemoprobe in peripheral blood mononuclear cells

  Up to 4 years

• BCL-2 mutations by next generations sequencing (NGS) in bone marrow (BM) of patients who initially respond and then progress

  At baseline, during treatment, and at progression of disease, up to 4 years

Study Arms (1)

Treatment (iadademstat, venetoclax, azacitidine)

EXPERIMENTAL

INDUCTION: Patients receive iadademstat PO QD on days 1-5, 8-12, and may also receive it on days 15-19 of each cycle, venetoclax PO QD on days 1-14 or 1-21 of each cycle, and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle or days 1-5 and 8-9 after cycle 1. Cycles repeat every 28 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo buccal swab collection on study. CONSOLIDATION: Patients receive iadademstat PO QD on days 1-5, 8-12 and may also receive it on days 15-19 of each cycle, venetoclax PO QD on days 1-7 or 1-14 of each cycle, and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle or days 1-5 and 8-9 after cycle 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and may undergo bone marrow aspiration throughout the study.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Buccal Swab; Drug: Iadademstat; Drug: Venetoclax

Interventions

Azacitidine DRUG

Given IV or SC

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

Treatment (iadademstat, venetoclax, azacitidine)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

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

Treatment (iadademstat, venetoclax, azacitidine)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Treatment (iadademstat, venetoclax, azacitidine)

Buccal Swab PROCEDURE

Undergo buccal swab

Also known as: Buccal Scraping, Buccal Smear, Buccal swab/scraping, Buccal Swabbing

Treatment (iadademstat, venetoclax, azacitidine)

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 (iadademstat, venetoclax, azacitidine)

Venetoclax DRUG

Given PO

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

Treatment (iadademstat, venetoclax, azacitidine)

Eligibility Criteria

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

You may qualify if:

• Patients must have established and confirmed diagnosis of intermediate or adverse-risk AML according to the European LeukemiaNet 2022 classification criteria
• Previously untreated AML excluding hydroxyurea and all-trans retinoic acid (ATRA). ATRA would only be used for suspected AML
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of iadademstat in combination with venetoclax and azacitidine in patients \< 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Patient is able to swallow oral medications
• Patient must have a body weight of at least 50 kg due to the use of flat doses
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 x ULN or ≤ 3 x ULN if patient has Gilbert's disease
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN or \< 5 ULN if due to AML
• Chronic kidney disease (CKD)-epidemiology collaboration (EPI) glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m\^2
• Peripheral white blood cell (WBC) count \< 25 x 10\^9/L on day 1 prior to treatment initiation. Hydroxyurea for up to 2 weeks is allowed for cytoreduction until 24 hours prior to study treatment
• 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. Patients with a troponin leak (i.e. elevated troponin levels at presentation without evidence of an active myocardial infarction (MI) are eligible

You may not qualify if:

• Patients are willing and able to receive intensive induction chemotherapy
• Patients have isolated myeloid sarcoma or acute promyelocytic leukemia (APL) French-American-British (FAB) M3
• Patients who have not recovered from adverse events of grade 3 or more 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
• Patients who have active central nervous system (CNS) involvement by AML
• Patients who have disseminated intravascular coagulopathy with active systemic bleeding or venous or atrial signs of thrombosis
• Patients who require treatment while on study with concomitant drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline) except for drugs that are considered absolutely essential for the care of the patient and with appropriate treatment monitoring
• Patients with manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of oral drugs. In addition, patients with enteric stomata are also excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to iadademstat, azacitidine, mannitol, or venetoclax
• 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 \[as non-prescription drugs, herbal medicine and homeopathy\])
• Patients should not use strong CYP3A inhibitors with the exception of antifungals for which standard of care (SOC) dose modifications of venetoclax exist
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. This includes, but is not limited to:
• Myocardial infarction with evidence of residual abnormalities within 3 months prior to enrollment (Troponin leak alone not included if no residual dysfunction);
• New York Heart Association (NYHA) Class III or IV heart failure;
• Severe uncontrolled ventricular arrhythmias;

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California, 92612, United States

SUSPENDED

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

RECRUITING

University of Cincinnati Cancer Center-UC Medical Center

Cincinnati, Ohio, 45219, United States

RECRUITING

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine; Specimen Handling; iadademstat; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

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

Study Officials

• Annie P Im

  University of Pittsburgh Cancer Institute LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2024
• First Posted: July 23, 2024
• Study Start: December 18, 2024
• Primary Completion (Estimated): September 16, 2026
• Study Completion (Estimated): September 16, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (4)