Iadademstat With Hypomethylating Agent in Patients With Myelodysplastic Syndrome

This is a phase I study with a primary objective of determining the recommended phase II dose of iadademstat with azacitidine in adult subjects with myelodysplastic syndrome (MDS).

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Azacitidine Level -1; Drug: Iadademstat Level -1; Drug: Azacitidine Level 0; Drug: Iadademstat Level 0; Drug: Azacitidine Level 1; Drug: Iadademstat Level 1

Detailed Description

This is a single-arm, open-label phase 1 study designed to evaluate the safety of iadademstat with azacitidine therapy. The trial will follow a 3+3 phase 1 dose-escalation design.

First, three participants are given a low dose of the experimental treatment and monitored for pre-specified toxicity events. If 0 participants experience one of these toxicity events, then the next group of three participants is enrolled at a higher dose. If two or three participants experience toxicity, then the next group of three participants is enrolled at a lower dose (or the study ends). If one participant experiences toxicity, another group of three participants is enrolled at the same dose (hence the name, 3+3): if one or more of those participants experience toxicity, then the dose is lowered for the next group of the study ends. Otherwise, if 0 of the additional participants experience toxicity, the next group is enrolled at a higher dose.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Medical College of Wisconsin Cancer Center Clinical Trials Office; Phone Number: 8900 866-680-0505; Email: cccto@mcw.edu

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert Hospital & the Medical College of Wisconsin
      • Contact: Guru Subramanian Guru Murthy, MD, MS; Email: gmurthy@mcw.edu
      • Principal Investigator: Guru Subramanian Guru Murthy, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female 18 years or older.
2. Patients must have a diagnosis of myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) as defined by the World Health Organization (WHO) criteria.
3. Intermediate, high, or very-high risk by the Revised International Prognostic Scoring System (IPSS-R).
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (0-3 if performance status is considered due to MDS).
5. Patient must have a body weight of at least 50 kg.

6. Patient must meet the following screening clinical laboratory values as specified below:

   a. Hematologic: white blood cell (count) (WBC) below 30 x 109/L. Hydroxyurea can be used to achieve this level b. Hepatic: i. Total bilirubin ≤1.5 x upper limit of normal (ULN). Patients with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits.

   ii. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN.

   c. Renal: Serum creatinine ≤1.5 x ULN.

7. Patient is able to swallow oral medications.

8. Female subjects who:

   1. Are postmenopausal for at least one year before the screening visit, OR
   2. Are surgically sterile, OR
   3. If they are of childbearing potential:

   i. Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through six months after the last dose of study drug (female and male condoms should not be used together), OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).

   iii. Agree to not to donate or freeze egg(s) during the course of this study or within 180 days after receiving their last dose of study drug.

9. Male subjects, even if surgically sterilized (i.e., status post vasectomy), who:

   1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through six months after the last dose of study drug (female and male condoms should not be used together), OR
   2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
   3. Agree to not to donate or freeze sperm during the course of this study or within 180 days after receiving their last dose of study drug.
10. Ability to provide informed consent or have a legally authorized representative provide consent.

Exclusion Criteria:

A potential study subject who meets any of the following exclusion criteria is ineligible to participate in the study:

1. Prior therapy with hypomethylating agent or Lysine-specific histone demethylase 1A (LSD1) inhibitor. If patients were treated with any other agents having KDM1A/LSD1 inhibitory activity (such as tranylcypromine or phenelzine or similar drugs), they are only allowed if treatment finalized at least 3 weeks prior to first dose on study.
2. Patient will require treatment while on study with concomitant drugs that target the 5- hydroxytryptamine2B (5-HT2B) 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.
3. Treatment with systemic antineoplastic chemotherapy within 14 days or 5 half-lives from the last dose - whichever is sooner - before Cycle 1, Day 1 of therapy. Radiation within 14 days before Cycle 1, Day 1 of therapy. The use of hydroxyurea for leukoreduction is permitted. Similarly, prior ESA, luspatarcept, or lenalidomide is allowed. Subjects must have recovered from the side effects of prior therapy per the treating physician's discretion.
4. Patient is on treatment with any investigational products within 3 weeks prior to the first dose of study treatment.
5. Patient has had major surgery within 4 weeks prior to the first study dose.
6. Patients with 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 Cycle 1, Day 1 is allowed.
7. Patients with known poorly controlled diabetes (glycosylated hemoglobin (HbA1c) ≥8%) unless actively managed with appropriate therapy; 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.
8. Patient has known active congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patients with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 1 month prior to study entry demonstrates a left ventricular ejection fraction that is ≥40%.
9. Patients with known long QT Syndrome at screening.
10. History of allogeneic stem cell transplantation or CAR-T therapy within past 60 days.
11. Patient has evidence of active uncontrolled viral, bacterial, or systemic fungal infection (i.e., no signs of severe systemic inflammatory response that makes patient clinically unstable in the opinion of the investigator, and patient is hemodynamically stable, with sustained body temperature under 38°C for 48-72 hours before starting study treatment and does not need oxygen supplementation or pressors to maintain blood pressure). Patients with uncontrolled infection shall not be enrolled until the infection is treated and brought under control.
12. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease that may alter the absorption of iadademstat.
13. Pregnant or lactating / breastfeeding women.
14. Patient has any condition which, in the investigator's opinion, makes the patient unsuitable for study participation. For example, any inter-current illness or social situation that will limit compliance with study requirements. Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand the informed consent form or that in the opinion of the investigator would contraindicate the patient's participation in the study or confound the results of the study.
15. Patient presents a known contraindication to any of the treatment drug excipients.
16. Patient has known active hepatic disorder or is known to be positive for hepatitis B or C infection with the exception of those with undetectable viral load within 3 months (Hepatitis B or C testing is not required for eligibility assessment).
17. Patient is known to have human immunodeficiency virus infection. (HIV testing is not required for eligibility assessment).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level -1; Dose level -1 will be considered only if there are dose-limiting toxicities at dose level 0. This is a regimen of azacitidine and iadademstat.	Drug: Azacitidine Level -1; Intravenous (IV) or subcutaneous (SC) 75 mg / m^2 days 1-7 X 28 days.; Other Names: Vidaza; Onureg; Drug: Iadademstat Level -1; 75 µg by mouth (PO) 5 days on, 2 days off for 2 weeks every 28 days.
Experimental: Dose level 0; This is a regimen of azacitidine and iadademstat.	Drug: Azacitidine Level 0; Intravenous (IV) or subcutaneous (SC) 75 mg / m^2 days 1-7 X 28 days.; Other Names: Vidaza; Onureg; Drug: Iadademstat Level 0; 75 µg PO 5 days on, 2 days off for 3 weeks every 28 days.
Experimental: Dose level 1; This is a regimen of azacitidine and iadademstat.	Drug: Azacitidine Level 1; Intravenous (IV) or subcutaneous (SC) 75 mg / m^2 days 1-7 X 28 days.; Other Names: Vidaza; Onureg; Drug: Iadademstat Level 1; 100 µg PO 5 days on, 2 days off for 3 weeks every 28 days.
Experimental: Maximum Tolerated Dose (MTD); The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.	Drug: Iadademstat Level -1; 75 µg by mouth (PO) 5 days on, 2 days off for 2 weeks every 28 days.; Drug: Iadademstat Level 0; 75 µg PO 5 days on, 2 days off for 3 weeks every 28 days.; Drug: Iadademstat Level 1; 100 µg PO 5 days on, 2 days off for 3 weeks every 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase II dose of Iadademstat.	The dose identified in this trial that will be used in future clinical trials.	Up to two years

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Guru Subramanian Guru Murthy, MD, MS, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: July 9, 2024
• First Submitted That Met QC Criteria: July 9, 2024
• First Posted (Actual): July 16, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine
• Other Study ID Numbers: PRO00053184

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No