Iadademstat + Azacitidine for Myelodysplastic Syndrome

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Medical College of Wisconsin

Must not be taking: Antidepressants, Chemotherapy

Disqualifiers: Uncontrolled hypertension, Diabetes, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: iadademstat (an experimental treatment) and azacitidine (also known as Vidaza or 5-azacytidine) for individuals with myelodysplastic syndrome (MDS), a condition where the bone marrow doesn't produce enough healthy blood cells. The goal is to determine the best dose for future studies. Participants will receive varying doses to assess safety and effectiveness. The trial seeks individuals diagnosed with MDS who have not undergone certain previous treatments and experience daily impacts from their condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot take certain drugs that target specific receptors unless they are essential for your care. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of iadademstat and azacitidine is generally safe for patients. Previous studies found that iadademstat alone is safe and offers benefits for patients with relapsed or hard-to-treat acute myeloid leukemia (AML). When combined with azacitidine, this treatment also demonstrated positive safety results in patients newly diagnosed with AML.

Another study showed that this combination was well-tolerated and produced promising results. While these findings are encouraging, it's important to note that this trial remains in the early stages. Researchers aim to determine the safest and most effective dose. Overall, studies so far have indicated that the combination of iadademstat and azacitidine has a good safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining iadademstat with azacitidine for treating myelodysplastic syndrome (MDS) because iadademstat has a unique mechanism of action. Unlike most standard treatments that often target DNA or the growth of cancer cells directly, iadademstat is a novel LSD1 inhibitor. This means it works by blocking a specific enzyme, LSD1, that plays a crucial role in regulating genes linked to cancer cell survival and proliferation. By pairing it with azacitidine, which is already a staple in MDS treatment for its ability to demethylate DNA and reactivate tumor suppressor genes, the combo could offer a more comprehensive approach to tackling the disease. This dual action has the potential to improve outcomes for patients with MDS by targeting the disease from multiple angles.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

Research has shown that combining iadademstat and azacitidine holds promise for treating blood conditions like acute myeloid leukemia (AML). Iadademstat blocks an enzyme that aids cancer cell growth. When combined with azacitidine, this treatment has proven safe and effective for AML patients, a condition similar to myelodysplastic syndrome (MDS). Results from earlier studies showed positive outcomes and manageable side effects. This trial will explore different dose levels of the iadademstat and azacitidine combination to determine the most effective and safe regimen for MDS patients, offering hope for better management of the condition. ^{1 3 6 7 8}

Who Is on the Research Team?

Guru Subramanian Guru Murthy, MD, MS

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

This trial is for adults with Myelodysplastic Syndrome (MDS), a condition that can lead to leukemia. Participants should not have received certain treatments before and must meet specific health requirements, which will be determined by the study team.

Inclusion Criteria

Patient must meet specified screening clinical laboratory values for hematologic, hepatic, and renal criteria

Ability to provide informed consent or have a legally authorized representative provide consent

I am following the required birth control measures.

Exclusion Criteria

I have received chemotherapy within the specified timeframes.

I had major surgery less than 4 weeks ago.

I do not have active heart failure, long QT Syndrome, or recent cell therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive iadademstat with azacitidine in a 3+3 dose-escalation design to determine the maximum tolerated dose

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Iadademstat

Trial Overview The trial is testing different doses of a drug called Iadademstat in combination with Azacitidine to find the safest and most effective dose for treating MDS. It's an early-stage study (phase I) focused on dosage recommendations.

How Is the Trial Designed?

Group I: Maximum Tolerated Dose (MTD) Experimental Treatment 3 Interventions

The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.

Group II: Dose level 1 Experimental Treatment 2 Interventions

This is a regimen of azacitidine and iadademstat.

Group III: Dose level 0 Experimental Treatment 2 Interventions

This is a regimen of azacitidine and iadademstat.

Group IV: Dose level -1 Experimental Treatment 2 Interventions

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.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Published Research Related to This Trial

In a phase 2 clinical trial involving 102 patients with higher-risk myelodysplastic syndromes (MDS), the combination of azacitidine and pracinostat did not significantly improve the complete response rate compared to placebo, with rates of 18% versus 33% respectively.

Patients receiving pracinostat experienced more severe adverse events (98% vs 74% in the placebo group), leading to higher treatment discontinuation rates, which may have impacted the overall effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Garcia-Manero, G., Montalban-Bravo, G., Berdeja, JG., et al.[2018]

Azacitidine significantly improves overall survival in patients with myelodysplastic syndromes and related disorders, with a median survival of 24.5 months compared to 15 months for conventional care, based on a trial of 358 patients.

While azacitidine offers a viable treatment option when stem cell transplantation is not possible, it carries risks of severe toxicity and other side effects, highlighting the need for careful patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine. Poor-prognosis myelodysplasia: promising, but more data needed. [2013]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

A randomized 'pick-a-winner' study evaluated the effectiveness of adding lenalidomide, valproic acid, or idarubicin to azacitidine in patients with higher-risk myelodysplastic syndromes, which is the current standard treatment.

The study aimed to determine if these combinations could improve outcomes compared to azacitidine alone, highlighting the potential for enhanced treatment strategies in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes. Wei, AH., Seymour, JF.[2022]

5-azacytidine (5-AZA) has shown clinical and hematological improvement in elderly patients with high-risk myelodysplastic syndromes (MDS), based on the treatment of three case studies.

The use of 5-AZA is associated with acceptable side effects, making it a promising therapeutic option for managing high-risk MDS in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacytidine for the treatment of myelodysplastic syndromes in the elderly. Diez Campelo, M., Delgado, RG., Molias, AC., et al.[2014]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

Azacitidine has been shown to significantly prolong the time to progression to acute myeloid leukemia or death in myelodysplastic syndromes (MDS) patients, with a median time of 21 months compared to 13 months for supportive care in a study of 191 patients.

In a larger trial with 358 patients, azacitidine also significantly improved overall survival, extending it to 24.5 months compared to 15.0 months with conventional care, establishing it as a key first-line treatment for higher-risk MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Fenaux, P., Ades, L.[2022]

In a study of 196 patients with higher-risk myelodysplastic syndromes (MDS) and low blast count acute myeloid leukemia (AML), azacitidine treatment showed a higher response rate (63% complete or partial remission) when administered at the standard dose of 75 mg/m² for 7 days compared to a higher dose of 100 mg for 5-7 days (29% response).

The median overall survival for patients was 17.1 months, with better survival rates linked to lower MDS-comorbidity index scores and achieving complete or partial remission, highlighting the importance of treatment duration and dosing in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia. Voso, MT., Niscola, P., Piciocchi, A., et al.[2016]

In a study of 149 patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, azacitidine (AZA) alone achieved a hematologic normalization (HN) rate of 32%, while the combination of AZA and entinostat resulted in a lower HN rate of 27%.

The addition of entinostat did not enhance the clinical response and was associated with less demethylation, indicating a potential antagonistic effect, while AZA alone showed promise with a median overall survival of 18 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. Prebet, T., Sun, Z., Figueroa, ME., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06357182

Study Details | NCT06357182 | Iadademstat in ... Giving iadademstat with azacitidine and venetoclax may be safe, tolerable and/or effective in treating patients with newly diagnosed AML who cannot undergo ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7768337/

First-in-Human Phase I Study of Iadademstat (ORY-1001) Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity.

3. targetedonc.com targetedonc.com/view/the-targeted-pulse-new-trial-evaluating-iadademstat-azacitidine-in-mds-and-positive-trends-in-hnscc

New Trial Evaluating Iadademstat/Azacitidine in MDS and ... Our study is evaluating a novel combination regimen for the frontline management of patients with MDS using LSD1 inhibitor iadademstat, in ...

4. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/1711/491634/Iadademstat-Combination-with-Azacitidine-Is-a-Safe

Iadademstat Combination with Azacitidine Is a Safe and ... Iadademstat combination with azacitidine is a safe and effective treatment in first line acute myeloid leukemia. Final results of the Alice trial.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352302624001327

Iadademstat in combination with azacitidine in patients ... The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid ...

6. curetoday.com curetoday.com/view/a-phase-1-trial-of-iadademstat-plus-vidaza-has-dosed-a-patient-with-mds

A Phase 1 Trial of Iadademstat Plus Vidaza Has Dosed ... Iadademstat, a selective LSD1 inhibitor, is being tested with azacitidine in a phase 1 trial for MDS patients to assess safety and dosing. · MDS, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06502145

NCT06502145 | Iadademstat With Hypomethylating Agent ... 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 ...

8. oryzon.com oryzon.com/en/news-events/news/oryzon-announces-positive-clinical-data-iadademstat-ash-2025

ORYZON announces positive clinical data of iadademstat ... Iadademstat has shown encouraging safety and strong clinical activity in combination with azacitidine in a Phase IIa trial in elder 1L AML ...