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

Trial Summary

What is the purpose of this trial?

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).

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.

What data supports the effectiveness of the drug azacitidine for treating myelodysplastic syndrome?

Azacitidine has been shown to significantly prolong survival in patients with higher-risk myelodysplastic syndromes, as demonstrated in large clinical trials where it extended median survival compared to conventional care. It is considered a standard treatment for these patients, especially when stem cell transplantation is not an option. ^{1 2 3 4 5}

Is the combination of Iadademstat and Azacitidine safe for treating myelodysplastic syndrome?

Azacitidine, also known as Vidaza, has been used safely in patients with myelodysplastic syndromes, but it can cause side effects like blood cell issues, stomach problems, and reactions at the injection site. More data is needed to fully understand the safety of Iadademstat in combination with Azacitidine. ^{1 4 5 6 7}

What makes the drug combination of Iadademstat and Azacitidine unique for treating myelodysplastic syndrome?

The combination of Iadademstat and Azacitidine is unique because it pairs a novel drug, Iadademstat, with Azacitidine, a standard treatment for higher-risk myelodysplastic syndromes. Iadademstat is a new type of drug that may enhance the effects of Azacitidine, potentially improving outcomes for patients who do not respond well to Azacitidine alone. ^{1 5 8 9 10}

Research Team

Guru Subramanian Guru Murthy, MD, MS

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

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

I am following the required contraceptive measures.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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 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]

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]

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]

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]

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]

References

1. England 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). [2019]

2. England 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. [2016]

3. England pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. [2022]

4. England 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. [2015]

5. France pubmed.ncbi.nlm.nih.gov

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

6. United States 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. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes. [2022]

9. United States 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. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Azacytidine for the treatment of myelodysplastic syndromes in the elderly. [2014]