Ivosidenib + Azacitidine for MDS

(PyramIDH Trial)

Recruiting at 54 trial locations

Overseen By Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Institut de Recherches Internationales Servier

Must not be taking: HMA's, Cytotoxic chemotherapy

Disqualifiers: Prior anticancer treatment, >20% blasts, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 4 months

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, ivosidenib (a targeted therapy) and azacitidine (a hypomethylating agent), for individuals with myelodysplastic syndromes (MDS), a condition where the bone marrow fails to produce enough healthy blood cells. Participants will receive one of these treatments to determine which more effectively manages MDS with a specific mutation in the IDH1 protein. The trial aims to help researchers identify the best way to improve survival and quality of life for those with this condition. Individuals with MDS and the IDH1 mutation who have not yet received treatment with a hypomethylating agent may be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have received certain treatments for MDS before, you may not be eligible to participate.

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

Previous studies have shown ivosidenib to be generally safe and manageable. For patients with certain genetic mutations, it often led to long-lasting remissions, indicating that the treatment was usually well-tolerated with controllable side effects. However, the specific side effects were not detailed in the sources.

Azacitidine is already used to treat some blood disorders, including MDS. Research has shown it is often well-tolerated, even by older patients. However, safety concerns exist, as most unwanted effects were serious, and some were fatal. While many patients do not experience severe problems, there is a risk of serious complications.

Both treatments have been studied thoroughly, enhancing doctors' understanding of their safety. Those considering joining the trial should discuss these findings with a healthcare professional for more personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ivosidenib and Azacitidine for treating myelodysplastic syndromes (MDS) because of their unique mechanisms of action. Most treatments for MDS focus on boosting blood cell production or slowing disease progression. However, Ivosidenib is different because it targets specific genetic mutations commonly found in MDS, potentially offering a more personalized approach. Azacitidine, on the other hand, helps by modifying the DNA of cancer cells to stop their growth. These innovative approaches could lead to more effective and tailored treatments for patients with MDS.

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

Research shows that ivosidenib may benefit patients with myelodysplastic syndromes (MDS) who have an IDH1 mutation. One study found that 72% of previously untreated patients with this mutation experienced either full or partial improvement with ivosidenib alone. Another report indicated that 63.6% of high-risk MDS patients, who did not respond to other treatments, improved with ivosidenib. In this trial, some participants will receive ivosidenib monotherapy.

For azacitidine, studies indicate a 60% overall improvement rate in high-risk MDS patients. Patients treated with azacitidine lived for about 13.4 months on average. Other participants in this trial will receive azacitidine monotherapy. Both treatments have proven effective for MDS, offering different benefits based on patient needs and previous treatments. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with myelodysplastic syndromes (MDS) who have an IDH1 mutation and haven't been treated with hypomethylating agents before. They should be at moderate to very high risk per IPSS-M score, have low blood counts related to MDS, and a blast count of 5-19%. Those eligible for HMA therapy can join except if they're at very low risk.

Inclusion Criteria

My blood counts are low due to myelodysplastic syndromes.

My blood has 5-19% blast cells.

My MDS is classified as moderate high, high, or very high risk with less than 20% blasts.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ivosidenib (IVO) daily or azacitidine (AZA) for the first 7 days of each 28-day cycle. Study visits occur weekly during Cycle 1 and on Day 1 of each subsequent cycle.

4 months

Weekly visits during Cycle 1, then Day 1 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a safety follow-up visit and assessment of overall survival.

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Ivosidenib

Trial Overview The study tests Ivosidenib (IVO) alone versus Azacitidine (AZA) alone in treating MDS with IDH1 mutations. IVO is taken daily, while AZA is given for the first week of each treatment cycle. Participants will undergo regular check-ups including bone marrow exams and heart monitoring.

How Is the Trial Designed?

Group I: Ivosidenib monotherapy Experimental Treatment 1 Intervention

Group II: Azacitidine monotherapy Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Servier Bio-Innovation LLC

Industry Sponsor

Trials

9

Recruited

670+

Published Research Related to This Trial

In a study of 110 high-risk myelodysplastic syndrome (MDS) patients treated with 5-azacitidine, the overall survival rates were 66.1% at 1 year and 38.3% at 2 years, with significant differences based on risk stratification; very high-risk patients had a much lower 2-year survival rate of 17%.

Factors such as being transfusion independent at baseline and the absence of infections during treatment were associated with better survival outcomes, highlighting the importance of these factors in managing MDS with 5-azacitidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of predictive factors for overall survival at baseline and during azacitidine treatment in high-risk myelodysplastic syndrome patients treated in the clinical practice. Scalzulli, E., Molica, M., Alunni Fegatelli, D., et al.[2019]

Azacitidine has been shown to prolong overall survival in patients with higher risk-myelodysplastic syndromes (HR-MDS), with a median overall survival of 18.6 months based on a systematic review of 237 clinical studies involving 2820 patients.

The study found a weak correlation between complete response rates and overall survival, but a much stronger correlation with median progression-free survival, suggesting that progression-free survival may be a more reliable endpoint for evaluating treatment efficacy in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival. Garcia, JS., Swords, RT., Roboz, GJ., et al.[2021]

In a study of 88 patients with intermediate-2 or high-risk myelodysplastic syndromes (MDS), azacitidine treatment resulted in a 37.7% overall response rate, indicating its efficacy in improving hematologic conditions.

The treatment was associated with a 33.0% hematologic improvement rate and a 6.8% transformation rate to acute myeloid leukemia (AML), supporting its potential to modify disease progression while maintaining a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of azacitidine treatment in patients with intermediate-2 or high risk myelodysplastic syndromes in a real-world clinical setting in Greece. Pappa, V., Anagnostopoulos, A., Bouronikou, E., et al.[2018]

In a phase Ib trial involving 23 patients with newly diagnosed IDH1-mutant acute myeloid leukemia, the combination of ivosidenib and azacitidine resulted in a high overall response rate of 78.3% and a complete remission rate of 60.9%.

The treatment was well tolerated, with a safety profile similar to that of each drug alone, and 71.4% of patients achieving complete remission showed clearance of the mIDH1 mutation in their bone marrow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. DiNardo, CD., Stein, AS., Stein, EM., et al.[2022]

Ivosidenib has shown the ability to induce remission in 30.4% of patients with relapsed or refractory acute myeloid leukemia that have IDH1 mutations, indicating its potential efficacy as a treatment.

The most common serious side effects observed were prolonged QT interval and IDH differentiation syndrome, highlighting the importance of monitoring for these conditions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Deemed Safe, Effective in AML. [2019]

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 134 higher-risk MDS patients treated with azacitidine, karyotype and mutational profiles were found to significantly influence survival outcomes, with high-risk cytogenetics leading to poorer survival rates (median 10 months) compared to those with favorable mutations (median 22 months).

Specifically, mutations in histone modulators like ASXL1 and EZH2 were associated with improved survival, suggesting that integrating mutational screening with cytogenetic analysis could enhance therapeutic decision-making for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutations in histone modulators are associated with prolonged survival during azacitidine therapy. Tobiasson, M., McLornan, DP., Karimi, M., et al.[2018]

In a study involving 277 patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), azacitidine combined with lenalidomide showed a higher overall response rate (ORR) of 68% in CMML patients compared to 28% for azacitidine alone, indicating a potential benefit for this specific group.

Overall, the combination therapies (azacitidine plus lenalidomide and azacitidine plus vorinostat) did not significantly outperform azacitidine monotherapy in terms of ORR, suggesting that while combinations may be beneficial for certain patients, they may also be impacted by dose modifications and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. Sekeres, MA., Othus, M., List, AF., et al.[2022]

In two large phase III trials involving 325 patients with myelodysplastic syndrome (MDS), azacitidine was associated with common adverse events (AEs) such as cytopenias and gastrointestinal issues, but most were transient and manageable, allowing patients to continue treatment.

The frequency of hematologic AEs decreased over time, and effective management strategies, including dosing delays and supportive medications, helped patients tolerate azacitidine better, maximizing the potential benefits of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Santini, V., Fenaux, P., Mufti, GJ., et al.[2021]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11011162/

Real-World Outcome and Prognostic Factors in MDS ... Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: Results from the Spanish registry. Leukemia. 2015;29:1875 ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2152265023021973

Real-world Effectiveness of Azacitidine in Treatment-Naive ... The real-world outcomes from AZA have been lower than expected with a registry of the Spanish cooperative group on MDS reporting a median OS of 13.4 months from ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6697/528518/Outcome-of-Low-Dose-Azacitidine-in-Patients-of

Outcome of Low Dose Azacitidine in Patients of Lower Risk ... Conclusions: Azacitidine can be a cost-effective treatment for transfusion-dependent LR-MDS, particularly in an emerging market and mid-income ...

4. haematologica.org haematologica.org/article/view/11858

Treatment of high-risk myelodysplastic syndromes The overall response rate after azacitidine was 60% versus 5% in the best supportive care group (P<0.0001) and time to leukemic transformation ...

5. nature.com nature.com/articles/leu2015115

Effectiveness of azacitidine in unselected high-risk ... Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8–16) months for azacitidine-treated patients and 12.2 (11– ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... A subset analysis of the AZA-001 trial in patients older than 75 years demonstrated higher overall survival rates at 2 years in the azacitidine group (55%) than ...

7. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18578

Efficacy and safety of azacitidine in the treatment of elderly ... Conclusions: AZA monotherapy is well-tolerated and effective in higher-risk MDS, even in very elderly patients (>80 years). Compared to clinical ...

9. hematologyadvisor.com hematologyadvisor.com/news/azacitidine-myelodysplastic-syndrome-mds-adverse-events-safety-concerns/

New Adverse Events Highlight Safety Concerns With ... Most AEs (95.78%) were classified as serious, and 40.87% resulted in death. Health professionals submitted nearly 90% of the reports, with the ...