Ivosidenib + Azacitidine for MDS

(PyramIDH Trial)

Recruiting at 20 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

Trial Summary

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.

What data supports the effectiveness of the drug azacitidine for MDS?

Research shows that azacitidine can significantly prolong survival in patients with higher-risk myelodysplastic syndromes (MDS), with studies indicating improved overall survival compared to conventional care. It is considered a standard first-line treatment for these patients. ^{1 2 3 4 5}

Is the combination of Ivosidenib and Azacitidine safe for humans?

Azacitidine has been shown to cause both non-serious and serious side effects in about half of the patients with myelodysplastic syndromes (MDS), but it is generally considered to have a favorable risk-benefit profile. Ivosidenib, used for acute myeloid leukemia (AML), is generally safe but can cause serious side effects like prolonged QT interval (a heart rhythm condition) and IDH differentiation syndrome. ^{1 6 7 8 9}

How is the drug combination of Ivosidenib and Azacitidine unique for treating MDS?

The combination of Ivosidenib and Azacitidine is unique because Ivosidenib specifically targets and inhibits the mutant IDH1 enzyme, which is not addressed by standard treatments for MDS. This combination may enhance the effects of Azacitidine, a drug already established as a first-line treatment for higher-risk MDS, by promoting cancer cell differentiation and death. ^{1 2 7 8 10}

What is the purpose of this trial?

This study will enroll participants with myelodysplastic syndromes (MDS) with an Isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have not received treatment with a hypomethylating agent previously. Participants will be randomized to receive either ivosidenib (IVO) alone or azacitidine (AZA) alone. IVO will be administered daily throughout the 28-day treatment cycle and AZA will be administered for the first 7 days of each 28-day cycle. Study visits will be conducted every week during Cycle 1 (Days 1, 8, 15, and 22), and Day 1 of each cycle thereafter. After the last dose of treatment, participants will attend an safety follow-up visit and participants will be followed to assess overall survival. Study visits may include a bone marrow aspirate, physical exam, echocardiogram (ECHO), electrocardiogram (ECG), blood and urine analysis, and questionnaires.

Eligibility Criteria

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.

I am eligible for HMA therapy and not considered very low risk.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

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]

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]

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]

References

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

Mutations in histone modulators are associated with prolonged survival during azacitidine therapy. [2018]

2. England pubmed.ncbi.nlm.nih.gov

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

3. England 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. [2021]

4. 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]

5. United States 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. [2021]

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

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. [2022]

8. Japan 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. [2018]

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

Ivosidenib Deemed Safe, Effective in AML. [2019]

10. Germany 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. [2019]