Ivosidenib + Azacitidine for Acute Myeloid Leukemia

(AGILE Trial)

Not currently recruiting at 189 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Institut de Recherches Internationales Servier

Must be taking: Azacitidine

Must not be taking: IDH1 inhibitors, Hypomethylating agents

Disqualifiers: Prior AML treatment, Active infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 28

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, ivosidenib (AG-120) and azacitidine, to determine their effectiveness in treating acute myeloid leukemia (AML) in individuals who haven't received prior treatment. The focus is on participants with a specific genetic marker (IDH1 mutation) who are not suitable for aggressive chemotherapy. The trial aims to assess the treatment's efficacy and safety by measuring how long participants remain cancer-free and their overall survival. Individuals with untreated AML and the IDH1 mutation, who cannot undergo intensive chemotherapy, might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants access to potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but if you are on medications that prolong the QT interval (a heart rhythm measure), you may need to switch to other medications before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that the combination of ivosidenib and azacitidine is generally well-tolerated in people with acute myeloid leukemia (AML) who have an IDH1 mutation. Studies indicate that this treatment significantly improves both the time patients live without disease progression and overall survival rates compared to other treatments. This suggests it is effective and safe for most patients.

Previous studies have reported some side effects, but these are usually manageable. The most common issues are nausea and tiredness, which are not severe for most people receiving the treatment. Importantly, serious side effects are rare, and the benefits of the treatment often outweigh these risks for many patients. This information can reassure potential participants about the safety of ivosidenib and azacitidine in ongoing trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Researchers are excited about Ivosidenib (AG-120) combined with Azacitidine for treating Acute Myeloid Leukemia (AML) because it offers a unique mechanism of action targeting the IDH1 mutation, which is present in some AML patients. Unlike standard treatments like chemotherapy, which indiscriminately attack rapidly dividing cells, Ivosidenib specifically inhibits the mutated IDH1 enzyme, potentially leading to less collateral damage to healthy cells. This precision targeting could result in fewer side effects and improved outcomes for patients with this specific genetic profile. Combining Ivosidenib with Azacitidine, a drug that modulates gene expression, might enhance the overall effectiveness, offering hope for better responses in AML treatment.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research shows that using ivosidenib with azacitidine holds promise for treating acute myeloid leukemia (AML) with an IDH1 mutation. In this trial, some participants will receive this combination. Studies have found that it helps patients live longer without their cancer worsening. Specifically, one study reported a median survival of 29.3 months, a positive outcome for this challenging leukemia. Patients receiving this treatment also achieved higher rates of complete remission, with no signs of cancer detected. Overall, ivosidenib and azacitidine together offer significant benefits for people with this type of AML. ^{2 3 4 5 6}

Are You a Good Fit for This Trial?

This trial is for adults with previously untreated Acute Myeloid Leukemia (AML) who have an IDH1 mutation and are not suitable for intensive chemotherapy. They must have good liver and kidney function, agree to regular blood and bone marrow tests, understand the study, consent to it, and if of childbearing potential, use two forms of contraception.

Inclusion Criteria

Be able to understand and willing to sign an informed consent form (ICF)

Be willing to complete Quality of Life assessments during the study

If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Females of reproductive potential, as well as fertile men and their female partners of reproductive potential, must agree to use 2 effective forms of contraception

Exclusion Criteria

I am currently pregnant or breastfeeding.

I have been treated with a drug to modify my DNA for MDS.

I have waited the required time after my last dose of an experimental MDS treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AG-120 or placebo in combination with azacitidine for a minimum of 6 cycles

24 weeks

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 52 months

What Are the Treatments Tested in This Trial?

Interventions

• AG-120 (Ivosidenib)
• Azacitidine
• Placebo

Trial Overview The trial is testing AG-120 (Ivosidenib) combined with Azacitidine against a placebo plus Azacitidine in patients with AML. It's a global Phase 3 study where participants are randomly assigned to either treatment group. The main goal is to see how long patients live without their disease getting worse.

How Is the Trial Designed?

Group I: AG-120 + Azacitidine Experimental Treatment 2 Interventions

Participants received AG-120 500 mg orally, once daily (QD) in combination with azacitidine 75 milligrams per square meter per day (mg/m\^2/day) subcutaneously (SC) or intravenously (IV), on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.

Group II: Placebo + Azacitidine Placebo Group 2 Interventions

Participants received AG-120 matching placebo orally, QD in combination with azacitidine 75 mg/m\^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation .

Who Is Running the Clinical Trial?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Published Research Related to This Trial

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]

Ivosidenib, when combined with azacitidine, significantly improves event-free survival and overall survival in older adults or those with comorbidities suffering from IDH1-mutated acute myeloid leukemia, as shown in a phase 3 study with improved survival rates (HR 0.35 and HR 0.44).

The combination therapy also resulted in a higher complete remission rate (47% vs. 15% with placebo) and maintained a safety profile similar to ivosidenib alone, with notable adverse effects including differentiation syndrome and QT interval prolongation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. Woods, A., Norsworthy, KJ., Wang, X., et al.[2023]

A phase III study demonstrated that combining azacitidine with the IDH1 inhibitor ivosidenib significantly improves treatment outcomes for patients with acute myeloid leukemia who cannot undergo intensive chemotherapy.

The combination therapy tripled overall survival rates and enhanced complete remission and event-free survival compared to azacitidine alone, indicating a substantial efficacy boost from this drug pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

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 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]

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]

Citations

1. ashpublications.org ashpublications.org/bloodadvances/article/9/20/5177/546354/Long-term-results-from-the-AGILE-study-of

Long-term results from the AGILE study of azacitidine plus ... In long-term follow-up, ivosidenib-azacitidine, with a median OS of 29.3 months, sustained survival and hematologic benefits in mutant IDH1 AML.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40706052/

Long-term results from the AGILE study of azacitidine plus ... These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2117344

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid ... Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population.

4. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(23)01066-2/fulltext

AML-469 Ivosidenib + Azacitidine vs Placebo ... In the AGILE study, ivosidenib (IVO) plus azacitidine (AZA) significantly improved event-free survival, overall survival (OS), complete remission (CR), ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7012

Updated efficacy and safety data from the AGILE study in ... IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10428678/

P490: UPDATED SURVIVAL, BLOOD COUNT RECOVERY ... IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial ...