IDH Mutant Targeted Therapies + Azacitidine for Acute Myeloid Leukemia

Not currently recruiting at 126 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Celgene

Must not be taking: IDH inhibitors

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 26 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for people with acute myeloid leukemia (AML), a cancer affecting the blood and bone marrow. Researchers are testing combinations of two drugs, AG-120 (Ivosidenib or Tibsovo) and AG-221 (Enasidenib or Idhifa), each paired with azacitidine, to assess their safety and effectiveness compared to azacitidine alone. The goal is to determine the best dose and evaluate how well these combinations work for patients with specific gene mutations, IDH1 or IDH2. People newly diagnosed with AML and having at least 20% leukemic blasts in their bone marrow might be suitable for this study. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in AML treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that both AG-120 and AG-221, when combined with azacitidine, hold promise for treating acute myeloid leukemia (AML) with specific IDH mutations.

For AG-120 (also called ivosidenib), studies have found that its combination with azacitidine significantly improves survival and remission rates. Patients tolerated the combination well over time, with manageable side effects.

Similarly, for AG-221 (also known as enasidenib), research indicates it was well-tolerated when used with azacitidine. Patients experienced better response rates compared to azacitidine alone, and side effects were generally manageable.

Both combinations have demonstrated safety for people with specific types of AML, with strong evidence supporting their use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Acute Myeloid Leukemia (AML) because they target a specific mutation in the IDH gene, which is not a focus of standard treatments like chemotherapy. Unlike traditional options, AG-120 and AG-221 are IDH inhibitors, meaning they directly target and disrupt the abnormal enzyme activity caused by IDH mutations. This targeted approach can potentially lead to more effective treatment with fewer side effects. Additionally, combining these IDH inhibitors with Azacitidine, a drug that helps modify DNA to stop cancer growth, offers a novel strategy that might enhance treatment efficacy and improve patient outcomes.

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

In this trial, participants will receive one of the following treatment combinations: AG-120 (ivosidenib) with azacitidine, AG-221 (enasidenib) with azacitidine, or azacitidine alone. Research has shown that combining AG-120 with azacitidine benefits patients with a specific type of acute myeloid leukemia (AML) that has an IDH1 mutation. One study found that patients lived for a median of 29.3 months, with ongoing improvements in survival and blood health in this challenging group. Similarly, AG-221 combined with azacitidine has shown positive results for patients with an IDH2 mutation in AML. These patients experienced better overall response rates, indicating that this combination can effectively address the disease. Both treatments are supported by evidence suggesting they offer hope for patients with these specific genetic mutations in AML. ^{1 2 3 5 6}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for adults with a new diagnosis of acute myeloid leukemia (AML) that has IDH mutations and can't handle strong chemotherapy. They should be able to undergo regular bone marrow tests, have an ECOG performance status of 0-2, and not have had previous IDH-targeted treatments or certain types of AML.

Inclusion Criteria

I have been diagnosed with AML with more than 20% cancer cells in my bone marrow.

I can take care of myself and am up and about more than half of my waking hours.

I agree to have multiple bone marrow tests.

Exclusion Criteria

My AML developed from chronic myelogenous leukemia.

I might have leukemia affecting my brain or spinal cord.

There are other requirements or restrictions for participating in the study that are specified in the study protocol.

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 AG-221 in combination with azacitidine to determine the recommended dose and assess safety, tolerability, and efficacy

Up to approximately 26 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• AG-120
• AG-221
• Azacitidine

Trial Overview

The study is testing the safety and effectiveness of two drug combinations: AG-120 plus Azacitidine, and AG-221 plus Azacitidine. It aims to find the best doses when used together and compare them against using Azacitidine alone in treating AML with specific genetic changes.

How Is the Trial Designed?

Group I: Azacitidine Experimental Treatment 1 Intervention

Group II: AG-221 + Azacitidine Experimental Treatment 2 Interventions

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

AG-120 is already approved in United States for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with a susceptible IDH1 mutation

Who Is Running the Clinical Trial?

Celgene

Lead Sponsor

Trials

649

Recruited

130,000+

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

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]

Acute myeloid leukemia (AML) treatment has seen little change in 40 years, but new agents like IDH inhibitors and antibody-drug conjugates show promise in improving outcomes, either alone or with traditional chemotherapy.

A variety of novel therapies, including cytotoxic agents, epigenetic modifiers, and targeted inhibitors, are currently being tested in clinical trials, indicating a potential shift in AML management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. Saygin, C., Carraway, HE.[2023]

Ivosidenib has been approved by the FDA for treating patients with IDH1-mutant relapsed/refractory acute myeloid leukemia, highlighting its significance in targeted cancer therapy.

In a phase I trial, 32.8% of patients achieved either a complete remission or a complete remission with partial hematologic recovery, demonstrating the drug's efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Gets Go-Ahead for AML. [2019]

Ivosidenib is an FDA-approved treatment for adults with relapsed or refractory acute myeloid leukemia (R/R AML) with an IDH1 mutation, showing a complete remission (CR) + partial hematologic recovery (CRh) rate of 33% in a study of 174 patients over an 8.3-month follow-up.

While ivosidenib demonstrated short-term efficacy, including a median duration of response of 8.2 months and a 37% conversion rate from transfusion dependence to independence, serious adverse reactions such as differentiation syndrome and QT interval prolongation were noted, highlighting the need for ongoing safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. Norsworthy, KJ., Luo, L., Hsu, V., et al.[2020]

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]

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]

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.

tibsovo.com

tibsovo.com/aml/results

AML Clinical Trial Results | TIBSOVO® (ivosidenib tablets)

THE TIBSOVO + AZACITIDINE CLINICAL STUDY. TIBSOVO was studied in the following patients: 146 adult patients with newly diagnosed acute myeloid leukemia ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03173248

NCT03173248 | Study of AG-120 (Ivosidenib) vs. Placebo ...

Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of ...

5.

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.

6.

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 ...