IDH Mutant Targeted Therapies + Azacitidine for Acute Myeloid Leukemia

Recruiting at 114 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

130 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study are 1. to determine the recommended combination dose of AG-120 and AG-221 separately when administered with azacitidine and, 2. to investigate the safety, tolerability, and efficacy of the combinations of AG-120 with azacitidine and AG-221 with azacitidine versus with azacitidine alone in participants with acute myeloid leukemia (AML) with the isocitrate dehydrogenase (IDH) enzyme isoforms 1 or 2 mutations, respectively.

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.

What data supports the effectiveness of the drug combination of Ivosidenib and Azacitidine for treating acute myeloid leukemia?

Research shows that the combination of Ivosidenib and Azacitidine is more effective than Azacitidine alone for patients with acute myeloid leukemia, especially those who cannot undergo intensive chemotherapy. This combination has been shown to improve overall survival, complete remission rates, and event-free survival. ^{1 2 3 4 5}

Is the combination of IDH mutant targeted therapies and azacitidine generally safe for humans?

The combination of ivosidenib (Tibsovo) and azacitidine has been studied in patients with acute myeloid leukemia, showing some serious side effects like differentiation syndrome and QT interval prolongation (a heart rhythm issue). Common side effects include fatigue, nausea, and rash, but long-term safety is still being evaluated. ^{1 2 3 6 7}

How is the drug combination of Ivosidenib and Azacitidine unique for treating acute myeloid leukemia?

This drug combination is unique because it targets a specific mutation (IDH1) in acute myeloid leukemia, using Ivosidenib to inhibit the mutant enzyme and Azacitidine to enhance the treatment's effectiveness, leading to improved survival rates in patients who are not suitable for intensive chemotherapy. ^{1 2 3 8 9}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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]

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]

References

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

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. [2022]

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

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

3. United States 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. [2023]

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

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. [2023]

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

Ivosidenib Gets Go-Ahead for AML. [2019]

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

FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia. [2022]

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

IDH Inhibitors in AML-Promise and Pitfalls. [2021]