AG-120 for Blood Cancers

Recruiting at 32 trial locations

Overseen By Institut de Recherches Internationales Servier Clinical Studies Department

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Institut de Recherches Internationales Servier

Must not be taking: QT prolonging drugs

Disqualifiers: Recent HSCT, Severe infection, Heart failure, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 56

291 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the AG-120 trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does exclude patients taking medications that prolong the QT interval (a measure of heart rhythm). It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug AG-120 (Ivosidenib) for blood cancers?

Ivosidenib has been shown to be effective in treating acute myeloid leukemia (AML) with IDH1 mutations, achieving complete remission in about 33% of patients with relapsed or refractory AML. It also improved survival rates when combined with azacitidine in newly diagnosed AML patients with IDH1 mutations. ^{1 2 3 4 5}

Is ivosidenib (AG-120, Tibsovo) safe for humans?

Ivosidenib has been studied in patients with certain blood cancers and is generally considered safe, but it can cause serious side effects like differentiation syndrome (a condition where cancer cells rapidly change), high white blood cell counts, and heart rhythm changes. Common side effects include tiredness, nausea, diarrhea, and rash. Long-term safety is still being evaluated. ^{1 2 3 4 5}

How is the drug ivosidenib unique for treating blood cancers?

Ivosidenib is unique because it specifically targets and inhibits the mutant IDH1 protein, which is responsible for producing a harmful substance called 2-hydroxyglutarate (2-HG) that contributes to cancer growth. This drug is taken orally and is particularly effective for patients with blood cancers that have an IDH1 mutation, offering a targeted approach compared to traditional chemotherapy. ^{1 2 3 4 6}

What is the purpose of this trial?

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Additionally, the study includes a substudy evaluating the safety and tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome with an IDH1 mutation. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Eligibility Criteria

Adults (18+) with advanced blood cancers like AML or MDS that have a specific IDH1 mutation can join. They must be able to undergo regular bone marrow, blood, and urine tests, not be pregnant, and have an ECOG performance status of 0-2. Adequate liver and kidney function is required. Those with severe heart problems, recent cancer treatments within 14 days (except hydroxyurea), active infections including HIV or hepatitis B/C, CNS leukemia symptoms or history of it without clinical suspicion are excluded.

Inclusion Criteria

My platelet count is at least 20,000/µL, transfusions included.

My blood cancer has a specific IDH1 R132 gene mutation.

I am willing to undergo repeated bone marrow biopsies, blood, and urine tests.

Exclusion Criteria

I haven't had cancer treatment or radiotherapy in the last 14 days, except for hydroxyurea.

I do not have a severe infection or unexplained fever over 38.5°C.

I have severe heart failure or my heart's pumping ability is less than 40%.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Cohorts of patients receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose

Up to 26 weeks

Continuous dosing in 28-day cycles

Dose Expansion

Four cohorts of patients receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose

Up to 26 weeks

Continuous dosing in 28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AG-120

Trial Overview AG-120 is being tested in patients with certain mutations in their blood cancer cells. The trial has two parts: first finding the highest dose people can take without too many side effects (dose escalation) and then giving more people this dose to see how well it works and if it's safe (dose expansion). There's also a special part for those whose myelodysplastic syndrome came back after treatment.

Participant Groups

Group I: AG-120 Experimental Treatment 1 Intervention

AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.

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?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Findings from Research

Ivosidenib (Tibsovo®) is an oral medication that specifically inhibits mutated IDH1 enzymes, which are linked to the production of 2-hydroxyglutarate (2-HG), a metabolite that contributes to the development of certain cancers like acute myeloid leukaemia (AML).

The drug has received approval in the USA for treating patients with relapsed or refractory AML who have a specific IDH1 mutation, and ongoing clinical trials are exploring its efficacy in other cancers such as cholangiocarcinoma and glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib: First Global Approval. Dhillon, S.[2021]

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]

Ivosidenib, a targeted oral inhibitor of mutant IDH1, effectively reduces levels of the oncometabolite 2-hydroxyglutarate (2-HG) in patients with advanced hematologic malignancies, particularly at a dose of 500 mg once daily, achieving levels similar to those in healthy individuals.

The drug demonstrated favorable pharmacokinetics, with a long half-life of 72-138 hours and consistent efficacy across various patient demographics, indicating it is safe and effective for treating patients with IDH1 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation. Fan, B., Dai, D., DiNardo, CD., 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]

Ivosidenib, an oral medication targeting IDH1 mutations, was well-tolerated in a phase 1 study of 34 newly diagnosed acute myeloid leukemia (AML) patients, with a complete remission (CR) rate of 30.3% and a combined CR plus partial hematologic recovery rate of 42.4%.

The treatment led to significant outcomes, including 61.5% of patients remaining in remission after one year and 42.9% of transfusion-dependent patients becoming transfusion independent, demonstrating its efficacy in managing AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Roboz, GJ., DiNardo, CD., Stein, EM., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Ivosidenib: First Global Approval. [2021]

2. 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]

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. Germany pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation. [2022]

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

Ivosidenib Deemed Safe, Effective in AML. [2019]

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

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. [2023]