Ivosidenib for Advanced Solid Cancers, Lymphoma & Histiocytosis

Recruiting at 183 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Infection, Organ transplant, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

Duration: Up to 2 years

3 Participants Needed

Trial Summary

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

The trial protocol does not specify if you must stop taking your current medications, but you cannot take certain drugs like strong inducers or inhibitors of CYP3A4, and you must avoid investigational drugs and other anti-cancer agents. If you're on medications that prolong the QTc interval, you should discuss alternatives with your doctor.

What is known about the safety of ivosidenib (Tibsovo) in humans?

Ivosidenib (Tibsovo) has been studied for safety in people with certain types of leukemia and cholangiocarcinoma. Common side effects include fatigue, nausea, diarrhea, and rash, while serious side effects can include differentiation syndrome (a condition where cancer cells rapidly change), high white blood cell counts, and heart rhythm changes. Long-term safety is still being evaluated. ^{1 2 3 4 5}

What makes the drug Ivosidenib unique for treating advanced solid cancers, lymphoma, and histiocytosis?

Ivosidenib is unique because it specifically targets and inhibits the mutated IDH1 enzyme, which is responsible for producing a harmful substance called 2-hydroxyglutarate (2-HG) that contributes to cancer development. This targeted approach is different from traditional treatments that may not specifically address the underlying genetic mutation. ^{1 2 4 6 7}

What is the purpose of this trial?

This phase II Pediatric MATCH trial studies how well ivosidenib works in treating patients with solid tumors that have spread to other places in the body (advanced), lymphoma, or histiocytic disorders that have IDH1 genetic alterations (mutations). Ivosidenib may block the growth of cancer cells that have specific genetic changes in an important signaling pathway called the IDH pathway.

Research Team

Elizabeth D Alva

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for young patients aged between 12 months and 21 years with advanced solid tumors, lymphoma, or histiocytic disorders that have a specific genetic change (IDH1 mutation). They must be able to swallow tablets, have not used IDH1 inhibitors before, and meet certain health criteria like adequate blood counts and organ function. Pregnant individuals or those on certain medications are excluded.

Inclusion Criteria

My white blood cell count is healthy for cancer treatment.

I am between 12 and 21 years old.

I can swallow pills without any issues.

Exclusion Criteria

I am taking medication to prevent graft-versus-host disease after a bone marrow transplant.

I do not have any infections that are currently uncontrolled.

Pregnant or breast-feeding women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ivosidenib orally once daily. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 5 years

Treatment Details

Interventions

• Ivosidenib

Trial Overview The trial is testing Ivosidenib's effectiveness in treating cancers with IDH1 mutations. It's a phase II study focusing on whether this drug can stop cancer cells from growing by targeting the IDH pathway—a critical cell signaling route involved in tumor development.

Participant Groups

Group I: Treatment (ivosidenib) Experimental Treatment 1 Intervention

Patients receive ivosidenib PO QD. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Ivosidenib is already approved in United States, European Union for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Approved in European Union as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Children's Oncology Group

Collaborator

Trials

467

Recruited

241,000+

Findings from Research

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 (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, 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, an IDH1 inhibitor, significantly improved progression-free survival in patients with IDH1 mutated cholangiocarcinoma, with a median of 2.7 months compared to 1.4 months for placebo (p < 0.0001).

While overall survival showed a trend towards improvement with 10.8 months for ivosidenib versus 9.7 months for placebo (p = 0.06), the results suggest that ivosidenib is a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date. Uson Junior, PLS., Borad, MJ.[2023]

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, 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]

References

1. 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]

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

Ivosidenib: First Global Approval. [2021]

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

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, absorption, metabolism, and excretion of [14C]ivosidenib (AG-120) in healthy male subjects. [2020]

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

Ivosidenib Deemed Safe, Effective in AML. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

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