Ivosidenib for Chondrosarcoma

(CHONQUER Trial)

Recruiting at 127 trial locations

Overseen By Institut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Servier Bio-Innovation LLC

Must not be taking: IDH1 inhibitors, Steroids

Disqualifiers: Pregnancy, Brain metastases, Cardiac disease, 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

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

Compensation: Varies

Number of Visits: Unknown

Duration: Estimated average of 2 years

136 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ivosidenib for individuals with certain types of chondrosarcoma, a bone cancer that has recurred or spread. Researchers aim to determine if this medicine can slow the cancer's growth compared to a placebo (a pill with no active medication). Participants will be randomly assigned to receive either ivosidenib or the placebo for comparison. The trial seeks individuals diagnosed with chondrosarcoma that cannot be surgically removed and have a specific gene mutation called IDH1, which will be checked during screening. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received systemic anticancer therapy or radiotherapy within 2 weeks before starting the trial.

Is there any evidence suggesting that ivosidenib is likely to be safe for humans?

Research has shown that ivosidenib is generally well tolerated by patients with chondrosarcoma. Previous studies indicated that the treatment caused only minor side effects. In these studies, patients experienced a significant decrease in 2-HG, a substance linked to tumor growth, and the treatment effectively controlled the disease for an extended period. This means it helped prevent the cancer from worsening for a significant time.

Furthermore, the safety of ivosidenib in these trials aligns with its use in other conditions, such as blood disorders and solid tumors. This history suggests that ivosidenib is safe for people, with side effects being minimal and manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for chondrosarcoma?

Ivosidenib is unique because it targets a specific mutation in the IDH1 gene, which is found in some chondrosarcomas. This is different from the typical chemotherapy and radiation treatments that don't discriminate based on genetic makeup. Researchers are excited about Ivosidenib because it offers a more personalized approach, potentially leading to better outcomes for patients with this mutation.

What evidence suggests that ivosidenib might be an effective treatment for chondrosarcoma?

Research has shown that ivosidenib, which participants in this trial may receive, may help treat chondrosarcoma with an IDH1 mutation. In earlier studies, patients with this type of cancer who took ivosidenib experienced a significant halt in cancer growth. The treatment also greatly reduced a harmful substance called 2-HG, linked to tumor growth. Importantly, ivosidenib was generally well tolerated, causing no severe side effects for most people. These findings suggest ivosidenib could be an effective option for managing this specific form of cancer. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for people with a specific bone cancer called conventional chondrosarcoma that's advanced or spread and can't be removed by surgery. They should have had no more than one previous systemic treatment, must show disease progression on scans, and have an IDH1 gene mutation.

Inclusion Criteria

I have a tumor that can be measured by scans.

Have radiographic progression/recurrence of disease according to RECIST v1.1

My diagnosis is advanced chondrosarcoma (Grade 1-3) and cannot be surgically cured.

Exclusion Criteria

Pregnant or lactating women

Are participating in another interventional study at the same time

I had radiotherapy less than 2 weeks ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral ivosidenib 500mg once daily or a matching placebo until disease progression or other criteria are met

Estimated average of 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

28-33 days

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ivosidenib

Trial Overview The CHONQUER study tests ivosidenib (500mg daily) against a placebo in patients with IDH1-mutated chondrosarcoma. It's double-blind, meaning neither doctors nor participants know who gets the real drug. The main goal is to see if ivosidenib stops the cancer from getting worse.

How Is the Trial Designed?

Group I: Ivosidenib Experimental Treatment 1 Intervention

Taken continuously until BICR-confirmed disease progression, unacceptable toxicity, confirmed pregnancy, death, withdrawal of consent, lost to follow-up, or the Sponsor ends the study (estimated average treatment duration of two years).

Group II: Placebo Placebo Group 1 Intervention

Taken continuously until BICR-confirmed disease progression, unacceptable toxicity, confirmed pregnancy, death, withdrawal of consent, lost to follow-up, or the Sponsor ends the study (estimated average treatment duration of two years). Participants randomized to the placebo arm who experience BICR-confirmed disease progression and meet the crossover eligibility criteria will be given the opportunity to cross over and receive ivosidenib.

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?

Servier Bio-Innovation LLC

Lead Sponsor

Trials

9

Recruited

670+

Institut de Recherches Internationales Servier

Collaborator

Trials

91

Recruited

67,100+

Published Research Related to This Trial

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]

In a phase 2 trial involving 26 patients with advanced chondrosarcoma, imatinib mesylate (IM) was well-tolerated but did not show any objective responses or significant clinical benefits, indicating limited efficacy for this treatment.

The study found a 4-month progression-free survival rate of 31% and a median overall survival of 11 months, highlighting the need for more effective targeted therapies for advanced chondrosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 trial of imatinib mesylate in patients with recurrent nonresectable chondrosarcomas expressing platelet-derived growth factor receptor-α or -β: An Italian Sarcoma Group study. Grignani, G., Palmerini, E., Stacchiotti, S., et al.[2015]

The JJ012 chondrosarcoma cell line showed significantly higher tumor growth and invasive properties compared to the FS090 cell line, making it a more relevant model for studying chondrosarcoma in vivo.

The established JJ012 mouse model successfully mimics human chondrosarcoma characteristics, including local bone invasion and lung metastasis, providing a valuable platform for testing new targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis. Clark, JC., Akiyama, T., Dass, CR., et al.[2021]

In a phase 2 study involving 47 patients with unresectable or metastatic conventional chondrosarcoma, pazopanib demonstrated a disease control rate of 43% at 16 weeks, indicating its potential effectiveness in managing this type of cancer.

The median overall survival for patients was 17.6 months, with manageable side effects, primarily hypertension (26%) and elevated liver enzymes (9%), suggesting that pazopanib is a relatively safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma. Chow, W., Frankel, P., Ruel, C., et al.[2021]

In a phase I study involving 21 patients with advanced chondrosarcoma, ivosidenib treatment resulted in a significant reduction of the oncometabolite D-2-hydroxyglutarate (2-HG) in all patients, indicating effective targeting of the mutant IDH1 enzyme.

The treatment demonstrated minimal toxicity, with most adverse events being mild (grade 1 or 2), and a median progression-free survival of 5.6 months, suggesting potential for durable disease control in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma. Tap, WD., Villalobos, VM., Cote, GM., et al.[2021]

In a phase II trial involving 45 patients with advanced chondrosarcoma, the Hedgehog pathway inhibitor GDC-0449 showed a 6-month clinical benefit rate of 25.6%, which did not meet the target of 40% for efficacy.

The treatment was associated with manageable side effects, primarily grade 1 or 2 symptoms like myalgia and alopecia, suggesting that while GDC-0449 did not achieve its primary endpoint, it may still have potential benefits for certain patients with specific tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study. Italiano, A., Le Cesne, A., Bellera, C., et al.[2022]

Ivosidenib, a small molecule inhibitor targeting mutated IDH1, has shown promising results in clinical trials, particularly in patients with advanced cholangiocarcinoma, achieving a 32% progression-free survival rate at 6 months compared to 0% with placebo.

The treatment is generally well tolerated, with serious adverse events occurring in only 2%-26% of patients, and just 3.6% among those with solid tumors, indicating a favorable safety profile for patients with mtIDH1 malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of IDH1 inhibitors for cancer therapy. Zarei, M., Hue, JJ., Hajihassani, O., et al.[2022]

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]

The study developed in vitro and in vivo models of mesenchymal chondrosarcoma (MCS) driven by the HEY1-NCoA2 gene fusion, which is present in 80% of MCS tumors, allowing for better understanding and testing of treatments.

Imatinib and specific inhibitors targeting PDGFR showed a strong ability to reduce tumor growth in these models, suggesting that imatinib could be a promising therapeutic option for patients with HEY1-NCoA2-driven MCS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-derived xenografts and in vitro model show rationale for imatinib mesylate repurposing in HEY1-NCoA2-driven mesenchymal chondrosarcoma. Safaric Tepes, P., Segovia, D., Jevtic, S., et al.[2023]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7238491/

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS11582

Phase 3 study of ivosidenib vs placebo in locally advanced ... The current phase 3 CHONQUER study was designed to assess the efficacy and safety of ivosidenib treatment in patients with grades 1, 2 and 3 conventional CS.

3. servier.us servier.us/blog/servier-announces-expansion-of-its-tibsovo-ivosidenib-development-program-investigating-its-safety-and-efficacy-in-patients-living-with-idh1-mutated-cancers-in-both-hematological-malignancies-and-so/

Servier Announces Expansion of its Tibsovo (ivosidenib) ... Servier today announced updates to two of its Phase 3 programs evaluating TIBSOVO (ivosidenib tablets) in isocitrate dehydrogenase 1 (IDH1)-mutated cancers.

4. aacrjournals.org aacrjournals.org/clincancerres/article/31/11/2108/762527/Phase-I-Study-of-the-Mutant-IDH1-Inhibitor

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Long ... In this phase I dose-escalation and expansion study, ivosidenib demonstrated clinical activity and was well tolerated in patients with mIDH1 conventional CS.

5. prnewswire.com prnewswire.com/news-releases/servier-announces-expansion-of-its-tibsovo-ivosidenib-development-program-investigating-its-safety-and-efficacy-in-patients-living-with-idh1-mutated-cancers-in-both-hematological-malignancies-and-solid-tumors-302347478.html

Servier Announces Expansion of its Tibsovo (ivosidenib) ... Servier announces expansion of its Tibsovo (ivosidenib) development program investigating its safety and efficacy in patients living with IDH1-mutated cancers.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.11532

Phase I study of the mutant IDH1 inhibitor ivosidenib Phase I study of the mutant IDH1 inhibitor ivosidenib: Long-term safety and clinical activity in patients with conventional chondrosarcoma.

7. onclive.com onclive.com/view/ivosidenib-shows-durable-disease-control-in-advanced-idh1mutant-chondrosarcoma

Ivosidenib Shows Durable Disease Control in Advanced ... Ivosidenib showed minimal toxicity, substantial 2-hydroxyglutarate reduction, and durable disease control in patients with chondrosarcoma.

8. serviermedical.us serviermedical.us/materials/Tap_CTOS%202024_pres_3049.pdf

Phase 3 study of ivosidenib vs placebo in locally advanced or • Well tolerated safety profile in the phase 1 trial aligned with the broader knowledge of ivosidenib's safety across indications (heme and solid tumors) ...