Ivosidenib for Chondrosarcoma

(CHONQUER Trial)

Recruiting at55 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Servier Bio-Innovation LLC

Must not be taking: IDH1 inhibitors, Steroids

Disqualifiers: Pregnancy, Brain metastases, Cardiac disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

Study CL3-95031-007 (CHONQUER) is a Phase 3, international, multicenter, double-blind, randomized, placebo-controlled study of orally administered ivosidenib. Participants are required to have a histopathological diagnosis consistent with isocitrate dehydrogenase-1 (IDH1) gene-mutated, locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection. IDH1 mutant status will be determined during pre-screening/screening phase. Participant must have radiographic progression/recurrence of disease according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and have received 0 to 1 prior systemic treatment regimen in the advanced/metastatic setting for conventional chondrosarcoma. The primary endpoint is progression-free survival (PFS) in Grades 1 and 2 participants. Key secondary endpoints are PFS in all randomized participants, overall survival (OS) in Grades 1 and 2 participants, and OS in all randomized participants. Participants who meet enrollment criteria will be randomized 1:1 to receive oral ivosidenib 500mg once daily, or a matching placebo once daily.

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.

What data supports the effectiveness of the drug Ivosidenib for treating chondrosarcoma?

Ivosidenib is a drug that targets a specific mutation in the IDH1 enzyme, which is found in many chondrosarcomas. It has shown effectiveness in treating other cancers with this mutation, like certain types of leukemia, suggesting it might also help in chondrosarcoma cases with the same mutation. ^{1 2 3 4 5}

Is Ivosidenib safe for use in humans?

Ivosidenib has been studied in various clinical trials for different cancers, including chondrosarcoma and acute myeloid leukemia. Common side effects include fatigue, nausea, and rash, while serious side effects can include differentiation syndrome and heart rhythm changes. The long-term safety of ivosidenib is still being evaluated. ^{2 3 6 7 8}

How is the drug Ivosidenib unique in treating chondrosarcoma?

Ivosidenib is unique because it targets a specific mutation in the IDH1 enzyme found in many chondrosarcomas, which leads to the accumulation of a harmful substance called 2-HG. Unlike other treatments, it specifically inhibits this mutated enzyme, offering a potential option for patients with advanced chondrosarcoma where no effective systemic therapy currently exists. ^{2 6 8 9 10}

Research Team

Eligibility Criteria

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

I have not had cancer treatment in the last 2 weeks.

Pregnant or lactating women

Are participating in another interventional study at the same time

Trial Timeline

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

Treatment Details

Interventions

• Ivosidenib (IDH1 Inhibitor)

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.

Participant Groups

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.

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+

Olivier Laureau

Institut de Recherches Internationales Servier

Chief Executive Officer since 2014

Degree in Law from Panthéon-Assas University, Paris

Dr. Arnaud Lallouette

Institut de Recherches Internationales Servier

Chief Medical Officer since 2021

MD from Lille 2 University of Science and Technology

Findings from Research

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 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 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 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]

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]

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, 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]

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, 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]

References

1. England pubmed.ncbi.nlm.nih.gov

New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis. [2021]

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

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma. [2021]

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

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma. [2021]

4. England 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. [2022]

5. United States 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. [2015]

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

Ivosidenib: First Global Approval. [2021]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical development of IDH1 inhibitors for cancer therapy. [2022]

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

Patient-derived xenografts and in vitro model show rationale for imatinib mesylate repurposing in HEY1-NCoA2-driven mesenchymal chondrosarcoma. [2023]

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

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