AG-120 for Chondrosarcoma

Recruiting at 6 trial locations

Overseen By Ciara Kelly, MBBCh BAO

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A4 inducers, QT prolongers

Disqualifiers: Brain metastasis, Active cancer, 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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to see whether AG-120 is an effective and safe treatment for people with advanced/metastatic or recurrent chondrosarcoma that has IDH1 mutation.

Do I need to stop my current medications to join the trial?

The trial requires a washout period (time without taking certain medications) for some treatments. If you are taking strong CYP3A4 inducers or certain other medications, you may need to switch to different ones before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug AG-120 (Ivosidenib) for treating chondrosarcoma?

Ivosidenib (AG-120) is a drug that targets a specific mutation found in many chondrosarcomas, and it has shown safety and some clinical activity in patients with advanced chondrosarcoma. It is already approved for certain cases of acute myeloid leukemia, suggesting its potential effectiveness in targeting similar mutations in chondrosarcoma. ^{1 2 3 4 5}

Is Ivosidenib (AG-120) safe for humans?

Ivosidenib (AG-120) has been studied for safety in patients with advanced solid tumors, including chondrosarcoma. It showed good oral exposure, was well absorbed, and had a long half-life, with no significant safety concerns across different doses. The treatment was generally well-tolerated in these studies. ^{3 4 6 7 8}

How is the drug AG-120 (Ivosidenib) unique for treating chondrosarcoma?

AG-120 (Ivosidenib) is unique for treating chondrosarcoma because it specifically targets and inhibits mutant IDH1 enzymes, which are present in up to 65% of chondrosarcoma cases. This is significant because there are no effective systemic therapies for advanced chondrosarcoma, and Ivosidenib reduces the harmful oncometabolite D-2-hydroxyglutarate (2-HG) that these mutations produce. ^{1 3 7 9 10}

Research Team

Ciara Kelly, MBBCh BAO

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with advanced or recurrent chondrosarcoma and an IDH1 gene mutation. Participants must have stable vital organ functions, no severe infections, not be pregnant or breastfeeding, agree to use two forms of contraception if they can reproduce, and not have used certain other treatments recently.

Inclusion Criteria

I can take pills by mouth.

You are expected to live for at least four more months.

I am not pregnant or have confirmed contraception use if capable of becoming pregnant.

Exclusion Criteria

My heart's pumping ability is below 40% as shown by recent tests.

I haven't had radiotherapy or local treatment for cancer spread in the last 2 weeks.

I have previously been treated with an IDH1 inhibitor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AG-120 for the treatment of IDH1 mutant chondrosarcoma

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AG-120

Trial Overview The study tests AG-120's effectiveness and safety in treating chondrosarcoma with the IDH1 mutation. It examines how well patients respond to this oral medication when their cancer has returned or spread despite previous treatment.

Participant Groups

Group I: Chondrosarcoma Experimental Treatment 1 Intervention

Participants will have locally advanced/metastatic or recurrent operable chondrosarcoma

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Agios Pharmaceuticals, Inc.

Industry Sponsor

Trials

55

Recruited

4,200+

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]

BH3 mimetics ABT-737 and ABT-263 effectively inhibit the growth of chondrosarcoma cells in vitro and induce apoptosis, suggesting a potential new treatment approach for this chemotherapy-resistant cancer.

In vivo studies using a mouse model demonstrated that ABT-263 not only inhibited chondrosarcoma growth but also improved survival, highlighting its efficacy as a therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models. Morii, T., Ohtsuka, K., Ohnishi, H., et al.[2014]

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 (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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival. [2020]

2. England pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. 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]

5. Greece pubmed.ncbi.nlm.nih.gov

BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models. [2014]

6. 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]

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

Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. [2021]

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

Ivosidenib: First Global Approval. [2021]

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

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth. [2020]