Phase 3 Double-Blind Study of Ivosidenib in Adults with IDH1-Mutant Locally Advanced or Metastatic Conventional Chondrosarcoma

Trial ID: 2023-508507-20-00
Protocol: CL3-95031-007
Sponsor: Institut De Recherches Internationales Servier IRIS

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Diseases & Conditions

Chondrosarcoma

Objectives

The primary objective of this study is to evaluate the **efficacy** of ivosidenib treatment based on tumor assessments by a Blinded Independent Central Reviewer (BICR) in participants with Grade 1 and Grade 2 locally advanced or metastatic conventional chondrosarcoma with an IDH1 mutation. This is clinically relevant as it aims to determine the potential therapeutic benefit of ivosidenib in a specific subset of chondrosarcoma patients, which could lead to improved treatment strategies for this condition.

Secondary objectives include:

Assessing the efficacy of ivosidenib treatment based on tumor assessments by a BICR in all randomized participants.
Evaluating the efficacy of ivosidenib treatment based on Overall Survival (OS).
Assessing the additional efficacy of ivosidenib treatment in Grade 1 and Grade 2 participants and all randomized participants.
Evaluating the safety and tolerability of treatment with ivosidenib.
Assessing the impact of treatment on health-related quality of life (HRQoL) and health economic outcomes assessments.
Evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of ivosidenib.

Participants

The clinical trial involves a total of **75 participants** diagnosed with **locally advanced or metastatic conventional chondrosarcoma** with an IDH1 mutation. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, including a histopathological diagnosis consistent with chondrosarcoma Grades 1, 2, or 3, and the presence of at least one measurable lesion confirmed by a Blinded Independent Central Reviewer (BICR). The trial includes individuals who have received 0 or 1 prior systemic treatment regimen in the advanced/metastatic setting, with an allowance for up to 2 prior regimens for those with Grade 3 chondrosarcoma. Participants must have documented radiographic progression or recurrence of disease and an IDH1 gene mutation. The trial population is characterized by a vulnerable group, indicating the inclusion of individuals who may require additional considerations during the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase 3**, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy of **ivosidenib** in participants aged 18 years and older with locally advanced or metastatic conventional **chondrosarcoma** harboring an IDH1 mutation. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response, and disease control, among others. The study will involve the administration of AG-120/S95031 250mg film-coated tablets or **Ivosidenib-matched Placebo Tablets** via oral use, with a maximum daily dose of 500 mg over a treatment period of up to 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histopathological diagnosis, measurable lesions, and documented IDH1 gene mutation. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with tumor assessments conducted by a Blinded Independent Central Reviewer (BICR) using RECIST v1.1 criteria. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.

The expected duration of participant involvement in the trial is approximately 24 months, with conditions for early termination including disease progression, adverse events, or withdrawal of consent. The trial is estimated to conclude by April 2031, with recruitment anticipated to start in May 2024. Participants' involvement will be closely monitored to ensure adherence to the protocol and to address any safety concerns promptly.

Treatment

The clinical trial involves the administration of **ivosidenib**, an experimental medication, in the form of a film-coated tablet. The product, identified as AG-120/S95031, is manufactured by the Institut de Recherches Internationales Servier (I.R.I.S). Each tablet contains 250 mg of ivosidenib, a chemical substance. The medication is administered orally, with a maximum daily dose of 500 mg, equating to two tablets per day. The treatment period extends up to 24 months, depending on the participant's response and tolerance. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study employs a placebo control group. Participants in this group receive Ivosidenib-matched placebo tablets, which are designed to mimic the appearance of the active medication but contain no active substance. The placebo is administered in the same manner as the active treatment, ensuring blinding and maintaining the integrity of the study design. The use of a placebo allows for a rigorous assessment of ivosidenib's efficacy and safety in comparison to a non-active treatment.

Efficacy

The efficacy of ivosidenib in the treatment of locally advanced or metastatic conventional chondrosarcoma with an **IDH1** mutation will be assessed in a Phase 3, multicenter, double-blind, randomized, placebo-controlled study. The primary endpoint for evaluating efficacy is progression-free survival (PFS) based on assessments by a Blinded Independent Central Reviewer (BICR) in participants with Grade 1 and Grade 2 chondrosarcoma. Secondary endpoints include PFS in all randomized participants, overall survival (OS) in both Grade 1 and Grade 2 participants and all randomized participants, and objective response (OR) using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Additional secondary endpoints encompass the duration of response (DOR), time to response (TTR), disease control (DC), and duration of disease control (DoDC) in both Grade 1 and Grade 2 participants and all randomized participants. The study will also monitor the number of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), as well as any AEs leading to discontinuation, treatment interruption, or dose reduction. Patient-reported outcomes will be measured using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) score, and the Patient-Reported Outcomes Measurement Information System (PROMIS) score. Additionally, the concentration of ivosidenib and 2-hydroxyglutarate (2-HG) in plasma will be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Have a histopathological diagnosis consistent with locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection or other local therapeutic options as per standard of care such as definitive radiotherapy for skull base lesions.
Have at least one BICR-confirmed measurable lesion as defined by RECIST v1.1. Participants who have received prior radiation therapy are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥20% growth in size since post-treatment assessment.
Have received 0 to 2 prior systemic treatment regimens in the advanced/metastatic setting for chondrosarcoma.
Have radiographic progression/recurrence of disease according to RECIST v1.1 defined as: - Radiographic progression of disease (local and/or distant) documented by 2 imaging assessments performed no more than 6 months (+3 weeks) apart within 12 months before randomization. OR - Any recurrence of disease (local and/or distant) after complete surgical resection and documented by imaging within 6 months (+3 weeks) before randomization.
Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or banked tumor tissue available that was sourced from either a primary or metastatic tumor lesion) based on central laboratory testing (R132C/L/G/H/S mutation variants)
Have recovered from any clinically relevant sequelae and toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.

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Exclusion Criteria

Are unable to swallow oral medication.
Pregnant or lactating women.
Are participating in another interventional study at the same time; participation in noninterventional registries or epidemiological studies is allowed.
Have received prior therapy with an IDH1 inhibitor
Have received systemic anticancer therapy <2 weeks prior to randomization (for investigational or immune-based anticancer therapy <4 weeks).
Have received radiotherapy <2 weeks prior to randomization.
Have known symptomatic brain metastases requiring steroids >10 mg per day prednisone (or equivalent). Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued or reduced corticosteroid treatment <=10 mg per day for these metastases for at least 4 weeks and have radiographically stable disease of brain lesions for at least 3 months prior to randomization.
Have a history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated carcinoma in situ; or c) pT1-2 prostatic cancer Gleason score ≤6 or d) participant is free of other primary solid or liquid tumor for ≥ 1 year prior to the start of study treatment and, in the opinion of the Investigator, the disease will not affect participant's outcome in the setting of current chondrosarcoma diagnosis.
Have had major surgery within 4 weeks prior to randomization.
Have significant active cardiac disease within 6 months prior to randomization, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke.
Have LVEF <40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to randomization.
Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome, familial history of sudden death or polymorphic ventricular arrhythmia). Participants with a bundle branch block combined with a prolonged QTcF interval may be permitted based on local cardiology assessment.
Have known medical history of progressive multifocal leukoencephalopathy (PML).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	06 May 2024	2
Denmark	Recruiting	06 May 2024	4
France	Recruiting	06 May 2024	10
Germany	Recruiting	06 May 2024	9
Italy	Recruiting	06 May 2024	10
The Netherlands	Recruiting	06 May 2024	—
Spain	Recruiting	06 May 2024	12
Netherlands	—	—	3