Ivosidenib in Participants With Locally Advanced or Metastatic Conventional Chondrosarcoma Untreated or Previously Treated With 1 Systemic Treatment Regimen

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib in Participants ≥18 Years of Age With Locally Advanced or Metastatic Conventional Chondrosarcoma With an IDH1 Mutation, Untreated or Previously Treated With 1 Systemic Treatment Regimen

Conditions
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Locally Advanced or Metastatic Conventional Chondrosarcoma With an IDH1 Mutation, Untreated or Previously Treated With 1 Systemic Treatment Regimen

Intervention / Treatment
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* Drug: Ivosidenib 500mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a histopathological diagnosis (fresh or banked tumor biopsy sample collected within the last 3 years) consistent with locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection. 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 or 1 prior systemic treatment regimen 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 (±2 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 (±2 weeks) before randomization. Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent 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 tested) Have recovered from any clinically relevant sequelae and toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. 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). 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ivosidenib<br>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). | Drug: Ivosidenib 500mg<br>* Provided as tablets, taken orally as two 250mg tablets once daily.<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Provided as tablets, taken orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) based on Blinded Independent Central Reviewer (BICR) assessment in Grade 1 and Grade 2 participants | From randomization until BICR confirmed progressive disease or death due to any cause, whichever occurs first | Up to approximately 31 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS based on BICR assessment in all randomized participants | From randomization until BICR confirmed progressive disease or death due to any cause, whichever occurs first | Up to approximately 31 months | 
| Overall survival (OS) in Grade 1 and Grade 2 participants | From randomization until death | Up to 5 years | 
| OS in all randomized participants | From randomization until death | Up to 5 years | 
| PFS based on Investigator assessment in Grade 1 and Grade 2 participants | From randomization until BICR confirmed progressive disease or death due to any cause, whichever occurs first | Up to approximately 31 months | 
| PFS based on Investigator assessment in all randomized participants | From randomization until BICR confirmed progressive disease or death due to any cause, whichever occurs first | Up to approximately 31 months | 
| Objective response (OR) (confirmed complete response(CR) or confirmed partial response (PR)) of anti-tumor activity (using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1) in Grade 1 and Grade 2 participants | From randomization until confirmed CR or PR | Up to approximately 31 months | 
| OR (confirmed CR or confirmed PR) of anti-tumor activity (using RECIST v1.1) in all randomized participants | From randomization until confirmed CR or PR | Up to approximately 31 months | 
| Duration of response (DOR) in Grade 1 and Grade 2 participants | The time from date of first documented confirmed CR or confirmed PR to date of first documented disease progression or death due to any cause. | Up to approximately 31 months | 
| DOR in all randomized participants | The time from date of first documented confirmed CR or confirmed PR to date of first documented disease progression or death due to any cause. | Up to approximately 31 months | 
| Time to response (TTR) in Grade 1 and Grade 2 participants | The time from the date of randomization to date of first documented confirmed complete response (CR) or confirmed partial response (PR). | Up to approximately 31 months | 
| TTR in all randomized participants | The time from the date of randomization to date of first documented confirmed complete response (CR) or confirmed partial response (PR). | Up to approximately 31 months | 
| Disease control (DC) confirmed CR, confirmed PR, or stable disease (SD)) in Grade 1 and Grade 2 participants |  | Through the end of the study (a maximum of 5 years after the study start) | 
| DC (confirmed CR, confirmed PR, or SD) in all randomized participants |  | Through the end of the study (a maximum of 5 years after the study start) | 
| Duration of disease control (DoDC) in Grade 1 and Grade 2 participants |  | Through the end of the study (a maximum of 5 years after the study start) | 
| DoDC in all randomized participants |  | Through the end of the study (a maximum of 5 years after the study start) | 
| Number of Adverse Events (AEs) |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Number of Serious Adverse Events (SAEs) |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Number of Adverse Events of Special Interest (AESIs) |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Number of Adverse Events (AEs) leading to discontinuation, treatment interruption, and dose reduction |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) score | The EORTC-QLQ-C30 contains 30 items across 5 functional scales, 9 symptom scales and a global health status. Raw scores are converted to scales ranging from 0 - 100. For the functional scales and global health status, the higher score represents the better functioning or global health status; for the symptom scales, the higher score represents an increase in symptoms. | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) score | The 5-level EQ-5D-5L scores range from 5 to 25 with a higher number representing a worse health status. | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Patient-Reported Outcomes Measurement Information System (PROMIS) score | The PROMIS Item Bank v1.0 Physical Function with Mobility Aid - Short Form questionnaire score ranges from 1 Unable to do to 5 Can do without a problem for each capability. | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Ivosidenib concentration in plasma |  | Through the end of the study (a maximum of 5 years after the study start) | 
| 2-hydroxyglutarate (2-HG) concentration in plasma |  | Through the end of the study (a maximum of 5 years after the study start) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Conventional chondrosarcoma, IDH1, ivosidenib, locally advanced, metastatic