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

Official title

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

Overview

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.

Interventions

• Drug Ivosidenib 500mg
  Provided as tablets, taken orally as two 250mg tablets once daily.
• Drug Placebo
  Provided as tablets, taken orally once daily.

Primary outcome measures

• Progression-free survival (PFS) based on Blinded Independent Central Reviewer (BICR) assessment in Grade 1 and Grade 2 participants [Time frame: Up to approximately 31 months]

Secondary outcome measures (12)

• PFS based on BICR assessment in all randomized participants [Time frame: Up to approximately 31 months]
• Overall survival (OS) in Grade 1 and Grade 2 participants [Time frame: Up to 5 years]
• OS in all randomized participants [Time frame: Up to 5 years]
• PFS based on Investigator assessment in Grade 1 and Grade 2 participants [Time frame: Up to approximately 31 months]
• PFS based on Investigator assessment in all randomized participants [Time frame: 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 [Time frame: Up to approximately 31 months]
• OR (confirmed CR or confirmed PR) of anti-tumor activity (using RECIST v1.1) in all randomized participants [Time frame: Up to approximately 31 months]
• Duration of response (DOR) in Grade 1 and Grade 2 participants [Time frame: Up to approximately 31 months]
• DOR in all randomized participants [Time frame: Up to approximately 31 months]
• Time to response (TTR) in Grade 1 and Grade 2 participants [Time frame: Up to approximately 31 months]
• TTR in all randomized participants [Time frame: Up to approximately 31 months]
• Disease control (DC) confirmed CR, confirmed PR, or stable disease (SD)) in Grade 1 and Grade 2 participants [Time frame: Through the end of the study (a maximum of 5 years after the study start)]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 22 centers

• Usc Norris Comprehensive Cancer Center — Los Angeles
• Sarcoma Oncology Research Center — Santa Monica
• University of Colorado Cancer Center — Aurora
• Yale Cancer Center — New Haven
• Mayo Clinic - Jacksonville, Fl — Jacksonville
• University of Miami — Miami
• Emory Winship Cancer Institute — Atlanta
• Robert H. Lurie Comprehensive Cancer Center of Northwestern University — Chicago
• … and 14 more centers

Brazil · 11 centers

• Liga Norte Riograndense Contra O Cancer — Natal
• Hospital de Amor - Barretos — Barretos
• Hospital Das Clínicas Da Ufmg — Belo Horizonte
• CIONC — Curitiba
• Cepon - Centro de Pesquisas Oncologicas — Florianópolis
• Fundação Amaral Carvalho - Jaú/ Sp — Jaú
• Instituto Nacional Do Câncer - Inca — Rio de Janeiro
• Icesp - Instituto Do Câncer Do Estado de São Paulo — São Paulo
• … and 3 more centers

Japan · 11 centers

Center list to be confirmed — check the primary protocol.

China · 10 centers

• The First Affiliated Hospital of Sun Yat-Sen University — Guangzhou
• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan
• Shanghai Changzheng Hospital — Shang'ai
• Shanghai Ruijin Hospital — Shanghai
• Shanghai General Hospital — Shanghai
• West China Hopital of Sichuan University — Chengdu
• The Second Affiliated Hospital Zhejiang University School of Medical — Hangzhou
• Beijing Cancer Hospital — Beijing
• … and 2 more centers

France · 8 centers

• Institut Bergonié — Bordeaux
• Centre Oscar Lambret — Lille
• Hôpital Léon Bérard — Lyon
• Hopital de La Timone — Marseille
• Hôpital Cochin — Paris
• INSTITUT de CANCEROLOGIE de l'Ouest — Saint-Herblain
• Iuct-Oncopole Institut Universitaire Du Cancer — Toulouse
• Institut Gustave Roussy — Villejuif

Germany · 8 centers

• Helios Klinikum Bad Saarow — Bad Saarow
• Charite Universitatsmedizin — Berlin
• Universitätsklinikum Carl Gustav Carus Dresden — Dresden
• Universitatsklinikum Hamburg-Eppendorf — Hamburg
• Universitätsmedizin Mannheim (Umm) — Mannheim
• Lmu Klinikum — München
• Ukm - Sarkom-Zentrum — Münster
• Universitaetsklinikum Ulm — Ulm

Italy · 8 centers

• Irccs Istituto Ortopedico Rizzoli — Bologna
• Irccs Fondazione Istituto Nazionale Dei Tumori — Milan
• San Luigi Gonzaga University Hospital of Turin — Orbassano
• Istituto Oncologico Veneto Iov - Irccs — Padova
• Aou Policlinico Paolo Giaccone — Palermo
• Ospedale Santo Stefano — Prato
• Policlinico Universitario Campus Biomedico — Roma
• … and 1 more center

Spain · 7 centers

Center list to be confirmed — check the primary protocol.

Australia · 6 centers

• Flinders Medical Centre — Bedford Park
• Chris O'Brien Lifehouse — Camperdown
• Chris O'Brien Lifehouse — Camperdown
• St Vincent'S Hospital Melbourne — Fitzroy
• Sir Charles Gairdner Hospital — Nedlands
• Princess Alexandra Hospital — Woolloongabba

United Kingdom · 5 centers

Center list to be confirmed — check the primary protocol.

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

Belgium · 3 centers

• Cliniques Universitaires St. Luc — Brussels
• U.Z. Gent — Ghent
• Centre Multidisciplinaire de Oncologie Medicale — Liège

Canada · 3 centers

• Alberta Health Services — Calgary
• University Health Network — Toronto
• Muhc Glen Site — Montreal

Netherlands · 3 centers

Center list to be confirmed — check the primary protocol.

Denmark · 2 centers

• Aarhus Universitetshospital — Aarhus
• Herlev & Gentofte Hospital — Herlev

Taiwan · 2 centers

Center list to be confirmed — check the primary protocol.

Puerto Rico · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Tap WD, Cote GM, Burris H, Gore L, Elias A, Beeram M, Conley AP, Gianolio DA, Qu Z, Pandya S, Trent JC. Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Long-term Safety and Clinical Activity in Patients with Conventional Chondrosarcoma. Clin Cancer Res. 2025 Jun 3;31(11):2108-2114. doi: 10.1158/1078-0432.CCR-24-4128. PMID 40100120

Identifiers

NCT: NCT06127407 · CL3-95031-007

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗