A randomized, placebo-controlled, phase 2 trial of INBRX-109 in unresectable or metastatic conventional chondrosarcoma.

TPS11582 Background: Chondrosarcomas (CS) are the third most common type of primary bone cancer after myeloma and osteosarcoma. Conventional CS represent 85–90% of all cases and are typically treated with surgical resection. However, there are no approved systemic treatment options for patients with unresectable or metastatic conventional CS, and outcomes remain poor. INBRX-109 is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to overcome the limitations of earlier-generation agonists and exploit the tumor-specific cell death induced by DR5 activation. DR5 is one of two pro-apoptotic receptors for the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Early clinical activity of INBRX-109 was observed in an ongoing phase 1 trial and warrants further investigation. INBRX-109 has been granted an FDA fast-track designation for conventional CS. Methods: This is a multicenter, randomized, blinded, placebo-controlled phase 2 study in patients with unresectable or metastatic conventional CS, measurable disease by RECIST 1.1, and radiologic disease progression within 6 months prior to screening. Any number of prior lines of therapy are allowed, except for prior DR5 agonists. Patients must be ≥18 years of age and have an ECOG performance status of 0/1 and have archival or fresh tissue available. Approximately 201 patients will be randomized (2:1) to INBRX-109 (3 mg/kg intravenously, every 21 days) or placebo, stratified by histologic grade (Grade 1/2 vs 3), isocitrate dehydrogenase (IDH)1 R132/IDH2 R172 status (wildtype vs mutation), and line of systemic therapy (none vs prior). Treatment will continue until disease progression/unacceptable toxicity. Patients treated with a placebo will have the option to cross over to INBRX-109 upon disease progression. The primary endpoint is progression-free survival (PFS) by independent radiology review. Secondary endpoints are overall survival, PFS by investigator assessment, quality of life, overall response rate, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity. Adverse events will be recorded and graded by NCI CTCAE Version 5.0. Median PFS of 7.0 months is projected for INBRX-109 and 4.0 months for placebo (corresponding hazard ratio of 0.571); INBRX-109 will be declared superior if the 1-sided p-value from the stratified log-rank test is <0.025. More than 50 sites are planned across the US/Europe. The study is actively enrolling. Clinical trial information: NCT04950075.