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CCS Clinical Trials
Efficacy and safety of vebreltinib in advanced clear cell sarcoma (VEBrant): A multicenter, phase II study.
Publication Date:
June 1, 2026
Abstract
Background: Clear cell sarcoma (CCS) is an ultra rare cancer with no established standard systemic therapy of proven efficacy. The c-MET pathway plays an important role in CCS, with MET overexpression frequently observed. Targeted therapy by type Ia MET inhibitor crizotinib revealed a disease control rate (DCR) at 69.2% and objective response rate (ORR) at 3.8%. Vebreltinib is a highly selective type Ib MET inhibitor with verified efficacy in solid tumor harboring MET alterations, such as NSCLC with MET amplification or overexpression. This phase II study aimed to assess the efficacy and safety of Vebreltinib for advanced CCS.
Methods: Patients (pts) with histopathologically confirmed, unresectable or metastatic CCS were enrolled (NCT07153887), regardless of prior therapy except for any MET inhibitors. Eligible pts received Vebreltinib (200 mg BID) until disease progression, intolerable toxicity, or death occurs. Prior PD1/PDL1 treatment for at least 4 months without tumor reduction are allowed to continue using the same PD1/PDL1 medicine after thorough evaluation by the investigator. Evaluation of tumor response was performed every 2 months. Primary endpoints was ORR per RECIST v1.1. Secondary endpoints included DCR, PFS, OS, 12m-OSR, DoR and treatment safety. MET expression by immunohistochemistry was collected when possible. A Simon’s two-stage design was applied: if no responses were seen in the first 13 pts, the study would stop; otherwise, 14 additional pts would be enrolled (total N=27).
Results: At data cutoff on January 23, 2026, 23 pts were enrolled. Median age was 29 years (range: 16–59), 47.8% were male, 91.3% had prior surgery, and 95.7% received prior systemic therapy. All had metastatic disease, primarily to lung (78.3%), lymph nodes (56.5%), and bone (30.4%). With median follow-up of 134 days and median treatment duration of 103 days, 17 pts were evaluable for response. ORR was 41.2% (7 partial responses) and DCR was 70.6% (7 PR, 5 stable disease), meeting the pre-specified threshold for stage I continuation. Median PFS was 4.14 months (95% CI: 2.3–NA); 6-month PFS rate was 42.8%. Median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 87.0% of pts, mostly grade 1-2. Grade 3-4 TRAEs occurred in 21.7% (n=5; rash n=4, fever n=1). Notably, 4 pts discontinued due to grade 4 rash within 2 weeks of starting vebreltinib combined with immunotherapy.
Conclusions: Vebreltinib demonstrated notable antitumor activity for advanced CCS, representing a marked improvement over existing therapeutic options. Attention should be paid to the risk of severe rash, particularly when combined with immunotherapy. Longer follow-up is required to further confirm the efficacy and safety.
Author(s)
Li, Binghao & Jiang, Yaling & Huang, Xin & Lin, Nong & ye, Zhaoming.
Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'
Publication Date:
December 1, 2017
Abstract
Background: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA.
Patients and methods: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization.
Results: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)].
Conclusions: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients.
Author(s)
P Schöffski 1 2, A Wozniak 2, S Stacchiotti 3, P Rutkowski 4 5, J-Y Blay 6, L H Lindner 7, S J Strauss 8, A Anthoney 9, F Duffaud 10 11, S Richter 12 13, V Grünwald 14, M G Leahy 15, P Reichardt 16, J Sufliarsky 17, W T van der Graaf 18 19, R Sciot 20, M Debiec-Rychter 21, T van Cann 1 2, S Marréaud 22, M Lia 22, T Raveloarivahy 22, L Collette 22, S Bauer 23
Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial
Publication Date:
December 1, 2012
Abstract
Background: Microphthalmia transcription factor (MITF)-associated (MiT) tumors are a family of rare malignancies, including alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), and translocation-associated renal cell carcinoma (tRCC) that have dysregulated expression of oncogenic MITF family proteins. The MET receptor tyrosine kinase gene is transcriptionally activated by MITF family proteins, making MET a potential therapeutic target for MiT tumors. This study assessed the activity of tivantinib (ARQ 197), a selective MET inhibitor, in patients with MiT-associated tumors.
Methods: This multicenter, single-arm, phase 2 trial enrolled patients with advanced MiT tumors. Patients initially received tivantinib 120 mg orally twice daily, then 360 mg twice daily per protocol amendment. The primary endpoint was overall response rate. Secondary endpoints included safety, progression-free survival, pharmacokinetics, and correlative studies.
Results: A total of 47 patients (median age, 25 years; range, 11-73 years) with ASPS (n = 27), CCS (n = 11), tRCC (n = 6), or other tumor types (n = 3) were enrolled. Common grade 3/4 drug-related adverse events included anemia (4%) and neutropenia (4%). Three patients (6.4%) experienced 4 treatment-related serious adverse events (grade 3 febrile neutropenia, thrombocytopenia, and deep vein thrombosis, and grade 4 thrombocytopenia). Best response was partial response in 1 CCS patient (2%) and stable disease in 28 patients (60%). Median progression-free survival was 3.6 months (overall), 5.5 months (ASPS), and 1.9 months (CCS and tRCC). Baseline MET expression was strongly or focally positive in tumor samples from 14 of 19 patients (74%).
Conclusions: Tivantinib was safe and tolerable in patients with MiT tumors, but antitumor activity was modest.
Author(s)
Andrew J Wagner 1, John M Goldberg, Steven G Dubois, Edwin Choy, Lee Rosen, Alberto Pappo, James Geller, Ian Judson, David Hogg, Neil Senzer, Ian J Davis, Feng Chai, Carol Waghorne, Brian Schwartz, George D Demetri
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