Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: Results of a multicenter phase 2 trial

Andrew J. Wagner, John M. Goldberg, Steven G. Dubois, Edwin Choy, Rosen Lee, Alberto Pappo, James Geller, Ian Judson, David Hogg, Neil Senzer, Ian J. Davis, Chai Feng, Carol Waghorne, Brian Schwartz, George D. Demetri

Research output: Contribution to journalArticle

101 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5894-5902
Number of pages9
JournalCancer
Volume118
Issue number23
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

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Microphthalmia-Associated Transcription Factor
Clear Cell Sarcoma
Alveolar Soft Part Sarcoma
Neoplasms
Renal Cell Carcinoma
Disease-Free Survival
Proto-Oncogene Proteins c-met
ARQ 197
Febrile Neutropenia
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Venous Thrombosis
Thrombocytopenia
Anemia
Proteins
Pharmacokinetics

Keywords

  • alveolar soft part sarcoma
  • antagonists and inhibitors
  • ARQ 197
  • clear cell sarcoma
  • microphthalmia-associated transcription factor
  • pediatric
  • protein kinase inhibitors/pharmacokinetics
  • proto-oncogene proteins c-met/
  • renal cell carcinoma
  • tivantinib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors : Results of a multicenter phase 2 trial. / Wagner, Andrew J.; Goldberg, John M.; Dubois, Steven G.; Choy, Edwin; Lee, Rosen; Pappo, Alberto; Geller, James; Judson, Ian; Hogg, David; Senzer, Neil; Davis, Ian J.; Feng, Chai; Waghorne, Carol; Schwartz, Brian; Demetri, George D.

In: Cancer, Vol. 118, No. 23, 01.12.2012, p. 5894-5902.

Research output: Contribution to journalArticle

Wagner, AJ, Goldberg, JM, Dubois, SG, Choy, E, Lee, R, Pappo, A, Geller, J, Judson, I, Hogg, D, Senzer, N, Davis, IJ, Feng, C, Waghorne, C, Schwartz, B & Demetri, GD 2012, 'Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: Results of a multicenter phase 2 trial', Cancer, vol. 118, no. 23, pp. 5894-5902. https://doi.org/10.1002/cncr.27582
Wagner, Andrew J. ; Goldberg, John M. ; Dubois, Steven G. ; Choy, Edwin ; Lee, Rosen ; Pappo, Alberto ; Geller, James ; Judson, Ian ; Hogg, David ; Senzer, Neil ; Davis, Ian J. ; Feng, Chai ; Waghorne, Carol ; Schwartz, Brian ; Demetri, George D. / Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors : Results of a multicenter phase 2 trial. In: Cancer. 2012 ; Vol. 118, No. 23. pp. 5894-5902.
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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.",
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AU - Judson, Ian

AU - Hogg, David

AU - Senzer, Neil

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N2 - 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.

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