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 language | English |
|---|---|
| Pages (from-to) | 5894-5902 |
| Number of pages | 9 |
| Journal | Cancer |
| Volume | 118 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2012 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors
T2 - Results of a multicenter phase 2 trial
AU - Wagner, Andrew J.
AU - Goldberg, John M.
AU - Dubois, Steven G.
AU - Choy, Edwin
AU - Lee, Rosen
AU - Pappo, Alberto
AU - Geller, James
AU - Judson, Ian
AU - Hogg, David
AU - Senzer, Neil
AU - Davis, Ian J.
AU - Feng, Chai
AU - Waghorne, Carol
AU - Schwartz, Brian
AU - Demetri, George D.
PY - 2012/12/1
Y1 - 2012/12/1
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.
AB - 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.
KW - alveolar soft part sarcoma
KW - antagonists and inhibitors
KW - ARQ 197
KW - clear cell sarcoma
KW - microphthalmia-associated transcription factor
KW - pediatric
KW - protein kinase inhibitors/pharmacokinetics
KW - proto-oncogene proteins c-met/
KW - renal cell carcinoma
KW - tivantinib
UR - http://www.scopus.com/inward/record.url?scp=84869493002&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869493002&partnerID=8YFLogxK
U2 - 10.1002/cncr.27582
DO - 10.1002/cncr.27582
M3 - Article
C2 - 22605650
AN - SCOPUS:84869493002
VL - 118
SP - 5894
EP - 5902
JO - Cancer
JF - Cancer
SN - 0008-543X
IS - 23
ER -