A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors

Darren R. Feldman, Lawrence H. Einhorn, David I. Quinn, Yohann Loriot, Johnathan K. Joffe, David J. Vaughn, Aude Fléchon, Julio Hajdenberg, Abdel Baset Halim, Hamim Zahir, Robert J. Motzer

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Summary: Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.

Original languageEnglish (US)
Pages (from-to)1016-1022
Number of pages7
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 1 2013

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Germ Cell and Embryonal Neoplasms
Multicenter Studies
Disease-Free Survival
Nervous System Neoplasms
Proto-Oncogene Proteins c-met
Neoplasms
Survival
ARQ 197
Syncope
Mediastinum
Testis
Pneumonia
Histology
Survival Rate
Safety
Pharmaceutical Preparations
Population

Keywords

  • ARQ 197
  • Germ cell tumor
  • MET inhibitor
  • MET receptor tyrosine kinase
  • Relapsed
  • Tivantinib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors. / Feldman, Darren R.; Einhorn, Lawrence H.; Quinn, David I.; Loriot, Yohann; Joffe, Johnathan K.; Vaughn, David J.; Fléchon, Aude; Hajdenberg, Julio; Halim, Abdel Baset; Zahir, Hamim; Motzer, Robert J.

In: Investigational New Drugs, Vol. 31, No. 4, 01.08.2013, p. 1016-1022.

Research output: Contribution to journalArticle

Feldman, DR, Einhorn, LH, Quinn, DI, Loriot, Y, Joffe, JK, Vaughn, DJ, Fléchon, A, Hajdenberg, J, Halim, AB, Zahir, H & Motzer, RJ 2013, 'A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors', Investigational New Drugs, vol. 31, no. 4, pp. 1016-1022. https://doi.org/10.1007/s10637-013-9934-y
Feldman, Darren R. ; Einhorn, Lawrence H. ; Quinn, David I. ; Loriot, Yohann ; Joffe, Johnathan K. ; Vaughn, David J. ; Fléchon, Aude ; Hajdenberg, Julio ; Halim, Abdel Baset ; Zahir, Hamim ; Motzer, Robert J. / A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 1016-1022.
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abstract = "Summary: Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 {\%}, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.",
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AU - Feldman, Darren R.

AU - Einhorn, Lawrence H.

AU - Quinn, David I.

AU - Loriot, Yohann

AU - Joffe, Johnathan K.

AU - Vaughn, David J.

AU - Fléchon, Aude

AU - Hajdenberg, Julio

AU - Halim, Abdel Baset

AU - Zahir, Hamim

AU - Motzer, Robert J.

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N2 - Summary: Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.

AB - Summary: Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.

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