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

Abstract

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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 4 Pg. 1016-22 (Aug 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23417696 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• ARQ 197
• Antineoplastic Agents
• Pyrrolidinones
• Quinolines
• Proto-Oncogene Proteins c-met

Topics

• Adolescent
• Adult
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Demography
• Disease-Free Survival
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasms, Germ Cell and Embryonal (drug therapy, pathology)
• Proto-Oncogene Proteins c-met (metabolism)
• Pyrrolidinones (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Quinolines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Recurrence
• Treatment Outcome
• Young Adult