A phase 1 study of the c-Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors: A Children's Oncology Group study phase 1 and pilot consortium trial (ADVL1111)

Pediatr Blood Cancer. 2017 Nov;64(11):10.1002/pbc.26565. doi: 10.1002/pbc.26565. Epub 2017 Apr 27.


Background: The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors.

Methods: Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2 /dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed.

Results: Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2 ). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response.

Conclusions: The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Infant
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Pilot Projects
  • Prognosis
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyrrolidinones / pharmacokinetics
  • Pyrrolidinones / pharmacology*
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology*
  • Salvage Therapy*
  • Tissue Distribution
  • Young Adult


  • ARQ 197
  • Pyrrolidinones
  • Quinolines
  • MET protein, human
  • Proto-Oncogene Proteins c-met