Format

Send to

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

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).

Author information

1
Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
2
Children's Oncology Group, Monrovia, CA.
3
Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX.
4
Mayo Clinic, Rochester, MN.
5
Children's Hospital of Philadelphia, Philadelphia, PA.
6
Masonic Children's Hospital, University of Minnesota Medical Center, Minneapolis, MN.

Abstract

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.

PMID:
28449393
PMCID:
PMC5657151
DOI:
10.1002/pbc.26565
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center