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)

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 I and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors. Methods Oral tivantinib capsules were administered bid with food, continuously in 28-day cycles. Dose levels 170, 200 and 240 mg/m2/dose were evaluated using a rolling 6 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 to a PK expansion cohort, and 10 to Part B. Fifteen patients had primary CNS tumors and 21 had solid tumors. In Part A, there were no DLTs. 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 inter-patient 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 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 I trial.

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…In the study, which comprised 36 patients, including 4 glioma, 4 MB, 4 EPN, 4 EWS, 4 OS, 3 RMS, 2 WT and 2 NB, suboptimal responses were achieved when tivantinib was given with food to children with refractory solid tumors is 240 mg/m 2 /dose. Moreover, while the drug was well tolerated, its pharmacokinetic profile was also variable, discouraging further investigation in this setting [ 705 ]. However, two of those patients (alveolar soft part sarcoma) who responded to tivantinib administration and were transitioned to a follow-up protocol experienced extended progression-free survival receiving 360 mg twice every day without adverse events [ 706 ].…”

The hepatocyte growth factor/mesenchymal epithelial transition factor axis in high-risk pediatric solid tumors and the anti-tumor activity of targeted therapeutic agents

“…While oral tivantinib was well tolerated, there was marked pharmacokinetic variability among patients, and no objective responses were seen. Tumor samples (solid tumors including CNS tumors) were analyzed for c-MET expression by IHC, and the majority of samples [81% (26/32)] were found to have undetectable levels of c-MET ( 183 ).…”

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment

“…To date, there are no reports of clinical trials using tivantinib in children with brain tumors. Only one report of a phase I trial in children with relapsed/refractory solid tumors reported no objective response with tivantinib treatment ( Geller et al, 2017 ). Foretinib is another multityrosine kinase inhibitor of c-Met, c-ros oncogene (ROS), receptor d’origine nantain (RON), AXL, TIE2, and VEGFR2 ( Faria et al, 2015 ).…”