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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(s) -
Geller James I.,
Perentesis John P.,
Liu Xiaowei,
Minard Charles G.,
Kudgus Rachel A.,
Reid Joel M.,
Fox Elizabeth,
Blaney Susan M.,
Weigel Brenda J.
Publication year - 2017
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.26565
Subject(s) - medicine , refractory (planetary science) , pharmacokinetics , cohort , response evaluation criteria in solid tumors , tyrosine kinase inhibitor , oncology , gastroenterology , clinical trial , cancer , phases of clinical research , physics , astrobiology
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/m 2 /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/m 2 ). PK analysis showed marked interpatient variability (20‐fold) in the C max and AUC 0‐8h 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/m 2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.