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)

James I. Geller, John P. Perentesis, Xiaowei Liu, Charles G. Minard, Rachel A. Kudgus, Joel M Reid, Elizabeth Fox, Susan M. Blaney, Brenda J. Weigel

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere26565
JournalPediatric Blood and Cancer
Volume64
Issue number11
DOIs
StatePublished - Nov 1 2017

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Pharmacokinetics
Neoplasms
Proto-Oncogene Proteins c-met
Food
Powders
Central Nervous System Neoplasms
Intracranial Hemorrhages
ARQ 197
Brain Neoplasms
Capsules
Pediatrics

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

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). / 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.

In: Pediatric Blood and Cancer, Vol. 64, No. 11, e26565, 01.11.2017.

Research output: Contribution to journalArticle

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. / 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). In: Pediatric Blood and Cancer. 2017 ; Vol. 64, No. 11.
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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.",
author = "Geller, {James I.} and Perentesis, {John P.} and Xiaowei Liu and Minard, {Charles G.} and Kudgus, {Rachel A.} and Reid, {Joel M} and Elizabeth Fox and Blaney, {Susan M.} and Weigel, {Brenda J.}",
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TY - JOUR

T1 - A phase 1 study of the c-Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors

T2 - A Children's Oncology Group study phase 1 and pilot consortium trial (ADVL1111)

AU - Geller, James I.

AU - Perentesis, John P.

AU - Liu, Xiaowei

AU - Minard, Charles G.

AU - Kudgus, Rachel A.

AU - Reid, Joel M

AU - Fox, Elizabeth

AU - Blaney, Susan M.

AU - Weigel, Brenda J.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

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U2 - 10.1002/pbc.26565

DO - 10.1002/pbc.26565

M3 - Article

VL - 64

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 11

M1 - e26565

ER -