TY - JOUR
T1 - A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors
AU - Tibes, Raoul
AU - Fine, Gil
AU - Choy, Gavin
AU - Redkar, Sanjeev
AU - Taverna, Pietro
AU - Oganesian, Aram
AU - Sahai, Amarpal
AU - Azab, Mohammad
AU - Tolcher, Anthony W.
N1 - Funding Information:
Conflict of interest This study was sponsored, monitored, and funded by Astex Pharmaceuticals, Inc. (formerly SuperGen, Inc.). R. Tibes and A. Tolcher have received research funding from Astex Pharmaceuticals, Inc. for conducting the clinical trial. G. Fine, G. Choy, S. Redkar, P. Taverna, A. Oganesian, A. Sahai, and M. Azab are employees of Astex Pharmaceuticals, Inc. and own stock in Astex Pharmaceuticals, Inc.
PY - 2013/2
Y1 - 2013/2
N2 - Purpose: Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial (clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed. Methods: Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated. Results: No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2-[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29. Conclusions: Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.
AB - Purpose: Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial (clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed. Methods: Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated. Results: No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2-[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29. Conclusions: Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.
KW - Amuvatinib
KW - GIST
KW - KIT
KW - MP-470
KW - Phase I
KW - Tyrosine kinase inhibitor
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U2 - 10.1007/s00280-012-2019-3
DO - 10.1007/s00280-012-2019-3
M3 - Article
C2 - 23178951
AN - SCOPUS:84874118848
SN - 0344-5704
VL - 71
SP - 463
EP - 471
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 2
ER -