Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer
Date
2018
Authors
Goldman, J.W.
Rosen, L.S.
Tolcher, A.W.
Papdopolous, K.
Beeram, M.
Shi, P.
Pitou, C.
Bell, R.
Kulanthaivel, P.
Zhang, Xuekui
Journal Title
Journal ISSN
Volume Title
Publisher
Invest New Drugs
Abstract
Background The signaling protein p38 mitogenactivated
protein kinase (MAPK) regulates the tumor cell microenvironment,
modulating cell survival, migration, and invasion.
This phase 1 study evaluated the safety of p38 MAPK
inhibitor LY3007113 in patients with advanced cancer to establish
a recommended phase 2 dose. Methods In part A (dose
escalation), LY3007113 was administered orally every 12 h
(Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-
day cycle until the maximum tolerated dose (MTD) was
reached. In part B (dose confirmation), patients received
MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor
response data were evaluated. Results MTD was 30 mg
Q12H. The most frequent treatment-related adverse events
(>10%) were tremor, rash, stomatitis, increased blood creatine
phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse
events included upper gastrointestinal haemorrhage and
increased hepatic enzyme, both occurring at 40 mg Q12H and
considered dose-limiting toxicities. LY3007113 exhibited an
approximately dose-proportional increase in exposure and
time-independent pharmacokinetics after repeated dosing.
Maximal inhibition (80%) of primary biomarker MAPKactivated
protein kinase 2 in peripheral blood mononuclear
cells was not reached, and sustained minimal inhibition
(60%) was not maintained for 6 h after dosing to achieve a
biologically effective dose (BED). The best overall response
in part B was stable disease in 3 of 27 patients. Conclusions
The recommended phase 2 dosage of LY3007113 was 30 mg
Q12H. Three patients continued treatment after the first radiographic
assessment, and the BED was not achieved. Further
clinical development of this compound is not planned as toxicity
precluded achieving a biologically effective dose.
Description
Keywords
advanced cancer, inhibitor, p38 mitogen-activated protein kinase
Citation
Goldman, J.W., Rosen, L.S., Tolcher, A.W., Papadopoulos, K., Beeram, M., Shi, P., Pitou, C., Bell, R., Kulanthaivel, P., Zhang, X., Fink, A., Chan, E.M., Shahir, A., Farrington, D., Patnaik, A. (2018). Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer. Invest New Drugs, 36, 629-637. https://doi.org/10.1007/s10637-017-0532-2