Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer

Simple item page
dc.contributor.authorGoldman, J.W.
dc.contributor.authorRosen, L.S.
dc.contributor.authorTolcher, A.W.
dc.contributor.authorPapdopolous, K.
dc.contributor.authorBeeram, M.
dc.contributor.authorShi, P.
dc.contributor.authorPitou, C.
dc.contributor.authorBell, R.
dc.contributor.authorKulanthaivel, P.
dc.contributor.authorZhang, Xuekui
dc.contributor.authorFink, A.
dc.contributor.authorChan, E.M.
dc.contributor.authorShahir, A.
dc.contributor.authorFarrington, D.
dc.contributor.authorPatnaik, A.
dc.date.accessioned2021-08-18T18:20:06Z
dc.date.available2021-08-18T18:20:06Z
dc.date.copyright2018en_US
dc.date.issued2018
dc.description.abstractBackground 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.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThis study was sponsored by Eli Lilly & Company.en_US
dc.identifier.citationGoldman, 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/s10637-017-0532-2en_US
dc.identifier.urihttps://doi.org/10.1007/s10637-017-0532-2
dc.identifier.urihttp://hdl.handle.net/1828/13274
dc.language.isoenen_US
dc.publisherInvest New Drugsen_US
dc.subjectadvanced cancer
dc.subjectinhibitor
dc.subjectp38 mitogen-activated protein kinase
dc.subject.departmentDepartment of Mathematics and Statistics
dc.titlePhase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced canceren_US
dc.typeArticleen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
goldman_jonathan_Invest.New.Drugs_2018.pdf
Size:
978.01 KB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

Faculty and Staff Publications
 
University of Victoria Libraries

We acknowledge and respect the Lək̓ʷəŋən (Songhees and Esquimalt) Peoples on whose territory the university stands, and the Lək̓ʷəŋən and W̱SÁNEĆ Peoples whose historical relationships with the land continue to this day.