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Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer
- Source :
- Investigational new drugs, vol 36, iss 4, Investigational New Drugs
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- Summary Background The signaling protein p38 mitogen-activated 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 MAPK-activated 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.
- Subjects :
- Male
0301 basic medicine
Pharmacology
p38 Mitogen-Activated Protein Kinases
0302 clinical medicine
Phase I Studies
Neoplasms
Medicine
Pharmacology (medical)
6.2 Cellular and gene therapies
Cancer
Tumor
P38 MAPK Inhibitor LY3007113
Pharmacology and Pharmaceutical Sciences
Middle Aged
Effective dose (pharmacology)
Treatment Outcome
Oncology
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Toxicity
Female
Patient Safety
Drug
Adult
Inhibitor
Maximum Tolerated Dose
Clinical Trials and Supportive Activities
Antineoplastic Agents
Peripheral blood mononuclear cell
Dose-Response Relationship
03 medical and health sciences
Pharmacokinetics
Clinical Research
Advanced cancer
Biomarkers, Tumor
Humans
Oncology & Carcinogenesis
Dosing
Adverse effect
Protein Kinase Inhibitors
Aged
Dose-Response Relationship, Drug
business.industry
p38 mitogen-activated protein kinase
Evaluation of treatments and therapeutic interventions
030104 developmental biology
Pharmacodynamics
Digestive Diseases
business
Biomarkers
Subjects
Details
- ISSN :
- 15730646 and 01676997
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....c4e36bef4b87b33b6e9fa922aec568f0