Abstract
SummaryBackground 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.
Highlights
The signaling protein p38 mitogen-activated protein kinase (MAPK) is activated by cancer cells downstream of oncogenic receptor tyrosine kinases and in response to both radiation and chemotherapy [1]
Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose
It phosphorylates a number of substrates, including MAPK-activated protein kinase 2 (MAPKAP-K2), and regulates the production of key cytokines in the microenvironment, such as tumor necrosis factor α, interleukin-1β,interleukin-6 (IL-6), and interleukin-8 [2,3,4]. These cytokines are up-regulated in many human malignancies and promote cancer cell survival, growth, invasion, and metastasis [4, 5], including non–small cell lung cancer, ovarian cancer, glioblastoma, multiple myeloma, lymphoma, breast cancer, and colon cancer
Summary
The signaling protein p38 mitogen-activated protein kinase (MAPK) is activated by cancer cells downstream of oncogenic receptor tyrosine kinases and in response to both radiation and chemotherapy [1] It phosphorylates a number of substrates, including MAPK-activated protein kinase 2 (MAPKAP-K2), and regulates the production of key cytokines in the microenvironment, such as tumor necrosis factor α, interleukin-1β,interleukin-6 (IL-6), and interleukin-8 [2,3,4]. P38 MAPK plays a role in angiogenesis and may be inhibited to reduce the secretion of Invest New Drugs (2018) 36:629–637 cytokines that promote angiogenesis [7] As it relates to the tumor microenvironment, p38 MAPK controls the senescence-associated secretory phenotype and, when inhibited, mitigates against the tumor-forming activities of the cancer associated fibroblasts [8]. Pharmacologic inhibition of p38 MAPK directed to both the cancer and its supportive microenvironment represents a novel therapeutic strategy for improving outcomes for individuals with these cancers
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