A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer

Abstract

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a doseescalation phase performed in a 3þ3 design (Part A; n ¼ 54), two dose-confirmation phases [Part B at 420 mg (n ¼ 18) and Part C at 300 mg (n ¼ 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n ¼ 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia

“…Similar results were obtained with the newly developed p38 kinase inhibitor ralimetinib, currently in Phase II clinical trials for ovarian cancer (NCT01663857) (Patnaik et al, 2016). Ralimetinib inhibited p38MAPK and the activity of its downstream substrate MK2 (Figure 4D).…”

“…Additionally, we demonstrate that p38MAPK inhibition suppressed the IL-1-mediated secretion of additional pro-inflammatory cytokines (Figure 6). Given the numerous p38MAPK inhibitors already in clinical development (Bachegowda et al, 2016; Patnaik et al, 2016), our findings provide strong pre-clinical data to extend these efforts to AML. Furthermore, from a clinical application standpoint, our data together suggest that in vitro IL-1 or p38MAPK inhibitor sensitivity, increased expression of IL-1 and its receptors, and/or increased p38MAPK phosphorylation in AML cells may serve as biomarkers for dependence on IL-1 signaling, warranting their potential translation to routinely available clinical screening assays in order to aid stratification of patients for such therapy.…”

Cytokine Production and NET Formation by Monosodium Urate-Activated Human Neutrophils Involves Early and Late Events, and Requires Upstream TAK1 and Syk

“…Thus, our findings unveil several potentially important therapeutic targets for acute episodes of gouty arthritis, which feature a massive neutrophil influx. The fact that inhibitors for several of these molecular targets are already undergoing clinical trials (48)(49)(50)(51) makes an eventual translation to the patient more than a remote possibility.…”

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

“…Thus, inhibiting the nuclear translocation of p38s and possibly also of JNKs should be beneficial in treating inflammation-related diseases, including inflammation-induced cancer. The inhibition of the nuclear translocation affects only a small number of the total JNK and p38 activities without affecting negative feedback loops; therefore, this inhibitor should be much less toxic than the ATP competitors that are in clinical trials [130]. …”