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

Clin Cancer Res. 2016 Mar 1;22(5):1095-102. doi: 10.1158/1078-0432.CCR-15-1718. Epub 2015 Nov 18.


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 dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 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 = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.

Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥ 6 cycles.

Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology*
  • Female
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / pharmacokinetics
  • Leukocytes, Mononuclear / pathology
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Pyridines / administration & dosage*
  • Pyridines / pharmacokinetics
  • Tumor Microenvironment / drug effects
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*


  • Imidazoles
  • Pyridines
  • ralimetinib
  • p38 Mitogen-Activated Protein Kinases