A first-in-human phase i study of the oral p38 MAPK inhibitor, ralimetinib (LY2228820 Dimesylate), in patients with advanced cancer

Amita Patnaik, Paul Haluska, Anthony W. Tolcher, Charles Erlichman, Kyriakos P. Papadopoulos, Janet L. Lensing, Muralidhar Beeram, Julian R. Molina, Drew W. Rasco, Rebecca R. Arcos, Claudia S. Kelly, Sameera R. Wijayawardana, Xuekui Zhang, Louis F. Stancato, Robert Bell, Peipei Shi, Palaniappan Kulanthaivel, Celine Pitou, Lynette B. Mulle, Daphne L. FarringtonEdward M. Chan, Matthew P. Goetz

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 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.

Original languageEnglish (US)
Pages (from-to)1095-1102
Number of pages8
JournalClinical Cancer Research
Issue number5
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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