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 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.

• Authors: 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 Farrington, Edward M Chan, Matthew P Goetz
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 5 Pg. 1095-102 (Mar 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26581242 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

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

Topics

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