title: A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: START, San Antonio, Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: START, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: START, San Antonio, Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Lensing
authors.affiliation: START, San Antonio, Texas.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.affiliation: START, San Antonio, Texas.
authors.forename: Drew W
authors.initials: DW
authors.lastname: Rasco
authors.affiliation: START, San Antonio, Texas.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Arcos
authors.affiliation: Formerly Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Kelly
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Sameera R
authors.initials: SR
authors.lastname: Wijayawardana
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Xuekui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Robert
authors.initials: R
authors.lastname: Bell
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Peipei
authors.initials: P
authors.lastname: Shi
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Kulanthaivel
authors.affiliation: Eli Lilly and Company, Guildford, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Pitou
authors.affiliation: inVentiv Health, Indianapolis, Indiana.
authors.forename: Lynette B
authors.initials: LB
authors.lastname: Mulle
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: Farrington
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.affiliation: Mayo Clinic, Rochester, Minnesota. goetz.matthew@mayo.edu.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D059016:Tumor Microenvironment / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D011725:Pyridines; C580958:ralimetinib; D048051:p38 Mitogen-Activated Protein Kinases