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Ref Type Journal Article
PMID (26581242)
Authors Patnaik A, Haluska P, Tolcher AW, Erlichman C, Papadopoulos KP, Lensing JL, Beeram M, Molina JR, Rasco DW, Arcos RR, Kelly CS, Wijayawardana SR, Zhang X, Stancato LF, Bell R, Shi P, Kulanthaivel P, Pitou C, Mulle LB, Farrington DL, Chan EM, Goetz MP
Title A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 5
Date 2016 Mar 01
URL
Abstract Text 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.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.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.Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Ralimetinib Ralimetinib 1 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ralimetinib LY2228820 p38-alpha Inhibitor 1 Ralimetinib (LY2228820) is a selective ATP competitive inhibitor of p38 MAPK alpha (MAPK14) and beta (MAPK11), which inhibits tumor growth (PMID: 26581242, PMID: 24356814).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Ralimetinib Phase I Actionable In a Phase I trial, Ralimetinib (LY2228820) resulted in stable disease in 21.3% (19/74) of patients with an advanced solid tumor, which lasted a median duration of 3.7 months (PMID: 26581242). 26581242