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

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

Clinical cancer research, 2016-03, Vol.22 (5), p.1095-1102 [Periódico revisado por pares]

United States

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Título:
A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer
Autor: Patnaik, Amita ; Haluska, Paul ; Tolcher, Anthony W ; Erlichman, Charles ; Papadopoulos, Kyriakos P ; Lensing, Janet L ; Beeram, Muralidhar ; Molina, Julian R ; Rasco, Drew W ; Arcos, Rebecca R ; Kelly, Claudia S ; Wijayawardana, Sameera R ; Zhang, Xuekui ; Stancato, Louis F ; Bell, Robert ; Shi, Peipei ; Kulanthaivel, Palaniappan ; Pitou, Celine ; Mulle, Lynette B ; Farrington, Daphne L ; Chan, Edward M ; Goetz, Matthew P
Assuntos: 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 ; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Pyridines - administration & dosage ; Pyridines - pharmacokinetics ; Tumor Microenvironment - drug effects
É parte de: Clinical cancer research, 2016-03, Vol.22 (5), p.1095-1102
Descrição: 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.
Editor: United States
Idioma: Inglês

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

United States

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