Details der Publikation - Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors

Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors

Abstract RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors..

Medienart:	E-Artikel

Erscheinungsjahr:	2015
Erschienen:	2015

Enthalten in:	Zur Gesamtaufnahme - volume:33
Enthalten in:	Investigational new drugs - 33(2015), 3 vom: 27. März, Seite 641-651

Sprache:	Englisch

Beteiligte Personen:	Nakamichi, Shinji [VerfasserIn] Nokihara, Hiroshi [VerfasserIn] Yamamoto, Noboru [VerfasserIn] Yamada, Yasuhide [VerfasserIn] Fujiwara, Yutaka [VerfasserIn] Tamura, Yosuke [VerfasserIn] Wakui, Hiroshi [VerfasserIn] Honda, Kazunori [VerfasserIn] Mizugaki, Hidenori [VerfasserIn] Kitazono, Satoru [VerfasserIn] Tanabe, Yuko [VerfasserIn] Asahina, Hajime [VerfasserIn] Yamazaki, Naoya [VerfasserIn] Suzuki, Shigenobu [VerfasserIn] Matsuoka, Mieko [VerfasserIn] Ogita, Yoshitaka [VerfasserIn] Tamura, Tomohide [VerfasserIn]

Links:	Volltext [lizenzpflichtig]

BKL:	44.40$jPharmazie$jPharmazeutika
Themen:	Dose escalation Japanease MAPK pathway MEK inhibitor Phase I study

Anmerkungen:	© Springer Science+Business Media New York 2015

doi:	10.1007/s10637-015-0229-3

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC2112997815

Internformat


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520			\|a Abstract RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
650		4	\|a Phase I study
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700	1		\|a Yamada, Yasuhide \|4 aut
700	1		\|a Fujiwara, Yutaka \|4 aut
700	1		\|a Tamura, Yosuke \|4 aut
700	1		\|a Wakui, Hiroshi \|4 aut
700	1		\|a Honda, Kazunori \|4 aut
700	1		\|a Mizugaki, Hidenori \|4 aut
700	1		\|a Kitazono, Satoru \|4 aut
700	1		\|a Tanabe, Yuko \|4 aut
700	1		\|a Asahina, Hajime \|4 aut
700	1		\|a Yamazaki, Naoya \|4 aut
700	1		\|a Suzuki, Shigenobu \|4 aut
700	1		\|a Matsuoka, Mieko \|4 aut
700	1		\|a Ogita, Yoshitaka \|4 aut
700	1		\|a Tamura, Tomohide \|4 aut
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Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors

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