Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors.

Autor:	Fujiwara, Yutaka, Nokihara, Hiroshi, Yamada, Yasuhide, Yamamoto, Noboru, Sunami, Kuniko, Utsumi, Hirofumi, Asou, Hiroya, TakahashI, Osamu, Ogasawara, Ken, Gueorguieva, Ivelina, Tamura, Tomohide
Předmět:	TRANSFORMING growth factors-beta KINASE inhibitors JAPANESE people ANTINEOPLASTIC agents DRUG dosage DISEASES ASIANS BIOTRANSFORMATION (Metabolism) CELL receptors CLINICAL trials COMPARATIVE studies CONSTIPATION DOSE-effect relationship in pharmacology EXANTHEMA HETEROCYCLIC compounds INSOMNIA RESEARCH methodology MEDICAL cooperation PHARMACOKINETICS QUINOLINE RESEARCH TRANSFERASES TUMORS EVALUATION research TREATMENT effectiveness THERAPEUTICS
Zdroj:	Cancer Chemotherapy & Pharmacology; Dec2015, Vol. 76 Issue 6, p1143-1152, 10p
Abstrakt:	Purpose: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.Methods: Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).Results: Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.Conclusions: Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV.Identifier: NCT01722825. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink