Yutaka Fujiwara1, Hiroshi Nokihara2, Yasuhide Yamada3, Noboru Yamamoto2, Kuniko Sunami2, Hirofumi Utsumi2,4, Hiroya Asou5, Osamu TakahashI5, Ken Ogasawara6, Ivelina Gueorguieva7, Tomohide Tamura2,8. 1. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. yutakafu@ncc.go.jp. 2. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. 3. Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan. 4. Respiratory Medicine, The Jikei University School of Medicine, Tokyo, Japan. 5. Medical Science, Eli Lilly Japan K.K., Kobe, Japan. 6. Japan PK/PD, Eli Lilly Japan K.K., Kobe, Japan. 7. Global PK/PD, Lilly Research Laboratories, Windlesham, Surrey, UK. 8. St Luke's International Hospital, Tokyo, Japan.
Abstract
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.
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.
Authors: Hung C Tran; Zesheng Wan; Michael A Sheard; Jianping Sun; Jeremy R Jackson; Jemily Malvar; Yibing Xu; Larry Wang; Richard Sposto; Eugene S Kim; Shahab Asgharzadeh; Robert C Seeger Journal: Clin Cancer Res Date: 2016-10-10 Impact factor: 12.531
Authors: S Mazher Hussain; Rita G Kansal; Marcus A Alvarez; T J Hollingsworth; Abul Elahi; Gustavo Miranda-Carboni; Leah E Hendrick; Ajeeth K Pingili; Lorraine M Albritton; Paxton V Dickson; Jeremiah L Deneve; Danny Yakoub; D Neil Hayes; Michio Kurosu; David Shibata; Liza Makowski; Evan S Glazer Journal: Cell Oncol (Dordr) Date: 2021-03-10 Impact factor: 6.730