Masafumi Ikeda1, Hideaki Takahashi2, Shunsuke Kondo3, Michael Mauritius Fabio Lahn4, Ken Ogasawara5, Karim A Benhadji6, Hisaki Fujii7, Hideki Ueno3. 1. National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. masikeda@east.ncc.go.jp. 2. National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 3. National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan. 4. , 6820 Wisconsin Avenue, Bethesda, MD, 20815, USA. 5. Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA. 6. Eli Lilly and Company, Bridgewater, NJ, USA. 7. Eli Lilly Japan K.K., 7-1-5 Isogamidori, Chuo-Ku, Kobe, 651-0086, Japan.
Abstract
PURPOSE: Transforming growth factor-beta inhibitors may enhance the antitumor activity of gemcitabine with acceptable safety and tolerability. This open-label, multicenter, non-randomized phase 1b study assessed the safety/tolerability, pharmacokinetics, and tumor response of galunisertib plus gemcitabine in Japanese patients with advanced or metastatic pancreatic cancer. METHODS: During each 28-day cycle, galunisertib 150 mg was administered orally twice daily (300 mg/day) for 14 days, followed by 14 days of rest. Gemcitabine 1000 mg/m2 was intravenously given on Days 8, 15, and 22. Safety was assessed by the incidence of dose-limiting toxicities (DLTs) in the first cycle and treatment-emergent adverse events (TEAEs). Efficacy was assessed by antitumor activity and changes in carbohydrate antigen 19-9 (CA19-9). RESULTS: No DLTs were reported. All 7 enrolled patients had ≥1 TEAE, of which the most common included anorexia, decreased neutrophil count, and decreased white blood cell count. Grade ≥3 TEAEs were observed in 6 patients; 4 patients had Grade ≥3 TEAEs (decreased neutrophil, white blood cell, and lymphocyte count; hypophosphatemia) considered possibly related to study drug(s). The pharmacokinetic profile of galunisertib in combination with gemcitabine was similar to that previously observed for galunisertib alone. The clinical response [complete response (CR), partial response (PR), or stable disease] rate was 42.9%, and the median progression-free survival was 64 days; no CR/PR were achieved. CONCLUSION: Galunisertib plus gemcitabine had an acceptable safety/tolerability profile with evidence of efficacy in Japanese patients with advanced or metastatic pancreatic cancer.
PURPOSE: Transforming growth factor-beta inhibitors may enhance the antitumor activity of gemcitabine with acceptable safety and tolerability. This open-label, multicenter, non-randomized phase 1b study assessed the safety/tolerability, pharmacokinetics, and tumor response of galunisertib plus gemcitabine in Japanese patients with advanced or metastatic pancreatic cancer. METHODS: During each 28-day cycle, galunisertib 150 mg was administered orally twice daily (300 mg/day) for 14 days, followed by 14 days of rest. Gemcitabine 1000 mg/m2 was intravenously given on Days 8, 15, and 22. Safety was assessed by the incidence of dose-limiting toxicities (DLTs) in the first cycle and treatment-emergent adverse events (TEAEs). Efficacy was assessed by antitumor activity and changes in carbohydrate antigen 19-9 (CA19-9). RESULTS: No DLTs were reported. All 7 enrolled patients had ≥1 TEAE, of which the most common included anorexia, decreased neutrophil count, and decreased white blood cell count. Grade ≥3 TEAEs were observed in 6 patients; 4 patients had Grade ≥3 TEAEs (decreased neutrophil, white blood cell, and lymphocyte count; hypophosphatemia) considered possibly related to study drug(s). The pharmacokinetic profile of galunisertib in combination with gemcitabine was similar to that previously observed for galunisertib alone. The clinical response [complete response (CR), partial response (PR), or stable disease] rate was 42.9%, and the median progression-free survival was 64 days; no CR/PR were achieved. CONCLUSION:Galunisertib plus gemcitabine had an acceptable safety/tolerability profile with evidence of efficacy in Japanese patients with advanced or metastatic pancreatic cancer.
Authors: Yuan Yang; Howard H Yang; Binwu Tang; Alex Man Lai Wu; Kathleen C Flanders; Nellie Moshkovich; Douglas S Weinberg; Michael A Welsh; Jia Weng; Humberto J Ochoa; Tiffany Y Hu; Michelle A Herrmann; Jinqiu Chen; Elijah F Edmondson; R Mark Simpson; Fang Liu; Huaitian Liu; Maxwell P Lee; Lalage M Wakefield Journal: Clin Cancer Res Date: 2019-10-03 Impact factor: 12.531
Authors: Jonathan M Yingling; William T McMillen; Lei Yan; Huocong Huang; J Scott Sawyer; Jeremy Graff; David K Clawson; Karen S Britt; Bryan D Anderson; Douglas W Beight; Durisala Desaiah; Michael M Lahn; Karim A Benhadji; Maria J Lallena; Rikke B Holmgaard; Xiaohong Xu; Faming Zhang; Jason R Manro; Philip W Iversen; Chandrasekar V Iyer; Rolf A Brekken; Michael D Kalos; Kyla E Driscoll Journal: Oncotarget Date: 2017-12-31
Authors: Rodolfo Daniel Cervantes-Villagrana; Damaris Albores-García; Alberto Rafael Cervantes-Villagrana; Sara Judit García-Acevez Journal: Signal Transduct Target Ther Date: 2020-06-18
Authors: Kasia Trebska-McGowan; Mehdi Chaib; Marcus A Alvarez; Rita Kansal; Ajeeth K Pingili; David Shibata; Liza Makowski; Evan S Glazer Journal: J Gastrointest Surg Date: 2021-07-14 Impact factor: 3.452
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