Kohei Shitara1, Shigenori Kadowaki2, Tomohiro Nishina3, Daisuke Sakai4, Reigetsu Yoshikawa5, Yongzhe Piao5, Akihiro Ozeki5, Koichi Inoue5, Ismael Gritli5, Kei Muro2. 1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. kshitara@east.ncc.go.jp. 2. Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan. 3. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan. 4. Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Osaka, Japan. 5. Eli Lilly Japan K.K., Kobe, Japan.
Abstract
BACKGROUND: We evaluated the safety, tolerability, pharmacokinetics, and tumor response of ramucirumab in combination with one of three platinum/fluoropyrimidine regimens in Japanese patients with chemotherapy-naïve metastatic gastric/gastroesophageal junction cancer. METHODS: In this phase 1b study, patients received 8 mg/kg ramucirumab on days 1 and 8 every 3 weeks, following one of three regimens: capecitabine + cisplatin, XP; S-1 + cisplatin, SP; or S-1 + oxaliplatin, SOX. The primary objective was to assess safety and tolerability; the secondary objectives were to evaluate pharmacokinetics and tumor response. RESULTS: Six patients were treated in each cohort. All regimens were generally well tolerated, although 1 patient in SOX was associated with grade 3 enterocolitis, which was considered a dose-limiting toxicity. Common grade 3 or higher adverse events included neutropenia (1 in XP, 3 in SP, and 2 in SOX), decreased appetite (1 in SP), and hypertension (2 in XP). The mean trough ramucirumab concentrations were consistent across all cohorts, and those of most patients exceeded target levels, which were estimated from previous studies of the approved ramucirumab dose (8 mg/kg every 2 weeks). Among the 11 patients with measurable disease, overall response rate and disease control rate were 45.5% and 100.0%, respectively. Median progression-free survival (95% CI) was 7.6 months (6.0 to not estimable). CONCLUSION: Ramucirumab 8 mg/kg on days 1 and 8 every 3 weeks in combination with XP, SP, or SOX was generally well tolerated and demonstrated preliminary anti-tumor activity in chemotherapy-naïve Japanese metastatic gastric/gastroesophageal junction cancer patients.
BACKGROUND: We evaluated the safety, tolerability, pharmacokinetics, and tumor response of ramucirumab in combination with one of three platinum/fluoropyrimidine regimens in Japanese patients with chemotherapy-naïve metastatic gastric/gastroesophageal junction cancer. METHODS: In this phase 1b study, patients received 8 mg/kg ramucirumab on days 1 and 8 every 3 weeks, following one of three regimens: capecitabine + cisplatin, XP; S-1 + cisplatin, SP; or S-1 + oxaliplatin, SOX. The primary objective was to assess safety and tolerability; the secondary objectives were to evaluate pharmacokinetics and tumor response. RESULTS: Six patients were treated in each cohort. All regimens were generally well tolerated, although 1 patient in SOX was associated with grade 3 enterocolitis, which was considered a dose-limiting toxicity. Common grade 3 or higher adverse events included neutropenia (1 in XP, 3 in SP, and 2 in SOX), decreased appetite (1 in SP), and hypertension (2 in XP). The mean trough ramucirumab concentrations were consistent across all cohorts, and those of most patients exceeded target levels, which were estimated from previous studies of the approved ramucirumab dose (8 mg/kg every 2 weeks). Among the 11 patients with measurable disease, overall response rate and disease control rate were 45.5% and 100.0%, respectively. Median progression-free survival (95% CI) was 7.6 months (6.0 to not estimable). CONCLUSION:Ramucirumab 8 mg/kg on days 1 and 8 every 3 weeks in combination with XP, SP, or SOX was generally well tolerated and demonstrated preliminary anti-tumor activity in chemotherapy-naïve Japanese metastatic gastric/gastroesophageal junction cancerpatients.
Authors: Y Yamada; K Higuchi; K Nishikawa; M Gotoh; N Fuse; N Sugimoto; T Nishina; K Amagai; K Chin; Y Niwa; A Tsuji; H Imamura; M Tsuda; H Yasui; H Fujii; K Yamaguchi; H Yasui; S Hironaka; K Shimada; H Miwa; C Hamada; I Hyodo Journal: Ann Oncol Date: 2014-10-14 Impact factor: 32.976
Authors: Sameer Doshi; Per Olsson Gisleskog; Yilong Zhang; Min Zhu; Kelly S Oliner; Elwyn Loh; Juan Jose Perez Ruixo Journal: Clin Cancer Res Date: 2015-02-24 Impact factor: 12.531
Authors: Charles S Fuchs; Jiri Tomasek; Cho Jae Yong; Filip Dumitru; Rodolfo Passalacqua; Chanchal Goswami; Howard Safran; Lucas Vieira Dos Santos; Giuseppe Aprile; David R Ferry; Bohuslav Melichar; Mustapha Tehfe; Eldar Topuzov; John Raymond Zalcberg; Ian Chau; William Campbell; Choondal Sivanandan; Joanna Pikiel; Minori Koshiji; Yanzhi Hsu; Astra M Liepa; Ling Gao; Jonathan D Schwartz; Josep Tabernero Journal: Lancet Date: 2013-10-03 Impact factor: 79.321
Authors: David Cunningham; Naureen Starling; Sheela Rao; Timothy Iveson; Marianne Nicolson; Fareeda Coxon; Gary Middleton; Francis Daniel; Jacqueline Oates; Andrew Richard Norman Journal: N Engl J Med Date: 2008-01-03 Impact factor: 91.245
Authors: Y-K Kang; W-K Kang; D-B Shin; J Chen; J Xiong; J Wang; M Lichinitser; Z Guan; R Khasanov; L Zheng; M Philco-Salas; T Suarez; J Santamaria; G Forster; P I McCloud Journal: Ann Oncol Date: 2009-01-19 Impact factor: 32.976
Authors: H H Yoon; J C Bendell; F S Braiteh; I Firdaus; P A Philip; A L Cohn; N Lewis; D M Anderson; E Arrowsmith; J D Schwartz; L Gao; Y Hsu; Y Xu; D Ferry; S R Alberts; Z A Wainberg Journal: Ann Oncol Date: 2016-10-20 Impact factor: 51.769
Authors: Ursula M Vogl; Laurenz Vormittag; Thomas Winkler; Alice Kafka; Olivia Weiser-Jasch; Bettina Heinrich; Sophie Roider-Schur; Haleh Andalibi; Eva Autzinger; Wolfgang Schima; Alexander Klaus; Johannes Zacherl; Günter Michael Wimberger; Leopold Öhler Journal: J Gastrointest Oncol Date: 2020-04