PMID- 27909950 OWN - NLM STAT- MEDLINE DCOM- 20170727 LR - 20181202 IS - 1936-0541 (Electronic) IS - 1936-0533 (Print) IS - 1936-0533 (Linking) VI - 11 IP - 2 DP - 2017 Mar TI - HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma. PG - 199-208 LID - 10.1007/s12072-016-9774-x [doi] AB - BACKGROUND: Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. METHODS: All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. RESULTS: The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade >/=3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. CONCLUSIONS: There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing. FAU - Lin, Shi-Ming AU - Lin SM AD - Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou and Taipei Chang Gung Memorial Hospital Chang Gung University, No. 5 Fuhsing Street, Kuei Shan Hsiang, Taoyuan, Taiwan. lsmpaicyto@gmail.com. FAU - Lu, Sheng-Nan AU - Lu SN AD - Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, 100 Tapei Road, Niaosung, Kaohsiung, 833, Taiwan. FAU - Chen, Ping-Tsung AU - Chen PT AD - The Division of Hematology & Oncology, Chiayi Chang Gung Memorial Hospital, 6 W Sec, Chia Pu Road, Pu-Tz City, 613, Chiayi, Taiwan. FAU - Jeng, Long-Bin AU - Jeng LB AD - Organ Transplantation Center, China Medical University Hospital, North District, Taichung City, 404, Taiwan. FAU - Chen, Shinn-Cherng AU - Chen SC AD - Division of Hepato-Biliary-Pancreatic Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan. FAU - Hu, Chi-Tan AU - Hu CT AD - Division of Hepato-Gastroenterology, Buddhist Tzu Chi General Hospital, Tzu Chi University, No. 707, Sec. 3 Chung Yang Road, Hualian City, 970, Hualien County, Taiwan. FAU - Yang, Sien-Sing AU - Yang SS AD - Liver Center, Cathay General Hospital, Taipei and Medical Faculty, Fu-Jen Catholic University, No. 280, Sec. 4 Jen-Ai Road, Taipei, 10630, Taiwan. FAU - Le Berre, Marie-Aude AU - Le Berre MA AD - Clinical Statistics, Bayer HealthCare Pharmaceuticals, Medical Affairs, Building C2 1.11, 220 Ave de la Recherche, Loos, 59120, France. FAU - Liu, Xuan AU - Liu X AD - Global Clinical Development, Bayer HealthCare Co. Ltd., 18F Tower B, Bayer Center, No. 27, Dong San Huan North Road, Chaoyang District, Beijing, China. FAU - Mitchell, David Y AU - Mitchell DY AD - Mitchell Pharmaceutical Consulting, 1188 Hawk Ridge Road, Lafayette, CO, 80026, USA. FAU - Prins, Klaas AU - Prins K AD - qPharmetra, LLC, Kwakkenbergweg 39, 6523, MK, Nijmegen, The Netherlands. FAU - Grevel, Joachim AU - Grevel J AD - BAST Inc Limited, 7 Wellingtonia Close, Shepshed, LE12 9FB, UK. FAU - Pena, Carol A E AU - Pena CA AD - Clinical Sciences, Bayer Healthcare Pharmaceuticals, 100 Bayer Road, Whippany, NJ, USA. FAU - Meinhardt, Gerold AU - Meinhardt G AD - Global Clinical Development Oncology, Bayer Healthcare Pharmaceuticals, 100 Bayer Road, Whippany, NJ, USA. LA - eng PT - Clinical Trial, Phase IV PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20161201 PL - United States TA - Hepatol Int JT - Hepatology international JID - 101304009 RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antineoplastic Agents) RN - 0 (Ointments) RN - 0 (Phenylurea Compounds) RN - 25X51I8RD4 (Niacinamide) RN - 9ZOQ3TZI87 (Sorafenib) SB - IM MH - Administration, Topical MH - Adrenal Cortex Hormones/administration & dosage/therapeutic use MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/adverse effects/*therapeutic use MH - Carcinoma, Hepatocellular/*drug therapy MH - Disease-Free Survival MH - Female MH - Hand-Foot Syndrome/drug therapy/etiology MH - Humans MH - Liver Neoplasms/*drug therapy MH - Male MH - Middle Aged MH - Niacinamide/adverse effects/*analogs & derivatives/therapeutic use MH - Ointments MH - Phenylurea Compounds/adverse effects/*therapeutic use MH - Sorafenib MH - Taiwan PMC - PMC5362674 OTO - NOTNLM OT - Advanced hepatocellular carcinoma OT - Metastatic hepatocellular carcinoma OT - Overall survival OT - Sorafenib OT - Taiwanese patients OT - Time to progression COIS- CONFLICT OF INTEREST: Shi-Ming Lin, Sheng-Nan Lu, Ping-Tsung Chen, Long-Bin Jeng, Shinn-Cherng Chen, Chi-Tan Hu, Sien-Sing Yang, and Klaas Prins declare that they have no conflicts of interest. Marie-Aude Le Berre, Xuan Liu, Carol Pena, and Gerold Meinhardt are employees of Bayer HealthCare Pharmaceuticals. David Y. Mitchell is a paid consultant for Bayer Healthcare Pharmaceuticals. Joachim Grevel is an employee of BAST Inc Limited and paid consultant for Bayer Healthcare Pharmaceuticals. ETHICAL APPROVAL: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. The trial protocol was approved by the institutional review boards of all seven institutions. The trial has been registered at clinicaltrials.gov as NCT01098760. INFORMED CONSENT: Informed consent was obtained from all patients for being included in the study. EDAT- 2016/12/03 06:00 MHDA- 2017/07/28 06:00 PMCR- 2016/12/01 CRDT- 2016/12/03 06:00 PHST- 2016/03/14 00:00 [received] PHST- 2016/11/09 00:00 [accepted] PHST- 2016/12/03 06:00 [pubmed] PHST- 2017/07/28 06:00 [medline] PHST- 2016/12/03 06:00 [entrez] PHST- 2016/12/01 00:00 [pmc-release] AID - 10.1007/s12072-016-9774-x [pii] AID - 9774 [pii] AID - 10.1007/s12072-016-9774-x [doi] PST - ppublish SO - Hepatol Int. 2017 Mar;11(2):199-208. doi: 10.1007/s12072-016-9774-x. Epub 2016 Dec 1.