Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study
Journal
The Lancet Gastroenterology and Hepatology
Journal Volume
3
Journal Issue
1
Pages
37-46
Date Issued
2018
Author(s)
Kudo M.
Park J.-W.
Park J.H.
Hidaka H.
Izumi N.
Heo J.
Lee Y.J.
Sheen I.-S.
Chiu C.-F.
Arioka H.
Morita S.
Arai Y.
Abstract
Background Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. Methods This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ?400 ng/mL), and size of the largest lesion (?50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. Findings Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3–26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5–34·5] vs 32·3 months [28·4–not reached]; hazard ratio 1·090, 95% CI 0·878–1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. Interpretation Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. Funding Taiho Pharmaceutical. ? 2018 Elsevier Ltd
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; bilirubin; hemoglobin; orantinib; placebo; platelet derived growth factor BB; vasculotropin C; antineoplastic agent; indole derivative; orantinib; protein kinase inhibitor; pyrrole derivative; abdominal pain; adult; aged; Article; ascites; backache; cancer staging; chemoembolization; Child Pugh score; clinical outcome; constipation; controlled study; creatinine blood level; decreased appetite; diarrhea; double blind procedure; drug dose reduction; drug withdrawal; enzyme linked immunosorbent assay; face edema; fatigue; female; fever; gastrointestinal disease; hepatobiliary disease; human; hypertension; hypoalbuminemia; incidence; infection; leukocyte count; liver cell carcinoma; major clinical study; malaise; male; multicenter study; nausea; overall survival; patient compliance; peripheral edema; phase 3 clinical trial; priority journal; randomized controlled trial; vomiting; clinical trial; early termination of clinical trial; liver cell carcinoma; liver tumor; middle aged; multimodality cancer therapy; procedures; survival analysis; treatment outcome; very elderly; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrroles; Survival Analysis; Treatment Outcome
Type
journal article