Doxorubicin-Loaded Nanoparticles for Patients with Advanced Hepatocellular Carcinoma after Failure of Sorafenib: RELIVE, a Phase-3 Trial

Abstract

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma (HCC). We evaluated the intravenous perfusion of doxorubicin-loaded nanoparticles (DT) in HCC patients with prior failure of sorafenib therapy. Methods: We conducted a randomized, open label, 3 parallel groups, phase-3 trial at 70 sites in 11 countries. Patients with HCC with prior one or more systemic therapies including sorafenib were randomised 1:1:1 for DT-30 mg/m2 (DT-30), DT-20 mg/m2 (DT-20) or best standard of care (BSC); stratified by performance status, Child-Pugh score, DT dosage, macrovascular invasion, extrahepatic spread, alpha-fetoprotein level, number of prior systemic lines, reason of sorafenib discontinuation, and aetiology of HCC. The primary endpoint was overall survival. This trial is registered at ClinicalTrials.gov, number NCT01655693. Findings: Between June 2012 and January 2017, 541 patients were screened, 397 randomized (DT-30=133; DT-20=130; BSC=134; population for efficacy analysis), and 376 initiated treatments (DT-30=120; DT-20=122; BSC=134; population for safety analysis). After pooling the DT-30 and DT-20 arms in the analysis, pooled DT (pDT) did not improve overall survival with a hazard ratio of 1.00 (95% CI 0.78-1.28; p=0.99); median overall survival (95%CI) was 9.1 months (8.1-10.4) for pDT versus 9.0 months (7.1-11·8) for BSC. The hazard ratio for progression-free survival was 0.95 (95% CI 0.74-1.22; p=0.70) and for time to progression 0.96 (95%CI 0.74-1.23; p=0.74). Adverse events were reported in 94% (247/263) of pDT and 75% (100/134) of BSC. The most common grade 3 or 4 treatment-emergent adverse events included (pDT; BSC) neutropenia (8% [20/242]; 5% [6/134]), asthenia (3% [6/242]; 3% [4/134]), and thrombocytopenia (1% [3/242]; 7% [9/134]). Rates of drug-related death per investigators were 1% (3/242; pDT) and 1% (2/193; BSC). Interpretation: DT doesn't show benefit on survival in HCC patients with failure on prior sorafenib treatment, but it has a comforting safety profile. Trial Registration Number: ClinicalTrials.gov, number NCT01655693 Funding: ONXEO Conflict of Interest: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, BMS, and MSD. JFB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. JPB has received consultancy and advisory fees from Onxeo, and Bayer. GP has received consultancy and advisory fees from Bayer, AbbVie, Novartis, and Gilead. AA has received consultancy and advisory fees from AbbVie, MSD, and Gilead. IW has received consultancy and advisory fees from Janssen, AbbVie, MSD, Marcyrl, Pharco, and Gilead. NY has received consultancy and advisory fees from Halozyme, Boston Biomedical Inc., Pharmacyclics, EMD Serono, Merck, Onxeo, Regeneron, and Momenta. Ethical Approval: The trial was approved by each centre’s ethics committee or institutional review board and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws.