Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial

Philippe Merle, Jean Frederic Blanc, Jean Marc Phelip, Gilles Pelletier, Jean Pierre Bronowicki, Yann Touchefeu, Georges Pageaux, René Gerolami, François Habersetzer, Eric Nguyen-Khac, Andrea Casadei-Gardini, Ivan Borbath, Albert Tran, Henning Wege, Amr Shafik Saad, Massimo Colombo, Armand Abergel, Carine Richou, Imam Waked, Nelson S. YeeAudrey Molé, Pierre Attali, Julie Le Boulicaut, Bérangère Vasseur, Driffa Moussata, Jean Didier Grangé, Vlad Ratziu, Faiza Khemissa-Akouz, Hélène Regnault, Barbara Dauvois, Jean Pierre Zarski, Isabelle Ollivier-Hourmand, Sylvain Manfredi, Marilyne Debette-Gratien, Alice Gangloff, Thierry Fontanges, Aurore Baron, Mohamed Bouattour, Julie Vincent, Wolfgang Sieghart, Andreas Maieron, Marc Peeters, Jean Delwaide, Luc Lasser, Thomas Berg, Michael Schultheiß, Alexander Zipprich, Joerg Trojan, Ursula Ehmer, Gabriele Luppi, Giovanni Luca, Stefano Tamberi, Domenico Amoroso, Oscar Alabiso, Angela Buonadonna, Pierluigi Toniutto, Emiliano Tamburini, Antonio Cubillo, Andrés Muñoz, Carmen Guillén, Gloria Sánchez, Hermini Manzano, Victor Navarro, Inmaculada Ales, Bartomeu Massuti, Magdolna Dank, György Bodoky, Zsuzsanna Kahan, Zsolt Horváth, Nashat Gabrail, Howard Ozer, Christos Galanopoulos, Ralph Hauke, Moses Raj, Hakan Harputluoglu, Alper Sevinc, Erdem Goker, Ahmet Coker, Suayib Yalcin, Muhammet Ali, Ozlem Ata, Ilkay Tugba, Mohammed ElKassas, Amr Abdel, Imam Wakid, Sameh Shamaa, Nasr El, Hanaa Kohail, Jawad Makarem, Issam Chehade, Fadi Farhat, Carlos López, Miguel Marín

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Abstract

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. Methods: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. Findings: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2–34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1–10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1–11·8) in the control group (HR 1·00 [95% CI 0·78–1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. Interpretation: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. Funding: Onxeo.

Original languageEnglish (US)
Pages (from-to)454-465
Number of pages12
JournalThe Lancet Gastroenterology and Hepatology
Volume4
Issue number6
DOIs
StatePublished - Jun 2019

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All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Merle, P., Blanc, J. F., Phelip, J. M., Pelletier, G., Bronowicki, J. P., Touchefeu, Y., Pageaux, G., Gerolami, R., Habersetzer, F., Nguyen-Khac, E., Casadei-Gardini, A., Borbath, I., Tran, A., Wege, H., Saad, A. S., Colombo, M., Abergel, A., Richou, C., Waked, I., ... Marín, M. (2019). Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. The Lancet Gastroenterology and Hepatology, 4(6), 454-465. https://doi.org/10.1016/S2468-1253(19)30040-8