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. Yee; Audrey 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

doi:10.1016/S2468-1253(19)30040-8

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

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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 language	English (US)
Pages (from-to)	454-465
Number of pages	12
Journal	The Lancet Gastroenterology and Hepatology
Volume	4
Issue number	6
DOIs	https://doi.org/10.1016/S2468-1253(19)30040-8
State	Published - Jun 2019

All Science Journal Classification (ASJC) codes

Hepatology
Gastroenterology

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10.1016/S2468-1253(19)30040-8

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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

@article{6f5364b88e764b27b6dc703f9e6c46d6,

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

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.",

author = "Philippe Merle and Blanc, {Jean Frederic} and Phelip, {Jean Marc} and Gilles Pelletier and Bronowicki, {Jean Pierre} and Yann Touchefeu and Georges Pageaux and Ren{\'e} Gerolami and Fran{\c c}ois Habersetzer and Eric Nguyen-Khac and Andrea Casadei-Gardini and Ivan Borbath and Albert Tran and Henning Wege and Saad, {Amr Shafik} and Massimo Colombo and Armand Abergel and Carine Richou and Imam Waked and Yee, {Nelson S.} and Audrey Mol{\'e} and Pierre Attali and {Le Boulicaut}, Julie and B{\'e}rang{\`e}re Vasseur and Driffa Moussata and Grang{\'e}, {Jean Didier} and Vlad Ratziu and Faiza Khemissa-Akouz and H{\'e}l{\`e}ne Regnault and Barbara Dauvois and Zarski, {Jean Pierre} and Isabelle Ollivier-Hourmand and Sylvain Manfredi and Marilyne Debette-Gratien and Alice Gangloff and Thierry Fontanges and Aurore Baron and Mohamed Bouattour and Julie Vincent and Wolfgang Sieghart and Andreas Maieron and Marc Peeters and Jean Delwaide and Luc Lasser and Thomas Berg and Michael Schulthei{\ss} and Alexander Zipprich and Joerg Trojan and Ursula Ehmer and Gabriele Luppi and Giovanni Luca and Stefano Tamberi and Domenico Amoroso and Oscar Alabiso and Angela Buonadonna and Pierluigi Toniutto and Emiliano Tamburini and Antonio Cubillo and Andr{\'e}s Mu{\~n}oz and Carmen Guill{\'e}n and Gloria S{\'a}nchez and Hermini Manzano and Victor Navarro and Inmaculada Ales and Bartomeu Massuti and Magdolna Dank and Gy{\"o}rgy Bodoky and Zsuzsanna Kahan and Zsolt Horv{\'a}th and Nashat Gabrail and Howard Ozer and Christos Galanopoulos and Ralph Hauke and Moses Raj and Hakan Harputluoglu and Alper Sevinc and Erdem Goker and Ahmet Coker and Suayib Yalcin and Muhammet Ali and Ozlem Ata and Ilkay Tugba and Mohammed ElKassas and Amr Abdel and Imam Wakid and Sameh Shamaa and Nasr El and Hanaa Kohail and Jawad Makarem and Issam Chehade and Fadi Farhat and Carlos L{\'o}pez and Miguel Mar{\'i}n",

note = "Funding Information: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, Bristol-Myers Squibb (BMS), and Merck Sharp & Dohme (MSD). J-FB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. J-PB 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. NSY reports grants from Penn State Cancer Institute, Halozyme, Boston Biomedical, Caris Life Sciences, Foundation Medicine, Pharmacyclics, EMD Serono, Onxeo, Regeneron, Momenta, Merck, Daiichi Sankyo, Eli Lilly, Novartis, Taiho, Bayer, Celgene, Lexicon, Incyte, Pfizer, and BMS. PA is an Onxeo shareholder and an author of a patent for nanoparticles loaded with chemotherapeutic antitumoral drug (US Patent and Trademark Office 9763874). All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = jun,

doi = "10.1016/S2468-1253(19)30040-8",

language = "English (US)",

volume = "4",

pages = "454--465",

journal = "The Lancet Gastroenterology and Hepatology",

issn = "2468-1253",

publisher = "Elsevier Limited",

number = "6",

}

Merle, P, Blanc, JF, Phelip, JM, Pelletier, G, Bronowicki, JP, Touchefeu, Y, Pageaux, G, Gerolami, R, Habersetzer, F, Nguyen-Khac, E, Casadei-Gardini, A, Borbath, I, Tran, A, Wege, H, Saad, AS, Colombo, M, Abergel, A, Richou, C, Waked, I, Yee, NS, Molé, A, Attali, P, Le Boulicaut, J, Vasseur, B, Moussata, D, Grangé, JD, Ratziu, V, Khemissa-Akouz, F, Regnault, H, Dauvois, B, Zarski, JP, Ollivier-Hourmand, I, Manfredi, S, Debette-Gratien, M, Gangloff, A, Fontanges, T, Baron, A, Bouattour, M, Vincent, J, Sieghart, W, Maieron, A, Peeters, M, Delwaide, J, Lasser, L, Berg, T, Schultheiß, M, Zipprich, A, Trojan, J, Ehmer, U, Luppi, G, Luca, G, Tamberi, S, Amoroso, D, Alabiso, O, Buonadonna, A, Toniutto, P, Tamburini, E, Cubillo, A, Muñoz, A, Guillén, C, Sánchez, G, Manzano, H, Navarro, V, Ales, I, Massuti, B, Dank, M, Bodoky, G, Kahan, Z, Horváth, Z, Gabrail, N, Ozer, H, Galanopoulos, C, Hauke, R, Raj, M, Harputluoglu, H, Sevinc, A, Goker, E, Coker, A, Yalcin, S, Ali, M, Ata, O, Tugba, I, ElKassas, M, Abdel, A, Wakid, I, Shamaa, S, El, N, Kohail, H, Makarem, J, Chehade, I, Farhat, F, López, C & 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, vol. 4, no. 6, pp. 454-465. https://doi.org/10.1016/S2468-1253(19)30040-8

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE) : a phase 3 randomised controlled trial. / Merle, Philippe; Blanc, Jean Frederic; Phelip, Jean Marc et al.

In: The Lancet Gastroenterology and Hepatology, Vol. 4, No. 6, 06.2019, p. 454-465.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE)

T2 - a phase 3 randomised controlled trial

AU - Merle, Philippe

AU - Blanc, Jean Frederic

AU - Phelip, Jean Marc

AU - Pelletier, Gilles

AU - Bronowicki, Jean Pierre

AU - Touchefeu, Yann

AU - Pageaux, Georges

AU - Gerolami, René

AU - Habersetzer, François

AU - Nguyen-Khac, Eric

AU - Casadei-Gardini, Andrea

AU - Borbath, Ivan

AU - Tran, Albert

AU - Wege, Henning

AU - Saad, Amr Shafik

AU - Colombo, Massimo

AU - Abergel, Armand

AU - Richou, Carine

AU - Waked, Imam

AU - Yee, Nelson S.

AU - Molé, Audrey

AU - Attali, Pierre

AU - Le Boulicaut, Julie

AU - Vasseur, Bérangère

AU - Moussata, Driffa

AU - Grangé, Jean Didier

AU - Ratziu, Vlad

AU - Khemissa-Akouz, Faiza

AU - Regnault, Hélène

AU - Dauvois, Barbara

AU - Zarski, Jean Pierre

AU - Ollivier-Hourmand, Isabelle

AU - Manfredi, Sylvain

AU - Debette-Gratien, Marilyne

AU - Gangloff, Alice

AU - Fontanges, Thierry

AU - Baron, Aurore

AU - Bouattour, Mohamed

AU - Vincent, Julie

AU - Sieghart, Wolfgang

AU - Maieron, Andreas

AU - Peeters, Marc

AU - Delwaide, Jean

AU - Lasser, Luc

AU - Berg, Thomas

AU - Schultheiß, Michael

AU - Zipprich, Alexander

AU - Trojan, Joerg

AU - Ehmer, Ursula

AU - Luppi, Gabriele

AU - Luca, Giovanni

AU - Tamberi, Stefano

AU - Amoroso, Domenico

AU - Alabiso, Oscar

AU - Buonadonna, Angela

AU - Toniutto, Pierluigi

AU - Tamburini, Emiliano

AU - Cubillo, Antonio

AU - Muñoz, Andrés

AU - Guillén, Carmen

AU - Sánchez, Gloria

AU - Manzano, Hermini

AU - Navarro, Victor

AU - Ales, Inmaculada

AU - Massuti, Bartomeu

AU - Dank, Magdolna

AU - Bodoky, György

AU - Kahan, Zsuzsanna

AU - Horváth, Zsolt

AU - Gabrail, Nashat

AU - Ozer, Howard

AU - Galanopoulos, Christos

AU - Hauke, Ralph

AU - Raj, Moses

AU - Harputluoglu, Hakan

AU - Sevinc, Alper

AU - Goker, Erdem

AU - Coker, Ahmet

AU - Yalcin, Suayib

AU - Ali, Muhammet

AU - Ata, Ozlem

AU - Tugba, Ilkay

AU - ElKassas, Mohammed

AU - Abdel, Amr

AU - Wakid, Imam

AU - Shamaa, Sameh

AU - El, Nasr

AU - Kohail, Hanaa

AU - Makarem, Jawad

AU - Chehade, Issam

AU - Farhat, Fadi

AU - López, Carlos

AU - Marín, Miguel

N1 - Funding Information: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, Bristol-Myers Squibb (BMS), and Merck Sharp & Dohme (MSD). J-FB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. J-PB 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. NSY reports grants from Penn State Cancer Institute, Halozyme, Boston Biomedical, Caris Life Sciences, Foundation Medicine, Pharmacyclics, EMD Serono, Onxeo, Regeneron, Momenta, Merck, Daiichi Sankyo, Eli Lilly, Novartis, Taiho, Bayer, Celgene, Lexicon, Incyte, Pfizer, and BMS. PA is an Onxeo shareholder and an author of a patent for nanoparticles loaded with chemotherapeutic antitumoral drug (US Patent and Trademark Office 9763874). All other authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065066341&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065066341&partnerID=8YFLogxK

U2 - 10.1016/S2468-1253(19)30040-8

DO - 10.1016/S2468-1253(19)30040-8

M3 - Article

C2 - 30954567

AN - SCOPUS:85065066341

SN - 2468-1253

VL - 4

SP - 454

EP - 465

JO - The Lancet Gastroenterology and Hepatology

JF - The Lancet Gastroenterology and Hepatology

IS - 6

ER -

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

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