Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma (ReLive)

Multicentre, Randomised, Controlled, Open-label Study Comparing the Efficacy and Safety of Doxorubicin Transdrug™ to Best Standard of Care in Patients With Advanced Hepatocellular Carcinoma. ReLive Study.

The purpose of this phase III study is to determine whether Doxorubicin Transdrug (DT) is effective in the treatment of patients suffering from advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to Sorafenib. Patients with HCC with or without cirrhosis and with good liver functions are eligible. Only those who can not benefit from treatment for which efficacy is demonstrated are eligible.

These patients are usually proposed either best standard of care (BSC) or participation to clinical trials. Patients eligible for the RELIVE study will receive either DT at 20 mg/m2 or DT at 30 mg/m2 or the BSC.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: Doxorubicin 20 mg/m2; Drug: Doxorubicin 30 mg/m2; Drug: Best Standard of Care

Detailed Description

Doxorubicin-Transdrug™ (DT) is a nanoparticle formulation of doxorubicin.In in vitro and in vivo models, DT was shown to overcome the multidrug resistance (MDR) and to be more effective than doxorubicin on both sensitive and resistant tumour models and in particular in the X/myc bi-transgenic MDR murine model of HCC.

• Study Type: Interventional
• Enrollment (Actual): 397
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz GmbH
  • Vienna, Austria, 1090
    • Medical University Vienna
• Belgium
  • Brussels, Belgium, 1020
    • CHU Brugmann
  • Brussels, Belgium, 1200
    • UCL Saint-Luc
  • Liège, Belgium, 4000
    • Chu Sart Tilman
  • Yvoir, Belgium
    • CHU UCL Mont-Godinne Dinant
• Egypt
  • Alexandria, Egypt
    • Clinical Research Center/ Alexandria university hospital
  • Alexandria, Egypt
    • Oncology Department, Medical Research Institute, Alexandria University
  • Cairo, Egypt
    • National Hepatology and Tropical Medicine Research Institute
  • Cairo, Egypt
    • Medical Oncology department /Ain Shams University Hospitals
  • Mansoura, Egypt, 35516
    • Medical Oncology department /Mansoura University Hospitals
  • Menofia, Egypt, 32700
    • National Liver Institute / Menoufyia University
• France
  • Amiens, France, 80054
    • Hospital Amiens
  • Besançon, France, 25000
    • Hospital Jean Minjoz
  • Bordeaux, France, 33075
    • Hospital Saint Andre
  • Bourgoin-Jallieu, France, 38302
    • Centre hospitalier P Oudot
  • Clermont-Ferrand, France, 63003
    • Hospital Estaing
  • Clichy, France, 92110
    • Centre Hospitalier Beaujon
  • Creteil, France, 94010
    • Hospital Henri-Mondor
  • Dijon, France
    • CHU
  • Dijon, France, 21079
    • Centre Jean-François Leclerc
  • La Tronche, France, 38700
    • Hospital Grenoble
  • Limoges, France, 87042
    • CHU Dupuytren
  • Lyon, France, 69317
    • Hospital Croix Rousse
  • Marseille, France, 13005
    • Hospital La Timone
  • Montpellier, France, 34295
    • Hospital Saint Eloi
  • Nancy, France, 54511
    • Hospital Brabois
  • Nantes, France, 44093
    • Hospital Hôtel Dieu
  • Nice, France
    • CHU - Hôpital Archet
  • Orleans, France, 45067
    • Hospital La SOURCE
  • Paris, France, 75020
    • Hospital Tenon
  • Paris, France, 75013
    • Hospital Pitié-Salpêtrière
  • Perpignan, France, 66046
    • Hospital Saint Jean
  • Rouen, France, 76031
    • CHU de Rouen- Hôpital Charles Nicolle
  • Saint-Etienne, France
    • IC LOIRE
  • Strasbourg, France, 67091
    • Hospital Civil
  • Villejuif, France, 94804
    • Hospital Paul Brousse
• Germany
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg
  • Halle An Der Saale, Germany, 06120
    • Universitätsklinikum Halle (Saale)
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Leipzig, Germany, 04103
    • Universität Leipzig AöR
  • Munchen, Germany, 81675
    • Klinikum rechts der Isar der TU Munchen II
• Hungary
  • Budapest, Hungary, 1082
    • Semmelweis Egyetem Radiologiai és Onkoterapias Klinika
  • Budapest, Hungary, 1097
    • Egyesitett Szent Istvan es Szent Laszlo Korhaz - Rendelointezet
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet
  • Szeged, Hungary, 6720
    • Szegedi Tudomanyegyetem Onkoterapias Klinika
• Italy
  • Aviano, Italy, 33081
    • Irccs Centro Di Riferimento Oncologico (CRO)
  • Faenza, Italy, 48018
    • Ospedale Civile e degli Infermi
  • Lido di Camaiore, Italy, 55041
    • Ausl 12 Livorno Ospedale Unico della Versilia
  • Meldola, Italy, 47014
    • IRST Istituto Romagnolo Ricerca e Cura dei Tumori
  • Milano, Italy, 20122
    • Granda Osp. Magg. Policlinico
  • Modena, Italy, 41124
    • Azienda Ospedaliera Policlinico di Modena
  • Novara, Italy, 28100
    • A.O. Ospedale Maggiore della carità
  • Rimini, Italy, 47900
• Lebanon
  • El Chouf, Lebanon
    • Ain Wazein Hospital
• Spain
  • Alicante, Spain, 03010
    • Hospital General Universitario de Alicante
  • El Palmar Murcia, Spain, 30120
    • Hospital Universitario Virgen de la Arrixaca
  • Jaen, Spain, 23006
    • Complejo Hospitalario de Jaen
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28050
    • Hospital Universitario Madrid Sanchinarro
  • Madrid, Spain, 28007
    • Hospital General Universario Gregorio Maranon
  • Malaga, Spain, 29010
    • Hospital Carlos Haya
  • Palma De Mallorca, Spain, 07010
    • Hospital Universario Son Espaces
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Valladolid, Spain, 47012
    • Hospital Universitario Rio Hortega
• Turkey
  • Ankara, Turkey
    • Hacettepe University Medical Faculty
  • İzmir, Turkey
    • Ege Univeristy Medical Faculty,
• United States
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Cancer Institute
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or non-pregnant, non-breast feeding female;
• Aged ≥ 18 years;

• Patient with:

  • advanced HCC (BCLC-C according to BCLC staging classification) having progressed under Sorafenib therapy or intolerant to Sorafenib, or;
  • intermediate HCC (BCLC-B) non eligible or non responders to transarterial chemoembolization (TACE), and having progressed under or intolerant to Sorafenib therapy
• Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without extension in inferior/superior vena cava, are eligible;

• HCC diagnosed according to the American Association for Study of Liver Diseases (AASLD) and/or European Association for the Study of the Liver (EASL) criteria:

  • Radiological Criteria applicable in cirrhotic liver:
• Nodule ≥ 10 mm: one imaging technique among MRI and CT-scan showing typical appearances for HCC defined as arterial enhancement and rapid washout in portal venous or delayed phase;

• If appearance not typical for HCC on initial imaging: second contrast enhanced study (CT or MRI) showing typical appearances for HCC defined as arterial enhancement and rapid wash-out in portal venous or delayed phase;

  • And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, absence of cirrhosis);
• Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;

• Laboratory tests as follows:

  • Platelets ≥ 50,000 /mm3
  • Neutrophil count ≥ 1000/mm3
  • Hemoglobin ≥ 10g/dL
  • Serum transaminases < 5 upper limit normal (ULN) (NCI/common toxicity criteria (CTC) grades 0, 1, or 2)
  • Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2)
  • Serum bilirubin < 35 micromolar (µM)/L (or 2.0 mg/dL);
• Signed and dated written informed consent form.

Exclusion Criteria:

• Cirrhosis with a Child-Pugh score B8-C15;
• Untreated chronic hepatitis B;
• Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment);
• Patients eligible for palliative treatments with demonstrated efficacy: TACE, Sorafenib; Patients who failed to Sorafenib treatment or intolerant to sorafenib are eligible and can be included if Sorafenib has been stopped at least 2 weeks before randomization;
• Prior history of malignancy with the exception of adequately treated basal cell carcinoma or in situ cervical cancer in complete remission since five years at least;
• HCC developed on transplanted liver;
• HIV infection;
• Risk of variceal bleeding;
• Oxygen saturation (SaO2) < 95%;
• Presence of a significant acute or chronic respiratory disease defined as NCI/CTCAE > grade 2;
• Presence of recent (< 6 months) or current cardiac failure (class III or IV New York Heart Association (NYHA) classification), recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke, myocardial infarction (MI)…);
• Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent;
• Patients currently treated with immunosuppressive agents that cannot be stopped;
• Patients whose medical or surgical conditions are unstable and may not allow the study completion or compliance, and specially patients with uncontrolled diabetes;
• Uncontrolled systemic infection;
• Patients with a life expectancy of less than 2 months;
• Patients who have received an experimental drug in another clinical trial in the last 30 days prior to randomization in the present clinical trial;
• Women of child-bearing age who are unwilling or unable to use an effective contraception method during the study treatment period and for 6 months after the last administration of study drug, and their male partner(s) refusing to use a condom (if applicable);
• Men who are unwilling or unable to use a condom during the study treatment period and for 6 months after the last administration of study drug, and their female partner(s) refusing to use one of the appropriate effective contraception methods (if applicable);
• Patients unwilling or unable to comply with protocol requirements and scheduled visits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxorubicin Transdrug (DT) at 20 mg/m2; DT will be infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity	Drug: Doxorubicin 20 mg/m2; Other Names: Doxorubicin Transdrug (DT) at 20 mg/m2
Experimental: Doxorubicin Transdrug (DT) at 30 mg/m2; DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity	Drug: Doxorubicin 30 mg/m2; Other Names: Doxorubicin Transdrug (DT) at 30 mg/m2
Active Comparator: Best Standard of Care; Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity	Drug: Best Standard of Care; Other Names: BSC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from date of randomization to the date of death from any cause.	Time from date of randomization to the date of death from any cause with initial assessment up to 24 months and follow-up assessment up to 45 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS is defined as time from the date of randomisation to the date of the first documented progression or death from any cause. PFS determined by independent radiological review according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 is determine by at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.	Time from date of randomization to date of first documented progression or death from any cause, which ever came first, assessed up to 20 months.
Objective Response Rate (ORR)	ORR is defined as percent of patients whose best overall response is complete response (CR) or partial response (PR) during the study treatment period and based on the evaluation of independent radiological review according to RECIST 1.1 for target lesions and assessed by MRI: CR is disappearance of all targets extra nodal lesions and the regression of all nodal lesions to < 10 mm; PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. PD is at least a 20% increase in the sum of diameters of target lesions, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.	Time from date of first treatment cycle to date of last cycle of treatment for the full duration of study treatment up to 24 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death	The number of participants experiencing TEAEs considered related to treatment and categorized by severity of all related TEAEs according to National Cancer Institute/Common Toxicity Criteria (NCI-CTCAE) v4.0 and resulting in patient withdrawal from study or death.	Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study.
Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug	The number of participants with cardiovascular and respiratory adverse events (AEs) were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The AE numbers reported are those considered related to treatment. Related AEs are those that are judged unlikely, possibly, probably or definitely related to the study or study drug by the investigator.	Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study.
Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion	Number of participants experiencing an SaO2 reduction defined as a decrease =< 90% during or after DT infusion until resolution to =>93%. Participants had continuous monitoring of SaO2 saturation with pulse oximeter during 6 hour infusion and up to 24 hour after infusion start. SaO2 measures the amount of oxygen (in percent) bound to hemoglobin in red blood cells. SaO2 saturation was only monitored and reported in the DT infusion group. Reduction in SaO2 could result in modify DT dosing regimen. Decreases in SaO2 are a known and expected occurrence with DT infusions, and close monitoring of SaO2 was specified by the protocol to protect patients from potential respiratory distress during infusions.	Time from start of infusion to resolution of reduction in oxygen saturation.
Number of Participants With Clinically Significant Abnormal Change in Respiratory Function	Number of participants with any clinically significant abnormal change in respiratory function test over the study to include carbon monoxide diffusing capacity to measure lung function, forced expiratory volume in 1 second to measure ability to expel air from your lungs, total lung capacity to measure total amount of air in the lungs after taking the deepest breath possible, and vital capacity to measure the greatest volume of air that can be expelled from the lungs after taking the deepest breath possible. Clinically significant abnormal changes in respiratory function was determined by the investigator.	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline	Number of participants experiencing clinically significant abnormal ECG changes from baseline over the course of the study. ECG were completed every month before each infusion. ECG will detect changes in heart rhythm. Clinically significant abnormal changes in ECG were determined by the investigator.	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event	Number of participants that experienced a change from baseline in LVEF with severity of LVEF noted as follows: Normal: 100 - 50%, 0 - 9% drop from baseline resting ejection fraction (EF), Grade 2 = 50 - 40%, 10 - 19% drop from baseline resting EF; Grade 3 = 39 - 20%, >20% drop from baseline; Grade 4 = <20%. LVEF was monitored every other month. LVEF measures how much blood the left ventricle of the heart pumps out with each contraction and is used to assess the severity of left ventricle dysfunction in the heart. Clinical significance changes were determined by the investigator.	Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.

Collaborators and Investigators

• Sponsor: Onxeo
• Investigators: Principal Investigator: Philippe Merle, MD, Croix-Rousse Hospital - Lyon-France

Publications and helpful links

General Publications

• 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, Mole A, Attali P, Le Boulicaut J, Vasseur B; RELIVE Investigators. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jun;4(6):454-465. doi: 10.1016/S2468-1253(19)30040-8. Epub 2019 Apr 4. Erratum In: Lancet Gastroenterol Hepatol. 2019 Jul;4(7):e6. Lancet Gastroenterol Hepatol. 2020 Feb;5(2):e1.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2012
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: July 26, 2012
• First Submitted That Met QC Criteria: July 31, 2012
• First Posted (Estimate): August 2, 2012

Study Record Updates

• Last Update Posted (Actual): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Intermediate/advanced hepatocellular carcinoma; After failure or intolerance to Sorafenib.
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: BA2011/03/04; 2011-002843-92 (EudraCT Number)