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

NCT ID: NCT01655693

Last Updated: 2021-06-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 397 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2019-05-31

Brief Summary

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.

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.

Conditions

Carcinoma, Hepatocellular

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Doxorubicin 20 mg/m2

Intervention Type: DRUG

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

Group Type: EXPERIMENTAL

Doxorubicin 30 mg/m2

Intervention Type: DRUG

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

Group Type: ACTIVE_COMPARATOR

Best Standard of Care

Intervention Type: DRUG

Interventions

Doxorubicin 20 mg/m2

Intervention Type: DRUG

Doxorubicin 30 mg/m2

Intervention Type: DRUG

Best Standard of Care

Intervention Type: DRUG

Other Intervention Names

Doxorubicin Transdrug (DT) at 20 mg/m2; Doxorubicin Transdrug (DT) at 30 mg/m2; BSC

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Valerio Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe Merle, MD

Role: PRINCIPAL_INVESTIGATOR

Croix-Rousse Hospital - Lyon-France

Locations

Gabrail Cancer Center

Canton, Ohio, United States

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, United States

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States

Krankenhaus der Elisabethinen Linz GmbH

Linz, , Austria

Medical University Vienna

Vienna, , Austria

CHU Brugmann

Brussels, , Belgium

UCL Saint-Luc

Brussels, , Belgium

CHU Sart Tilman

Liège, , Belgium

CHU UCL Mont-Godinne Dinant

Yvoir, , Belgium

Medical Oncology department /Mansoura University Hospitals

Al Mansurah, , Egypt

Clinical Research Center/ Alexandria university hospital

Alexandria, , Egypt

Oncology Department, Medical Research Institute, Alexandria University

Alexandria, , Egypt

Medical Oncology department /Ain Shams University Hospitals

Cairo, , Egypt

National hepatology and tropical medicine research institute

Cairo, , Egypt

National Liver Institute / Menoufyia University

Menofia, , Egypt

Hospital Amiens

Amiens, , France

Hospital Jean Minjoz

Besançon, , France

Hospital Saint André

Bordeaux, , France

Centre hospitalier P Oudot

Bourgoin, , France

Hospital Estaing

Clermont-Ferrand, , France

Centre Hospitalier Beaujon

Clichy, , France

Hospital Henri-Mondor

Créteil, , France

Centre Jean-François Leclerc

Dijon, , France

CHU

Dijon, , France

Hospital Grenoble

La Tronche, , France

CHU Dupuytren

Limoges, , France

Hospital Croix Rousse

Lyon, , France

Hospital La Timone

Marseille, , France

Hospital Saint Eloi

Montpellier, , France

Hospital Brabois

Nancy, , France

Hospital Hotel Dieu

Nantes, , France

CHU - Hôpital Archet

Nice, , France

Hospital La Source

Orléans, , France

Hospital Pitié-Salpetriere

Paris, , France

Hospital Tenon

Paris, , France

Hospital Saint Jean

Perpignan, , France

CHU de Rouen- Hôpital Charles Nicolle

Rouen, , France

IC LOIRE

Saint-Etienne, , France

Hospital Civil

Strasbourg, , France

Hospital Paul Brousse

Villejuif, , France

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Universitätsklinikum Halle (Saale)

Halle, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Universität Leipzig AöR

Leipzig, , Germany

Klinikum rechts der Isar der TU Munchen II

München, , Germany

Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika

Budapest, , Hungary

Egyesített Szent István és Szent László Kórház - Rendelőintézet

Budapest, , Hungary

Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet

Debrecen, , Hungary

Szegedi Tudományegyetem Onkoterápiás Klinika

Szeged, , Hungary

Irccs Centro Di Riferimento Oncologico (Cro)

Aviano, , Italy

Ospedale Civile e degli Infermi

Faenza, , Italy

Ausl 12 Livorno Ospedale Unico della Versilia

Lido di Camaiore, , Italy

IRST Istituto Romagnolo Ricerca e Cura dei Tumori

Meldola, , Italy

Granda Osp. Magg. Policlinico

Milan, , Italy

Azienda Ospedaliera Policlinico di Modena

Modena, , Italy

A.O. Ospedale Maggiore della Carità

Novara, , Italy

Rimini, , Italy

Ain Wazein Hospital

El Chouf, , Lebanon

Hospital General Universitario de Alicante

Alicante, , Spain

Hospital Universitario Virgen de la Arrixaca

El Palmar Murcia, , Spain

Complejo Hospitalario de Jaen

Jaén, , Spain

Hospital General Universario Gregorio Maranon

Madrid, , Spain

Hospital Universitario Ramón y Cajal

Madrid, , Spain

Hospital Universitario Madrid Sanchinarro

Madrid, , Spain

Hospital Carlos Haya

Málaga, , Spain

Hospital Universario Son Espaces

Palma de Mallorca, , Spain

Hospital Universitario Marques de Valdecilla

Santander, , Spain

Hospital Universitario Río Hortega

Valladolid, , Spain

Hacettepe University Medical Faculty

Ankara, , Turkey (Türkiye)

Ege Univeristy Medical Faculty,

Izmir, , Turkey (Türkiye)

Countries

United States; Austria; Belgium; Egypt; France; Germany; Hungary; Italy; Lebanon; Spain; Turkey (Türkiye)

References

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.

Reference Type: DERIVED

PMID: 30954567 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2011-002843-92

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BA2011/03/04

Identifier Type: -

Identifier Source: org_study_id