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

NCT01655693 | Completed Phase 3 Results DMC

• 2 other identifiers: BA2011/03/042011-002843-92
• Study Type: interventional
• Target: 397
• Locations: 11 countries
• Sites: 70

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.

Conditions

Carcinoma, Hepatocellular

Keywords

Intermediate/advanced hepatocellular carcinoma; After failure or intolerance to Sorafenib.

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Progression-free Survival (PFS)

  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)

  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 Outcomes (6)

• Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, 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

  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

  Time from start of infusion to resolution of reduction in oxygen saturation.

Study Arms (3)

Doxorubicin Transdrug (DT) at 20 mg/m2

EXPERIMENTAL

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

Doxorubicin Transdrug (DT) at 30 mg/m2

EXPERIMENTAL

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

Best Standard of Care

ACTIVE COMPARATOR

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

Interventions

Doxorubicin 20 mg/m2 DRUG

Also known as: Doxorubicin Transdrug (DT) at 20 mg/m2

Doxorubicin Transdrug (DT) at 20 mg/m2

Doxorubicin 30 mg/m2 DRUG

Also known as: Doxorubicin Transdrug (DT) at 30 mg/m2

Doxorubicin Transdrug (DT) at 30 mg/m2

Best Standard of Care DRUG

Also known as: BSC

Best Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• Valerio Therapeutics: lead

Study Sites (70)

Gabrail Cancer Center

Canton, Ohio, 44718, United States

Location

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, 17033, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Krankenhaus der Elisabethinen Linz GmbH

Linz, 4020, Austria

Location

Medical University Vienna

Vienna, 1090, Austria

Location

CHU Brugmann

Brussels, 1020, Belgium

Location

UCL Saint-Luc

Brussels, 1200, Belgium

Location

CHU Sart Tilman

Liège, 4000, Belgium

Location

CHU UCL Mont-Godinne Dinant

Yvoir, Belgium

Location

Medical Oncology department /Mansoura University Hospitals

Al Mansurah, 35516, Egypt

Location

Clinical Research Center/ Alexandria university hospital

Alexandria, Egypt

Location

Oncology Department, Medical Research Institute, Alexandria University

Alexandria, Egypt

Location

Medical Oncology department /Ain Shams University Hospitals

Cairo, Egypt

Location

National hepatology and tropical medicine research institute

Cairo, Egypt

Location

National Liver Institute / Menoufyia University

Menofia, 32700, Egypt

Location

Hospital Amiens

Amiens, 80054, France

Location

Hospital Jean Minjoz

Besançon, 25000, France

Location

Hospital Saint André

Bordeaux, 33075, France

Location

Centre hospitalier P Oudot

Bourgoin, 38302, France

Location

Hospital Estaing

Clermont-Ferrand, 63003, France

Location

Centre Hospitalier Beaujon

Clichy, 92110, France

Location

Hospital Henri-Mondor

Créteil, 94010, France

Location

Centre Jean-François Leclerc

Dijon, 21079, France

Location

CHU

Dijon, France

Location

Hospital Grenoble

La Tronche, 38700, France

Location

CHU Dupuytren

Limoges, 87042, France

Location

Hospital Croix Rousse

Lyon, 69317, France

Location

Hospital La Timone

Marseille, 13005, France

Location

Hospital Saint Eloi

Montpellier, 34295, France

Location

Hospital Brabois

Nancy, 54511, France

Location

Hospital Hotel Dieu

Nantes, 44093, France

Location

CHU - Hôpital Archet

Nice, France

Location

Hospital La Source

Orléans, 45067, France

Location

Hospital Pitié-Salpetriere

Paris, 75013, France

Location

Hospital Tenon

Paris, 75020, France

Location

Hospital Saint Jean

Perpignan, 66046, France

Location

CHU de Rouen- Hôpital Charles Nicolle

Rouen, 76031, France

Location

IC LOIRE

Saint-Etienne, France

Location

Hospital Civil

Strasbourg, 67091, France

Location

Hospital Paul Brousse

Villejuif, 94804, France

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Universitätsklinikum Halle (Saale)

Halle, 06120, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universität Leipzig AöR

Leipzig, 04103, Germany

Location

Klinikum rechts der Isar der TU Munchen II

München, 81675, Germany

Location

Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika

Budapest, 1082, Hungary

Location

Egyesített Szent István és Szent László Kórház - Rendelőintézet

Budapest, 1097, Hungary

Location

Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet

Debrecen, 4032, Hungary

Location

Szegedi Tudományegyetem Onkoterápiás Klinika

Szeged, 6720, Hungary

Location

Irccs Centro Di Riferimento Oncologico (Cro)

Aviano, 33081, Italy

Location

Ospedale Civile e degli Infermi

Faenza, 48018, Italy

Location

Ausl 12 Livorno Ospedale Unico della Versilia

Lido di Camaiore, 55041, Italy

Location

IRST Istituto Romagnolo Ricerca e Cura dei Tumori

Meldola, 47014, Italy

Location

Granda Osp. Magg. Policlinico

Milan, 20122, Italy

Location

Azienda Ospedaliera Policlinico di Modena

Modena, 41124, Italy

Location

A.O. Ospedale Maggiore della Carità

Novara, 28100, Italy

Location

Unknown Facility

Rimini, 47900, Italy

Location

Ain Wazein Hospital

El Chouf, Lebanon

Location

Hospital General Universitario de Alicante

Alicante, 03010, Spain

Location

Hospital Universitario Virgen de la Arrixaca

El Palmar Murcia, 30120, Spain

Location

Complejo Hospitalario de Jaen

Jaén, 23006, Spain

Location

Hospital General Universario Gregorio Maranon

Madrid, 28007, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario Madrid Sanchinarro

Madrid, 28050, Spain

Location

Hospital Carlos Haya

Málaga, 29010, Spain

Location

Hospital Universario Son Espaces

Palma de Mallorca, 07010, Spain

Location

Hospital Universitario Marques de Valdecilla

Santander, 39008, Spain

Location

Hospital Universitario Río Hortega

Valladolid, 47012, Spain

Location

Hacettepe University Medical Faculty

Ankara, Turkey (Türkiye)

Location

Ege Univeristy Medical Faculty,

Izmir, Turkey (Türkiye)

Location

Related Publications (1)

• 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.

  PMID: 30954567 DERIVED

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Doxorubicin

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Olivier De Beaumont; Chief Medical Officer
• Organization: ONXEO

o.debeaumont@onxeo.com

+33 (0) 1 45 58 95 33

Study Officials

• Philippe Merle, MD

  Croix-Rousse Hospital - Lyon-France

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2012
• First Posted: August 2, 2012
• Study Start: June 1, 2012
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2019
• Last Updated: June 2, 2021
• Results First Posted: June 2, 2021

Record last verified: 2021-05

Locations

US (3); FR (25); EG (6); HU (4); LE (1); TU (2); IT (8); DE (5); AU (2); ES (10); BE (4)