Clinical trial NCT01655693: Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Keywords: Intermediate/advanced hepatocellular carcinoma
After failure or intolerance to Sorafenib.
Lead sponsor: Valerio Therapeutics
Sponsor class: INDUSTRY
First posted: 2012-08-02
Enrollment: 397
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: 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:
measure: Progression-free Survival (PFS)
timeFrame: 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.
measure: Objective Response Rate (ORR)
timeFrame: 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:
measure: Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death
timeFrame: Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study.
measure: Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug
timeFrame: Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study.
measure: Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion
timeFrame: Time from start of infusion to resolution of reduction in oxygen saturation.
measure: Number of Participants With Clinically Significant Abnormal Change in Respiratory Function
timeFrame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
measure: Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline
timeFrame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
measure: Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event
timeFrame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
Locations:
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Cancer Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz GmbH
city: Vienna
country: Austria
facility: Medical University Vienna
city: Brussels
country: Belgium
facility: CHU Brugmann
city: Brussels
country: Belgium
facility: UCL Saint-Luc
city: Liège
country: Belgium
facility: CHU Sart Tilman
city: Yvoir
country: Belgium
facility: CHU UCL Mont-Godinne Dinant
city: Alexandria
country: Egypt
facility: Clinical Research Center/ Alexandria university hospital
city: Alexandria
country: Egypt
facility: Oncology Department, Medical Research Institute, Alexandria University
city: Cairo
country: Egypt
facility: Medical Oncology department /Ain Shams University Hospitals
city: Cairo
country: Egypt
facility: National hepatology and tropical medicine research institute
city: Mansoura
country: Egypt
facility: Medical Oncology department /Mansoura University Hospitals
city: Menofia
country: Egypt
facility: National Liver Institute / Menoufyia University
city: Amiens
country: France
facility: Hospital Amiens
city: Besançon
country: France
facility: Hospital Jean Minjoz
city: Bordeaux
country: France
facility: Hospital Saint André
city: Bourgoin-Jallieu
country: France
facility: Centre hospitalier P Oudot
city: Clermont-Ferrand
country: France
facility: Hospital Estaing
city: Clichy
country: France
facility: Centre Hospitalier Beaujon
city: Creteil
country: France
facility: Hospital Henri-Mondor
city: Dijon
country: France
facility: Centre Jean-François Leclerc
city: Dijon
country: France
facility: CHU
city: La Tronche
country: France
facility: Hospital Grenoble
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Hospital Croix Rousse
city: Marseille
country: France
facility: Hospital La Timone
city: Montpellier
country: France
facility: Hospital Saint Eloi
city: Nancy
country: France
facility: Hospital Brabois
city: Nantes
country: France
facility: Hospital Hotel Dieu
city: Nice
country: France
facility: CHU - Hôpital Archet
city: Orleans
country: France
facility: Hospital La Source
city: Paris
country: France
facility: Hospital Pitié-Salpetriere
city: Paris
country: France
facility: Hospital Tenon
city: Perpignan
country: France
facility: Hospital Saint Jean
city: Rouen
country: France
facility: CHU de Rouen- Hôpital Charles Nicolle
city: Saint-Etienne
country: France
facility: IC LOIRE
city: Strasbourg
country: France
facility: Hospital Civil
city: Villejuif
country: France
facility: Hospital Paul Brousse
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Halle An Der Saale
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Leipzig
country: Germany
facility: Universität Leipzig AöR
city: Munchen
country: Germany
facility: Klinikum rechts der Isar der TU Munchen II
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika
city: Budapest
country: Hungary
facility: Egyesített Szent István és Szent László Kórház - Rendelőintézet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem Onkoterápiás Klinika
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (Cro)
city: Faenza
country: Italy
facility: Ospedale Civile e degli Infermi
city: Lido di Camaiore
country: Italy
facility: Ausl 12 Livorno Ospedale Unico della Versilia
city: Meldola
country: Italy
facility: IRST Istituto Romagnolo Ricerca e Cura dei Tumori
city: Milano
country: Italy
facility: Granda Osp. Magg. Policlinico
city: Modena
country: Italy
facility: Azienda Ospedaliera Policlinico di Modena
city: Novara
country: Italy
facility: A.O. Ospedale Maggiore della Carità
city: Rimini
country: Italy
city: El Chouf
country: Lebanon
facility: Ain Wazein Hospital
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: El Palmar Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: Madrid
country: Spain
facility: Hospital General Universario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Madrid Sanchinarro
city: Malaga
country: Spain
facility: Hospital Carlos Haya
city: Palma De Mallorca
country: Spain
facility: Hospital Universario Son Espaces
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Valladolid
country: Spain
facility: Hospital Universitario Río Hortega
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: İzmir
country: Turkey
facility: Ege Univeristy Medical Faculty,
Study officials:
affiliation: Croix-Rousse Hospital - Lyon-France
name: Philippe Merle, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.