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

Phase 3

Completed

Conditions: Carcinoma, Hepatocellular

Interventions: Drug: Doxorubicin 20 mg/m2
Drug: Doxorubicin 30 mg/m2
Drug: Best Standard of Care

Registration Number: NCT01655693

Lead Sponsor: Valerio Therapeutics

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 397

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Doxorubicin Transdrug (DT) at 20 mg/m2	Doxorubicin 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
Doxorubicin Transdrug (DT) at 30 mg/m2	Doxorubicin 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
Best Standard of Care	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

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	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.	OS is defined as the time from date of randomization to the date of death from any cause.

Secondary Outcome Measures

Name	Time	Method
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.	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.
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.	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.

Trial Locations

Locations (69): CHU Brugmann
🇧🇪
Brussels, Belgium
CHU Sart Tilman
🇧🇪
Liège, Belgium
Medical Oncology department /Ain Shams University Hospitals
🇪🇬
Cairo, Egypt
National hepatology and tropical medicine research institute
🇪🇬
Cairo, Egypt
Medical Oncology department /Mansoura University Hospitals
🇪🇬
Mansoura, Egypt
CHU Dupuytren
🇫🇷
Limoges, France
Medical University Vienna
🇦🇹
Vienna, Austria
CHU UCL Mont-Godinne Dinant
🇧🇪
Yvoir, Belgium
Hospital Jean Minjoz
🇫🇷
Besançon, France
Centre Hospitalier Beaujon
🇫🇷
Clichy, France
Krankenhaus der Elisabethinen Linz GmbH
🇦🇹
Linz, Austria
Hospital Amiens
🇫🇷
Amiens, France
Centre hospitalier P Oudot
🇫🇷
Bourgoin-Jallieu, France
Hospital Henri-Mondor
🇫🇷
Creteil, France
Hospital La Source
🇫🇷
Orleans, France
Hospital Paul Brousse
🇫🇷
Villejuif, France
Universitätsklinikum Halle (Saale)
🇩🇪
Halle An Der Saale, Germany
Clinical Research Center/ Alexandria university hospital
🇪🇬
Alexandria, Egypt
Oncology Department, Medical Research Institute, Alexandria University
🇪🇬
Alexandria, Egypt
Hospital General Universitario de Alicante
🇪🇸
Alicante, Spain
Centre Jean-François Leclerc
🇫🇷
Dijon, France
Hospital Universitario Virgen de la Arrixaca
🇪🇸
El Palmar Murcia, Spain
UCL Saint-Luc
🇧🇪
Brussels, Belgium
Hospital Estaing
🇫🇷
Clermont-Ferrand, France
Hospital Pitié-Salpetriere
🇫🇷
Paris, France
Hospital Tenon
🇫🇷
Paris, France
Azienda Ospedaliera Policlinico di Modena
🇮🇹
Modena, Italy
Hospital Grenoble
🇫🇷
La Tronche, France
Klinikum rechts der Isar der TU Munchen II
🇩🇪
Munchen, Germany
Hospital Civil
🇫🇷
Strasbourg, France
Universitätsklinikum Freiburg
🇩🇪
Freiburg, Germany
Hospital Universario Son Espaces
🇪🇸
Palma De Mallorca, Spain
National Liver Institute / Menoufyia University
🇪🇬
Menofia, Egypt
Ain Wazein Hospital
🇱🇧
El Chouf, Lebanon
CHU de Rouen- Hôpital Charles Nicolle
🇫🇷
Rouen, France
Universitätsklinikum Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet
🇭🇺
Debrecen, Hungary
Ausl 12 Livorno Ospedale Unico della Versilia
🇮🇹
Lido di Camaiore, Italy
Hospital General Universario Gregorio Maranon
🇪🇸
Madrid, Spain
Complejo Hospitalario de Jaen
🇪🇸
Jaen, Spain
Universität Leipzig AöR
🇩🇪
Leipzig, Germany
Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika
🇭🇺
Budapest, Hungary
Egyesített Szent István és Szent László Kórház - Rendelőintézet
🇭🇺
Budapest, Hungary
Szegedi Tudományegyetem Onkoterápiás Klinika
🇭🇺
Szeged, Hungary
Ospedale Civile e degli Infermi
🇮🇹
Faenza, Italy
Ege Univeristy Medical Faculty,
🇹🇷
İzmir, Turkey
Hospital Universitario Río Hortega
🇪🇸
Valladolid, Spain
Hospital Carlos Haya
🇪🇸
Malaga, Spain
Hospital Universitario Ramón y Cajal
🇪🇸
Madrid, Spain
Hospital Universitario Madrid Sanchinarro
🇪🇸
Madrid, Spain
Hacettepe University Medical Faculty
🇹🇷
Ankara, Turkey
Hospital Universitario Marques de Valdecilla
🇪🇸
Santander, Spain
Irccs Centro Di Riferimento Oncologico (Cro)
🇮🇹
Aviano, Italy
IRST Istituto Romagnolo Ricerca e Cura dei Tumori
🇮🇹
Meldola, Italy
Granda Osp. Magg. Policlinico
🇮🇹
Milano, Italy
A.O. Ospedale Maggiore della Carità
🇮🇹
Novara, Italy
Hospital La Timone
🇫🇷
Marseille, France
Hospital Saint Jean
🇫🇷
Perpignan, France
IC LOIRE
🇫🇷
Saint-Etienne, France
Gabrail Cancer Center
🇺🇸
Canton, Ohio, United States
Penn State Hershey Cancer Institute
🇺🇸
Hershey, Pennsylvania, United States
Hospital Saint André
🇫🇷
Bordeaux, France
CHU
🇫🇷
Dijon, France
Hospital Croix Rousse
🇫🇷
Lyon, France
Hospital Saint Eloi
🇫🇷
Montpellier, France
Hospital Brabois
🇫🇷
Nancy, France
Hospital Hotel Dieu
🇫🇷
Nantes, France
CHU - Hôpital Archet
🇫🇷
Nice, France
Allegheny General Hospital
🇺🇸
Pittsburgh, Pennsylvania, United States