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

Carcinoma, Hepatocellular Clinical Trial

— ReLive  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01655693
• Other study ID #: BA2011/03/04
• Secondary ID: 2011-002843-92
• Status: Completed
• Phase: Phase 3
• Start date: June 2012
• Est. completion date: May 2019

Study information

• Verified date: May 2021
• Source: Onxeo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 397
• Est. completion date: May 2019
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Drug:
• Doxorubicin 20 mg/m2

• Doxorubicin 30 mg/m2

• Best Standard of Care

Locations

Country	Name	City	State
Austria	Krankenhaus der Elisabethinen Linz GmbH	Linz
Austria	Medical University Vienna	Vienna
Belgium	CHU Brugmann	Brussels
Belgium	UCL Saint-Luc	Brussels
Belgium	CHU Sart Tilman	Liège
Belgium	CHU UCL Mont-Godinne Dinant	Yvoir
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	Medical Oncology department /Mansoura University Hospitals	Mansoura
Egypt	National Liver Institute / Menoufyia University	Menofia
France	Hospital Amiens	Amiens
France	Hospital Jean Minjoz	Besançon
France	Hospital Saint André	Bordeaux
France	Centre hospitalier P Oudot	Bourgoin-Jallieu
France	Hospital Estaing	Clermont-Ferrand
France	Centre Hospitalier Beaujon	Clichy
France	Hospital Henri-Mondor	Creteil
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	Orleans
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
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Halle (Saale)	Halle An Der Saale
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Universität Leipzig AöR	Leipzig
Germany	Klinikum rechts der Isar der TU Munchen II	Munchen
Hungary	Egyesített Szent István és Szent László Kórház - Rendelointézet	Budapest
Hungary	Semmelweis Egyetem Radiológiai és Onkoterápiás Klinika	Budapest
Hungary	Debreceni Egyetem Orvos- és Egészségtudományi Centrum Onkológiai Intézet	Debrecen
Hungary	Szegedi Tudományegyetem Onkoterápiás Klinika	Szeged
Italy	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	Milano
Italy	Azienda Ospedaliera Policlinico di Modena	Modena
Italy	A.O. Ospedale Maggiore della Carità	Novara
Lebanon	Ain Wazein Hospital	El Chouf
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar Murcia
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Hospital General Universario Gregorio Maranon	Madrid
Spain	Hospital Universitario Madrid Sanchinarro	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Carlos Haya	Malaga
Spain	Hospital Universario Son Espaces	Palma De Mallorca
Spain	Hospital Universitario Marques de Valdecilla	Santander
Spain	Hospital Universitario Río Hortega	Valladolid
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Ege Univeristy Medical Faculty,	Izmir
United States	Gabrail Cancer Center	Canton	Ohio
United States	Penn State Hershey Cancer Institute	Hershey	Pennsylvania
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Onxeo

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Egypt,  France,  Germany,  Hungary,  Italy,  Lebanon,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Primary	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	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.
Secondary	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.