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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Doxorubicin 20 mg/m2
* Drug: Doxorubicin 30 mg/m2
* Drug: Best Standard of Care


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxorubicin Transdrug (DT) at 20 mg/m2<br>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<br> <br> * Other names: Doxorubicin Transdrug (DT) at 20 mg/m2;|
| Experimental: Doxorubicin Transdrug (DT) at 30 mg/m2<br>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<br> <br> * Other names: Doxorubicin Transdrug (DT) at 30 mg/m2;|
| Active Comparator: Best Standard of Care<br>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<br> <br> * Other names: BSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intermediate/advanced hepatocellular carcinoma, After failure or intolerance to Sorafenib.