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

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 supportive 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.

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.

• Drug: Doxorubicin
  Other Name: Doxorubicin Transdrug (DT) at 20mg/m2
• Drug: Doxorubicin
  Other Name: Doxorubicin Transdrug (DT) at 30mg/m2
• Drug: Best Standard of Care

• Experimental: Doxorubicin Transdrug (DT) at 20mg/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 toxicity
  Intervention: Drug: Doxorubicin
• Experimental: Doxorubicin Transdrug (DT) at 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 toxicity
  Intervention: Drug: Doxorubicin
• Active Comparator: Best Standard of Care
  Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or toxicity
  Intervention: Drug: Best Standard of Care

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

• HCC diagnosed according to the AASLD criteria:

  • Cyto-histology criteria and/or Non-invasive criteria
• Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);
• ECOG Performance Status 0 or 1;

• Laboratory tests as follows:

  • Platelets ≥ 50,000 /mm3
  • Neutrophil count ≥ 1000/mm3
  • Hemoglobin ≥ 10g/dL
  • Serum transaminases < 5 ULN (NCI/CTC grades 0, 1, or 2)
  • Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2)
  • Serum bilirubin < 35 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 can be included);
• HCC developed on transplanted liver;
• HIV infection;
• Risk of variceal bleeding;
• SaO2 < 95%;
• Presence of a significant acute or chronic respiratory disease, pleural effusion;
• Presence of recent (< 6 months) or current cardiac failure (class III or IV NYHA classification), recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke, MI…);
• Patients having undergone a 450 mg/m² cumulated dose of doxorubicin;
• Patients currently treated with immunosuppressive agents that cannot be stopped;
• Patients with unstable ongoing medical/surgical problems;
• Patients with a life expectancy of less than 2 months;
• Patients who had participated in another clinical trial in the last 30 days;
• Women of child-bearing age who are unwilling or unable to use an effective contraception method during the study treatment period and for 2 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 2 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.