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

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.