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

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.

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 AASLD and/or 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);

- 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 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;

- 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 NYHA
classification), recent (< 6 months) acute coronary syndrome, clinically significant
ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke,
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.