E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced hepacellular carcinoma (HCC) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the overall survival (OS) of repeated slow IV infusions of 20 or 30 mg/m2 DT to the Best Standard of Care (BSC) in patients with advanced HCC after failure or intolerance to Sorafenib. |
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E.2.2 | Secondary objectives of the trial |
- To compare additional efficacy parameters such as tumor response rate, progression free-survival (PFS) and time to progression (TTP)
- To determine the optimal dose of DT infusions;
- To evaluate the safety of DT;
- To assess PK parameters of DT at the doses of 20 and 30 mg/m2;
- To evaluate pharmacodynamics parameters and predictive factors of safety and efficacy: relationship between efficacy and safety (clinical, biological…) parameters, concentrations of doxorubicin and blood biomarkers. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or non-pregnant, non-breast feeding female;
2. Aged ≥ 18 years;
3. Patients 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;
4. Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without extension in inferior/superior vena cava, are eligible;
5. 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);
6. Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);
7. ECOG Performance Status 0 or 1;
8. Adequate laboratory tests, in particular with:
- 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);
9. Signed and dated written informed consent form.
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E.4 | Principal exclusion criteria |
1. Cirrhosis with a Child-Pugh score B8-C15;
2. Untreated chronic hepatitis B (in case of chronic hepatitis B, an efficacious antiviral treatment should have been started before randomisation to be included in the study);
3. Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment);
4. 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;
5. 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;
6. HCC developed on transplanted liver;
7. HIV infection;
8. Risk of variceal bleeding - i.e. patients with stage 2-3 varices with fragility signs (patients at risk for variceal bleeding may be included after a preventive treatment (oesophageal varices ligation, beta blockers)) has been administered; DT will not be administered in case of digestive bleeding in the 4 previous weeks;
9. SaO2 < 95%;
10. Presence of a significant acute or chronic respiratory disease defined as NCI /CTCAE > grade 2;
11. 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…);
12. Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent;
13. Patients currently treated with immunosuppressive agents that cannot be stopped;
14. Patients whose medical or surgical conditions are unstable and may not allow the study completion or compliance, and specially patients with uncontrolled diabetes;
15. Uncontrolled systemic infection;
16. Patients with a life expectancy of less than 2 months;
17. Patients who have received an experimental drug in another clinical trial in the last 30 days prior to randomization in the present clinical trial;
18. Women of child-bearing age who are unwilling or unable to use an effective contraception method (oral contraception or intra-uterine device for woman) 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 method (if applicable);
19. Patients unwilling or unable to comply with protocol requirements and scheduled visits. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At each visit and until death |
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E.5.2 | Secondary end point(s) |
1. Time To Progression (TTP);
2. Time to Radiological Progression (TTRP);
3. Time to Symptomatic Progression (TTSP);
4. Objective Response Rate (complete + partial response) according to RECIST liver adapted criteria (mRECIST);
5. Disease Control Rate (complete response + partial response + stable disease) according to mRECIST criteria;
6. Time to Best Objective Response;
7. Duration of Response;
8. Progression-free survival (PFS);
9. Duration of Disease Control;
10. Decrease (incidence, and time to decrease) in serum alpha-fœtoprotein levels (AFP) and duration of normal AFP serum levels;
11. Pharmacokinetic profile of Doxorubicin and its metabolites;
12. Safety:
- Incidence and duration of reduction of SaO2;
- Incidence, duration and severity of respiratory events;
- Incidence, duration and severity of all TEAEs and SAEs according to NCI-CTCAE v4.0 scale;
- Incidence, duration and severity of cardiovascular events (including BP and HR )
- ECG and LVEF change ;
- Biological (haematolology and biochemistry analyses, and particularly AST/ALT, WBC);
13. Relationship between efficacy and safety (clinical, biological…) parameters, concentrations of doxorubicin and doxorubicinol and blood biomarkers
These endpoints will be evaluated with all doses pooled and by dose level.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy evaluation every 2 months
Safety evaluation during 2 days after the infusion, and at each visit.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Russian Federation |
Slovakia |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |