| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019830 |
| E.1.2 | Term | Hepatocellular carcinoma resectable |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019829 |
| E.1.2 | Term | Hepatocellular carcinoma recurrent |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Overall Progression Free Survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
Survival
- Overall survival (OS)
- Survival rate at week 6, 12, 18, 24
- PFS rate at week 6, 12, 18, 24
Tumour assessment:
- Overall Time to progression (TTP)
- Objective response rate (CR + PR) at week 6, 12, 18, 24
- Control disease rate (CR + PR + SD) at week 6, 12, 18, 24
- Best response during study treatment
- Time to response
- Quality of life assessment according to the EORTC QLQ-C30 questionnaire at week 6, 12, 18, 24
- ECOG Performance Status
Safety profile using the NCI CTC v4.02 classification
Pharmacokinetics
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient with histologically or cytologically confirmed advanced-stage hepatocellular carcinoma (HCC) (unresectable, and/or metastatic) or responding to the Barcelona diagnostic criteria
2. Patient who have discontinued from first line treatment with sorafenib monotherapy for any reason (ie, tumor disease progression, intolerance) at least 14 days prior to planned randomization but have not received any second line treatment for HCC
3. Patient who have recovered from any significant sorafenib-related treatment toxicities prior to randomization (≤Grade 2)
4. Patient with at least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)
5. Patients who have received local therapy prior to sorafenib administration (radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection [PEI] or cryoablation) are eligible. Local therapy must be completed at least 4 weeks prior to the baseline scan
6. Adequate antiviral systemic therapy in sympotomatic and asymptomatic HBV Ag carriers
7. Patient eligible for receiving a second line treatment including etoposide and irinotecan
8. Child-Pugh liver function class A
9. Barcelona Clinic Liver Cancer (BCLC) classification: class C
10. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
11. Patient with adequate organ function:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Haemoglobin ≥ 10 g/dL
• Platelets (PTL) ≥ 85 x 109/L
• AST/ALT ≤ 5 x ULN
• Gamma-GT ≤ 5 x ULN
• Bilirubin ≤ 1.5 x ULN
• Creatinin clearance ≥ 50 mL/min (Cockcroft and Gault formula)
• Albumin > LLN
• Urea ≤ 2 x ULN
• Proteinuria < 30 mg/dL; in case of proteinuria ≥ 30 mg/dL on the dipstick, 24 hours proteinuria < 1.5g/24 hours
12. Patient with life expectancy ≥ 3 months
13. Female or male patient ≥ 18 years
14. Patient weight > 40 kg and BMI > 18
15. Female patient of child bearing potential who agrees to use a method of medically acceptable forms of contraception during the study and 3 months after the last intake of study treatment
16. Patient able and willing to comply with study visits and procedures as per protocol
17. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures are performed
18. Patient affiliated to a social security regimen
|
|
| E.4 | Principal exclusion criteria |
1. Patient intolerant to etoposide or irinotecan
2. Patient who have received a liver transplant
3. Patient with clinically significant symptoms of hepatic encephalopathy
4. Patient who have received a previous systemic therapy (including investigational agents) other than sorafenib (see Inclusion Criterion 2) for treatment of HCC. Patients participating in surveys or observational studies are eligible to participate in this study
5. Patient who have had treatment with any of the following within the specified timeframe prior to randomization:
• Any sorafenib within the 14 days prior to randomization
• Major surgery within the 4 weeks prior to randomization
• Any transfusion, treatment with blood component preparation, received erythropoietin , albumin preparation, and granulocyte colony-stimulating factor (G CSF) within the 2 weeks prior to randomization
6. Patient with previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 3 years prior to entry is permitted
7. Patient presenting with at least one of the following condition:
- Ischemic heart disease, defined by at least one of the following condition:
a. Medical history of ischemic heart disease
b. Clinical symptoms of ischemic heart disease
c. Q wave > 3 mm on the electrocardiogram
d. ST elevation or depression > 2 mm on the electrocardiogram
e. Negative T wave in at least 2 leads of the electrocardiogram
- Cardiac failure, defined by at least one of the following condition:
a. Medical history of cardiac failure defined by a previous left ventricular ejection fraction ≤ 50%
b. Clinical symptoms of cardiac failure
c. Current treatment for cardiac failure
d. NT Pro-BNP ≥ 300 pg/mL or BNP ≥ 75 pg/mL and/or troponin T > 0.1 ng/mL or troponin I > 0.35 ng/mL
- Conduction disorders or arrhythmia, defined by at least one of the following and confirmed by electrocardiogram:
a. Severe ventricular arrhythmia (frequent premature ventricular beats)
b. Atrioventricular block at second or third level
c. Left bundle branch block
8. Pregnant or nursing female patient
9. Patient with active central nervous system (CNS) metastasis or with history of CNS metastasis
10. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
Previous treatment
11. Patient treated with any investigational agent within 4 weeks prior baseline
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) is defined as the time from the randomization to the date of documented progression or any cause of death during the study. Progression will be assessed by CT scan according to Modified-RECIST criteria version 1.1. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 |
| masitinib in combination with other medicinal product in each group |
|
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
| Patient could be treated until disease progression, limiting toxicity, or consent withdrawal |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 0 |
| 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 |
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