E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The primary objective of this study is to determine the efficacy of the combination of everolimus and capecitabine in a group of patients with metastatic or locally advanced HCC. In addition, to investigate biomarkers of HCC before and during the systemic treatment reflecting states of tumour cell growth and growth arrest (state of tumour cell dormancy). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019829 |
E.1.2 | Term | Hepatocellular carcinoma recurrent |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008452 |
E.1.2 | Term | Chemotherapy multiple agents systemic |
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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 |
1. Progression-free survival (PFS) at 6 months measured by CT-scan at 3-months intervals
2. Assessment of circulating levels of MP derived from vascular and/or tumour cells, and plasma MP-TF activity (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)
3. Circulating levels of biomarkers of the vasculature including endothelium activation marker such as VCAM, L-CAM, and P-selectin (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)
4. Investigation whether 2 and 3 are predictive factors for PFS and overall survival
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E.2.2 | Secondary objectives of the trial |
As secondary endpoints are defined:
1. Objective complete and partial response rate (RECIST criteria [appendix 1]/Waterfall plot)
2. Overall survival
3. One year survival rate
4. Safety
5. Alterations in cellular source of circulating MP during treatment as compared to pretreatment MP phenotype.
6. Assessment of development of venous thromboembolic events
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Cytological or histological confirmed HCC who failed the standard therapies or who are not suitable for the standard therapies, i.e. metastectomy or liver transplantation. - Age > 18 years. - ECOG Performance Status of 0-2. - Life expectancy of at least 12 weeks. - Subjects with at least one uni-dimensional measurable lesion. Lesions must be measured by CT-scan or MRI. - Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening: - Child-Pugh score of 7-9 points, i.e. Child-Pugh class B. - Total bilirubin < 4 times the upper limit of normal. - ALT and AST < 5 x upper limit of normal. - INR < 2.2 x upper limit of normal (patients who are being therapeutically anticoagulated with coumarin derivatives will be allowed to participate provided that no evidence of prior abnormality in these parameters exists). - Hemoglobin > 6 mmol/L. - Absolute neutrophil count (ANC) >1,500/mm3. - Platelet count 100,000/μl. - Serum creatinine < 2 x upper limit of normal. - Signed informed consent. - Sexually active patients, in conjunction with their partner, must practice birth control during and for 2 months after therapy. - Female patients at child-bearing age must have negative pregnancy test.
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E.4 | Principal exclusion criteria |
- History of cardiac disease: congestive heart failure >NYHA class 2; active coronary arterial disease (MI more than 6 mo prior to study entry is allowed); instable cardiac arrythmias; uncontrolled hypertension. - History of HIV infection. - Active clinically serious infections (> grade 2 NCI-CTC version 3.0) Hepatitis B carriers must be on lamivudine during and for 6 months after completion of study treatment. - Symptomatic metastatic brain or meningeal tumors - Patients with seizure disorder requiring medication (such as steroids or anti-epileptics). - Patients undergoing renal dialysis. - Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry. - Anticancer chemotherapy, immunotherapy, hormonal therapy, or radiotherapy during the study or within 4 weeks of study entry. Major surgery within 4 weeks of start of study. - Autologous bone marrow transplant or stem cell rescue within 4 months of study. - Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction]. Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study. - Investigational drug therapy outside of this trial during or within 4 weeks of study entry. - Prior exposure to the study drug. - Medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results. - Patients unstable to swallow oral medications.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to determine the efficacy of the combination of everolimus and capecitabine in a group of patients with metastatic or locally advanced HCC with Child-Pugh class B liver cirrosis. In addition, to investigate biomarkers of HCC before and during the systemic treatment reflecting states of tumour cell growth and growth arrest (state of tumour cell dormancy). Circulating proteins can be measured and used as reasonably reliable markers of changes in tumour cell load (e.g., alfa fertoprotein).
1. Progression-free survival (PFS) at 6 months measured by CT-scan at 3-months intervals
2. Assessment of circulating levels of MP derived from vascular and/or tumour cells, and plasma MP-TF activity (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)
3. Circulating levels of biomarkers of the vasculature including endothelium activation marker such as VCAM, L-CAM, and P-selectin (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)
4. Investigation whether 2 and 3 are predictive factors for PFS and overall survival
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
vascular abnormalities prior to, during and following systemic anti-cancer treatment |
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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) | 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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 3 |
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 | No |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |