E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with unresectable hepatocellular carcinoma. |
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MedDRA Classification |
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 |
Investigate if the combination of sorafenib plus everolimus can stop tumor progression, with a sorafenib monotherapy group used to control selection bias. No formal comparison is planned. |
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E.2.2 | Secondary objectives of the trial |
Quality of life, tumor density. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational research: analyses of specific blood proteins are planned. Possible targets for translational research analyses include, for instance, tissue factor (TF) and golgi phosphoprotein 2 (GOLPH2). The purpose is the evaluation of the predictive value of such proteins as biomarkers and tumor markers in the management of HCC. |
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E.3 | Principal inclusion criteria |
Histologically, cytologically or radiologically confirmed diagnosis of HCC, localized but surgically unresectable or metastatic. HCC stage B or C according to the Barcelona Clinic Liver Cancer (BCLC) staging classification. Child-Pugh class A or mildly decompensated Child-Pugh class B liver dysfunction. Measurable disease: spiral/multi-slice CT/MRI according to revised RECIST 1.1. WHO performance status 0-1. Adequate hematological values: hemoglobin ≥ 90 g/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 75 x 109/L. Adequate renal function: creatinine clearance ≥ 40 mL/min. Adequate hepatic function: ALT ≤ 5 x upper limit of normal (ULN). Adequate coagulation parameter: INR ≤ 2. Urine dipstick for proteinuria ≤ 1+ or protein in spot urine sample < 0.6 g/L. Age ≥ 18 years. Women are not breastfeeding, are using effective contraception if sexually active, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test is mandatory for all women < 50 years (unless considered unnecessary by the investigator). Men agree not to father a child during participation in the trial and during the 12 months thereafter. Patient compliance and geographic proximity allow proper staging and follow-up.
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E.4 | Principal exclusion criteria |
Prior systemic anti-cancer treatment for HCC. Treatment with estrogen containing supplementary therapy. Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer. Prior organ transplantation. Patients with locally advanced disease who are candidates for radical surgery. Known fibrolamellar HCC or mixed cholangiocarcinoma/HCC. History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months. Documented variceal hemorrhage within 3 months before randomization. Requirement of anticoagulant therapy except for low-dose anticoagulants for maintenance of patency of central venous access or prevention of deep vein thrombosis (DVT). History (within last six months) or presence of clinically significant acute or unstable cardiovascular, cerebrovascular, renal, gastrointestinal, pulmonary, endocrine, central nervous system or immunological disorders (with the exception of the presence of hepatitis B virus (HBV), HCV hepatitis, or cirrhosis). Clinical symptoms or history of CNS metastases or leptomeningeal disease (no imaging required). Encephalopathy. Known HIV infection. Active infection requiring i.v. antibiotics at randomization. Arterial hypertension ≥ 150/100 mmHg despite therapy. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2, or atrial fibrillation of any grade, prolongation of QTc > 500 msec in screening electrocardiogram (ECG) or history of familial long QT syndrome. Repeated paracentesis (more than 1 per month). Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization. Chronic treatment with systemic steroids or another immunosuppressive agent. Current use or anticipated need for drugs that are known CYP3A4 inhibitors or inducers (for a comprehensive list see http://medicine.iupui.edu/clinpharm/ddis/), unless the drugs are medically necessary and no substitutes are available. Inability to take oral medications. Psychiatric disorder precluding understanding of information of trial-related topics, giving informed consent or interfering with compliance for oral drug intake
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free at 12 weeks. Objective response. Disease stabilization (DS). Duration of DS. Progression free survival (PFS). Time to progression (TTP). Overall survival (OS). Adverse events (AEs). Serum alpha fetoprotein (AFP) level. Viral (re)-activation in patients with chronic hepatitis B/C virus infection. Vitamin B12 effect on OS. |
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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 | 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) | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 |
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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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The inclusion of patients is planned to start in Q3 2009 and will stop after the inclusion of 106 patients, which is expected in Q2 2011. End of trial treatment (last patient, last visit) is expected for Q4 2011. |
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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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |