E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
hepatocellular cancer (2nd/3rd line) |
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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 | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
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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 |
The primary objective of this study is to compare overall survival between the combination treatment of everolimus plus BSC to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objective: The key secondary objective of this study is to compare time to tumor progression (TTP) between the combination treatment of everolimus plus BSC to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib.
Other Secondary Objectives, please refer to protocol section 3.2
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years old 2. Diagnosis of advanced HCC according to the AASLD Guidelines (Bruix and Sherman 2005) 3. HCC stage B or C according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Llovet et al. 2008a) 4. Prior systemic treatment with sorafenib for advanced HCC and for whom their disease progressed during or after sorafenib treatment, or were intolerant to sorafenib treatment. Specifically, this can be defined as: • Documented radiological confirmation (radiology scans or report) of disease progression during or after sorafenib treatment • Intolerance to sorafenib (at any dose and/or duration) is defined as documented sorafenib-related grade 3 or 4 adverse events that led to sorafenib discontinuation. NOTE: • Sorafenib must be the last antineoplastic treatment before randomization • Prior local and/or hormonal therapy (e.g., tamoxifen) before sorafenib is allowed • One systemic chemotherapy regimen for advanced HCC is allowed before sorafenib treatment 5. Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy (although ascites controlled by diuretics is permitted in this study). Child-Pugh status must be calculated based on clinical findings and laboratory results during the screening period 6. ECOG performance status of ≤ 2 7. Adequate bone marrow function as shown by: • Absolute neutrophil count (ANC) ≥ 1.2 x 109/L (1200/mm3) • Platelets ≥ 100 x 109/L (100,000/mm3) • Hemoglobin (Hgb) ≥ 8.5 g/dL (5.3mmol/L) 8. Adequate liver function as shown by: • Serum alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) • Bilirubin ≤ 2 mg/dL 9. Adequate renal function as shown by: • Serum creatinine ≤ 1.5 x ULN 10. Written informed consent according to local guidelines and the ability to follow the visit schedule.
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E.4 | Principal exclusion criteria |
1. Any local antineoplastic therapy and/or investigational drugs within 28 days prior to randomization 2. Active bleeding within 28 days prior to Screening Visit 1 including variceal bleeding (esophageal varices should be treated according to standard practice e.g. ligation or banding and procedure completed 28 days prior to Visit 1) 3. Prior therapy with mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus) 4. Known previous/current malignancy within the last 3 years except for cervical carcinoma in situ, basal cell carcinoma or superficial bladder carcinoma 5. Prior liver or other organ transplantation which mandates systemic immunosuppression 6. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory) 7. Clinically significant third space fluid accumulation (i.e., ascites requiring tapping (despite use of diuretics) or pleural effusion that either requires tapping or is associated with shortness of breath 8. Any severe and/or uncontrolled medical conditions including: • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension • Previous Transient Ischemic Attack (TIA), Cerebrovascular Accident (CVA), symptomatic Peripheral Vascular Disease (PVD) within last 6 months prior to randomization • Uncontrolled diabetes as defined by glycosylated hemoglobin (HbA1c) > 8 % • Acute and chronic, active infectious disorders, including fungal infections, and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy, in the opinion of the investigator, except chronic HBV or HCV infection • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) • Other concurrent severe and/or uncontrolled medical conditions (e.g., chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol. 9. Patients with an active alcohol intake of 80 grams or more per day. 10. Patients receiving chronic treatment with corticosteroids (except for intermittent topical, local injection, eye drops or systemic aldosterone) or another immunosuppressive agent 11. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in both sexes. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug. 12. Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from surgery.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is this study is overall survival (OS). OS is defined as the time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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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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 | 4 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |