E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HCC without extrahepatic metastases |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027479 |
E.1.2 | Term | Metastatic liver carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 the trial is to determine whether the combination of TACE and Sorafenib (Arm A) in comparison to TACE plus placebo (Arm B) better controls tumor growth within the liver in patients with HCC in terms of Time to Progression (TTP) before curative liver transplantation. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to compare the rates of patients, who reach LTx and the frequencies of TACE treatments required between the 2 arms, to assess safety and toxicity, the progression-free interval, the 1-year and 2-year overall survival, overall response rate, complete response (CR) and partial response (PR), disease control rate (DCR) as well as the health-related quality of life (HQoL) and the influence of the treatment on the AFP-level during the trial. Furthermore it is planned to conduct biomarker studies which examine liver biopsies, whole liver specimen after LTx and serum samples for genetic, gene expression and protein alterations. The biomarker findings will be correlated with clinical parameters. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with hepatocellular carcinoma (HCC) without extrahepatic disease. Inclusion Criteria • Patients with HCC without prior therapy, basically eligible for LTx at screening HCC diagnosed by histology or per non-invasive European Association for the Study of the Liver (EASL) criteria (only cirrhotic patients): 1. Radiological criteria: two coincident imaging techniques: Focal lesion > 2 cm with arterial hypervascularization 2. Combined criteria: one imaging technique associated with alpha-Fetoprotein (AFP): Focal lesion > 2 cm with arterial hypervascularization + AFP levels > 400 ng/ml • Pretreatment CT or MRI and bone scan without evidence of radiographically definable vascular invasion or extrahepatic disease not older than 28 days, for bone scans not older than 8 weeks • Sufficient hematologic, liver and renal function: Hb>9.0g/%, WBC >3.000cells/mm³ (ANC>1.500cells/mm³), platelets >75.000 cells/mm³, Bilirubin <3mg/dl. Patients should have bilateral renal function, as determined by abdominal CT with serum creatinine <1.5mg/dl and Creatinine clearance (CrCL) >30ml/min in 24h urine or Modification of Diet in Renal Disease Rate (MDRD) • PT-INR/PTT <1.5x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists]. • Performance status: Karnofsky index >70% • No acute infections at the time of therapy initiation • Patients must sign a study specific informed consent form |
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E.4 | Principal exclusion criteria |
• Residual radiological definable extrahepatic disease, portal vein involvement or lymph node involvement in CT, MRI or bone scan. Patients who are not potentially eligible for LTx are excluded. • Patients with prior or concomitant systemic anticancer therapy or local tumor therapy (i.e. LITT; PEI, cryotherapy, RFA), or with prior TACE <= 3 days before randomisation or with concomitant biologic-response modifiers, strong CYP3A4 inhibitors • Patients with significant cardiovascular disease such as myocardial infarction <6months previously, chronic heart failure (revised New York Hearth Association (NYHA) grade III-IV) or unstable coronary artery disease • Patients with severe pulmonary disease that would be hazardous for LTx • Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure >90 mm Hg, despite optimal management • Thrombotic or embolic events including transient ischemic attacks within the past 6 months • Hemorrhage/bleeding event ≥Grade 3 within 4 weeks of first dose of study drug • Patients with contraindication to arterial procedure during TACE (portal or liver vein infiltration, allergy against contrast dye, uncontrolled hyperthyroidism) • Patients with previous malignancy other than carcinoma in situ of the skin and the cervix within 5 years prior treatment • Patients < 18 years • Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial (and men for at least 3 months after last administration of study medication). Women of childbearing potential must agree to practice adequate contraception and to refrain from breastfeeding, as specified in the informed consent. • Patients with uncontrolled infections or HIV sero-positive patients • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product • Mental conditions rendering the patient incapable to understand the nature, scope, and consequences of the study • No patient will be allowed to enroll in this study more than once • Prior organ transplantation (e.g. renal…) • Concomitant immunosuppressive treatment (steroids, mycophenolate mofetil, cyclosporine, temsirolimus, everolimus, tacrolimus, …)
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E.5 End points |
E.5.1 | Primary end point(s) |
TTP will be compared between Arm A and Arm B using a 1-sided log-rank test. Median TTP with corresponding 95% confidence intervals (CI) will be estimated using Kaplan-Meier (KM) methods. The hazard ratio (Arm A/Arm B) will be estimated by proportional Hazard regression. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
interim analysis after 60 events and at end of trial |
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E.5.2 | Secondary end point(s) |
Secondary objectives are to compare the rates of patients, who reach LTx and the frequencies of TACE treatments required between the 2 arms, to assess safety and toxicity, the progression-free survival, overall response rate, complete response (CR) and partial response (PR), disease control rate (DCR) as well as the health-related quality of life (HQoL) and the influence of the treatment on the AFP-level during the trial. Furthermore it is planned to conduct biomarker studies which examine liver biopsies, whole liver specimen after LTx and serum samples for genetic, gene expression and protein alterations. The biomarker findings will be correlated with clinical parameters. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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 | 10 |
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 | No |
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 | 6 |
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 |