| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Antiangiogenic Treatment of Advanced or Metastatic Hepatocellular Cancer (HCC) |
|
| 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 | 10049010 |
| E.1.2 | Term | Carcinoma hepatocellular |
|
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
Overall Survival at 24 and 48 weeks
Tumor Response according to modified RECIST criteria within the first 24 (-48) weeks of treatment
Time-to-Symptomatic Progression (TTSP)
Pharmacokinetics of RAD 001 depending on liver function (in subset of patients)
Changes in Biomarkers:
- tumor markers (AFP, s-IL2, PIVKA-II)
- angiogenesis markers (plasma VEGF-A, PDGF-BB, bFGF, sE-SEL, IGF-1)
- markers of circulating tumor cells and endothelial cells (CEC, CTC)
Predictive Factors for Treatment Response by baseline/follow-up evaluation of tumor tissue by means of IHC (phosphorylated mTOR and S6K protein expression) and PCR microarray (pathway specific gene selection)
Safety and Tolerability of RAD001/Bevacizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age >18 years
2. Patients with non-resectable locally advanced or metastatic hepatocellular cancer BCLC stage B and C. BCLC stage A can occasionally be included provided that other treatment options are unavailable: they can be denied by the patient, have been performed with documented disease progression or cannot be carried out for other resons such as comorbidities
3. Measurable disease: At least one measurable lesion (longest diameter ≥ 20 mm on conventional CT or MRI scan; ≥ 10 mm on spiral CT) according to RECIST criteria that has not been previously locally treated by irradiation, surgery, ethanol injection, radiofrequency ablation or transarterial chemoembolisation. If the patient has had any previous local treatment to the marker lesion(s), there must be evidence of progression since then. The last scans should be approximately ≤ 4 weeks old before randomisation to be used as baseline scans.
4. Confirmation of HCC disease by histology (preceeding liver resection or fine needle biopsy within the last 12 months);
5. Liver Function: Child A and B
6. Tumor extent: CLIP Score ≤ 3
7. ECOG Performance Status 0-2 (=Karnofsky-Index ≥ 60%)
8. No mental illness that prevent patients from comprehensiveness, written informed consent
9. Written, voluntary informed consent
10. Compliant patient, regular follow-up possible |
|
| E.4 | Principal exclusion criteria |
1. Participation in another clinical trial at the same time or ≤ during the last 4 weeks
2. Patient had received any prior systemic treatment (possible exception: sorafenib for a maximum of 3 months, last dose received at least 28 days before study inclusion)
3. Pat. has received any other investigational agents within 28 days of first day of study drug dosing
4. Pat. had a major surgery, local ablative treatments (RFA, PEI), or transarterial chemoembolisation therapy within 4 weeks prior to randomisation
5. Pat. with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
6. Further, if the patient is unable to refrain from alcohol or other substance abuses or any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study
7. Presence of a secondary malignancy either at the time of screening or in the past 5 years: An exception from this rule can be made in patients that were treated in curative intention within the last 3 years and are without any evidence of recurrence of this malignancy.
8. History or presence of central nervous system disease (i.e., primary brain tumor, malignant seizures, CNS metastases or carcinomatous meningitis) or other mental illness.
9. Clinically serious infections or uncontrolled infection (including HIV infection), increased risk for acquisition of opportunistic infections
10. Chronic treatment with systemic steroids or another immunosuppressive agent; interactions with other drugs interfering with the CYP3A4 system should be avoided but can be permitted under circumstances of clinical need and close patient monitoring, provided that the medication used will be kept constant over the first 24 weeks of treatment
11. Indequate organ functions, characterised by: cholestasis with elevated levels of bilirubin and/or alkaline phosphatase > 3x UNL (can be improved by biliary drainage if necessary) and/or elevated transaminases (ALAT/ASAT) ≥ 5 x UNL, hypoalbuminemia < 2.5 g/dl, renal impairment (serum creatinine < 1.5 x UNL ), inadequate Hematology: Platelets < 75.000, ANC < 1500, hemoglobine < 9.0 mg/dl, inadequate coagulation status, namely INR > 2 or Quick < 50%, aPTT >50 sec in the absence of any drugs interfering with coagulation such as warfarin, phenprocoumone, NMH or UFH. Low-dose aspirin up to 100 mg/d or clopidogrel up to 75 mg/d are permitted together with obligatory prophylactic proton-pump-inhibitor treatment; Fasting serum cholesterol ≤300 mg/dL OR 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN, patients with severe refractory therapy-resistant hyperlipidemia
12. Women who are pregnant or breast feeding, intended pregnancy, or women unable to conceive and unwilling to practice an effective method of birth control. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study
13. Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of RAD001 and cannot be controlled by adequate medical treatment (e.g. uncontrolled nausea, vomiting, diarrhoea which might result in malabsorption, any known malabsorption syndrome, bowel obstruction, or inability to swallow the tablets)
Criteria derived from special situations:
-Mixed tumors of HCC with cholangiocarcinoma or fibrolamellar HCC type
-Pat. with complications of liver cirrhosis such as recent spontaneous bacterial infection of ascites, hepatic encephalopathy > grade 2 during the last 2 weeks and not adequately controlled or hepatorenal syndrome not responding to conservative treatment within 2 weeks. It is recommended that pat. with 2 or more episodes of complications receive unlimited prophylactic antibiotic treatment (e.g. gyrase inhibitors) and lactulose.
-Pat. with any active gastrointestinal bleeding during the last 2 weeks
-Pat. without screening EGD during the last 2 weeks
-Pat. with nonbleeding gastroesophageal varices grade I° with red coloured signs or grade ≥ II° on EGD that do not undergo prophylactic ligation or sclerosing treatment at least one week before the first dose of study med. is taken. Betablocker treatm. is not a substitute for effective endoscopic treatment. Ligation treatm. should preferably have led down to a grade I° reduction in gastroesophageal varices before entering the study (circumscribed grade II° without red whale signs is acceptable)
-Pat. with unhealed GI ulcerations or wounds
-Pat. with a history of one of the following: bowel perforation, colon diverticulitis
-History of any thromboembolic events (except for portal vein infiltration and/or thrombosis)
-Pat. with an increased risk for the development of lymphoma or other malignant diseases, especially concerning the skin |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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 | 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 | No |
| 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 | No |
| 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 |
|
| 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 | 8 |
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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