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    Summary
    EudraCT Number:2008-004096-21
    Sponsor's Protocol Code Number:CRAD001O2101
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2008-09-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2008-004096-21
    A.3Full title of the trial
    A phase 1 open label/phase 2 randomized, double-blind, multicenter study investigating the combination of RAD001 and sorafenib (Nexavar®) in patients with advanced hepatocellular carcinoma
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberCRAD001O2101
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRAD001
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVEROLIMUS
    D.3.9.1CAS number 159351696
    D.3.9.2Current sponsor codeRAD001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRAD001
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVEROLIMUS
    D.3.9.1CAS number 159351696
    D.3.9.2Current sponsor codeRAD001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nexavar 200 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Health Care AG, Germany
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsorafenib
    D.3.9.1CAS number 284461-73-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    advanced hepatocellular carcinoma
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    This is a combined phase 1 and phase 2 study with the following primary objectives:

    Phase 1
    • safety and tolerability of daily RAD001 in combination with daily sorafenib in adult patients with advanced hepatocellular carcinoma (HCC) who have taken no prior systemic therapy for HC and to determine the maximum tolerated dose (MTD) of the combination of RAD001 plus sorafenib to bring forward into phase 2

    Phase 2
    • To estimate the hazard ratio of the treatment effect as a measure of anti-tumor activity in terms of Time to Progression (TTP) of the combination of RAD001 plus sorafenib, at the MTD level, as compared to sorafenib alone
    E.2.2Secondary objectives of the trial
    Phase 1

    • efficacy of RAD001 + sorafenib at the explored dose-levels in terms of best overall response as defined by RECIST
    • safety and tolerability of of RAD001 + sorafenib as measured by rate and severity of AEs
    • To determine the steady state exposure of RAD001 at pre-dose and 1 hour and 2 hours post-dose at the explored combination dose-levels using concentrations at pre-dose (Cmin) and at 1 hour (C1h) and 2 hours (C2h) post-dose

    Phase 2

    • clinical efficacy in terms of the following endpoints according to RECIST:
    • Best overall response
    • PFS
    • To compare overall survival of RAD001 + sorafenib with sorafenib alone
    • safety and tolerability of of RAD001 + sorafenib as measured by rate and severity of AEs
    To determine the steady state exposure of RAD001 at pre-dose and 1 hour and 2 hours post-dose at the explored combination dose-levels using concentrations at pre-dose (Cmin) and at 1 hour (C1h) and 2 hours (C2h) post-dose
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients = 18 years old with ability to take oral drugs
    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) (Llovet, et al 2008b)
    4. No previous systemic therapy for HCC, (tamoxifen is allowed as previous systemic therapy)
    5. Measurable disease according to RECIST, i.e. at least one measurable lesion. This lesion should not have been previously treated with local therapy. A treated lesion may be used where these lesions are the only lesions available for evaluation and have shown definite progression since their last local radiation treatment. Local therapy must have been completed at least four weeks prior to baseline evaluation
    6. Patients with ECOG performance status of 0 or 1 (see Section 7.5.4)
    7. Cirrhotic status of current Child-Pugh class A only (5-6 points) with no encephalopathy and no ascites (ascites controlled by diuretics is excluded). Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period.
    8. For patients with background chronic hepatitis B virus (HBV), they must be treated with lamivudine QD 100 mg, (or alternative treatment if resistant to lamivudine), as prophylaxis at least 2 weeks prior to receiving study drug, Visit 2.
    9. The following laboratory parameters at Visit 2:
    • Absolute Neutrophil Count (ANC) = 1.5 x 109/L
    • Platelets = 70000 x 106/L
    • Hemoglobin (Hgb) = 9 g/dL
    • Serum aspartate aminotransferase (AST) and alanine amino-transferase (ALT) = 5 x ULN
    • Serum creatinine = 1.5 x ULN
    10. Ability to understand and willingness to sign a written informed consent and to be able to follow the visit schedule
    E.4Principal exclusion criteria
    1. Patients currently receiving any anti cancer therapy or who have received any local anti cancer therapy = 4 weeks prior to baseline CT/MRI scan, Visit 2
    2. Active bleeding during the last 30 days prior to Visit 1 including variceal bleeding (Esophageal varices should be treated according to standard practice e.g. ligation/banding and procedure completed 30 days prior to Visit 1.)
    3. Patients with a known hypersensitivity to RAD001 (everolimus) or known hypersensitivity to sorafenib or contradictions to sorafenib based on the local sorafenib label
    4. Known previous/current malignancy requiring treatment within = 3 years except for cervical carcinoma in situ, basal cell carcinoma, and superficial bladder carcinoma 5. Known history of human immunodeficiency virus (HIV) seropositivity, (HIV testing is not mandatory)
    6. Any severe and/or uncontrolled medical conditions including:
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction = 6 months prior to Visit 1, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension
    • Previous TIA, CVA, symptomatic PVD within last 6 months of Visit 1
    • Patients with active alcohol intake
    • Uncontrolled diabetes as defined by HbA1c >8%
    • Greater or equal grade 3 hypercholesterolemia/hypertriglyceridemia or = grade 2 hypercholesterolemia/hypertriglyceridemia with history of coronary artery disease (despite lipid-lowering treatment if given)
    • Acute and chronic, active infectious disorders and nonmalignant 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 hepatitis C virus (HCV).
    • Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    • Significant deterioration of lung function, defined as any of the following: 30% decrease in predicted lung volumes, and/or 30% decrease in DLCO, and/or = 88% O2 saturation at rest on room air
    7. Patients receiving chronic treatment with corticosteroids (except for intermittent topical or
    local injection or aldosterone) or another immunosuppressive agent
    8. Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A (see Table 6-5) unless the drugs are medically necessary and no substitutes are available. If there are no acceptable substitutes, special precautions should be taken in these patients (see Section 6.5.8.8).
    9. Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from surgery
    10. Female patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. Adequate contraceptives must be used throughout the trial and for 3 months after last study drug administration in both sexes. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to administration of RAD001 and/or sorafenib.
    11. Patients who have received an investigative drug or therapy within the last 30 days prior to Visit 1
    12. Patients unwilling or unable to comply with the protocol, in the opinion of the investigator
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    • Probability of DLT (Dose Limiting Toxicity) occurring during the first 28
    days of combined treatment of RAD001 with sorafenib

    Phase 2
    • Time to Progression
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    combined phase 1 / phase 2 trial
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    phase 1: open, non-randomized; phase 2: double-blind, randomized
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    end of trial will be LPLV (last visit of the last patient of this trial)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 130
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-12-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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