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    Summary
    EudraCT Number:2008-003972-23
    Sponsor's Protocol Code Number:hcc1
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2008-09-15
    Trial 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 number2008-003972-23
    A.3Full title of the trial
    Hepatocellular carcinoma: vascular abnormalities prior to, during and following systemic anti-cancer treatment
    A.3.2Name or abbreviated title of the trial where available
    everolimus and capecitabine for HCC
    A.4.1Sponsor's protocol code numberhcc1
    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 SponsorLUMC
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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.2.1.1.1Trade name Xeloda
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd, United Kingdom
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameXeloda 500 mg and xeloda 150 mg
    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.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.75
    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
    The primary objective of this study is to determine the efficacy of the combination of everolimus and capecitabine in a group of patients with metastatic or locally advanced HCC. In addition, to investigate biomarkers of HCC before and during the systemic treatment reflecting states of tumour cell growth and growth arrest (state of tumour cell dormancy).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10019829
    E.1.2Term Hepatocellular carcinoma recurrent
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10008452
    E.1.2Term Chemotherapy multiple agents systemic
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Progression-free survival (PFS) at 6 months measured by CT-scan at 3-months intervals

    2. Assessment of circulating levels of MP derived from vascular and/or tumour cells, and plasma MP-TF activity (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)

    3. Circulating levels of biomarkers of the vasculature including endothelium activation marker such as VCAM, L-CAM, and P-selectin (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)

    4. Investigation whether 2 and 3 are predictive factors for PFS and overall survival
    E.2.2Secondary objectives of the trial
    As secondary endpoints are defined:

    1. Objective complete and partial response rate (RECIST criteria [appendix 1]/Waterfall plot)

    2. Overall survival

    3. One year survival rate

    4. Safety

    5. Alterations in cellular source of circulating MP during treatment as compared to pretreatment MP phenotype.

    6. Assessment of development of venous thromboembolic events
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Cytological or histological confirmed HCC who failed the standard therapies or who are not suitable for the standard therapies, i.e. metastectomy or liver transplantation.
    - Age > 18 years.
    - ECOG Performance Status of 0-2.
    - Life expectancy of at least 12 weeks.
    - Subjects with at least one uni-dimensional measurable lesion. Lesions must be measured by CT-scan or MRI.
    - Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
    - Child-Pugh score of 7-9 points, i.e. Child-Pugh class B.
    - Total bilirubin < 4 times the upper limit of normal.
    - ALT and AST < 5 x upper limit of normal.
    - INR < 2.2 x upper limit of normal (patients who are being therapeutically anticoagulated with coumarin derivatives will be allowed to participate provided that no evidence of prior abnormality in these parameters exists).
    - Hemoglobin > 6 mmol/L.
    - Absolute neutrophil count (ANC) >1,500/mm3.
    - Platelet count  100,000/μl.
    - Serum creatinine < 2 x upper limit of normal.
    - Signed informed consent.
    - Sexually active patients, in conjunction with their partner, must practice birth control during and for 2 months after therapy.
    - Female patients at child-bearing age must have negative pregnancy test.
    E.4Principal exclusion criteria
    - History of cardiac disease: congestive heart failure >NYHA class 2; active coronary arterial disease (MI more than 6 mo prior to study entry is allowed); instable cardiac arrythmias; uncontrolled hypertension.
    - History of HIV infection.
    - Active clinically serious infections (> grade 2 NCI-CTC version 3.0) Hepatitis B carriers must be on lamivudine during and for 6 months after completion of study treatment.
    - Symptomatic metastatic brain or meningeal tumors
    - Patients with seizure disorder requiring medication (such as steroids or anti-epileptics).
    - Patients undergoing renal dialysis.
    - Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry.
    - Anticancer chemotherapy, immunotherapy, hormonal therapy, or radiotherapy during the study or within 4 weeks of study entry. Major surgery within 4 weeks of start of study.
    - Autologous bone marrow transplant or stem cell rescue within 4 months of study.
    - Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction]. Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study.
    - Investigational drug therapy outside of this trial during or within 4 weeks of study entry.
    - Prior exposure to the study drug.
    - Medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
    - Patients unstable to swallow oral medications.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this study is to determine the efficacy of the combination of everolimus and capecitabine in a group of patients with metastatic or locally advanced HCC with Child-Pugh class B liver cirrosis. In addition, to investigate biomarkers of HCC before and during the systemic treatment reflecting states of tumour cell growth and growth arrest (state of tumour cell dormancy). Circulating proteins can be measured and used as reasonably reliable markers of changes in tumour cell load (e.g., alfa fertoprotein).

    1. Progression-free survival (PFS) at 6 months measured by CT-scan at 3-months intervals

    2. Assessment of circulating levels of MP derived from vascular and/or tumour cells, and plasma MP-TF activity (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)

    3. Circulating levels of biomarkers of the vasculature including endothelium activation marker such as VCAM, L-CAM, and P-selectin (prior to and during systemic treatment and following cessation of systemic treatment during progressive disease)

    4. Investigation whether 2 and 3 are predictive factors for PFS and overall survival
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    vascular abnormalities prior to, during and following systemic anti-cancer treatment
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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 Information not present in EudraCT
    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 state28
    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 Decision2008-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-01-09
    P. End of Trial
    P.End of Trial StatusOngoing
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