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    Summary
    EudraCT Number:2009-009992-36
    Sponsor's Protocol Code Number:S51532
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-10-18
    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 ConcernedAustria - BASG
    A.2EudraCT number2009-009992-36
    A.3Full title of the trial
    A two arm phase II study of FOLFIRI in combination with standard or escalating dose of cetuximab as first line treatment of K-Ras wild type metastatic colorectal cancer: Everest 2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Everest 2. A study for previously not treated patients with spread colorectal cancer characterized by the presence of wild non mutated K-Ras gene involving standard chemotherapy (FOLFIRI) and cetuximab either at standard or increased doses depending on the skin reactions determined by treatment.
    A.3.2Name or abbreviated title of the trial where available
    Everest 2
    A.4.1Sponsor's protocol code numberS51532
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01251536
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Leuven
    B.1.3.4CountryBelgium
    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 supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Leuven
    B.5.2Functional name of contact pointDigestive Oncology Unit
    B.5.3 Address:
    B.5.3.1Street AddressHerestraat 49
    B.5.3.2Town/ cityLeuven
    B.5.3.3Post code3000
    B.5.3.4CountryBelgium
    B.5.4Telephone number3216340495
    B.5.5Fax number3216344419
    B.5.6E-mailpharmacovigilance_everest2@uzleuven.be
    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 Yes
    D.2.1.1.1Trade name Erbitux 5 mg/ml solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderMerck KGaA
    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 Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCETUXIMAB
    D.3.9.1CAS number 205923564
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    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
    K-Ras wild type metastatic colorectal cancer
    E.1.1.1Medical condition in easily understood language
    Spread colorectal cancer (stage IV) with K-Ras gene present in Wild Type form
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To provide an estimate (+/- 15%) of the progression-free survival (PFS) rate at 9 months, in patients without skin toxicity at 3 weeks (according to NCI CTCAE v. 4.0), treated with FOLFIRI + escalating dose of cetuximab (arm A). It is expected that the PFS rate will be similar to that observed after standard cetuximab treatment + FOLFIRI in patients with grade 1-4 skin toxicity in a K-Ras wild type population (CRYSTAL study).
    E.2.2Secondary objectives of the trial
    To evaluate PFS, overall survival (OS), overall response and response rate in liver-limited disease, disease control rate, duration of response, general resection rate and R0 resection rate for metastatic lesions, skin toxicity, general safety, biomarkers, proteomics, expression profiling, mutations in each of the treatment arms.

    To evaluate pharmacokinetic parameters in patients in both treatment arms in selected centers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent (+ optional for PK and TR) must be given according to ICH/GCP and national/local regulations.
    2. Patient is at least 18 years of age.
    3. Patient’s body weight is ≤ 120 kg.
    4. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon or rectum, not in a previously irradiated area.
    5. K-Ras wild type tumour eligible for treatment with cetuximab.
    6. Unresectable metastatic disease.
    7. Metastatic lesion accessible for biopsy.
    8. Life expectancy of at least 12 weeks.
    9. WHO ECOG performance status: 0 or 1.
    10. Effective contraception for both male and female patients if the risk of conception exists.
    11. Adequate organ function.
    12. Adequate bone marrow, hepatic and renal function (assessed within 14 days prior to study entry):
    - Hemoglobin >10.0 g/dL, absolute neutrophil count > 1.5 x 109/L, platelet count > 100 x 109/L
    - ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver metastases
    - Total bilirubin < 1.5 x ULN
    - Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault)
    E.4Principal exclusion criteria
    1. Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on study).
    2. Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant settings.
    3. Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry.
    4. Administration of any investigational drug or agent/procedure and participation in another trial within 4 weeks before the conclusion.
    5. Radiotherapy within 3 weeks before inclusion. However, radiotherapy for symptom control not on target lesions may be permitted at the condition that grade >= 2 RT related adverse events have resolved at the time of inclusion.
    6. Any active dermatological condition of grade > 1.
    7. Brain metastasis (known or suspected).
    8. Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory bowel disease).
    9. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection.
    10. Uncontrolled coronary artery disease and/or unstable angina, a history of a myocardial infarction within the last 12 months or heart failure NYHA class III or IV. High risk of uncontrolled arrhythmia.
    11. Known allergy or any other adverse reaction to any of the drugs or to any related compound.
    12. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
    13. Gilbert disease.
    14. Previous (within 5 years) or concurrent malignancies at other sites with the exception of surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell carcinoma of the skin.
    15. Organ allografts requiring immunosuppressive therapy.
    16. Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in pre-menopausal women) or breast-feeding.
    17. Medical, social or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival rate at 9 months in the dose escalation arm.
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 months
    E.5.2Secondary end point(s)
    1. Progression Free Survival
    2. Overall Survival
    3. Response and disease control rate - response evaluation according to RECIST criteria (CT scan or MRI)
    4. Duration of response
    5. Response rate in liver-limited disease
    6. Skin toxicity
    7. Efficacy in patients experiencing skin toxicity and patients not experiencing skin toxicity after dose escalation in Arm A
    8. General safety
    9. Number of resections form metastatic lesions and R0 rate
    10 Pharmacokinetics
    11. Molecular studies
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. at 9 months
    2. every 6 month for a maximum of 3 years after the database lock
    3. every 8 weeks for 6 months and then every 12 weeks
    4. every 8 weeks or 12 weeks
    5. every 8 weeks or 12 weeks
    6. weekly for duration fo study
    7. every 8 during treatment or 12 weeks in follow up
    8. at each time point
    9. every 8 weeks or 12 weeks
    10 weekly steady state sampling until week 24 - 1 hour prior to cetuximab infusion
    11. Tissue sample collection at baselie, week 4 and progression, blood sample collection at baseline, 3 timepoints during treatment and at progression. Analyses to be performed after study closure.
    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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 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 No
    E.8.1.7Other No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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 No
    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
    LVLS and study discontinuation is at the discretion of the sponsor and Merck KGaA in any of the following events:
    • Medical or ethical reasons affecting the continued performance of the study.
    • Difficulties in the recruitment of patients.
    • Occurrence of AEs unknown to date in respect of their nature, severity and duration, or, unexpected incidence/severity of known AEs.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 130
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care
    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 Decision2010-11-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-10-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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