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    The EU Clinical Trials Register currently displays   42732   clinical trials with a EudraCT protocol, of which   7035   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2013-005428-41
    Sponsor's Protocol Code Number:02044190615-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-10-13
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-005428-41
    A.3Full title of the trial
    Phase III study of RegorAfenib VErsus placebo as maintenance therapy in RAS wiLd type metastatic coLOrectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    maintenance therapy with regorafenib
    A.3.2Name or abbreviated title of the trial where available
    RAVELLO
    A.4.1Sponsor's protocol code number02044190615-01
    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 SponsorDepartment of experimental and clincial medicine "F. Magrassi"
    B.1.3.4CountryItaly
    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 supportDepartment of experimental and clinical medicine Department of experimental and clinical medicine "F.Magrassi"
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportBayer
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of experimental and clincial medicine "F. Magrassi"
    B.5.2Functional name of contact pointProf. Dr. Fortunato Ciardiello
    B.5.3 Address:
    B.5.3.1Street AddressVia Pansini 5
    B.5.3.2Town/ cityNaples
    B.5.3.3Post code80131
    B.5.3.4CountryItaly
    B.5.4Telephone number+390815666745
    B.5.5Fax number+390815666732
    B.5.6E-mailfortunato.ciardiello@unina2.it
    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 Stivarga
    D.2.1.1.2Name of the Marketing Authorisation holderBayer
    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.3.1Product nameStivarga
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    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 INNRegorafenib
    D.3.9.1CAS number 755037-03-7
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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) 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 No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The present proposal is aimed to evaluate the efficacy and safety of regorafenib as maintenance therapy in increasing the efficacy of the best available therapy for first line treatment fluoropirimidine based chemotherapy , any variant, in combination with either cetuximab or panitumumab) of RAS wild type metastatic colorectal cancer patients.
    Ziel der vorliegenden Studie ist die Evaluierung der Wirksamkeit und Sicherheit von Regorafenib als Erhaltungstherapie zur Erhöhung der Wirksamkeit der besten verfügbaren Therapie zur Erstbehandlung (Fluoropirimidine basierte Chemotherapie in jeder Variante, in Kombination mit entweder Cetuximab oder Panitumumab) für Patienten mit metastasiertem Kolorektalkarzinom des Typs RASwild.
    E.1.1.1Medical condition in easily understood language
    Regorafenib as maintenance therapy of RAS wild type metastatic
    colorectal cancer patients.
    Regorafenib als Erhaltungstherapie für Patienten mit metastasiertem RAS Wildtyp Kolorektalkarzinom.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    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
    The objective of this study is to evaluate efficacy and safety of regorafenib in the maintenance of the response in patients with metastatic colorectal (CRC) RAS wild type after first line therapy
    (fluoropirimidine-based plus anti-EGFR Abs). The primary efficacy endpoint of this study is Progression Free Survival (PFS) defined as the time(days) from randomization for maintenance therapy with study drug to PD or death whichever comes first.
    Ziel dieser Studie ist die Evaluierung der Wirksamkeit und Sicherheit von Regorafenib als Erhaltungstherapie zur Erhöhung der Wirksamkeit der besten verfügbaren Therapie zur Erstbehandlung (Fluoropirimidine basierte Chemotherapieplus EGFR Abs) für Patienten mit metastasiertem Kolorektalkarzinom des Typs RASwild. Der primäre Endpunkt ist das Progression Free Survival (PFS) definiert als die Zeitspanne (Anzahl der Tage) vom Zeitpunkt der Randomierierung bis zur Progression der Krankheit oder bis zum Tod, je nachdem welches Ereignis zuerst eintritt.
    E.2.2Secondary objectives of the trial
    - Overall survival (OS)
    - Safety Profile
    - Biomarker correlative studies
    - Überleben
    - Verträglichkeit / Nebenwirkungsprofil
    - Biomarker-Korrelationsstudien
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Signed informed consent obtained before any study specific procedures. Patients must be able to understand and willing to sign a written informed consent.
    •Male or female patients > 18 years
    •Histological or cytological documentation of adenocarcinoma of the colon or rectum
    •Genetic diagnosis of RAS(hot spot mutations KRAS codon 2-3-4 and NRAS at least codon 2-3) wild type tumor .
    •Previous standard first line treatment defined as fluoropirimidine based chemotherapy (any variant) in combination with either cetuximab or panitumumab for a minimum of 4 months and a maximum of 8 months.
    •Patients that have achieved either partial response (PR) , complete response (CR) or stable disease (SD) at the completion of the first line treatment after a minimum of 4 months (8 cycles) and a maximum of 8 months (16 cycles) .
    •Patients with PR/SD must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria, version 1.1).
    •Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
    •Life expectancy of at least 6months.
    •Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
    o Total bilirubin < 1.5 x the upper limit of normal (ULN).
    o Alanine transaminase (ALT) and aspartate aminotransferase (AST) <3 x ULN (<5 x ULN for patients with liver involvement of their cancer).
    o Serum creatinine< 1.5 x the ULN.
    o Estimated creatinine clearance (CLcr) ≥ 30 mL/min as calculated using the Cockcroft-Gault equation.
    o INR/PTT < 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g. heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.
    o Platelet count ¬> 100000 /mm3, Hemoglobin (Hb) > 9 g/dl, Absolute neutrophil count (ANC) > 1500/mm3
    o Alkaline phosphatase limit < 2.5 x ULN (<5 x ULN for patients with liver involvement of their cancer)
    o Lipase < 1.5 x ULN
    •Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
    •Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.
    E.4Principal exclusion criteria
    •Prior treatment with regorafenib.
    •Interruption of the first line treatment for progressive disease or in which progressive disease was diagnosed prior to entry into this study.
    •Assumption of strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort) (see Section 13.1)
    •Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Non invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
    •Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
    •Congestive heart failure > New York Heart Association (NYHA) class 2.
    •Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study medication.
    •Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
    •Uncontrolled hypertension. (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
    •Patients with phaeochromocytoma.
    •Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication.
    •Ongoing infection > grade 2 NCI-CTC version 3.0.
    •Known history of human immunodeficiency virus (HIV) infection.
    •Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiretroviral therapy.
    •Patients with seizure disorder requiring medication.
    •Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
    •History of organ allograft
    •Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks of start of study medication.
    •Non-healing wound, ulcer, or bone fracture.
    •Renal failure requiring hemo-or peritoneal dialysis.
    •Dehydration NCI-CTC version 3.0 grade > 1.
    •Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
    •Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
    •Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
    •Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
    •Patients unable to swallow oral medications
    •Persistent proteinuria of CTC Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
    •Any malabsorption condition
    •Unresolved toxicity higher than NCI-CTCAE (version 3.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia,oxaliplatin induced neurotoxicity and anti-EGFR Ab induced skin toxicity ≤ Grade 1
    •Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free Survival (PFS)
    Progressionsfreies Überleben
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 months
    9 Monate
    E.5.2Secondary end point(s)
    Overall Survival
    Safety
    Überleben
    Verträglichkeit
    E.5.2.1Timepoint(s) of evaluation of this end point
    20 months
    20 Monate
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    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
    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 months0
    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 months0
    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: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 480
    F.4.2.2In the whole clinical trial 480
    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)
    The post-trial treatment of the patients is carried out according to the standard of care at the discretion of the attending physician.
    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 Decision2014-11-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-01
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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