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    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-005655-16
    Sponsor's Protocol Code Number:Regard-CrC_2012
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-28
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-005655-16
    A.3Full title of the trial
    Regorafenib Assessment in Refractory advanced Colorectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Regorafenib in patients with a metastatic colorectal cancer resistant to all other therapies.
    A.3.2Name or abbreviated title of the trial where available
    Regard-C
    A.4.1Sponsor's protocol code numberRegard-CrC_2012
    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 SponsorInstitut Jules Bordet
    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 supportInstitut Jules Bordet
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut Jules Bordet
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address1, rue Heger Bordet
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1000
    B.5.3.4CountryBelgium
    B.5.4Telephone number003225413541
    B.5.5Fax number003225380858
    B.5.6E-mailalain.hendlisz@bordet.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 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 nameRegorafenib
    D.3.2Product code BAY 73-4506
    D.3.4Pharmaceutical form 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.3.9.2Current sponsor codeREGORAFENIB
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB30623
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced refractory colorectal cancer
    E.1.1.1Medical condition in easily understood language
    Metastatic colorectal cancer that do no longer respond to standard treatments
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    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 identify in a population of patients bearing advanced, refractory colorectal cancers, those who draw no benefit from treatment with regorafenib. There is no specific hypothesis underlying sample size and the study is therefore to be seen as exploratory. Overall Survival (OS) will be used as primary endpoint. Covariates that will be analyzed in relationship with OS will be metabolic parameters obtained at baseline and very early following treatment initiation as well as genetic, epigenetic and molecular aberrations (before and after treatment) assessed from tumor biopsies and blood samples, in addition to known clinical and pathological factors. The molecular aberrations will be investigated using gene expression profiling, RNA and exome sequencing, and methylation profiling of the tumor biopsies and repeated blood samples taken during therapy.
    E.2.2Secondary objectives of the trial
    • To analyze PFS and response rate (RR) in relationship with the same covariates as for OS
    • To assess regorafenib efficacy (OS, PFS, RR) and safety profile in this study population.
    • To assess the Disease control rate (DCR = Complete response [CR] + partial response [PR] + stable disease [SD])
    • To compare the relative benefit (OS, PFS) of regorafenib according to history of treatment with bevacizumab.
    •To validate the relationship that was found, in a previous study (the SoMore study ref 28) conducted in the same patients population treated with Sorafenib, between overall survival and early metabolic homogeneous response (all lesions responding, yes or no).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically proven adenocarcinoma of the colon or the rectum that is metastatic or unresectable and for which standard treatments do not exist or are no longer effective.
    2.The tumor should be refractory to all standard chemotherapy agents (fluoropyrimidines, irinotecan, and oxaliplatin) and anti-EGFR monoclonal antibodies in case of wild type K-ras (cetuximab or panitumumab) administered before study entry. Patients treated with oxaliplatin in an adjuvant setting should have progressed during adjuvant therapy or within 6 months of completion of this treatment. Patients who do not meet strictly this criteria, but for whom further treatment with oxaliplatin would be prohibited ( for instance allergic reaction, residual neurotoxicity grade ≥2) are allowed for inclusion. Prior treatment with bevacizumab and/or aflibercept is allowed but not mandatory.
    3. Age ≥ 18 years.
    4. Life expectancy of greater than 12 weeks.
    5. ECOG performance status ≤ 1.
    6. Participants must have normal organ and bone marrow function as defined below:
    o Leukocytes > 3,000/mcL, with an absolute neutrophil count > 1,500/mcL, platelets > 100,000/mcL, Hb9g/dl.
    o Total bilirubin ≤ 1.5 × institutional ULN.
    bilirubin total can be > 1.5× institutional ULN in case of Gilbert syndrome ( where direct bilirubin only should be ≤ 1.5 × institutional ULN)
    o AST/ALT levels ≤ 2.5 × institutional ULN (≤ 5x institutional ULN in case of liver metastatic involvement).
    o P-Alk levels ≤5 x institutional ULN except in case of bone metastasis (then the liver fraction of P-Alk should be less than 5x institutional ULN).
    o International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x institutional ULN. Note: Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
    o Creatinine ≤ 1.5× institutional ULN or creatinine clearance >30mL/min according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
    7. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, during regorafenib administration until at least 3 months after the last study drug administration (last day of the last cycle). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    8. Signed Written Informed Consent (IC) (approved by an Independent Ethics Committee (IEC) and obtained prior to any study related procedure).
    9Presence of a previously collected frozen or FFPE primary or metastatic tumor. Frozen tissue from the primitive tumor is preferred. In addition, the collection of fresh tissue in the primary or a metastatic FDG-PET targetable lesion before study entry is mandatory.
    10. Presence of at least one metabolically measurable tumoral lesion on FDG PET-CT, fulfilling following criteria:
    o Size ≥ 1.5cm; AND
    o FDG uptake above the background liver uptake as described below:
    i.e. with a marked accumulation of FDG, at least 1.5-fold greater than liver SUV mean + 2 SDs (in 3-cm spherical ROI in normal right lobe of liver). If liver is abnormal, target lesion should have uptake > 2.0 x SUV mean of blood pool (in 1-cm-diameter ROI in descending thoracic aorta)+ 3SDs.
    11. Participants must consent that biopsy could be taken from a PET-positive lesion before beginning the therapy.
    Archived tissue needs to be available at the study entry.
    E.4Principal exclusion criteria
    Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
    1. Prior treatment with sorafenib or regorafenib
    2. Patients with previous cancer that is not disease-free for at least for 5 years prior to registration, 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)].
    3. Participants who have had a major surgery, chemotherapy or radiotherapy within 4 weeks prior to entering the study.
    4. Unresolved toxicity higher than NCI-CTCAE (version 4.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤Grade 2.
    5. Participants receiving any experimental agents.
    6. Participants with known brain metastases.
    7. Bleeding diathesis, history of cardiovascular ischemic disease or cerebrovascular incident within the last six months.
    8. Any hemorrhage or bleeding event NCI-CTCAE v.4 Grade 3 within 4 weeks prior to the start of study medication.
    9. Uncontrolled concurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association (NYHA) class 2), unstable angina pectoris (defined by angina symptoms at rest or new-onset angina started within the last 3 months), cardiac arrhythmia requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
    10. Uncontrolled hypertension (defined by systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management).
    11. Patients with phaeochromocytoma.
    12. Patients with seizure disorder requiring medication.
    13 Any history of organ allograft.
    14. Pleural effusion or ascites affecting respiration (NCI CTCAEv.4 Grade ≥ 2 dyspnea).
    15. Uncontrolled diabetes.
    16. Non-healing wound, ulcer, or bone fracture.
    17. Known history of human immunodeficiency virus (HIV) infection, or active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
    18. Interstitial lung disease with ongoing signs and symptoms.
    19. Renal failure requiring hemo-or peritoneal dialysis.
    20. Dehydration NCI-CTCAE v.4 grade> 1.
    21. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s ability to understand informed consent and participation in the study or evaluation of the study results.
    22. Known hypersensitivity to the study drug or excipients in the formulation.
    23. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
    24. Pregnant or lactating women.
    25. Subjects unable to swallow oral medications.
    26. Refusal to undergo a PET-targeted fresh biopsy.
    27.Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment within 6 months of informed consent.
    28.Persistent proteinuria > Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hours, measured by urine protein: creatinine ratio on a random urine sample).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is OS of patients bearing an advanced refractory colorectal cancer treated with regorafenib, according to baseline variables, early metabolic response measured by serial FDG-PET/CT before and during the first course of therapy and early molecular changes. For this primary analysis, only patients who undergo the post therapeutic examinations ( (FDG/PET and the data generated from gene expression profiling, RNA, exome sequencing and methylation profiling) will be eligible for analysis. Overall Survival (OS) is defined as the time from the second examinations to death due to any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is overal survival. The timepoints will be death of the patients.
    E.5.2Secondary end point(s)
    • PFS and RR of patients bearing an advanced refractory colorectal cancer treated with regorafenib, according to baseline covariates and to early metabolic and molecular changes measured after the first course of therapy. For this secondary analysis, only patients who undergo the post-therapeutic examinations will be eligible. PFS is defined from the follow-up investigations to the first occurrence of progression of disease or death. RR will be defined according to radiological examinations and assessment will be done using RECIST 1.1.
    • PFS, OS safety profile and objective RR according to RECIST 1.1 for the whole “intent-to-treat” patients’ population. For this secondary analysis, all eligible patients included in the trial will be included and “time zero” will be the date of inclusion. Toxicity will be measured using the adverse events reported during the therapy according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. (Available on the NCI website at the following address (http://evs.nci.nih.gov/ftp1/CTCAE). See section 8: Assessment of Safety.
    • Description of the Disease Control Rate (DCR) of the patients at first radiological assessment.
    • Description of OS and PFS of patients pretreated and not pretreated by bevacizumab.
    E.5.2.1Timepoint(s) of evaluation of this end point
    .PFS and RR according to early metabolic changes : PFS and RR assessment, will be done every 8 weeks, or sooner if clinically justified and will be correlated with the early metabolic assessment done at day 14 after treatement begin.
    .PFS, OS safety profile and objective RR of the overall intent to treat population: PFS and RR assessment, will be done every 8 weeks, or sooner if clinically justified.
    .Description of OS and PFS of patients pretreated and not pretreated by bevacizumab.Analysis restricted to the bevacizumab pretreated population.

    . Description of the Disease Control Rate (DCR) of the patients at first radiological assessment : PFS and RR assessment, will be followed every 8 weeks, or sooner if clinically justified.
    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 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) 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 concerned18
    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 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 years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 140
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state140
    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)
    At the physician's discretion
    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 Decision2013-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-26
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