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    The EU Clinical Trials Register currently displays   37564   clinical trials with a EudraCT protocol, of which   6160   are clinical trials conducted with subjects less than 18 years old.
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    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
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    EudraCT Number:2012-004369-42
    Sponsor's Protocol Code Number:BAY73-4506/15983
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-09
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2012-004369-42
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled Phase-III Study of Adjuvant Regorafenib Versus Placebo for Patients with Stage IV Colorectal Cancer After Curative Treatment of Liver Metastases
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This clinical study evaluates and compares the efficacy and safety of Regorafenib versus placebo in patients with colorectal cancer after curative resection of liver metastasis and completion of all planned chemotherapy.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberBAY73-4506/15983
    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 SponsorBayer AG
    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 supportBayer AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team / Ref: "EU CTR" Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    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. name Stivarga
    D. of the Marketing Authorisation holderBayer Pharma AG.
    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 nameRegorafenib
    D.3.2Product code BAY 73-4506
    D.3.4Pharmaceutical form Film-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.3.9.2Current sponsor codeBay 73-4506
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboFilm-coated 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
    Metastatic Colorectal Cancer
    E.1.1.1Medical condition in easily understood language
    Cancer of the colon or rectum
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate and compare the efficacy and safety of regorafenib versus placebo in subjects with colorectal cancer (CRC) after curative resection of liver metastasis and completion of all planned chemotherapy.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible subjects must:

    1. Be male or female, and ≥ 18 years of age

    2. Have a history of a primary adenocarcinoma of the colon and / or

    3. Have a history of Stage IV CRC with metastases to the liver only

    4.Have received at least 3 months of neoadjuvant, adjuvant, or perioperative chemotherapy, including a fluoropyrimidine and either oxaliplatin or irinotecan or both for subjects with initial Stage IV CRC which were treated with surgery with curative intent for both primary and metastatic lesions. The total chemotherapy administered, including
    that administered prior to and after liver resection, should not exceed 9 months.


    Have received surgery with curative intent for primary CRC and at least 3 months of neoadjuvant, adjuvant, or perioperative chemotherapy for the primary tumor, including a fluoropyrimidine or a fluoropyrimidine and either oxaliplatin or irinotecan or both

    •For subjects with liver metastases developing > 6 months after completing treatment for primary CRC and having undergone surgery with curative intent for liver metastases, a second course of chemotherapy lasting at least 3 months needs to be administered,
    including a fluoropyrimidine and either oxaliplatin or irinotecan or both. The second course of chemotherapy should not exceed 9 months.

    •For subjects who developed liver metastases ≤ 6 months after completing treatment for primary CRC and having undergone surgery with curative intent for liver metastases, a second course of chemotherapy is not permitted unless initial adjuvant therapy consisted
    of fluoropyrimidine monotherapy. Subjects who received fluoropyrimidine alone must have received a second course of chemotherapy with fluoropyrimidine and either oxaliplatin or irinotecan or both, which should not exceed 9 months. For subjects with initial Stage I or II disease, no chemotherapy is required for a primary CRC lesion treated with surgery with curative intent. These subjects must receive chemotherapy for the treatment of
    liver metastases (which were also treated with surgery with curative intent), which must last at least 3 months, including a fluoropyrimidine and either oxaliplatin or irinotecan or both. The total course of chemotherapy should not exceed 9 months.

    Radiofrequency ablation and chemoembolization are not permitted. Subjects undergoing a planned 2-stage resection of liver metastases may be enrolled into the study.

    5. Have tumor tissue (of primary tumor and liver metastases or at least one of the two) available for biomarker analysis (to be collected as soon as possible before or after randomization).

    6. Prior to randomization, have histological confirmation that CRC lesions were adenocarcinoma (subtypes of adenocarcinoma, eg, mucinous adenocarcinoma, are allowed). Subjects with CRC lesions of other histologic types, including mixed type with predominant adenocarcinoma, will not be eligible to be randomized to study

    7. Prior to randomization, have pathology-proven complete removal of all primary and liver metastatic CRC lesions. Subjects with positive margins will not be eligible for the study.

    8.Have had a CT or MRI scan (chest, abdomen, pelvis and other suspected sites as applicable) to determine eligibility for randomization within 4 weeks prior to randomization (hereafter referred to as the "eligibility scan")

    9.Have absence of disease on the eligibility scan (CT/MRI) as assessed by the investigator and confirmed by central radiology review as defined in the imaging charter.

    10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to the initiation of study treatment

    11. Have adequate bone marrow function, liver function, and renal function, as measured by laboratory assessments conducted within 7 days prior to the initiation of study treatment.

    12. Understand, be willing to give consent, and sign the written informedconsent form (ICF) prior to undergoing any study-specific procedure.

    13. Be willing to give consent and sign the ICF for tumor tissue collection (primary tumor and liver metastases).

    14. Be willing to give consent and sign the ICF for the genetic testing unless precluded by local guidelines (eg, Independent Ethics Committee [IEC]/Institutional Review Board [IRB] or Regulatory Authority).

    15. If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment.

    16. If female and of childbearing potential, or if male, agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug.
    E.4Principal exclusion criteria
    1.Are taking strong CYP3A4 inhibitors(eg,clarithromycin,indinavir,itraconazole,ketoconazole,nefazod one,nelfinavir,posaconazole,ritonavir,saquinavir,telithromycin,voriconazole)or strong CYP3A4 inducers (eg,carbamazepine,phenobarbital,phenytoin,rifampin,St. John's Wort).
    2.Have used biologic response modifiers,such as granulocyte-colony stimulating factor,within 3 weeks prior to signing the ICF
    3.Have had prior treatment with regorafenib or any other VEGFRtargeting kinase inhibitor.
    4.Have had anti-cancer treatment following liver resection that exceeded a duration of 6 months.
    5.Have been treated with biologics(eg,antibodies targeting VEGFR or EFGR)after liver resection unless the administration of the biologic started prior to liver resection and continued after liver resection only to complete a pre-specified number of cycles.
    6.Completed their last dose of chemotherapy or had their last cancer surgery more than 10 weeks,whichever came later,prior to randomisation.
    7.Have extra-hepatic metastatic disease.Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease prior to submitting for central radiology review.
    8.Have been previously assigned to treatment during this study(subjects permanently withdrawn from study treatment will not be allowed to reenter the study).
    9.Have had prior or concurrent cancer distinct in primary site or histology from CRC within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ,nonmelanoma skin cancer.Stage 0 intramucosal gastric cancer after endoscopic complete removal,or superficial bladder tumors classified as noninvasive tumor(Ta),carcinoma in situ(Tis),or tumor invades lamina propria(T1).
    10.Have had systemic anticancer therapy including cytotoxic therapy,signal transduction inhibitors,immunotherapy,and/or hormonal therapy within 4 weeks prior to initiation of study treatment.
    11.Have unresolved toxicity higher than National Cancer Institute-
    Common Terminology for Adverse Events version 4.0(NCI-CTCAE v 4.0)Grade 1 attributed to any prior therapy/procedure,excluding alopecia and/or oxaliplatin-induced neurotoxicity≤Grade 2 and hemoglobin≥9g/dL as per inclusion criteria.
    12.Have had a major surgical procedure,open biopsy,or significant traumatic injury within 28 days prior to initiation of study treatment.
    13.Are pregnant.
    14.Are breastfeeding.
    15.Are unable to swallow oral tablets(crushing of study treatment tablets is not allowed).
    16.Have congestive heart failure classified as New York Heart Association Class 2 or higher.
    17.Have had unstable angina(angina symptoms at rest)or new-onset angina ≤3months prior to screening.
    18.Have had a myocardial infarction <6 months prior to initiation of study treatment.
    19.Have cardiac arrhythmias requiring anti-arrhythmic therapy,with the exception of beta blockers or digoxin.
    20.Have uncontrolled hypertension(systolic blood pressure >140 mmHg or diastolic blood pressure >90mmHg)despite optimal medical management.
    21.Have pheochromocytoma.
    22.Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident(including transient ischemic attacks),deep vein thrombosis,or pulmonary embolism within 6 months prior to the initiation of study treatment.
    23.Have an ongoing infection with severity of Grade 2 or above(NCICTCAE
    24.Have a known history of human immunodeficiency virus infection.
    25.Have either active hepatitis or chronic hepatitis B or C requiring treatment with antiviral therapy.
    26.Have a seizure disorder requiring medication.
    27.Have a history of organ allograft.
    28.Have evidence or history of any bleeding diathesis(including mild hemophilia), irrespective of severity.
    29.Have had a hemorrhage or a bleeding event ≥ Grade 3(NCI-CTCAE v 4.0)within 4 weeks prior to the initiation of study treatment.
    30.Have a nonhealing wound,ulcer,or bone fracture.
    31.Have renal failure requiring hemodialysis or peritoneal dialysis.
    32.Have dehydration ≥ Grade 1(NCI-CTCAE v 4.0).
    33.Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained.
    34.Have persistent proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCICTCAE v4.0).
    35.Have any other serious or unstable illness,or medical,psychological,or social condition,that could jeopardize the safety of the subject and/or
    his/her compliance with study procedures or may interfere with the
    subject's participation in the study or evaluation of the study results.
    36.Have a known hypersensitivity to any of the study drugs,study drug
    classes,or excipients in the formulation of the study drugs.
    37.Have any malabsorption condition.
    38.Have a close affiliation with the investigational site(eg,be a close relative of the investigator)or be a dependent person(eg,be an employee or student working at the investigational site).
    E.5 End points
    E.5.1Primary end point(s)
    Disease-free survival (DFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint, disease-free survival (DFS) as assessed by the investigator, will be measured by CT/MRI scans obtained at screening and every 3 months during the first 3 years of the study, then 6-monthly for a further year, then yearly until disease recurrence.
    E.5.2Secondary end point(s)
    Overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    All subjects will be followed until death (unless consent for Overall Survival follow-up is withdrawn).
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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. 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 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    United States
    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
    LVLS, however the end of the study as a whole will be reached when
    both event based endpoints , DFS and OS have been achieved according
    to the planned analyses of these endpoints
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    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: 375
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 375
    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 state29
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 271
    F.4.2.2In the whole clinical trial 750
    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)
    Following completion of treatment or withdrawal for any other reason, all subjects will have a 30-day Safety Follow-up visit. Subjects who finish treatment or withdraw from study treatment for any reason other than death or disease recurrence will enter Active Follow-up.
    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 Decision2013-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-09-28
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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