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    Summary
    EudraCT Number:2009-012787-14
    Sponsor's Protocol Code Number:BAY73-4506/14387
    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:2010-03-08
    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 ConcernedGermany - BfArM
    A.2EudraCT number2009-012787-14
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled phase III study of regorafenib plus BSC versus placebo plus BSC in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized, double-blind, placebo-controlled phase III study of regorafenib plus BSC versus placebo plus BSC in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapy
    A.3.2Name or abbreviated title of the trial where available
    CORRECT
    A.4.1Sponsor's protocol code numberBAY73-4506/14387
    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 HealthCare AG
    B.1.3.4CountryGermany
    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 HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer Healthcare 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
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.com
    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 codeBay 73-4506
    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 placeboTablet
    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 Carcinoma
    E.1.1.1Medical condition in easily understood language
    Metastatic Colorectal Carcinoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10010036
    E.1.2Term Colorectal carcinoma
    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 16.1
    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 16.1
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term 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
    To evaluate efficacy and safety of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapies.

    The primary efficacy endpoint of this study is Overall survival
    E.2.2Secondary objectives of the trial
    The secondary efficacy endpoints of this study are Progression free survival, objective tumor response rate and Disease control rate.
    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 of age.
    • Histological or cytological documentation of adenocarcinoma of the colon or rectum.
    All other histological types are excluded.
    • Patients with metastatic colorectal cancer (Stage IV).
    • Progression during or within 3 months following the last administration of approved standard therapies which must include fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and cetuximab or panitumumab (if KRAS WT). Patients treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy. Patients who progress more than 6 months after completion of oxaliplatin containing adjuvant treatment must be retreated with oxaliplatin-based therapy to be eligible. Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be allowed into the study. Patients with an unknown KRAS status at screening must have received prior anti-EGFR treatment.
    • Metastatic CRC patients must have measurable or non 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 3 months.
    • Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months 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.
    • 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) ≤ 2.5 x ULN
    (≤5 x ULN for patients with liver involvement of their cancer).
    o Amylase and lipase ≤ 1.5 x the ULN
    o Serum creatinine ≤ 1.5 x the ULN.
    o Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the MDRD (Modified diet in renal disease) abbreviated formula
    o INR/PTT ≤ 1.5 x ULN (Patients who are being therapeutically anti-coagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in this parameter 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 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)
    E.4Principal exclusion criteria
    • Prior treatment with regorafenib.
    • Previous assignment to treatment during this study. Patients permanently withdrawn from study treatment participation will not be allowed to re-enter the study.
    • 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)].
    • Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to randomization. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
    • 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 > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
    • Patients with phaeochromocytoma.
    • Pleural effusion or ascites that causes respiratory compromise (≥ CTC Grade 2 dyspnea).
    • 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.
    • Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
    • Patients with seizure disorder requiring medication.
    • Any history of or currently known brain metastases.
    • History of organ allograft
    • Patients with evidence or history of any bleeding diasthesis, irrespective of severity.
    • Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the 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
    • 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 that would have access to study records and eCRF data)
    • Unresolved toxicity higher than NCI-CTCAE (version 3.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤Grade 2
    • Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 4 weeks (or within 6 weeks for mitomycin C) before starting to receive study medication.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint: Overall survival (OS), improvement from 4.5 to 6 months median OS (33.3% improvement, HR of 0.75)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Will be evaluated when there are 582 events/deaths
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    Progression free survival
    Objective tumor response rate
    Disease control rate
    E.5.2.1Timepoint(s) of evaluation of this end point
    Will be evaluated when there are 582 events/deaths
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA73
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    China
    France
    Italy
    Japan
    Netherlands
    Australia
    Czech Republic
    Germany
    Hungary
    Spain
    Israel
    Switzerland
    Turkey
    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
    The end of the study will be reached when the last visit of the last patient for all centers in the respective country has occurred. However, as the primary endpoint of this study is event-based, the end of the study as a whole will only be reached when this endpoint has been achieved in patients in all participating centers (EU and non-EU).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 475
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 285
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 236
    F.4.2.2In the whole clinical trial 690
    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)
    Since patients have been already treated with all therapies for metastatic colorectal cancer, there are currently no other recommended approved treatments. Alternative treatments (experimental and/or not experimental) may include other drugs or drug combinations, radiation therapy, or supportive care therapy. Many doctors may choose to place patients in a clinical trial or treat patients for symptom relief only (best supportive 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 Decision2010-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-05-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-01-22
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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