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    The EU Clinical Trials Register currently displays   31416   clinical trials with a EudraCT protocol, of which   5045   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2009-017957-37
    Sponsor's Protocol Code Number:BAY73-4506/14874
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2010-11-11
    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 ConcernedUK - MHRA
    A.2EudraCT number2009-017957-37
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study is designed to compare the treatment with regorafenib plus best supportive care versus placebo plus best supportive care in patients suffering with gastrointestinal cancer whose disease has progressed despite prior treatment with at least imatinib and sunitinib.
    A.3.2Name or abbreviated title of the trial where available
    BAY73-4506 Phase III GIST 3rd/4th line
    A.4.1Sponsor's protocol code numberBAY73-4506/14874
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01271712
    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.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 AG
    B.4.2CountryGermany
    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
    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 monhydrate
    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 and /or unresectable gastrointestinal tumors (GIST)
    E.1.1.1Medical condition in easily understood language
    gastrointestinal cancer
    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 10062427
    E.1.2Term Gastrointestinal stromal tumor
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10051066
    E.1.2Term Gastrointestinal stromal tumour
    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 primary objective of this phase III study in subjects with metastatic and/or unresectable GIST who have progressed after therapy with at least imatinib and sunitinib is to compare the treatment groups in terms of Progression-Free Survival (PFS), per blinded central radiology review, according to RECIST criteria (version 1.1).
    E.2.2Secondary objectives of the trial
    The secondary objectives are to compare the regorafenib and placebo treatment groups in terms of overall survival (OS), time to progression (TTP), disease control rate (DCR), tumor response rate (RR), duration of response (DOR), and safety of regorafenib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent obtained before any study specific procedures. Subjects must be able to understand and willing to sign a written informed consent.
    2. Male or female subjects 18 years of age or older.
    3. Subjects with histologically confirmed metastatic and/or unresectable GIST.
    4. At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor (VEGFR) inhibitor.
    5. Subjects must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrollment.
    6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
    7. Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
    - Total bilirubin </= 1.5 x the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).
    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3.0 x ULN (</= 5 x ULN for subjects with liver involvement of their GIST).
    - Lipase </= 1.5 x the ULN
    - Serum creatinine </= 1.5 x the ULN.
    - Glomerular filtration rate (GFR) >/= 30 ml/min/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
    - International normalized ratio and partial thromboplastin time (INR and PTT) </= 1.5 x ULN.
    Subjects who are being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that 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.
    - Platelet count >/= 100000/mm3, hemoglobin (Hb) >/= 9.0 g/dl, absolute neutrophil count (ANC) >/=1500/mm3. Transfusion of subjects to meet the inclusion criteria will not be allowed.
    - Alkaline phosphatase limit </= 2.5 x ULN (</= 5 x ULN for subjects whose cancer involves their liver).
    8. Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).
    E.4Principal exclusion criteria
    1. Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
    2. Prior treatment with any vascular endothelial growth factor receptor (VEGFR) inhibitor except sunitinib.
    3. Subjects who have received:
    - any other approved tyrosine kinase inhibitor within 1 week or a minimum of 5 drug half-lives, whichever is longer (i.e. within 7 days for imitanib, or within 10 days for sunitinib).
    - any other investigational new drugs within 4 weeks or 5 drug half-lives (if drug half-life in subjects is known), whichever is shorter.
    4. Cancer other than GIST 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], and Tis [Carcinoma in situ]).
    5. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
    6. Pregnant or breast-feeding subjects. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study medication and a negative result must be documented before start of study medication.
    Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) since signing of the informed consent form until at least 3 months after the last study drug administration. The definition of adequate contraception will be based on the judgment of the treating investigator or a designated associate.
    7. Congestive heart failure New York Heart Association (NYHA) >/= class 2.
    8. Unstable angina (angina symptoms at rest, new-onset angina, i.e., within the last 3 months) or myocardial infarction (MI) within the past 6 months before start of study medication.
    9. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
    10. Uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
    11. Subjects with pheochromocytoma.
    12. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study drug.
    13. Venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug
    14. Ongoing infection > grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
    15. Known history of human immunodeficiency virus (HIV) infection.
    16. Subjects with seizure disorder requiring medication.
    17. Symptomatic metastatic brain or meningeal tumors
    18. History of organ allograft.
    19. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >/= NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of study drug.
    20. Non-healing wound, ulcer, or bone fracture.
    21. Renal failure requiring hemo- or peritoneal dialysis.
    22. Dehydration NCI-CTCAE version 4.0 grade >/= 1.
    23. Substance abuse or medical, psychological, or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
    24. Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
    25. Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study.
    26. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
    27. Subjects unable to swallow oral medications.
    28. Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).
    29. Any malabsorption condition.
    30. Close affiliation with the investigational site, e.g. a close relative of the investigator or dependent person (e.g. employee of or student at the investigational site who would have access to study records and eCRF data).
    31. Unresolved toxicity higher than NCI-CTCAE version 4.0 grade 1 (excluding alopecia and anemia) attributed to any prior therapy/procedure.
    32. Concomitant participation in another clinical study.
    33. Left ventricular ejection fraction (LEVF) < 50% or below the LLN for the institution (whichever is higher).
    34. Pleural effusion or ascites that causes respiratory compromise (>/= CTC Grade 2 dyspnea
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is Progression-Free Survival (PFS), per blinded central radiology review; the final analysis was to be performed when at least 122 PFS events had been observed. Based on the over-recruitment of 29 subjects to 199 total randomised subjects, the target number of PFS events is increased to maintain the grade of maturity of the study. The final analysis will be performed using a one-sided alpha of 0.01 when at least 144 PFS events have been observed.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will be performed when at least 144 PFS events are observed.
    E.5.2Secondary end point(s)
    Overall survival will be analysed with the same log-rank test as PFS. The final analysis of OS will be performed when approximately 136 events have been observed. 136 OS events will provide 80% power to detect a 67% increase when a 1-sided alpha of 0.025 is used. At the time of the PFS analysis an interim analysis of OS will be performed. An O'Brien-Fleming type alpha spending function approach will be used for determination of significance thresholds so that the overall 1-sided alpha for OS is 0.025 or less.
    E.5.2.1Timepoint(s) of evaluation of this end point
    As 199 subjects were randomised instead of the originally planned 170 subjects, the number of survival events will be increased by the same ratio as the number of PFS events. The final analysis of OS will be performed when approximately 160 events have been observed. As a consequence, the power will be increased from 80% to 86%.
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Austria
    Belgium
    Canada
    China
    Finland
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Singapore
    Spain
    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
    For each participating European Union (EU) country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject for all centers in the respective country has occurred.
    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 subjects 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 years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 102
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 72
    F.4.2.2In the whole clinical trial 170
    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 metastatic and / or unresectable GIST there are currently no other recommended approved treatment. 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 Decision2010-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-03-01
    P. End of Trial
    P.End of Trial StatusOngoing
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