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    Summary
    EudraCT Number:2010-020121-41
    Sponsor's Protocol Code Number:11728
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-02-03
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-020121-41
    A.3Full title of the trial
    An uncontrolled, open-label, phase II study in subjects with metastatic adenocarcinoma of the colon or rectum who are receiving first line chemotherapy with mFOLFOX6 (oxaliplatin/ folinic acid/5-fluorouracil [5-FU]) in combination with regorafenib
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code number11728
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameBAY 73-4506
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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.3.10 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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    Metastatic adenocarcinoma of the colon or rectum (metastatic CRC)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •Objective tumor response rate (ORR), centrally assessed
    E.2.2Secondary objectives of the trial
    •Overall survival (OS) •Progression-free survival (PFS), centrally assessed •Disease control rate (DCR), centrally assessed •Duration of response (DOR) and stable disease (SD), centrally assessed
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Male or female subjects aged  18 years •Histological or cytological documentation of adenocarcinoma of the colon or rectum •Suitable to receive mFOLFOX6 regimen as first line metastatic treatment •At least 1 measurable lesion as per RECIST version 1.1 •Unresectable or unlikely becoming resectable metastatic disease •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 •Life expectancy of at least 3 months •Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to first dose of study treatment •Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) •Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) •Amylase and lipase ≤ 1.5 x the ULN •Serum creatinine ≤ 1.5 x the ULN •Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 according to the modified diet in renal disease (MDRD) abbreviated formula •International normalized ratio (INR)/partial thromboplastin time (PTT) ≤ 1.5 x ULN. (Subjects who are being therapeutically anticoagulated 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 predose as defined by the local standard of care.) •Platelet count ≥ 100000/mm3, hemoglobin (Hb) ≥ 9 g/dl, absolute neutrophil count (ANC) ≥ 1500/mm3 •Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) •Spot urine must not show 1+ or more protein in urine or the subject will require a repeat urinalysis. If repeat urinalysis shows 1+ protein or more, a 24 hour urine collection will be required and must show total protein excretion <1000 mg/24 hours •Women of childbearing potential must have a 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. •Women of childbearing potential and men must agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) since signing of the informed consent form until at least 6 months after the last study treatment administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. •Signed informed consent must be obtained before any study specific procedure. Subjects must be able to understand and willing to sign the written informed consent.
    E.4Principal exclusion criteria
    •Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study. •Prior systemic anticancer therapy for metastatic CRC. Adjuvant chemotherapy for CRC (Stage I, II, III) is permitted, if the adjuvant therapy ended > 6 months before screening and recurrent disease was documented. •Prior treatment with anti-VEGF agents and any STIs •Previous or concurrent cancer that is distinct in primary site or histology from CRC within 5 years prior to screening, EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta , Tis and T1 ). •Pregnant or breastfeeding subjects. Women of childbearing potential not employing adequate contraception or < 2 years from last menstruation. •Congestive heart failure ≥ NYHA class II •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 treatment. •Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) •Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg despite optimal medical management) •Subjects 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 treatment •Ongoing infection > Grade 2 NCI - CTCAE v4.0. •Known history of human immunodeficiency virus (HIV) infection •Active or chronic hepatitis B or C infection with a need for antiviral treatment •Subjects with symptoms, signs, or history of brain metastases (in the case of suspected brain metastases, a cranial CT/MRI is required to exclude brain metastases) •History of organ allograft •Subjects with evidence or history of bleeding diathesis. •Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study treatment •Nonhealing wound, ulcer, or bone fracture •Renal failure requiring hemo-or peritoneal dialysis •Dehydration ≥ CTCAE Grade 1 •Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results •Known hypersensitivity to any drug of study treatment, study drug classes, or excipients in the formulation •Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study •Interstitial lung disease with ongoing signs and symptoms at the time of informed consent •Subjects unable to swallow oral medications •Any malabsorption condition •Close affiliation with the investigational site (eg, a close relative of the investigator, dependent person [eg, employee or student of the investigational site]) •Known dihydropyrimidine dehydrogenase deficiency •Sensory neuropathy (> CTCAE Grade 1), unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure excluding alopecia •Use of any herbal remedy (eg, St. John`s wort [Hypericum perforatum]) •Pernicious anemia or other anemias due to vitamin B12 deficiency •Subjects with seizure disorder requiring medications •Major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to first dose of study treatment. Minor surgery within 2 weeks prior to first dose of study treatment. Subjects must have recovered from all surgery-related toxicities •Radiotherapy within 4 weeks prior to first dose. Subjects must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease (PD) if this is the only site of disease. •Investigational drug treatment within 4 weeks prior to study entry.
    E.5 End points
    E.5.1Primary end point(s)
    Objective tumor response rate (ORR) based on blinded central radiological review of all tumor evaluations is the primary end point of the study. The study is planned according to the fixed-sample design for proving efficacy. The aim is to show that therapy with mFOLFOX6 for colorectal cancer in combination with regorafenib improves the response rate observed for the standard therapy alone. The response rate for the standard therapy is assumed to be 40%. The design specifications are as follows: one-sided type I error level = 10% , power = 90% (type II error rate = 10%), and ``response rate for standard therapy`` p0= 0.40 (null hypothesis), where the one-sided type I error level is the probability of rejecting the null hypothesis if the true response rate is less than or equal to 40% and 1-power is the probability of rejecting the alternative hypothesis if the true response rate is greater 40%. For the power calculation it is assumed, that under the alternative hypothesis the expected response rate for combination therapy may be 60%, ie, p1 = 0.6. These specifications result in the total sample size of 41 patients. The final analysis of efficacy will be performed after the last subject included into the treatment phase has been treated for at least 6 months. If this last subject discontinues from the study, for any reason, before being treated for 6 months then the preceding subject will be treated and followed for 6 months before the final analysis of efficacy will be performed.
    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 Yes
    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) 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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    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.1.3Elderly (>=65 years) Yes
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 41
    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 Decision2011-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-12-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-06-30
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