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    Summary
    EudraCT Number:2013-003579-36
    Sponsor's Protocol Code Number:BAY73-4506/15906
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-02-24
    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 ConcernedFrance - ANSM
    A.2EudraCT number2013-003579-36
    A.3Full title of the trial
    A multi-center, open-label, non-randomized, phase I dose escalation study of
    regorafenib (BAY 73-4506) in pediatric subjects with solid malignant tumors that are recurrent or refractory to standard therapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, tolerability and pharmacokinetics of regorafenib in pediatric subjects.
    A.4.1Sponsor's protocol code numberBAY73-4506/15906
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/258/2012
    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 AddressCPT 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 20 mg coated tablet
    D.3.2Product code BAY 73-4506 TABL 20MG 122 COAT
    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 number20
    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
    Pediatric patients with solid malignant tumors that are recurrent or refractory to standard therapy.
    E.1.1.1Medical condition in easily understood language
    Pediatric patients with cancer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To define the safety profile, maximum tolerated dose (MTD) and
    recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3-weeks-on / 1- week-off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy.
    - To characterize the pharmacokinetics (PK) of regorafenib.
    E.2.2Secondary objectives of the trial
    - To evaluate preliminarily anti-tumor activity of regorafenib
    - To evaluate pharmacodynamic parameters of regorafenib
    - Acceptability and palatability of the formulations - tablets and granulates (when available per amendment)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed Informed Consent Form by subjects and/or subjects’ parents/legal guardians and age appropriate Assent Form by the subjects obtained before any study specific procedure
    - Age: from 5 years to less than 18 years old
    - Pediatric subjects who are able to swallow tablets
    - Diagnosis: subjects must have had histologic verification of solid malignancy at original diagnosis. Subjects with recurrent or refractory solid tumors are eligible, including primary CNS tumors or subjects with known CNS metastases
    - Subject’s current disease state must be one for which there is no known effective therapy or therapy proven to prolong survival with an acceptable quality of life. Effective therapy may include surgery, radiation therapy, chemotherapy or any combination of these modalities.
    - Sexually active females of childbearing potential and sexually active males must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration. Abstinence is considered an adequate contraception method. For sexually active females, 2 forms of highly effective contraception are mandatory. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically
    recommended method (or combination of methods) as per standard of care.
    - Female subjects 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.
    - Subjects must have at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For neuroblastoma subjects with osteomedullary disease, the SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma Group) score will be used.
    - Life expectancy of at least 12 weeks from the time of signing informed
    consent/assent
    - Performance level: Karnofsky ≥ 70% for subjects > 10 years of age and Lansky ≥ 70% for subjects ≤ 10 years of age, except children with motor paresis due to disease. Neurological deficits in subjects must have been stable for a minimum of 1 week prior to first dose of study treatment.
    - Subjects with brain tumors or brain metastases must be on stable dose of corticosteroids for at least 1 week prior to first dose of study treatment.
    - Adequate hematological function assessed by the following laboratory
    requirements conducted within 7 days before starting study treatment:
    o Peripheral absolute neutrophil count (ANC): ≥ 1.0 x 10 9/L
    o Platelet count : ≥ 100 x 109/L (transfusion independent)
    o Hemoglobin : ≥ 8.0 g/ dL
    - Adequate renal function defined as creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 (1)
    - International normalized ratio (INR) ≤ 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
    - Lipase ≤ 1.5 x ULN
    - Adequate hepatic function defined as:
    o Aspartate aminotransferase/alanine aminotransferase (AST/ALT)
    ≤3.0 x ULN
    o Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 ULN
    o Alkaline phosphatase limit ≤ 2.5 x ULN for age (≤ 5 x ULN for
    subjects with bone tumors)
    E.4Principal exclusion criteria
    - Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
    - Active or uncontrolled infection (> National Cancer Institute Common
    Terminology Criteria for Adverse Events [NCI-CTCAE] Grade 2 at screening).
    - Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
    - Known history of human immunodeficiency virus (HIV) infection
    - Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Bone marrow biopsy and central lines will not be considered as a major surgical procedure.
    - Non-healing wound, ulcer, or bone fracture
    - Seizure disorder requiring medication with: carbamazepine, phenobarbital, phenytoin, ethosuximide, valproic acid, tiagabine, felbamate, tiagabine, zomisamide and lamotrigine. Subjects with history of seizures controlled with levetiracetam or gabapentin and subjects with brain tumors receiving prophylactic levetiracetam or gabapentin are allowed to enter the study.
    - Subjects with uncontrolled baseline hypertension higher than Grade 1 NCICTCAE v.4.0 (recurrent or persistent [≥24 hours] blood pressure [BP] >ULN: BP > the 95th percentile for age, height, and gender measured as described in Appendix 14.5). Additional information about hypertension is provided in Appendix 14.6.
    - Clinically significant bleeding (NCI-CTCAE v. 4.0 Grade 3 or higher) within 30 days before start of study medication
    - Arterial or venous thrombotic or embolic events such as deep vein thrombosis or pulmonary embolism within 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study medication)
    - Subjects with evidence or history of disorders of coagulation or thrombosis
    - Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure Classification for Children ≥ class 2) and cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
    - History of organ allograft (including allogeneic bone marrow transplant)
    - Unresolved toxicity higher than NCI-CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia, chemotherapy-induced ototoxicity, Grade 2 chemotherapy-induced neuropathy and, as per above eligibility criteria, anemia with hemoglobin ≥ 8 mg/dL and ANC ≥ 1.0 x 10 9/L )
    - Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE v. 4.0 Grade 2 dyspnea)
    - Known hypersensitivity to any of the study drugs, study drug classes, or
    excipients in the formulation
    - Pregnancy or breast feeding
    - Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn’s disease or any malabsorption condition
    - Interstitial lung disease with ongoing signs and symptoms at the time of screening
    - 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
    - Close affiliation with the investigational site, e.g. a close relative of the
    investigator or a dependent person (e.g. employee or student of the
    investigational site)
    E.5 End points
    E.5.1Primary end point(s)
    - To define the safety profile, maximum tolerated dose (MTD) and
    recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3-weeks-on / 1- week-off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy
    - To characterize the pharmacokinetics (PK) of regorafenib
    E.5.1.1Timepoint(s) of evaluation of this end point
    During cycle 1.
    E.5.2Secondary end point(s)
    - To evaluate preliminarily anti-tumor activity of regorafenib
    - To evaluate pharmacodynamic parameters of regorafenib
    - Acceptability and palatability of the formulations - tablets and granulates (when available per amendment)
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Tumor evaluation is conducted every 8 weeks.
    - Pharmacodynamic parameters evaluated during screening phase and end of treatment.
    -Taste and texture questionnaire is collected during cycle 1.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I dose escalation in pediatric subjects
    E.7.2Therapeutic exploratory (Phase II) No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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
    Last subject last visit.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 50
    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) Yes
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 35
    F.1.2Adults (18-64 years) No
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Consent obtained from subject's parents/legal guardians, if the subject is unable to give consent personally. Age appropriate assent form obtained from the subjects.
    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 50
    F.4.2.2In the whole clinical trial 50
    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)
    None.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation ITCC
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-02-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-12
    P. End of Trial
    P.End of Trial StatusCompleted
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