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    Summary
    EudraCT Number:2009-015459-25
    Sponsor's Protocol Code Number:CTKI258A2302
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-04-28
    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 ConcernedUK - MHRA
    A.2EudraCT number2009-015459-25
    A.3Full title of the trial
    An open-label, randomized, multi-center, Phase III study to compare the safety and efficacy of TKI258 versus sorafenib in patients with metastatic renal cell carcinoma after failure of anti-angiogenic (VEGF-targeted and mTOR inhibitor) therapies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of TKI258 compared to sorafenib in patients with advanced kidney cancer
    A.4.1Sponsor's protocol code numberCTKI258A2302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01223027
    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 SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma Services
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharmaceuticals UK Ltd
    B.5.2Functional name of contact pointMedical Information Services
    B.5.3 Address:
    B.5.3.1Street AddressFrimley Business Park
    B.5.3.2Town/ cityFrimley, Surrey
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4401276698370
    B.5.5Fax number4401276698449
    B.5.6E-mailmedinfo.uk@novartis.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 nameTKI258
    D.3.2Product code TKI258
    D.3.4Pharmaceutical form Capsule
    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 INNdovitinib
    D.3.9.1CAS number 915769-50-5
    D.3.9.2Current sponsor codeTKI258
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Nexavar 200mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Schering 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/207
    D.3 Description of the IMP
    D.3.1Product nameNexavar 200mg film-coated tablets
    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 INNSORAFENIB
    D.3.9.1CAS number 284461-73-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    metastatic renal cell carcinoma
    E.1.1.1Medical condition in easily understood language
    kidney cancer that has spread to other parts of the body
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10038410
    E.1.2Term Renal cell carcinoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare TKI258 vs. sorafenib with respect to progression-free survival (PFS) determined by central radiology assessment in patients with metastatic renal cell cancer (mRCC) after failure of anti-angiogenic (VEGF-targeted and mTOR inhibitor) therapies.
    E.2.2Secondary objectives of the trial
    Key Secondary:
    •To compare TKI258 vs. sorafenib with respect to overall survival (OS)

    Other Secondary:
    •To assess TKI258 vs. sorafenib with respect to:
    •Time to definitive worsening of Karnofsky performance status(KPS)
    •PFS determined by local review of tumor assessments
    •Overall response rate (ORR) by central and local radiology review
    •Safety
    •Patient-reported outcomes (PROs), including:
    1.Disease-related symptoms using the Functional assessment of cancer therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS)
    2.Quality of Life (QoL) using the EORTC QLQ-C30 questionnaire
    •To characterize the pharmacokinetics of TKI258 in patients with mRCC
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The sub-study is listed within the main protocol and thus has the same date and version. The title and objectives of the sub-study is listed in section 7.11.3 of the main protocol:

    7.11.3 Optional pharmacogenetics
    In order to understand the genetic contribution to variability in disposition of TKI258 in humans, the genetic variants of drug targets, metabolizing enzymes and transporters will be evaluated using blood samples from patients who have agreed to participate in this analysis after signing the additional biomarker consent. Genotyping of drug targets (including but not limited to VEGF/VEGFRs, FGF/FGFRs), drug metabolizing enzymes (like UGT1A1 and CYP1A2) and transporters may also be evaluated.
    E.3Principal inclusion criteria
    1. Written informed according to local guidelines must be obtained before any study assessments are performed.
    2. Age ≥ 18 years old.
    3. Patients with metastatic renal cell carcinoma (mRCC) with histological or cytological confirmation of clear cell carcinoma or a component of clear cell
    4. Patients receiving adjuvant VEGF targeted therapy or mTOR inhibitors may have this treatment count as part of one prior VEGF or one prior mTOR therapy if disease progression occurred on or within 6 months of stopping the adjuvant treatment.
    5. Prior treatment with cytokines and anti-cancer vaccines is permitted.
    6. Patients must have had disease progression on or within 6 months of stopping the last therapy (VEGF-targeted agent and/or the mTOR inhibitor therapy).
    7. Patients must have at least one measurable lesion at baseline (according to RECIST 1.1) using Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI). If skin lesions are selected as target lesions at baseline, follow procedure specified on Section 7.6.4.
    8. Karnofsky performance status ≥ 70%
    9. Patients must have the following laboratory values:
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin (Hgb) > 9 g/dL
    • Serum total bilirubin: ≤ 1.5 x ULN
    • ALT and AST ≤ 3.0 x ULN (Patients with or without liver metastases)
    • Serum creatinine ≤ 1.5 x ULN
    E.4Principal exclusion criteria
    1. Patients who have previously received sorafenib therapy in the neoadjuvant, adjuvant or metastatic setting
    2. Patients who have previously received TKI258 or other FGFR inhibitors such as brivanib in the neoadjuvant, adjuvant or metastatic setting
    3. Patients with brain metastases or any history of brain metastases. Radiological imaging (e.g. CT or MRI scan) of the brain is required at screening/baseline
    4. Patients with another primary malignancy within 3 years prior to starting study treatment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix
    5. Patients who have received the last administration of an anticancer targeted small molecule therapy ≤ 2 weeks prior to starting study treatment (e.g. sunitinib, pazopanib, axitinib, everolimus, temsirolimus), or who have not recovered from the side effects of such therapy
    6. Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6 weeks prior to starting study treatment, or who have not recovered from the side effects of such therapy
    7. Patients who have received the last administration of an anticancer monoclonal antibody, immunotherapy, or chemotherapy (except nitrosureas and mitomycin-C) ≤ 4 weeks prior to starting study treatment or who have not recovered from the side effects of such therapy
    8. Patients who have received radiotherapy ≤ 4 weeks prior to starting the study treatment or who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
    9. Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to starting study treatment or who have not recovered from side effects of such therapy
    10. Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months.
    11. Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
    • Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
    - History or presence of serious uncontrolled ventricular arrhythmias
    - Clinically significant resting bradycardia
    - LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (which ever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (which ever is higher),
    - Any of the following within 6 months prior to starting study treatment: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA)
    - Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to study entry.
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    • Cirrhosis, chronic active hepatitis or chronic persistent hepatitis
    • Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory but it should be performed if locally required.
    • Patients who are currently receiving full dose anticoagulation treatment with therapeutic doses of warfarin or anti-platelet therapy. Treatment with locally accepted low dose of acetylsalicyclic acid (i.e.,81 mg or 100mg daily) to prevent cardiovascular events or strokes is allowed
    • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
    12. Pregnant or breast-feeding women
    13. Women of child-bearing potential, who are biologically able to conceive, not employing two forms of highly effective contraception.
    14. Fertile males not willing to use contraception, as stated above.

    Other protocol defined exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    PFS is defined as the time from date of randomization to the date of first documented disease progression (based on central radiology assessment) or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment according to RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Post-baseline evaluations will be performed on Day 1 Week 9, and subsequently on Day 1 every 8 weeks (± 1 week) during the 1st year of study treatment and every 12 weeks (± 1 week) thereafter and at the end of the study
    E.5.2Secondary end point(s)
    Key Secondary:
    • OS as defined as the time from date of randomization to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the last date of contact.
    E.5.2.1Timepoint(s) of evaluation of this end point
    continuously
    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 Yes
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA77
    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
    Argentina
    Australia
    Brazil
    Canada
    China
    Colombia
    Israel
    Japan
    Korea, Republic of
    Saudi Arabia
    Switzerland
    Taiwan
    Thailand
    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
    Last patient last visit (LPLV)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    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: 370
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 180
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 241
    F.4.2.2In the whole clinical trial 550
    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)
    Normal treatment of that condition
    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 Decision2011-05-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-06-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-06-30
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