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    Summary
    EudraCT Number:2011-001230-42
    Sponsor's Protocol Code Number:CTKI258A2210
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-02-29
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2011-001230-42
    A.3Full title of the trial
    A multicenter, randomized, double blind, placebo controlled, phase II trial evaluating the safety and efficacy of TKI258 combined with fulvestrant, in postmenopausal patients with HER2- and HR+ breast cancer that have evidence of disease progression on or after prior endocrine therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An exploratory clinical study to evaluate the safety and efficacy of the new medicine TKI258 together with fulvestrant (a currently used medicinal product in the treatment of advanced breast cancer) compared to fulvestrant alone in postmenopausal women with specific kind of advanced breast cancer which has progressed after prior hormonal therapy.
    A.4.1Sponsor's protocol code numberCTKI258A2210
    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
    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 AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressForum 1, Novartis Campus
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4056
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41613241111
    B.5.5Fax number+41613248001
    B.5.6E-mailclinicaltrial.enquiries@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 nameDovitinib
    D.3.2Product code TKI258
    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 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Breast cancer, HER2 negative and HR positive, with evidence of disease progression after prior endocrine therapy
    E.1.1.1Medical condition in easily understood language
    Certain type of breast cancer which has progressed after prior hormonal treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the treatment effect of TKI258 in combination with fulvestrant vs. fulvestrant plus placebo on Progression-Free Survival (PFS) per local investigator assessment in patients with HER2-, HR+, locally advanced or metatastic breast cancer (LA/mBC) that have evidence of disease progression on or after prior endocrine therapy for each of the 2 groups, namely, i) FGF pathway amplified and ii) regardless of FGF pathway amplification status.
    E.2.2Secondary objectives of the trial
    To evaluate TKI258 in combination with fulvestrant vs. fulvestrant plus placebo with respect to Overall Response Rate (ORR) in patients with HER2-, HR+, LA/mBC that have evidence of disease progression on or after prior endocrine therapy for each of the 2 groups, namely, i) FGF pathway amplified and ii) regardless of FGF pathway amplification status.

    To evaluate TKI258 in combination with fulvestrant vs. fulvestrant plus placebo with respect to Duration of Response (DOR) for each of the 2 groups, namely, i) FGF pathway amplified and ii) regardless of FGF pathway amplification status

    To evaluate TKI258 in combination with fulvestrant vs. fulvestrant plus placebo with respect to Overall Survival (OS) for each of the 2 groups, namely, i) FGF pathway amplified and ii) regardless of FGF pathway amplification status.

    And other secondary objectives as per study protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Written informed consent obtained prior to any study procedures, including screening assessments

    Postmenopausal (≥ 18 years) women with HER2-, HR+ (ER+ and/or PgR+), locally advanced or metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Postmenopausal status is defined either by:
    • Age ≥ 55 years and one year or more of amenorrhea, or
    • Age < 55 years and one year or more of amenorrhea in the absence of ovarian suppression, with an estradiol assay < 20 pg/mL, or
    • Surgical menopause with bilateral oophorectomy. Note that it is not possible to assign menopause status to women who are receiving an LH-RH agonist or antagonist.

    Breast cancer that has progressed on or after prior endocrine therapy, with radiological evidence of recurrence or progression as follows:
    • While on, or within 12 months of end of adjuvant treatment with any endocrine therapy (e.g., tamoxifen, exemestane, anastrozole, letrozole, etc.)
    • While on, or within 1 month of end of any endocrine therapy treatment for LA/mBC

    Have measurable disease as per RECIST v1.1 (Appendix 1) or non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of measurable disease. Patients with only non-measurable lesions and no lytic or a mix of lytic and sclerotic bone metastasis (e.g. pleural effusion, ascites) are not eligible. Note: a) measurable lesions include lytic or mixed (lytic + blastic) bone lesions with an identifiable soft tissue component that meets the measurability criteria per RECIST v1.1, and; b) lesions in previously irradiated areas should not be considered measurable, unless they have clearly progressed since the radiotherapy

    Eastern Cooperative Oncology Group (ECOG) performance status that is not greater than 2 (i.e., either 0 or 1 or 2).

    Have the following laboratory values:
    a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    b. Platelets ≥ 100 x 109/L
    c. Hemoglobin (Hgb) > 9 g/dL
    d. Serum total bilirubin ≤ 1.5 x ULN
    e. ALT and AST ≤ 3.0 x ULN (with or without liver metastases)
    f. Serum creatinine ≤ 1.5 x ULN or Creatinine clearance by 24 hr urine is ≥ 30 mL/min
    OR: Serum creatinine >1.5 - 3 x ULN with calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation, per the formula provided here: CrCl = ([140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)]) x .85

    Have completely recovered from major effects of prior radiotherapy and from any drug-related adverse events (AEs) associated with previous treatments, excluding alopecia and grade 1 peripheral neuropathy according to the National Cancer Institute CTCAE, v. 4.03

    Provide archival (paraffin embedded tissue or a minimum of 20 unstained slides) or fresh tumor tissues from which the FGF pathway status can be determined by an Novartis designated laboratory
    E.4Principal exclusion criteria
    Evidence of central nervous system (CNS) or leptomeningeal metastases. A brain CT scan or MRI is mandatory at screening prior to study entry

    HER2 over expression as depicted by local laboratory IHC 3+ or FISH testing.

    Previously treated with fulvestrant as a single agent or in combination with other therapies or FGFR inhibitors

    Have any contraindication for being treated with fulvestrant 500 mg as described in the local approved prescribing information

    Received more than one line of any prior hormonal therapy for LA/mBC. Any adjuvant/neo adjuvant therapy is allowed

    Received any chemotherapy for LA/mBC

    Concurrent use of any other approved or investigational anticancer agents, including hormonal agents

    Having participated in a prior investigational study within 30 days prior to enrollment or ≤ 5 half-lives of the investigational product, whichever is longer

    Received the last administration of anti-cancer targeted small molecule therapy (e.g. sunitinib, sorafenib, pazopanib, axitinib, everolimus, temsirolimus, radaforolimus) ≤ 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy

    Received the last administration of an anti-cancer monoclonal antibody, immunotherapy, hormonal therapy, or chemotherapy (except nitrosoureas and mitomycin-C) ≤ 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy

    Received the last administration of nitrosourea or mitomycin-C ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy

    Received radiotherapy ≤ 4 weeks prior to starting the study drug or who have not recovered from radiotherapy-related toxicities (palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study drug is allowed)

    Undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such surgery

    With a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) ≤ 6 months prior to starting study drug

    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 (< 50 beats /minute)
    • LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever is higher)
    • Any of the following within 6 months prior to starting study drug: myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack
    • Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s). Initiation or adjustment of antihypertensive medication(s) is allowed prior to study entry

    Currently receiving anti-platelet therapy of prasugrel or clopidogrel, or full dose anticoagulation treatment with therapeutic doses of warfarin. However, treatment with low doses of warfarin (e.g., ≤ 2 mg/day) or locally accepted low doses of acetylsalicylic acid (up to 100 mg daily) to prevent cardiovascular events or strokes is allowed

    Concurrent malignancy or malignancy within 3 years prior to study enrollment, 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

    Bilateral diffuse lung lymphangitic carcinomatosis or other life-threatening visceral metastases requiring immediate cytotoxic therapy

    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 had gastric or small bowel resection)

    Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

    Have Child-Pugh B or worse hepatic impairment

    Known history of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory unless required by local regulations)

    Any concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study or interfere with study results

    Unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Progression-Free Survival (PFS).

    PFS is defined as date of randomization to the date of the first radiologically documented disease progression or death due to any cause per local investigator assessment as defined in Appendix 1 (RECIST 1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    This is an event driven trial and events will be monitored contineously. After at least 80 PFS events have occurred -including at least 50 events in patinets with FGF amplified breast cancer- data evaluation will take place. This is expected approximately 2 years after trial initiation nad is therfore projected for April 2014
    E.5.2Secondary end point(s)
    Overall Response Rate (ORR)
    ORR is defined as percentage of patients with a best overall response of CR or PR as defined in Appendix 1 (RECIST 1.1).

    Duration Of Response (DOR)
    DOR is defined as time from the date of the first documented response (CR or PR) to the date of the first documented PD or death due to disease as defined in Appendix 1 (RECIST 1.1). If a patient does not have a progression event, DOR will be censored on the date of the last adequate tumor assessment.

    Overall Survival (OS)
    OS is defined as time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.

    E.5.2.1Timepoint(s) of evaluation of this end point
    This is an event driven trial and events, duration of response etc. will be monitored contineously (see E.5.1.1)
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 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 EEA27
    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
    Brazil
    Egypt
    Israel
    Peru
    Russian Federation
    South Africa
    Taiwan
    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
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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 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: 150
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 state
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 150
    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)
    All patients must be followed for 30 days after the last dose of study treatment for safety assessment (AEs and/or SAEs).
    In addition, all new anticancer therapies given after the last dose of the study drug, until disease progression, death, lost to follow-up, or withdrawal of consent will be recorded in the electronic Case Report Forms (eCRFs).
    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 Decision2012-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-30
    P. End of Trial
    P.End of Trial StatusCompleted
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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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