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

Written informed consent obtained prior to any study procedures, including screening assessments;Postmenopausal (* 18 years) women with HER2-, HR+ (ER+ and/or PgR+), (based on most recent analyzed biopsy)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;Presence of either one of the following:
* Measurable disease as per RECIST v1.1 (Appendix 1).
Notes:
* 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
* Lesions in previously irradiated areas should not be considered measurable, unless they have clearly progressed since the radiotherapy.
* At least one non-measurable lytic or mixed (lytic + blastic) bone lesion in the absence of measurable disease.
Notes:
* If bone lesions have been previously irradiated, at least one lesion must have clearly progressed since the radiotherapy by CT, MRI or x-ray for trial entry.
* Patients with only non-measurable lesions and no lytic or mixed (lytic and blastic) bone metastases (e.g. pleural effusion, ascites) are not eligible.;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

Current or past 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 or chemotherapy (except nitrosoureas and mitomycin-C) * 4 weeks or last administration of hormonal therapy * 2 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 of the liver, or known hepatitis B or C infection that is either acute or is considered chronic because the virus did not become undetectable (see page 44 protocol excl.criteria 20 voor details);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