Breast cancer, HER2 negative and HR positive, with evidence of disease progression after prior endocrine therapy
Conditions
Interventions
Product Name: Dovitinib
Product Code: TKI258
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Dovitinib
CAS Number: 915769-50-5
Current Sponsor code: TKI258
Concentration unit: mg milligra
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
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 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 150 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 ca
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: 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;Primary 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).;Timepoint(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 20 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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. ;Timepoint(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) | — |
Countries
Argentina, Austria, Belgium, Brazil, Egypt, Hungary, Israel, Italy, Netherlands, Peru, Poland, Russian Federation, South Africa, Spain, Taiwan, United States
Contacts
Public ContactDrug Regulatory Affairs
Novartis Pharma GmbH
Outcome results
None listed