E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Breast cancer, HER2 negative and HR positive, with evidence of disease progression after prior endocrine therapy |
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E.1.1.1 | Medical condition in easily understood language |
Certain type of breast cancer which has progressed after prior hormonal treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | 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). |
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E.5.1.1 | 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 2014 |
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E.5.2 | 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.
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E.5.2.1 | 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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |