| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Breast Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
|
| 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 compare Progression Free Survival (PFS) in patients treated with sorafenib and capecitabine versus patients treated with placebo and capecitabine for locally advanced or metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the objective response rate, duration of response, Time to progression (TTP) and Overall Survival (OS) of patients treated with sorafenib and capecitabine versus placebo and capecitabine.
To compare the safety and tolerability of patients treated with sorafenib and capecitabine versus placebo and capecitabine.
Exploratory:
To compare change from baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B), Version 4 (See Appendix C) score in patients treated with sorafenib and capecitabine versus patients treated with placebo and capecitabine. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically or cytologically confirmed adenocarcinoma of the breast.
2.Measurable or evaluable locally advanced or metastatic disease. (Locally advanced disease must not be amenable to resection with curative intent.) All scans used to document measurable or evaluable disease must be done within 4 weeks prior to randomization.
3.Age ≥18 years.
4.Failed taxane and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
5.No more than one prior chemotherapy for locally advanced or metastatic breast cancer.
6.Patients must have discontinued chemotherapy at least 3 weeks prior to randomization.
7.Prior hormonal therapy for locally advanced or metastatic disease is allowed but must be discontinued at least 3 weeks prior to randomization.
8.Prior radiation therapy is allowed but must be completed at least 3 weeks prior to randomization. Previously radiated area(s) must not be the only site of disease.
9.ECOG Performance Status of 0 or 1.
10.Adequate bone marrow, liver, and renal function as assessed by the following:
•Hemoglobin >=9.0 g/dl
•Absolute neutrophil count (ANC) >=1,500/mm3
•Platelet count >=100,000/mm3
•Total bilirubin <=1.5 x the upper limit of normal (ULN)
•Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<=2.5 x ULN (<=5 x ULN for patients with liver involvement)
•International Normalized Ratio for Prothrombin Time (PT INR) <=1.5 and activated partial thromboplastin time (aPTT) within normal limits
•Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib/placebo and monitored at least weekly, or as defined by the local standard of care, until INR is stable
•Creatinine <=1.5 x ULN.
11.Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization, and must agree to use adequate contraception (barrier method of birth control) prior to randomization and for the duration of study participation.
12.Patients must be able and willing to sign a written informed consent. A signed informed consent must be appropriately obtained prior to any study specific procedures.
13.Patients must be able to swallow and retain oral medication.
|
|
| E.4 | Principal exclusion criteria |
1.Patients with breast cancer over-expressing human epidermal growth factor receptor 2 (HER-2) (gene amplification by fluorescence in situ hybridization (FISH) or 3+ over-expression by immunohistochemistry). Patients with unknown HER-2 status are not eligible.
2.Patients with active brain metastases. Patients with neurological symptoms must undergo a contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to exclude active brain metastasis. Patients with treated brain metastases are eligible provided they have no evidence of brain disease and are off definitive therapy (including steroids) at least 3 months prior to randomization.
3.Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization.
4.Evidence or history of bleeding diathesis or coagulopathy.
5.Serious, non-healing wound, ulcer, or bone fracture.
6.Substance abuse or medical, psychological, or social condition that may interfere with the patient’s participation in the study or evaluation of the study results.
7.Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital) is not allowed.
8.Cardiac disease:
•Congestive heart failure >class II New York Health Association (NYHA) , or
•Unstable angina (anginal symptoms at rest), or new-onset angina (began within the last 3 months), or myocardial infarction within the 6 months prior to randomization, or
•Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
9.Uncontrolled hypertension (systolic blood pressure >150 mm Hg or diastolic pressure >90 mm Hg) despite optimal medical management.
10.Thrombolic, embolic, venous, or arterial events, such as a cerebrovascular accident including transient ischemic attacks, within the past 6 months.
11.Pulmonary hemorrhage/bleeding event >National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 within 4 weeks of randomization.
12.Any other hemorrhage/bleeding event >=NCI-CTCAE Grade 3 within 4 weeks of randomization.
13.Active clinically serious infection >NCI-CTCAE Grade 2.
14.Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
15.Previous or concurrent cancer that is distinct in primary site or histology from breast cancer EXCEPT cervical cancer in-situ, treated basal cell carcinoma, superficial bladder tumors [Ta and Tis], or any cancer curatively treated >5 years prior to randomization.
16.Known or suspected allergy to sorafenib, or hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
17.History of severe and unexpected reactions to fluoropyrimidine therapy or patients with known dihydropyrimidine dehydrogenase deficiency.
18.Prior or concurrent treatment with sorivudine or its chemically related analogues, such as brivudine.
19.Concurrent or use of St. John’s Wort or rifampin (rifampicin) within 3 weeks of randomization.
20.Prior treatment with bevacizumab or any other drugs (licensed or investigational) that target vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR).
21.Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than capecitabine and sorafenib/placebo.
22.Women who are pregnant or breast-feeding.
23.Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is Progression Free Sirvival (PFS) |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
After 120 Progression Free Survival (PFS) Events are observed.
Accural is expected to take about 17 months. Time for observation 120 PFS events is expected to occur 19 months after the initiation of enrolment (i.e.; 3 months after the completion of enrolment) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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