| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Locally Recurrent 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 standard first-line therapy versus patients treated with placebo and standard first-line therapy for locally recurrent or metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the objective response rate (ORR), duration of response, time to progression (TTP), and overall survival of patients treated with sorafenib and standard first-line therapy versus patients treated with placebo and standard first-line therapy. To compare the safety of patients treated with sorafenib and standard first-line therapy versus patients treated with placebo and standard first-line therapy. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed adenocarcinoma of the breast.
2. Measurable or evaluable locally recurrent or metastatic disease. (Locally recurrent 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. Women who are ER+ or PgR+ and candidates for endocrine therapy, must be post-menopausal as defined below:
Bilateral oophorectomy; or
No menses for at least 12 months in patients with an intact uterus, not on gonadatropin suppressing agents; or
Follicle-stimulating hormone (FSH) in postmenopausal range in patients <60 years without prior hysterectomy; or
Pre-menopausal women undergoing pharmacological ovarian ablation.
4. Any adjuvant or neoadjuvant taxane therapy must have been completed at least 12 months prior to randomization.
5. Patients must have discontinued other adjuvant chemotherapy at least 3 weeks prior to randomization.
6. Adjuvant aromatase inhibitors must have been completed at least 12 months prior to randomization.
7. Adjuvant tamoxifen must have been completed at least 4 weeks prior to randomization
8. Prior radiation therapy is allowed but must be completed at least 3 weeks prior to randomization, with all acute toxicities recovered to baseline status. Previously radiated area(s) must not be the only site of disease and must not correspond to more than 25% of the bone marrow producing areas for patients who are candidate for chemotherapy.
9. ECOG Performance Status of 0 or 1 (see Appendix A).
10. Adequate bone marrow, liver, and renal function as assessed by the following:
Hemoglobin >= 9.0 g/dl
Absolute neutrophil count (ANC) >= 1,500/UL
Platelet count >= 100,000/UL
Total bilirubin <= 1.5 times 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 prothrombin 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 times the upper limit of normal.
11. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization, and patients must agree to use adequate contraception (barrier method of birth control) prior to randomization, for the duration of study participation, and for 28 days after the last dose of study treatment.
12. Patients must be willing and able 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, retain, and absorb whole oral tablets. |
|
| E.4 | Principal exclusion criteria |
1. Patients with breast cancer over-expressing human epidermal growth factor receptor 2 (HER2) [gene amplification by fluorescence in situ hybridization (FISH) or 3+ over-expression by immunohistochemistry (IHC)]. Patients with unknown HER-2 status are not eligible.
2. Patients with active brain metastases. Patients with neurological symptoms must undergo a contrast CT scan or MRI of the brain to exclude active brain metastasis. Patients with treated brain metastases are eligible provided they have no evidence of disease and are off definitive therapy (including steroids) at least 3 months prior to randomization.
3. Prior chemotherapy or endocrine therapy for locally recurrent or metastatic breast cancer.
4. Patients with unknown hormone receptor status.
5. Patients who are ER+ or PgR+ and are pre-menopausal and unwilling to undergo pharmacological ovarian ablation
6. Women who are pregnant or breast-feeding.
7. Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization.
8. Evidence or history of bleeding diathesis or coagulopathy.
9. Serious, non-healing wound, ulcer, or bone fracture.
10. 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.
11. Pre-existing peripheral neuropathy >= Grade 2.
12. Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital) is not allowed.
13. Cardiac disease:
Congestive heart failure >class II New York Heart Association (NYHA) (See Appendix B), 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. 14. Uncontrolled hypertension (systolic blood pressure >150 mm Hg or diastolic pressure >90 mm Hg) despite optimal medical management.
15. Thrombolic, embolic, venous, or arterial events, such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
16. Pulmonary hemorrhage/bleeding event >National Cancer Institute (NCI-CTCAE) Grade 2 within 4 weeks of first dose of study drug.
17. Any other hemorrhage/bleeding event >= NCI-CTCAE Grade 3 within 4 weeks of randomization.
18. Active clinically serious infection >NCI-CTCAE Grade 2.
19. Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
20. 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.
21. Known or suspected allergy to sorafenib, letrozole or hypersensitivity to docetaxel or drugs using the vehicles polysorbate 80 or ethanol.
22. Prior or concurrent use of St. John’s Wort or rifampin (rifampicin) within 3 weeks of randomization.
23. Prior or concurrent treatment with any agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR) (licensed or investigational).
24. Use of an 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) |
| Progression-free survival from the date of starting treatment. |
|
| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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