E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive locally recurrent or metastatic breast cancer. |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer that recurred at/near the same place as the original tumour or that spread to other non-adjacent tissues. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006198 |
E.1.2 | Term | Breast cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective is to evaluate the overall response rate (ORR) in patients with HER2-positive locally advanced or metastatic breast cancer receiving bevacizumab, trastuzumab and capecitabine as first-line treatment for metastatic disease. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate:
- Progression-Free Survival (PFS)
- Overall Survival (OS)
- Time to Progression (TTP)
- Safety and tolerability
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Histologically or cytologically confirmed breast adenocarcinoma with measurable (per RECIST), locally recurrent or metastatic lesions.
3. Candidates for capecitabine-based chemotherapy. Locally advanced disease must not be amenable to resection with curative intent.
4. Documented HER2 positive disease (HER2 overexpression indicated by IHC 3+ and/or FISH + and/or chromogenic in situ hybridization (CISH) + of the primary tumor or a metastasis).
5. Documented ER/PgR status (positive or negative).
6. ECOG Performance Status ≤ 2.
7. Able and willing to comply with the protocol.
8. Written and signed informed consent prior to beginning study-specific procedures showing the patient’s awareness and willingness to participate in the trial and comply with its proceedings and with the understanding that the patient has the right to withdraw from the study at any time without prejudice. (Note: the informed consent document must be approved by the institution’s Independent Ethics Committee). |
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E.4 | Principal exclusion criteria |
1. Previous treatment for locally advanced or mBC other than hormone therapy or radiotherapy. Anti-epidermal growth factor receptor or anti-HER2 agents or vaccines and cytotoxic chemotherapies for locally recurrent or mBC are not allowed. Patients must have fully recovered from side effects of any prior radiotherapy.
2. Any prior neoadjuvant or adjuvant treatment with anthracyclines completed less than 6 months prior to enrolment. The max. cumulative dose received must not have exceeded 360 mg/sqm for doxorubicin or 720 mg/sqm for epirubicin.
3. Chronic daily treatment with corticosteroids and/or with aspirin or clopidogrel.
4. Requirement for concurrent use of the antiviral agent sorivudine, or chemically related analogues, such as brivudine.
5. Minor surgical procedures, within 24 hours prior to enrolment.
6. Current or recent (within the 30 days prior to starting study treatment) treatment with another investigational drug or participation in another investigational study.
7. Inadequate bone marrow function, liver function and or renal function
8. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) > 1.5 or an activated partial thromboplastin time (aPTT) > 1.5 x ULN within 7 days prior to enrollment.
• Note: Patients receiving full dose oral or parenteral anticoagulants may be included as long as anticoagulant dosing has been stable for at least two weeks prior to study entry and the appropriate coagulation monitoring tests are within therapeutic limits.
9. Other primary malignancy (including primary brain tumors) within the last 5 years prior to enrolment, except for adequately treated carcinoma in situ of the cervix, squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.
10. Dyspnea at rest due to complications of advanced malignancy (e.g. pulmonary metastases with lymphangitis) or any condition necessitating supportive oxygen therapy.
11. Evidence of CNS metastasis.
12. Evidence of spinal cord compression caused by metastases.
13. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer (e.g. uncontrolled seizures) unless adequately treated with standard medical therapy.
14. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to enrolment, or anticipation of the need for major surgery during the course of the study treatment.
15. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease
16. Baseline LVEF < 50% measured by either echocardiography or MUGA.
17. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of enrolment.
19. Active infection requiring IV antibiotics at enrolment.
20. Serious non-healing wound, peptic ulcer, or bone fracture.
21. Clinically significant malabsorption syndrome, or inability to take oral medication.
22. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect patient compliance with study routines, or place the patient at high risk from treatment related complications.
23. Known hypersensitivity to any of the study drugs or excipients.
24. History of severe and unexpected reactions to fluoropyrimidine therapy or with known hypersensitivity to fluorouracil.
25. Known dihydropyrimidine dehydrogenase deficiency.
26. Pregnant or lactating females.
27. Fertile males or females of childbearing potential (<2 years after last menstruation) unwilling or unable to use effective non-hormonal means of contraception
28. Life expectancy ≤ 12 weeks.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR), assessed via best overall response defined as the best response recorded from the start of the trial treatment until disease progression /recurrence or death. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the study, at the end of 1st quarter 2013. |
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E.5.2 | Secondary end point(s) |
- Progression free survival (PFS)
- Overall survival (OS)
- Time to progression (TTP)
- Safety and tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of the study, at the end of 1st quarter 2013. |
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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 | No |
E.6.4 | Safety | Yes |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 19 |
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 |
Denmark |
France |
Russian Federation |
Slovakia |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
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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The study will end 3 years after the last patient has been randomized. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |