E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-negative metastatic breast cancer. |
|
E.1.1.1 | Medical condition in easily understood language |
Breast cancer that spread to other tissues |
|
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 | 100000004864 |
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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 |
To evaluate the efficacy of bevacizumab + paclitaxel compared with placebo + paclitaxel as first-line treatment in patients with HER2-negative metastatic breast cancer as measured by:
- PFS based on investigator tumor assessment in the intent-to treat (ITT) patient population
- PFS based on investigator tumor assessment in ITT patients with high plasma VEGF-A levels |
|
E.2.2 | Secondary objectives of the trial |
1) To evaluate on the ITT population and the VEGF-A high subset the efficacy of bevacizumab + paclitaxel compared with placebo + paclitaxel as first-line treatment in patients with HER2-negative MBC as measured by:
- OS
- Objective response rate for patients with measurable disease at baseline, as assessed by investigator
-Duration of objective response for patients with measurable disease at baseline
- One-year survival
2) In addition, an interaction of treatment effect with the VEGF-A level for PFS will be performed in the ITT population
3) To evaluate on the ITT population and the VEGF-A high subset the safety of bevacizumab + paclitaxel compared with placebo + paclitaxel as first-line treatment in patients with HER2-negative
MBC, focusing on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) all-grade treatment-emergent adverse events. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed, HER2 negative adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
2. Signed Informed Consent Form
3. Age ≥ 18 years
4. ECOG performance status of 0 or 1
5. Ability and capacity to comply with study and follow up procedures
6. For men and women with reproductive potential (women < 2 years
after last menstruation and not surgically sterile), use of an acceptable and
effective method of non-hormonal contraception (intrauterine contraceptive device or barrier method of contraception in conjunction with spermicidal jelly) during treatment and for at least 6 months after the completion of treatment; use of oral hormonal contraceptives is allowed, however, concurrent use of at least one non-hormonal contraceptive method is mandatory.
7. For patients who have received recent radiotherapy, recovery prior to randomization from any significant (Grade ≥ 3) acute toxicity, and radiation treatments have to be completed more than 3 weeks from randomization |
|
E.4 | Principal exclusion criteria |
Disease-Specific Exclusions
1. HER2-positive status.
2. Prior chemotherapy for locally recurrent or metastatic disease
3. Prior hormonal therapy < 2 weeks prior to randomization.
4. Prior adjuvant or neo-adjuvant chemotherapy is allowed, provided its conclusion has been for at least 12 months prior to randomization.
5. Investigational therapy within 28 days of randomization
General Medical Exclusions
6. Life expectancy of < 12 weeks
7. Inadequate organ function
8. Persistent Grade ≥ 3 sensory neuropathy
9. Uncontrolled serious medical or psychiatric illness
10. Active infection requiring intravenous (IV) antibiotics at screening
11. Pregnancy (positive pregnancy test) or lactation.
12. Patients with a history of bilateral breast cancer.
13. History of other malignancies within 5 years prior to screening, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
Bevacizumab-Specific Exclusions
14. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
15. Prior history of hypertensive crisis or hypertensive encephalopathy
16. New York Heart Association Class II or greater, CHF/left ventricular ejection fraction < 55%
17. History of myocardial infarction or unstable angina within 6 months prior to randomization
18. History of stroke or transient ischemic attack within 6 months prior to randomization
19. Known CNS disease except for treated brain metastasis.
20. Significant vascular disease
21. History of hemoptysis
22. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
23. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study
24. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to randomization
25. History of abdominal fistula or gastrointestinal (GI) perforation within 6 months prior to randomization
26. Serious, non-healing wound, active ulcer, or untreated bone fracture
27. Proteinuria at screening
28. Known hypersensitivity to any component of bevacizumab
29. Prior therapy with bevacizumab, sorafenib, sunitinib, or other
VEGF pathway–targeted therapy
Paclitaxel-Specific Exclusions
30. History of severe hypersensitivity to paclitaxel or to any of the excipients, especially macrogolglycerol ricinoleate
31. Paclitaxel should not be administered to patients with baseline neutrophil count <1500/mm3. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Coprimary endpoints:
1) PFS in the intention-to-treat population (all randomized patients)
2) PFS in the patients with high VEGF-A levels |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of PFS will occur when both (I) 326 PFS events in all patients and (II) 146 PFS events in the VEGF-A high subgroup have been observed. |
|
E.5.2 | Secondary end point(s) |
1) Objective Response Rate
2) Duration of Objective Response
3) 1-year Survival Rate
4) Overall Survival
5) Treatment/VEGF-A Interaction Test for PFS |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Objective response, 2)duration of response, first IA of OS, AEs will be analyzed at the same time with final PFS.
3) Primary 1-year survival rate will be analyzed when OS crosses the boundary or at the time of final OS event maturity.
4) Final OS will also be conducted when both (I) 309 deaths in all patients and (II) 170 deaths in the VEGF-A high subgroup have been observed.
5)At the timepoint of the primary analysis of 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 | 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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Bevacizumab + paclitaxel vs. bevacizumab placebo + paclitaxel |
|
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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Belgium |
Brazil |
Bulgaria |
Germany |
Italy |
Japan |
Romania |
Russian Federation |
Ukraine |
Korea, Republic of |
South Africa |
United Kingdom |
United States |
Vietnam |
Chile |
Panama |
|
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
|
The end of the study is defined as the date when 394 deaths in the ITT population have been observed. This follow-up OS analysis is expected approximately 6.5 years after the first patient is randomized. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |