| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Treated Metastatic Breast Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| 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 of the study is to determine the clinical benefit of the addition of bevacizumab to standard chemotherapy for previously treated metastatic breast cancer (MBC), as measured by progression-free survival (PFS). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the efficacy and safety of bevacizumab when combined with chemotherapy compared with chemotherapy alone in subjects receiving second-line therapy for MBC, as measured by the following:
• Estimation of the clinical benefit of the addition of bevacizumab to standard chemotherapy, as measured by overall survival
• Estimation of the clinical benefit of the addition of bevacizumab to each chemotherapy regimen,
• Determination of the clinical benefit, as measured by objective response rate, duration of objective response, one-year survival, and overall survival, of the addition of bevacizumab to standard chemotherapy options compared with standard chemotherapy alone
• To evaluate the toxicity, as measured by selected adverse events, adverse events resulting in treatment discontinuation, and serious adverse events, of standard chemotherapy options with or without bevacizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following criteria to be eligible for study entry:
• Signed Informed Consent Form
• ≥ 18 years of age
• Histologically confirmed carcinoma of the breast with measurable or
non-measurable metastatic disease that has progressed
Subjects with a history of brain metastasis are eligible for study participation,
as long as their brain metastases have been treated and they have no
evidence of progression or hemorrhage after treatment and no ongoing
requirement for dexamethasone, as ascertained by clinical examination and
brain imaging (MRI or CT scans) during the screening period. CT scan with
contrast or MRI scan of the brain must be performed at least 3 weeks after
completion of all therapy to the brain.
Treatment for brain metastasis may include the following: WBRT, SRS
(Gamma knife, LINAC, or equivalent), or a combination as deemed
appropriate by the treating physician. Radiotherapy and stereotactic
radiosurgery must be completed at least 4 weeks prior to Day 0.
Subjects may also have neurosurgical resection. Neurosurgery must be
completed at least 6 weeks prior to Day 0, and brain biopsy must be
completed at least 4 weeks prior to Day 0.
• Progression of disease during or following administration of one
(non-investigational) chemotherapy regimen, defined as single-agent
chemotherapy administered prior to or during disease progression or a
pre-specified combination or sequence of cytotoxic agents administered in
the first-line setting
Subjects whose initial treatment changed prior to progression in the
first-line setting are ineligible unless the change occurred within 30 days
of initial treatment due to toxicity.
• ECOG performance status of 0 or 1
• For women of childbearing potential, use of an effective means of
non-hormonal contraception
• Life expectancy ≥ 3 months
• Willingness and capacity to comply with study and follow-up procedures |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from study entry:
a. Disease Treatment History
• Prior hormonal therapy only as treatment for metastatic disease
without chemotherapy. Patients must have received chemotherapy for their
metastatic disease in the first-line setting. Hormone therapy alone is not allowed.
• For subjects who have received prior anthracycline-based therapy,
documentation of left ventricular ejection fraction < 50% by either
multiple gated acquisition (MUGA) or echocardiogram (ECHO)
• Treatment with more than one prior cytotoxic regimen for MBC
• HER2-positive status
In general, HER2-positive status will be identified by a fluorescence in situ
hybridization (FISH) assay as evaluated at the institution or, if FISH is
unavailable, a 2 + or 3 + immunohistochemistry result (but the method of
identification may vary by region or institution). Patients who have unknown
HER2 status, and for whom determination of HER2 status is not possible,
are eligible for this study.
• Unknown ER and PR status
• Radiation therapy other than for palliation or brain metastasis, biologic therapy,
or chemotherapy for MBC within 21 days prior to Day 0
• Prior therapy with bevacizumab or other VEGF pathway–targeted therapy
b. Bevacizumab Exclusion Criteria
• Untreated brain metastasis
• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on anti-hypertensive medications
• Unstable angina
• New York Heart Association Grade II or greater CHF (see Appendix C)
• History of myocardial infarction within 6 months prior to Day 0 (the day of the
first bevacizumab/placebo infusion)
• History of stroke or transient ischemic attack within 6 months prior to Day 0
• Clinically significant peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Major surgical procedure, open biopsy, or significant traumatic injury within
28 days prior to Day 0; anticipation of need for major elective surgical
procedure during the study
• Minor surgical procedures, fine-needle aspirations, or core biopsies within
7 days prior to Day 0
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 0
• Serious, non-healing wound, ulcer, or bone fracture
Subjects with fractures secondary to metastatic disease are eligible after
appropriate radiotherapy.
• History of anaphylactic reaction to monoclonal antibody therapy not controlled with
treatment premedication
c. General Exclusion Criteria
• Inadequate organ function, as evidenced by any of the following laboratory
values:
Absolute neutrophil count < 1500/µL
Platelet count < 100,000/µL
Total bilirubin > 1.5 mg/dL
AST and/or ALT > 2 × the upper limit of normal (ULN) ( > 5 × the ULN in
subjects with known liver involvement)
Alkaline phosphatase >2 × the ULN (>5 × the ULN in subjects with known liver involvement and >7 x the ULN in subjects with known bone involvement)
Serum creatinine > 2.0 mg/dL
International normalized ratio (INR) > 1.5 × and/or activated partial
thromboplastin time > 1.5 × the ULN (except for subjects receiving
anti-coagulation therapy)
Urine protein to creatinine ratio > 1.0 at screening for U.S. subjects
(see Appendix F) or urine dipstick for proteinuria ≥ 1+ at screening followed by
24-hour urine collection demonstrating > 1 g protein/24 hours for ROW subjects
• History of other malignancies within 5 years of Day 0, 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
Subjects with a history of bilateral breast cancer or history of breast cancer will be
eligible.
• Pregnancy (positive serum pregnancy test) or lactation
• Any other diseases, metabolic dysfunction, physical examination finding,
or clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug or that may
affect the interpretation of the results or renders the subject at high risk from
treatment complications |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Disease progression will be assessed by the investigator according to RECIST
PFS is defined as the time from randomization to disease progression or death due to any cause, whichever occurs first. Data for subjects without disease progression or death will be censored at the last tumor assessment plus 1 day prior to their withdrawal from study follow-up (or, if no tumor assessments were performed after the baseline visit, at the time of randomization plus 1 day).
PFS will be formally tested using a two-sided stratified log-rank test at α = 0.05
(equivalent to a one-sided test at α = 0.025 for the hypothesis that the addition of
bevacizumab to chemotherapy is superior to chemotherapy alone). The stratification
factors are chemotherapy chosen on study (taxane, gemcitabine, vinorelbine,
capecitabine), ER and PR status (ER and PR negative, other), and interval from
initial metastatic disease diagnosis to progression after first-line cytotoxic
chemotherapy (< 6 months, ≥ 6 months). Results from an unstratified log-rank test
will also be presented. Kaplan-Meier methodology will be used to estimate median
PFS for each treatment arm, and the Kaplan-Meier curve will be constructed to
provide a visual depiction of the difference between the treatment arms. |
|
| 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 | 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) | 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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
| |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
Print
