| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| 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 |
To compare Progression Free Survival (PFS) in patients randomised to
• bevacizumab 7.5 mg/kg and docetaxel 100 mg/m[2] q3wk versus docetaxel 100 mg/m[2] and bevacizumab placebo q3wk
or
• bevacizumab 15 mg/kg and docetaxel 100 mg/m[2] q3wk versus docetaxel 100 mg/m[2] and bevacizumab placebo q3wk
|
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| E.2.2 | Secondary objectives of the trial |
To compare
• Best Overall Response (OR)
• Duration of Response (DR)
• Time to treatment failure (TTF)
in patients randomized to
- bevacizumab 7.5 mg/kg and docetaxel 100 mg/m[2] q3wk versus docetaxel 100 mg/m[2] and bevacizumab placebo q3wk.
- bevacizumab 15 mg/kg and docetaxel 100 mg/m[2] q3wk versus docetaxel 100 mg/m[2] and bevacizumab placebo q3wk
To compare Overall Survival (OS) in patients randomized to bevacizumab plus docetaxel versus patients randomized to docetaxel plus placebo.
To determine the safety and tolerability of combining bevacizumab 7.5 mg/kg/q3wks or 15 mg/kg q3wks with docetaxel 100 mg/m[2]
To assess change in quality of life in the bevacizumab and control arms
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female only.
2. Age >= 18 years.
3. Able to comply with the protocol.
4. ECOG PS of 0 or 1
5. Life expectancy of >= 12 weeks.
6. Written informed consent (Informed Consent document to be approved by the institution’s Independent Ethics committee [IEC]) obtained prior to any study specific screening.
7. Patients with histologically or cytologically confirmed, HER 2 negative, pre- or postmenopausal adenocarcinoma of the breast with measurable or non measurable locally recurrent or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to resection with curative intent.
8. Documented ER/PR status.
9. Prior adjuvant/neo-adjuvant chemotherapy is allowed as long as the last dose of chemotherapy was not within 6 months prior to randomization. However, if chemotherapy:
- was taxane based, patients are only eligible if they received their last chemotherapy ≥12 months prior to randomization.
- was anthracycline based, the maximum cumulative dose of prior anthracycline therapy must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.
10. Adequate left ventricular ejection function at baseline, defined as LVEF not below the institutional lower limit of normal by either echocardiogram or MUGA.
11. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR, or appropriate monitoring test is within therapeutic limits and the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization:
- Patients on heparin treatment should have an aPTT between 1.5-2.5 x ULN (or patient value before starting heparin treatment).
- Patients on low molecular weight heparins should receive daily dose of 1.5–2.0 mg/kg (of enoxaparin) or appropriate dose of the correspondent anticoagulant, according to package insert.
- Patients on coumarin derivatives should have an INR between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1–4 days apart.
Patients not receiving anti coagulant medication must have an INR <= 1.5 and aPTT <= 1.5 x ULN within 7 days prior to randomization.
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| E.4 | Principal exclusion criteria |
1. Previous chemotherapy for metastatic or locally recurrent breast cancer.
– Prior hormonal therapy for locally recurrent or metastatic disease is allowed but must have been discontinued at least 2 weeks prior randomization.
2. Patients must have received no radiotherapy for the treatment of metastatic or locally recurent/advanced disease, however patients who have received adjuvant/neo-adjuvant radiotherapy as part of the treatment of early breast cancer are eligible if the last fraction of radiotherapy was administered occurred at least 6 months prior to randomization. Radiotherapy administered for the relief of metastatic bone pain is allowed prior to study entry, but
– No more than 30% of marrow-bearing bone should have been irradiated
– The last fraction of radiotherapy should not have been administered within 3 weeks prior to randomization.
3. Other primary tumors within the last 5 years before randomization, except for adequately controlled limited basal cell, or squamous carcinoma of the skin, or carcinoma in situ of the cervix
4. Evidence of spinal cord compression or brain metastases. A CT or MRI of the brain must be performed within 4 weeks prior to randomization if the presence of metastases at these sites is suspected.
5. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy e.g. uncontrolled seizures.
6. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment.
7. Minor surgical procedures, within 24 hours prior to randomization.
8. Pre-existing peripheral neuropathy > CTC grade 2 at randomization
9. Inadequate bone marrow function: ANC: < 1.5 x 109/L, Platelet count < 100 x 109/L and Hemoglobin < 9 g/dL.
10. Inadequate liver function:
- Serum (total) bilirubin above the normal limit for the institution
- AST & ALT >2.5 x ULN
Patients are not eligible for the study if they have:
– AST or ALT levels greater than 1.5 times ULN concurrent with serum alkaline phosphatase levels of greater than 2.5 times the ULN at baseline
11. Inadequate renal function
– Serum Creatinine >2.0 mg/dL or 177 micro mol/L
– Urine dipstick for proteinuria > 2+. Patients with > 2+ proteinuria on dipstick analysis at baseline should undergo a 24 hour urine collection and must demonstrate <=1g of protein/24hr.
12. Chronic daily treatment with aspirin (> 325 mg/day) or clopidogrel (>75 mg/day).
13. Chronic daily treatment with corticosteroids (dose of >= 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
14. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
15. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or clinically significant (i.e. active) cardiovascular disease: CVA/stroke (≤ 6 months prior to randomization), myocardial infarction (≤ 6 months prior to randomization), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
16. Serious non-healing wound, peptic ulcer, or bone fracture.
17. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomization.
18. Active infection requiring i.v. antibiotics at randomization
19. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
20. Women of childbearing potential (<2 years after last menstruation) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).
21. Current or recent (within 30 days of randomization) treatment with another investigational drug or participation in another investigational study.
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, or that may affect patient compliance with study routines, or places the patient at high risk from treatment related complications.
23. Known hypersensitivity to any of the study drugs or excipients.
24. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibodies.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The final analysis of the primary efficacy endpoint PFS will take place after approximately a total of 430 events have occurred in the three treatment arms, which is expected to be 8 months after the date of last patient entry. |
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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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers and markers of predictive value |
|
| 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) | 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.8.5.1 | Number of sites anticipated in the EEA | 68 |
| 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 |
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| 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
|
Follow-up for survival will continue until the last patient has completed 24 months of follow-up. End of the study will occur the date of the last visit of the last patient participating in this trial (after last patient last study drug administration).
For those patients who continue with bevacizumab following database lock for the Overall Survival analysis (see section 3.5 and section 8.2) only SAE data will continue to be collected. |
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| 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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