| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Patients with advanced 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 | 10006187 | | E.1.2 | Term | 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 | | To determine the preliminary antitumor activity of the combination in terms of progression-free survival (PFS). | |
| E.2.2 | Secondary objectives of the trial | To determine the objective response rate (RR) and overall survival (OS).
To evaluate the safety of this regimen. | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | Written informed consent (informed consent document to be approved by the Independent Ethics Committee [IEC]) obtained prior to any study-specific procedure
Age ﾳ18 years
Able to comply with the protocol
Histologically or cytologically confirmed, HER2-negative, pre- or post-menopausal women with adenocarcinoma of the breast with measurable or non-measurable LR or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to radiation therapy or resection with curative intent
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Life expectancy of >=12 weeks
Prior adjuvant chemotherapy is allowed Prior radiation therapy is allowed if:delivered in the adjuvant setting as a part of the treatment of early breast cancerdelivered prior to study entry for the relief of metastatic bone pain, provided that no more than 30% of marrow-bearing bone has been irradiated (if using chemotherapy backbone which is highly myelosuppressive)
Adequate haematological function:Absolute neutrophil count (ANC) >=1.5 x 109/L andPlatelet count >=100 x 109/L and Haemoglobin >=9 g/dL (may be transfused to maintain or exceed this level)
Adequate liver function: Total bilirubin <1.5 x upper limit of normal (ULN) andAST, ALT <2.5 x ULN in patients without liver metastases; <5 x ULN in patients with liver metastases
Adequate renal function: Serum creatinine <=1.25 x ULN or calculated creatinine clearance >=50 mL/min AND Urine dipstick for proteinuria <2+. Patients discovered to have >=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate <=1 g of protein in 24 hours.
International normalized ratio (INR) <=1.5 and PTT <=1.5 x ULN within 7 days prior to enrolment
Premenopausal patients should not be pregnant or breast-feeding. Women with an intact uterus (unless amenorrhoeic for the last 24 months) must have a negative serum pregnancy test within 28 days prior to inclusion into the study. If a serum pregnancy test is not performed within 7 days prior to the first dose of bevacizumab, a confirmatory urine test (within 7 days prior to the first dose of bevacizumab) is required. | |
| E.4 | Principal exclusion criteria | Previous chemotherapy for LR or mBC
If patients have received adjuvant chemotherapy, they must have relapsed more than 6 months since the last dose of chemotherapy. However if adjuvant chemotherapy was taxane based, patients are only elegible if they relapsed >= 12 monthsafter last dose of chemotherapy
Concomitant hormonal therapy for LR or metastatic disease, however previous hormonal therapy is allowed for adjuvant, LR, or mBC
Patients must have received no radiation therapy for the treatment of metastatic disease (apart from those who received it for the relief of metastatic bone pain and with the precautions mentioned above)
Evidence of CNS metastases (even if previously treated). If suspected, the patient should be scanned within 28 days prior to enrolment to rule out CNS metastases
Pre-existing peripheral neuropathy NCI CTC-AE Grade >2 at enrolment
Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrolment or anticipation of the need for major surgery during study treatment
Minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusionCurrent or recent (within 10 days of first dose of bevacizumab) use of aspirin (>325 mg/day)
Current or recent (within 10 days of first dose of bevacizumab) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. Prophylactic use of anticoagulants is allowed
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg)Clinically significant (i.e. active) cardiovascular disease for example CVA (<=6 months before enrolment), myocardial infarction (<=6 months before enrolment), unstable angina, congestive heart failure (CHF) NYHA Class >=II, serious cardiac arrhythmia requiring medication during the study, which might interfere with regularity of the study treatment, or not controlled by medication
Non-healing wound, active peptic ulcer or bone fracture
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment
Women with an intact uterus (unless amenorrhoeic for the last 24 months) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of 6 months following the last administration of bevacizumab. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolmentKnown hypersensitivity to bevacizumab and any of its excipients, and any of the chemotherapies
Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | To determine the preliminary antitumor activity of the combination in terms of progression-free survival (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 | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | 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.8.3 | 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
