| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic breast cancer, HER2-negative patients who have not received prior chemotherapy for mBC |
|
| 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 | 10006285 |
|
| 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 | 10055113 |
|
| 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 |
| Efficacy: objective response rate (CR and PR according to RECIST criteria) |
|
| E.2.2 | Secondary objectives of the trial |
| Efficacy: Progression-free survival (PFS), 1 year Overall survival (OS) Safety and tolerability: incidence of AEs Quality of Life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Signed informed consent (informed consent document to be approved by the Independent Ethics Committee) obtained prior to initiation of any study-specific procedure or treatment as confirmation of the patient’s awareness and willingness to comply with the study requirements
Age ≥18 years
Able to comply with the protocol
Histologically or cytologically confirmed and documented metastatic breast cancer women, proven HER2-negativity (secondary lesion or primitive tumor), who are candidates for chemotherapy
Lesions not amenable to curative surgery or radiotherapy. Limited /single cutaneous lesions or limited bone metastatis are considered amenable to curative surgery or radiotherapy
Previous cytotoxic anthracycline-based adjuvant chemotherapy
Measurable/evaluable metastatic disease (RECIST criteria)
Karnofsky performance status ≥ 70
Life expectancy of ≥ 12 weeks
Adequate haematological function
Absolute neutrophil count ≥1.5 x 109/L AND
Platelet count ≥100 x 109/L AND
Hemoglobin ≥9 g/dL
Adequate liver function
Serum (total) bilirubin <1.5 x the upper limit of normal (ULN) AND
AST/SGOT or ALT/SGPT <2.5 x ULN in patients without liver metastases; <5 x ULN in patients with liver metastases
Adequate renal function
Serum creatinine &#8804;1.25 x ULN or calculated creatinine clearance &#8805;50 mL/min AND
Urine dipstick for proteinuria <2+. Patients discovered to have &#8805;2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate &#8804;1 g of protein in the 24-hours urine
Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) &#8804;1.5 and an activated Partial Thromboplastin Time (PTT) &#8804;1.5 x ULN within 7 days prior to enrolment |
|
| E.4 | Principal exclusion criteria |
| Previous endocrine therapy or chemotherapy for mBC (previous endocrine therapy in the adjuvant or neo-adjuvant setting is allowed) Concomitant hormonal therapy for metastatic disease Prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to first study treatment administration. However, if chemotherapy: was taxane based, patients are only eligible if they received their last chemotherapy &#8805; 12 months prior to first study treatment. 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 Prior radiotherapy for the treatment of metastatic disease (radiotherapy administered for the relief of metastatic bone pain is allowed prior to study entry, provided that no more than 30 % of marrow-bearing bone has been irradiated; previous radiation therapy in the adjuvant or neo-adjuvant setting as a part of the treatment of early breast cancer is allowed) Evidence of CNS metastases (even if previously treated). If suspected, the patient should be scanned within 28 days prior to enrollment to rule out CNS metastases Other malignancy (including primary brain tumors) within the last 5 years, which could affect the diagnosis or assessment of breast cancer, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer Pre-existing peripheral neuropathy NCI CTC-AE grade > 2 at enrolment Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrollment 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 infusion Current (chronic daily) or recent (within 10 days of first dose of bevacizumab) treatment with aspirin (> 325 mg/day) or clopidogrel (>75 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 including cerebrovascular accident/stroke (&#8804;6 months before enrolment), myocardial infarction (&#8804;6 months before enrolment), unstable angina, congestive heart failure (CHF) NYHA Grade &#8805;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 Serious active infection requiring IV antibiotics at enrolment, HIV, HBV, HCV Women with an intact uterus (unless amenorrhoeic for the last 24 months or surgically sterile) not using effective means of contraception during the study and for a period of 6 months following the last administration of bevacizumab (etc.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
This phase II design implies a direct “screening” comparison of the experimental therapeutic approach against a randomized standard-treatment control arm, within a trial with a moderate sample size
Rubinstein LV et al. suggested 20% for both &#945; (1-sided) and &#946; errors as appropriate for phase II screening trials
Therefore, assuming for the control arm a RR of 35% and aiming to a 50% RR for the experimental arm, 92 patients are to be enrolled in arm A and 46 patients in arm B. Estimating a rate of up to 8-10% of non-evaluable patients, enrolment can be extended up to 153 patients in total. |
|
| 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 | 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| 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 | 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 |
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