An international multi-centre open-label 2-arm phase III trial of adjuvant bevacizumab in triple negative breast cancer. - BEATRICE

• Register: EUCTR
• Last refreshed on: 21 August 2017
• Main ID: EUCTR2007-001128-11-BE
• Date of registration: 26/09/2007
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd.
• Public title: An international multi-centre open-label 2-arm phase III trial of adjuvant bevacizumab in triple negative breast cancer. - BEATRICE
• Scientific title: An international multi-centre open-label 2-arm phase III trial of adjuvant bevacizumab in triple negative breast cancer. - BEATRICE
• Date of first enrolment: 19/12/2007
• Target sample size: 2530
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-001128-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Finland, France, Germany, Greece, Italy, Netherlands, Poland, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
Life expectancy of = 10 yrs (excluding the breast cancer diagnosis).
Must be able to fulfil all of the protocol requirements during the treatment and FU period.
PATIENT SPECIFIC AND GENERAL INCLUSION CRITERIA
1. Patient must have signed and dated an informed consent form
2. = 18 yrs old
3. ECOG Performance Status of 0 or 1
DISEASE SPECIFIC INCLUSION CRITERIA
4. Operable primary invasive carcinoma of the breast. Patients with multifocal and synchronous bilateral cancers are eligible if
-all cancers (excluding any associated ductal carcinoma-in-situ/DCIS) are of the triple negative phenotype and
-the eligibility is based on the highest stage grouping
5. Definitive loco-regional surgery has been completed
a) patients must have undergone either breast conservation surgery or a total mastectomy and the surgical margins of the resected specimen must be histologically free of invasive adenocarcinoma and DCIS.
-if the radial surgical margins are not histologically free of invasive adenocarcinoma and DCIS, these patients must proceed to a re-excision in order to obtain microscopically clear margins; when there is a close chest wall margin, no further excision is required if a boost is delivered to the tumour bed.
-surgical margins involved with lobular carcinoma-in-situ/LCIS will not be considered as a positive margin and therefore such patients would be eligible without additional resection
-post-mastectomy surgical margins must be free of gross residual tumour – when post-mastectomy margins are microscopically positive, such patients will be eligible if it is agreed that adjuvant radiotherapy to the chest wall will be delivered
b) patients must have completed one of the following axillary procedure for the pathological evaluation of axillary lymph nodes
I. sentinel node biopsy (SNB) or/and
II. sampling procedure or/and
III. axillary dissection
-patients in whom a SNB yields a metastatic nodal disease, must proceed to either the removal of additional non-sentinel lymph nodes or a completion axillary dissection to retrieve = 6 lymph nodes. Patients will be defined as having node negative disease either after SNB/sampling procedure or after = 4 axillary nodes have been removed.
6. The interval between the last loco-regional surgery (including re-excision of involved surgical margins) and randomisation must be between 4–11 weeks.
CLINICAL AND PATHOLOGIC STAGING CRITERIA REQUIREMENTS
PRIMARY TUMOUR
7. The primary tumour must be identified and by clinical and pathologic evaluation be T1a – 3
-if the ipsilateral axilla is microscopically involved the 1° tumour must be at least a pT1a (i.e. >1mm) in greatest dimension or
-if the ipsilateral axilla is uninvolved, the 1° tumour must be at least a pT1b (i.e.>5mm) in greatest dimension and according to clinically judgement it is expected that the patient would derive benefit from adjuvant chemotherapy
8. Central laboratory testing of the primary invasive tumour must confirm HER2 negativity and the endocrine receptor expression (ER and PgR) must be either negative (i.e. a total Allred score of 0 or 2) or low (i.e. a total Allred score of 3).
IPSILATERAL AXILLARY LYMPH NODES
9. Pathologic examination of the axillary nodes must reveal either
a) node positive disease (pN1a, pN2a or pN3a) OR
b) node negative disease (pN0)
SYSTEMIC EVALUATION
10. Chest, abdominal, and where applicable, bone imaging performed within 3 months prior to randomization did not reveal evidence of distant spread
CRITERIA FOR ADEQU
Exclusion criteria:
CANCER HISTORY
1. Patients with T4 tumours (incl. inflammatory carcinomas and tumours with direct extension to chest wall or directly involving skin)
2. Patients in whom the surgeon was unable to surgically clear the axilla from all macroscopic disease / Presence of grossly microscopic evident extracapsular nodal extension.
PREVIOUS CANCER HISTORY
3. Prior history of breast cancer, incl. DCIS (patients with a history of LCIS are eligible).
4. Any previous malignancy treated with curative intent and patient has been disease-free for less than 5 years prior to randomization – exceptions are:
carcinoma in situ of the cervix, melanoma in situ, squamous or basal cell carcinoma of the skin.
5. Any prior systemic chemotherapy for any malignancy or treatment with an anti-angiogenic treatment that modifies VEGF molecular pathway. Previous chemotherapy for non-malignant disease should be discussed with a member of the medical support team.
Chemoprevention
6. Patients receiving chemoprevention with any hormonal agent such as raloxifene, tamoxifen or other SERM and not willing to discontinue these medications prior to study entry
MEDICAL HISTORY
7. Clinically significant cardiac diseases including
(a) Clinical evidence of transmural myocardial infarction
(b) Unstable angina
(c) Evidence of ischaemic heart disease (requiring antianginal medication with calcium channel blockers, nitrates and ß-blockers)
(d) High risk uncontrolled arrhythmias (ventricular tachycardia, supraventricular tachycardia not adequately rate controlled and high grade atrio-ventricular block)
(e) History of documented CHF or systolic dysfunction (LVEF < 55%)
8. Uncontrolled hypertension as defined as a systolic pressure > 150 mm Hg and/or diastolic pressure > 90 mm Hg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
9. History of transient ischaemic attacks or cerebrovascular accident
10. When the risk for the development of venous thrombo-embolism outweighs the benefits of participating in the trial.
11. Patients on a therapeutic dose of an anticoagulant for a venous thrombo-embolism
12. History or evidence of an inherited bleeding diathesis or coagulopathy at risk of bleeding
13. Gastroduodenal ulcer(s) determined by endoscopy to be active
14. Patients with an infection requiring intravenous antibiotics at randomization
15. Patients who have any other disease, metabolic or psychological, or who have any evidence on clinical examination or special investigations (including a lab finding) which gives reasonable suspicion of a disease or condition that contraindicates the use of the investigational drug, or that may affect the patient’s compliance with study requirements, or would place the patient at higher risk of potential treatment complications
16. Pregnant or lactating women
SURGICAL HISTORY
17. Invasive procedures within 28 days prior to randomization and defined as follows: major surgical procedure, open biopsy or significant traumatic injury (placement of a vascular access device is not considered a major surgical procedure)
18. Anticipation of need for major surgical procedures (other than the required breast surgery) during the course of the study
19. Unhealed wound, skin ulcers or incompletely healed bone fracture
20. Recent history (i.e. within 6 months of randomization) of an abdominal fistula incl. any othe

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Early primary invasive adenocarcinoma of the breast (triple negative and/or basal-like phenotype)
MedDRA version: 9.1 Level: HLGT Classification code 10006291 Term: Breast neoplasms malignant and unspecified (incl nipple)

Intervention(s)

Trade Name: Avastin
Product Name: Avastin
Product Code: RO4876646
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Bevacizumab
CAS Number: 216974-75-3
Current Sponsor code: RO4876646
Other descriptive name: rhuMAb, VEGT, anti-VEGF
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

Primary end point(s): The primary endpoint of the present trial is Invasive Disease-Free Survival (IDFS). It is a composite endpoint which is defined as the time from randomisation until the date of the first occurrence of one of the following events:
-An ipsilateral invasive breast cancer recurrence (i.e. an invasive breast cancer
involving the same breast parenchyma as the original primary)
-Ipsilateral local – regional invasive breast cancer recurrence (i.e. an invasive
breast cancer in the axilla, regional lymph nodes, chest wall or/and skin of the
ipsilateral breast)
-Distant recurrence (i.e. evidence of breast cancer in any anatomic site – other
than the two above mentioned sites – that has either been histologically confirmed
or clinically diagnosed as recurrent invasive breast cancer)
-Death attributable to any cause including breast cancer, non-breast cancer or
unknown cause.
-Contralateral invasive breast cancer
-Second primary non-breast invasive cancer (with the exception of nonmelanoma
skin cancers)

Main Objective: To compare Invasive Disease-Free Survival (IDFS) of patients randomised to treatment with adjuvant chemotherapy alone or to adjuvant chemotherapy with 1 year of bevacizumab.

Secondary Objective: -The secondary objectives of this trial are to compare Overall Survival (OS), Breast Cancer-Free Interval (BCFI), Disease- Free Survival (DFS) and Distant Disease-Free Survival (DDFS) of patients randomised to treatment with adjuvant chemotherapy alone or to adjuvant chemotherapy in combination with 1 year of bevacizumab.
-Identification of a biomarkers (from tumour or serum) predictive of toxicity and for the level of benefit from the addition of bevacizumab to standard adjuvant systemic treatment.
-To evaluate the safety and tolerability of bevacizumab.

Secondary ID(s)

BO20289

2007-001128-11-GB