| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early primary invasive adenocarcinoma of the breast (triple negative and/or basal like phenotype) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10006291 |
| E.1.2 | Term | Breast neoplasms malignant and unspecified (incl nipple) |
|
| 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 Invasive Disease-Free Survival (IDFS) of patients randomised to treatment with adjuvant chemotherapy alone or to adjuvant chemotherapy with 1 year of bevacizumab. |
|
| E.2.2 | Secondary objectives of the trial |
-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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ADEQUATE ORGAN FUNCTION
11. Within 7 days prior to randomisation, the following criteria (according to the local lab) must be met:
a) Bone Marrow Function
-ANC ≥1.5 x 109/l or 1500/mm3
-Platelet count ≥ 100 x 109/l
-Haemoglobin ≥ 10 g/dl
b) Coagulation
-INR must be less than the lower limit of therapeutic range and the aPTT ≤ 1.5 times the ULN
c) Renal Function
-Serum creatinine ≤ ULN for the local lab
-Urine dipstick must indicate 0 or 1+ protein.
If the dipstick reading for protein is ≥2, a 24-hour urine collection must be obtained and demonstrate ≤ 1g of protein
d) Liver Function
-Total bilirubin ≤ULN unless the patient has a grade 1 bilirubin elevation (ULN < total bilirubin <1.5 times the ULN) due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin
-ALP <2.5 times the ULN
-AST ≤1.5 times the ULN
ALP and AST may not both be above the ULN.
e) Cardiac function:
-Left ventricular systolic function (ejection fraction) assessed by 2–D echocardiogram 3 months prior to randomization, must be ≥55% regardless of the institution’s LLN. |
|
| E.4 | Principal 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 β-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 other grade 4 non-GI fistula, GI perforation, or intra-abdominal abscess
CURRENT MEDICATION
21. Patients who require ongoing daily treatment with aspirin (> 325 mg/day) or clopidrogel (> 75 mg / day)
22. Women of reproductive potential, female patients within 1 yr of entering menopause as well as males who are unwilling to agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last dose of bevacizumab.
23. Current or recent (within 30 days prior of randomization) treatment with another investigational drug or participation in another investigational study
24. Any sex hormonal therapy, and patient is not willing to discontinue treatment before study entry.
ALLERGIES
25. Known hypersensitivity to any of the study drugs or excipients
26. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody
|
|
| E.5 End points |
| E.5.1 | 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) |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 181 |
| 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
|
Primary endpoint analysis will be done when 388 events have been confirmed in 2530 pts randomised. Overall Survival analysis (OSA) is done ca. 52 mths after randomisation of the last patient or when 340 death events have been observed, whichever occurs first. The end of the trial is the date of the final scheduled clinic visit for the last patient to complete the study or the date on which the last data point from the last patient required for the OSA is received, whichever occurs later.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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