| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| early stage HER2 positive breast cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
|
| 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 |
| The primary objective is to compare the complete pathological response rates (evaluation according to Chevallier’s criteria, review by an independent Committee) between the two randomized arms (neoadjuvant regimens) in patients with a relative change in [18F]-FDG tumoral uptake < 70% |
|
| E.2.2 | Secondary objectives of the trial |
For all patients (Arms A, B and Standard) :
-to describe the complete pathological response rates evaluated according to local procedures,
- to describe the ultrasound response rate, rate of conservative surgery, disease-free survival, distant disease-free survival, local relapse-free survival and overall survival,
- to assess the role of PET in early detection of pathological response,
- to search for predictive factors of response to treatment [on the basis HER2/RH status, pathological complete response, imaging results (PET and mammary DCE-US), and pharmacokinetics, immunology, and pharmacogenetics (only for patients who agree to participate, specific consent)] study results],
- to assess the safety according to CTC-AE v 4.0.
For the randomized Arms A and B (patients with ∆ SUV < 70%) :
to search for predictive factors of response to treatment on the basis of angiogenesis biomarkers (biology and imaging). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy n° 1: Pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD)
Protocol version : part of the main protocol (refer to section A4)
Objectives :
- to describe patient exposure by measuring bevacizumab and trastuzumab concentrations during the neoadjuvant treatment,
-to study if pathological complete response rate, DFS and OS are influenced by bevacizumab and trastuzumab serum concentrations,
- to study if patients developing certain adverse events during bevacizumab or trastuzumab treatment have higher serum concentrations than those who do not develop these adverse events.
Substudy n° 2: Immunology
Protocol version : part of the main protocol (refer to section A4)
Objectives :
- to study whether the pCR,DFS and OS are influenced by the number of peripheral blood CD56+CD16+ NK cells before therapy,
- to study whether the pCR, DFS and OS are influenced by the number of peripheral blood CD16 positive cells before therapy,
- to study whether the number of peripheral blood CD16 positive cells is related to the results of ∆SUV, studied with PET.
Substudy n° 3: Pharmacogenetic
Protocol version : part of the main protocol (refer to section A4)
Objectives :
- to describe FCGR3A, FCGR2A and VEGF genetic polymorphisms distribution in the study population,
-to study if pCR, DFS and OS are influenced by FCGR3A, FCGR2A or VEGF genetic polymorphisms,
- to study if patients developing certain adverse events during bevacizumab and trastuzumab treatment have specific FCGR3A, FCGR2A or VEGF genotypes.
Substudy n° 4: Angiogenesis Biomarkers
Protocol version : part of the main protocol (refer to section A4)
Objectives :
to describe the variation of CTC (Circulating Tumour Cells), CEC (Circulating Endothelial Cells), VEGF, and its soluble receptor VEGFR2, and endothelial and adhesion cell markers, like E-Selectin, P-Selectin, or ICAM-1 levels between screening period (before first administration of neoadjuvant treatment), and before the 3 subsequent neoadjuvant cycles (with or without bevascizumab at C3 and C4),
and to evaluate the predictive value of the variation of them on disease free survival (DFS) and overall survival (OS) after a neoadjuvant treatment with bevacizumab, docetaxel and trastuzumab,
and to correlate them with pathological response.
|
|
| E.3 | Principal inclusion criteria |
General inclusion criteria:
1. Woman
2. Age ≥ 18 years
3. Patient must have signed a written informed consent form prior to any study specific screening procedures
4. Patients able to undergo a pre-treatment PET and a second course PET
5. Affiliated to the ”Sécurité Sociale” or beneficiary to such a regimen
Disease specific inclusion criteria:
1. Patient with invasive, T2 or T3 and histologically confirmed breast cancer, who is
scheduled to receive neoadjuvant therapy with the objective of conservative surgery
(see Appendix 2)
2. Nx ou N0 or N1 (see Appendix 2)
3. HER2 positive (needle core biopsy only) assessed by ICH [HER2 +++ or HER2 ++
(and FISH or CISH + or SISH+)] or FISH + or CISH + or SISH +, on the basis of
ASCO 2007 criteria (see Appendix 3)
4. Known hormone receptors status.
5. Performance status (ECOG Scale, see Appendix 4): 0, 1 or 2 |
|
| E.4 | Principal exclusion criteria |
Cancer related Exclusion Criteria:
1. Partially or totally lobular carcinoma
2. Inflammatory breast cancer
3. Bifocal and/or bilateral tumor
4. Metastases
5. Previous treatment with chemotherapy, radiation therapy or hormonal therapy for
breast tumor
6. Previous history of cancer (other than curatively treated basal and squamous cell
carcinoma of the skin and/or in-situ carcinoma of the cervix) relapsing within the 5
years before study entry or in situ contralateral breast carcinoma.
Haematological, biochemical and organ function:
1. Absolute neutrophil count (ANC) < 1.2 x 109/L
2. Platelet count <100 x 109/L
3. Haemoglobin < 9.00 g/dL
4. Impaired liver function: Serum (total) bilirubin: > 1.5 x ULN (except if Gilbert
hemolysis); AST or ALT: > 2.5 x ULN
5. Inadequate kidney function: serum creatinine > 1.25 ULN or creatinine clearance < 50 mL/min according to the Cockroft and Gault formula
6. 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
7. Patients not receiving anticoagulant medication and having an International
Normalized Ratio (INR) >1.5 or an activated Partial Thromboplastin Time (aPTT) or
PTT >1.5 x ULN within 7 days prior to first study treatment (4).
Note: Patients receiving full dose oral or parenteral anticoagulants may be included in the study as long as anticoagulant dosing has been stable for at least two weeks prior to study entry and the appropriate coagulation monitoring tests are within local therapeutic limits (4).
Other Study Drug Related Exclusion Criteria
1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic >100 mmHg), with or without anti-hypertensive medication. Patients with high initial blood pressure are eligible if entry criteria are met after initiation or adjustment of antihypertensive medication.
2. History of thrombotic disorders within the last 6 months prior to enrolment (i.e.
cerebrovascular accident, transient ischaemic attacks).
3. History of abdominal fistula, tracheo-oesophageal fistula or any grade 4 non gastrointestinal
fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.
4. History or evidence of inherited bleeding diathesis or coagulopathy.
5. Non-healing wound, active peptic ulcer or bone fracture.
6. 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.
7. Minor surgery, including insertion of an indwelling catheter, within 24 hours prior to
the first bevacizumab infusion (4).
8. Current or recent use of any non-steroidal anti inflammatory agent (aspirin > 325
mg/day), or anti aggregation agents (dypiridamole, ticlopidine, clopidogrel > 75
mg/day), within 10 days before the first administration of bevacizumab (4).
General Exclusion Criteria
1. Severe resting dyspnea due to complications or oxygen dependency
2. Clinically significant (i.e. active) cardiovascular disease, i.e. myocardial infarction
within the last 6 months before inclusion, unstable angina, congestive heart failure
NYHA Class ≥ II (see Appendix 5), serious cardiac arrhythmia requiring medication
during the study which might interfere with regularity of the study treatment or not
controlled by medication.
3. LVEF ≤ 50% by local definition using MUGA or echo cardiogram
4. Patient suffering from an uncontrolled diabetes (> 11 mmoles/L) (5)
5. Diabetic patient treated with oral antidiabetics or insulin with an underlying
cardiopathy at ultrasound.
6. Evidence of ongoing or active infection (requiring IV antibiotics), 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 increases the patient’s risk of treatment-related
complications
7. Pregnant or lactating women
8. Patients with reproductive potential not willing to use effective method of
contraception
9. Treatment with any other investigational agent, or participation in another clinical
trial within 28 days prior to enrolment.
10. Vaccination by modified live vaccines, vaccination against yellow fever during study treatment period
11. Patients with known infection with HIV, HBV, HCV
12. Patients with a known allergy or sensitivity to monoclonal antibodies (bevacizumab, trastuzumab), to murine proteins, to hormonal therapies, to Chinese hamster ovary
cell products or other study chemotherapies (docetaxel) or any of their excipients.
13. Patients assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pathological complete response rates.
pCR will be evaluated post-surgery (Chevallier criteria) by an independent Committee (for all patients).
The patients with ∆ SUV < 70% will be randomized (2:1) to received either docetaxel + trastuzumab + bevacizumab or docetaxel + trastuzumab.
84 patients (docetaxel + trastuzumab + bevacizumab: 56 patients; docetaxel + trastuzumab: 28 patients) will allow to detect a difference between the two treatment groups of 30% in pCR rates in favor of docetaxel + trastuzumab + bevacizumab Arm with a power of 80% assuming a pCR rate of 10% in either docetaxel + trastuzumab Arm and a two sided type I error of 5%.
According to the hypothesis that 60% of patients will have a ∆ SUV < 70% before Cycle 2 of neoadjuvant treatment (Berriolo-Riedinger et al. 2008), 56 further patients (with ∆SUV ≥70%) are necessary (these patients will continue docetaxel + trastuzumab neadjuvant treatment). The total of assessable patients is 140.
Furthermore, 156 subjects will be enrolled in the study taking into account that 10% of the enrolled patients will drop out before randomization (after the second PET), to obtain 84 randomized patients
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| bevacizumab & trastuzumab & docetaxel vs trastuzumab & docetaxel |
|
| 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 | 25 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
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