E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary inflammatory HER2+ breast cancer |
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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 | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
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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 | 10021974 |
E.1.2 | Term | Inflammatory breast cancer |
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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 assess the rate of pathological complete response on surgical samples according to the Sataloff classification, by a centralized review, following a neoadjuvant treatment with bevacizumab combined to trastuzumab based chemotherapy in HER2+ inflammatory breast cancer |
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E.2.2 | Secondary objectives of the trial |
To Assess:
- Disease Free Survival (DFS). - Recurrence free interval (RFI). - Overall survival (OS). - Safety according to CTC-AE v3.0. - Cardiac safety based on NYHA classification. - Predictive factors of efficacy (biology, pharmacokinetics, pharmacogenetics, pharmacogenomics, proteomics, imaging.)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients must have signed a written informed consent form prior to any study specific screening procedures, • Women , • 18 years or older, • Performance status 0 to 2, • Life expectancy ≥ 3 months, • Able to comply with the protocol, • Patient affiliated to the national “Social Security” regimen or beneficiary of this regimen. • Histologically confirmed breast cancer and confirmed inflammatory breast cancer defined as follows: - T4d any N - or PeV II IGR - or PeV III IGR - or skin biopsy with tumor emboles in the lymph vessels of the superficial derma. • HER2 positive tumors by immunohistochemistry (IHC +++) or fluorescent/chromogenic in situ hybridization (FISH+ or CISH+) • Hormone receptors status known. • No metastases. • Adequate hematologic function: - Absolute neutrophil count ≥ 1.2 x 10exp9/L AND - platelets ≥ 100 x 10exp9/L AND - Hb ≥ 9 g/dL • Adequate liver function: - Total bilirubin ≤ 1.5 ULN unless elevation is due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin AND - ASAT < 2.5 ULN AND - ALAT < 2.5 ULN • Adequate kidney function: - Serum creatinine ≤ 1.25 ULN or Creatinine clearance ≥ 50 mL/min according to the Cockroft and Gault formula 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 • Adequate coagulation function - International normalized ratio (INR) ≤ 1.5 (except for patients with prophylactic use of anticoagulant) and - TCA ≤ 1.5 x ULN within 7 days prior to enrolment. • Adequate cardiac function - Left ventricular ejection fraction (LVEF) ≥ 55% (isotopic or ultrasound methods)
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E.4 | Principal exclusion criteria |
• Incapacitated adults not able to give informed legal consent. Pregnant or breast feeding women. • Women with an intact uterus (unless amenorrhoeic for the last 24 months) not using effective means of contraception • Patient considered socially or psychologically unable to comply with the treatment and the required medical follow-up. • Non inflammatory breast cancer with lymphatic skin permeation. • Metastases. Previous Cancer History • 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. • Patient previously treated with chemotherapy, radiation therapy or hormone therapy for a breast tumor. • History or evidence of inherited bleeding diathesis or coagulopathy. • 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. • 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, serious cardiac arrhythmia requiring medication during the study which might interfere with regularity of the study treatment or not controlled by medication. • History of thrombotic disorders within the last 6 months prior to enrolment (i.e. cerebrovascular accident, transient ischaemic attacks). • Severe resting dyspnea due to complications or oxygen dependency. • Diabetic patient treated with oral antidiabetics or insulin with an underlying cardiopathy at ultrasound. • 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.
• Major surgery (including open biopsy), significant traumatic injury within 28 days prior to study treatment start 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. • Non-healing wound, active peptic ulcer or bone fracture • History of abdominal fistula, diagnosed with a tracheo-oesophageal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment. Current Medication • 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. • 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. • Patient with known contra-indication to radiotherapy. • Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment. • Vaccination by modified live vaccines, vaccination against yellow fever during study treatment period. • Administration of phenytoïn (Di-hydan®, Dilantin®) during study treatment period. • 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 (epirubicin, cyclophosphamide, docetaxel, 5-FU) or any of their excipients.
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of pathological complete response on surgical samples, according to Sataloff classification, by a centralized review, following a neoadjuvant treatment with bevacizumab combined to trastuzumab based chemotherapy in HER2+ inflammatory breast cancer |
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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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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.8.4.1 | Number of sites anticipated in Member State concerned | 36 |
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 | 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
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The end of the study is defined in section 3.1.3 of the protocol as 5 years after the inclusion of the last patient (inclusion is defined as start of the neoadjuvant treatment). |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 0 |