| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| breast cancer, primary systemic therapy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 the pCR rates of neoadjuvant treatment of epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without bevacizumab (EC-T vs ECB-TB) in patients with Her 2 negative primary breast cancer (Setting I).
To compare the pCR rates of neoadjuvant treatment with weekly paclitaxel with or without Everolimus (RAD001) (Pw vs PwR) in patients with Her 2 negative primary breast cancer showing no sonographic response to 4 cycles of EC+/-B (Setting II).
To compare the pCR rates of neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel with either trastuzumab or lapatinib (ECH-TH vs ECL-TL) in patients with Her 2 positive primary breast cancer (Setting III).
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| E.2.2 | Secondary objectives of the trial |
1. Toxicity of and compliance to all six treatments.
2. Response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after treatment in all arms.
3. Rates of pCR breast, pCR invasive, pCR invasive and nodes.
4. Breast conservation rate after each treatment.
5. (Loco-regional and distant) disease-free and overall survival after each treatment. In Her-2 positive disease, the cerebral disease-free survival will be determined separately.
6. Treatment efficacies in subgroups defined according to tumor stage (T2-3 vs. T4), receptor status (ER and / or PgR positive vs. ER and PgR negative) and response by best appropriate imaging method to the first four cycles of treatment (complete vs. partial vs. no change).
7. Examination and comparing pre-specified molecular markers such as Ki-67, phospho-mTOR, YB-1, COX-2, HuR, phospho-p70 S6K, p65 NF kappa B and other ongoing translational research projects.
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| 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 |
1. To assess and correlate circulating tumor cells and proteins with the effect of treatment (CTC Substudy).
2. To compare the pathologic complete response (pCR), breast conservation, clinical and imaging response rate (after four cycles and before surgery) in patients where the tumor shows a favorable profile of a predetermined combined biomarker set to those where the tumor does not show it (PREDICT Substudy).
3. To evaluate the combination of a molecular biomarker test and magnetic resonance-based imaging (DCE-MRI, DWI) for the prediction of the pathological remission in patients of the PREDICT substudy (M-PREDICT).
4. To determine the percentage of patients in which conventional axillary clearance can be substituted by sentinel node biopsy when a predetermined clinical algorithm is used (SENTINA Substudy).
5. To assess the surgical outcome according to patient's and surgeon's perspectives
in correlation with clinical and pathological response to systemic treatment
(SOS – Surgical Outcome Substudy).
6. To correlate Single Nucleotide Polymorphisms (SNPs) of genes which are either involved in the metabolism or in the effectiveness of the distinct therapies with the associated toxicity and histologically assessed treatment effect (Pharmacogenomic Substudy). |
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| E.3 | Principal inclusion criteria |
1. Written informed consent for all study procedures including an additional core biopsy after the first four cycles of EC +/-B must be obtained and documented according to local regulatory requirements prior to beginning specific protocol procedures.
2. Patient has consented to the biomaterial collection and the paraffin-embedded tumor tissue block of diagnostic core has been sent to central biomaterial banks.
3. Complete baseline documentation must be sent to GBG Forschungs GmbH.
4. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
5. Tumor lesion in the breast with a palpable size of 2 cm or a sonographical size of 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
6. Patients should be in a stage of disease in which adjuvant chemotherapy would be considered. Therefore the following tumor stages are eligible *:
- locally advanced tumors with cT3 or cT4 or
- Estrogen (ER) and progesterone (PgR) receptor negative tumors or
- ER or PgR positive tumors which are cN+ (for cT2) or pNSLN+ (for cT1).
* During the Run-In Phase only patients with cT4 or cT3 cN+ disease are eligible.
In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
7. Known HER-2/neu status detected on core biopsy. HER-2/neu positive is defined as HercepTest IHC 3+ or FISH+.
8. Age 18 years.
9. Karnofsky Performance status index 80%.
10. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution and above 55%.
11. Laboratory requirements:
a) Hematology
- Absolute neutrophil count (ANC) 2.0 x 109 / L and
- Platelets 100 x 109 / L and
- Hemoglobin 10 g/dL ( 6.2 mmol/L)
b) Hepatic function
- Total bilirubin < 1x UNL and
- ASAT (SGOT) and ALAT (SGPT) 2.5x UNL and
- Alkaline phosphatase 5x UNL.
Patients with ASAT and / or ALAT > 1.5x UNL and associated with alkaline phosphatase > 2.5x UNL are not eligible for the study.
c) Renal function
Creatinine 175 µmol/L (2 mg/dL) < 1.5x UNL
(or the calculated creatinine clearance should be 30 mL/min).
d) Proteinuria
Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must demonstrate
≤ 1 g of protein in 24 hours.
12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
13. Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound ( 21 days), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
14. Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating or at a cooperating center. |
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| E.4 | Principal exclusion criteria |
1. Patients with low or moderate risk, who are only doubtful candidates for adjuvant chemotherapy and do not fulfil the inclusion criterion No. 5.
2. Evidence of distant metastasis.
3. Prior chemotherapy for any malignancy.
4. Prior radiation therapy for breast cancer.
5. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
6. Inadequate general condition (not fit for anthracycline-taxane based chemotherapy).
7. Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
8. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >160 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
9. Previous thromboembolic event (except pregnancy-related thromboembolic events without genetic disposition).
10. Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.
11. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
12. Pre-existing motor or sensory neuropathy of a severity grade 2 by NCI criteria.
13. Currently active infection.
14. Active peptic ulcer, incomplete wound healing or unhealed bone fracture.
15. Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome, resection of the stomach or small bowel, ulcerative colitis.
16. History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.
17. Severe pulmonary condition / illness.
18. Unstable diabetes mellitus; Insulin-dependent type II diabetes mellitus.
19. Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment with bevacizumab. No minor surgeries including insertion of an indwelling catheter within 24 h prior to chemotherapy.
20. Definite contraindications for the use of corticosteroids.
21. Known hypersensitivity reaction to one of the investigational compounds or incorporated substances; or known dihydropyrimidine dehydrogenase deficiency.
22. Concurrent treatment with:
a) oral chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose ( 10 mg methylprednisolone or equivalent).
b) oral contraception and hormone replacement therapy. Prior treatment must be stopped before study entry.
c) virostatic agents like sorivudine or analogs like brivudine, concurrent treatment with aminoglycosides.
d) anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a dose of > 325 mg/day or clopidogrel at a dose of > 75 mg/day.
e) other experimental drugs or any other anti-cancer therapy.
f) drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A, e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin, Erythromycin, Verapamil, Diltiazem (see appendix 6) within the last 5 days or the expected need for these treatments during study participation.
23. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
24. Male patients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pathological complete response of breast and lymph nodes (pCR breast and nodes; primary endpoint).
No microscopic evidence of residual viable tumor cells (invasive or noninvasive) in any resected specimens of the breast and axillary nodes.
Pathological complete response of breast (pCR breast; secondary endpoint - corresponding to score 4).
No microscopic evidence of residual viable tumor cells (invasive or noninvasive) in all resected specimens of the breast. The pathological examination of axillary lymph nodes is not to be considered.
Pathological complete response of invasive tumor (pCR invasive; secondary endpoint - corresponding to score 3).
No microscopic evidence of residual viable invasive tumor cells in all resected specimens of the breast. The pathological examination of axillary lymph nodes is not to be considered.
Pathological complete response of invasive tumor and nodes (pCR invasive and nodes; secondary endpoint).
No microscopic evidence of residual viable invasive tumor cells in all resected specimens of the breast and no microscopic evidence of residual viable tumor cells in axillary nodes. |
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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 | 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 | No |
| 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) | 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 | 125 |
| 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 | 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 |
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| 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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| End of study is event-driven and will be when 379 events occured in setting I and 120 events occured in setting III of the study. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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