| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Node positive and high risk node negative patients with operable breast cancer containing the HER2 alteration | |
| E.1.1.1 | Medical condition in easily understood language | | Node positive and high risk node negative patients with operable breast cancer containing the HER2 alteration | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10057654 | | E.1.2 | Term | Breast cancer female | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| 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 disease-free survival after treatment with doxorubicin and cyclosphosphamide followed by docetaxel (Taxotere®) (AC-T) with doxorubicin and cyclosphosphamide followed by docetaxel and trastuzumab (Herceptin®) (AC-TH) and with docetaxel in combination with carboplatin and Herceptin® (TCH) in the adjuvant treatment of node positive and high risk node negative patienst with operable breast cancer containing the HER2 alteration | |
| E.2.2 | Secondary objectives of the trial | To compare overall survival between the 3 above mentioned arms.
To compare cardiac toxicity between the 3 above mentioned arms.
To compare toxicity and quality of life between the 3 above mentioned arms.
To evaluate pathologic and molecular markers for predicting efficacy in these patient groups.
In addition, an independent socio-economic study will be conducted in parallel with the clinical study. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to local regulatory requirements.
2. Histologically proven breast cancer with an interval between definitive surgery that includes axillary lymph node involvement
assessment and registration of less than or equal to 60 days. If the definite surgery and the axillary node dissection are performed in two different days, both days should be within the 60 days window. A central pathology review may be performed post randomization for confirmation of diagnosis and molecular studies. The same block used for HER2 determination prior to randomization may be used for the central pathology review. See Appendix 3* for details on this process.
3. Definitive surgical treatment must be either mastectomy with axillary lymph node involvement assessment, or breast
conserving surgery with axillary lymph node involvement assessment for operable breast cancer . Margins of resected specimen from definitive surgery must be histologically free of invasive adenocarcinoma and/or ductal carcinoma in situ (DCIS). The finding of lobular carcinoma in-situ will not be scored as a positive margin.
4. Patients must be either lymph node positive or high risk node negative. Lymph node positive patients will be defined as
patients having invasive adenocarcinoma with at least one axillary lymph node (pN1) showing evidence of tumor among a
minimum of six resected lymph nodes.
High risk lymph node negative patients will be defined as patients having invasive adenocarcinoma with either 0 (pN0) among a minimum of 6 resected lymph nodes or negative sentinel node biopsy (pN0) AND at least one of the following factors: tumor size > 2 cm, ER and PR status is negative, histologic and/or nuclear grade 2-3, or age < 35 years.
Tumor must show the presence of the HER2 gene amplification by Fluorescence In-Situ Hybridization (FISH analysis) by a designated central laboratory (see Appendix 3 for complete details).
6. Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to randomization. Results must be
known at the time of randomization.
(Note: Patients whose tumor is estrogen receptor negative with progesterone receptor status unknown or undetermined,
MUST have the PR assayed in order to determine hormonal receptor status. Patients whose tumor is progesterone receptor negative with estrogen receptor status unknown or undetermined, MUST have the ER assayed in order to determine
hormonal receptor status.)
7. Age ≥ 18 years and age ≤ 70 years. The upper age limit is not meant to be exclusionary but rather is based on the lack of safety data for the TCH regimen in women >70 years of age.
8. Karnofsky Performance status index ≥ 80%.
9. Normal cardiac function must be confirmed by LVEF (echocardiography or MUGA scan) and ECG within 3 months prior to registration. The result of the echocardiography or MUGA must be equal to or above the lower limit of normal for the
institution.
10. Laboratory requirements: (within 14 days prior to registration)
a) Hematology:
i) Neutrophils ≥ 2.0 109/L
ii) Platelets ≥ 100 109/L
iii) Hemoglobin ≥ 10 g/dL
b) Hepatic function:
i) Total bilirubin < 1 UNL
ii) ASAT (SGOT) and ALAT (SGPT) ≤ 2.5 UNL
iii) Alkaline phosphatase ≤ 5 UNL
iv) Patients with ASAT and/or ALAT > 1.5 x UNL associated with alkaline phosphatase > 2.5 x UNL are not eligible for
the study.
c) Renal function:
i) Creatinine ≤ 175 μmol/L (2 mg/dL)
ii) If creatinine between 140 and 175 μmol/L, the calculated creatinine clearance should be ≥ 60 mL/min.
11 Complete staging work-up within 3 months prior to registration. All patients will have contralateral mammography and/or
ultrasound (mammogram is preferred), chest X-ray (PA and lateral) and/or CT and/or MRI, abdominal ultrasound and/or CT scan and/or MRI, and bone scan. In cases of positive bone scans, bone X-ray or bone MRI evaluation is mandatory to rule out the possibility of metastatic bone scan positivity. Other tests may be performed as clinically indicated (see appendix 5).
12. Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at
participating centers which will include Principal or Co-investigator’s sites.
13. Negative pregnancy test (urine or serum) within 7 days prior to registration for all women of childbearing potential. | |
| E.4 | Principal exclusion criteria | 1. Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy).
2. Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for any malignancy.
3. Prior radiation therapy for breast cancer.
4. Bilateral invasive breast cancer.
5. Pregnant, or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive
measures during study treatment (chemotherapy, Herceptin® and tamoxifen therapy) and must have negative urine or
serum pregnancy test within 7 days prior to registration.
6. Any T4 or N2 or known N3 or M1 breast cancer.
7. Pre-existing motor or sensory neurotoxicity of a severity ≥ grade 2 by NCI criteria.
8. Cardiac disease that would preclude the use of doxorubicin, docetaxel and Herceptin®.
a) any documented myocardial infarction
b) angina pectoris that requires the use of antianginal medication
c) any history of documented congestive heart failure
d) Grade 3 or Grade 4 cardiac arrhythmia (NCI CTC, version 2.0)
e) clinically significant valvular heart disease
f) patients with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG, unless they demonstrate by
echocardiography or MUGA scan within the past 3 months that the LVEF is ≥ the lower limit of normal for the
radiology facility;
g) patients with poorly controlled hypertension i.e. diastolic greater than 100 mm/Hg. (Patients who are well
controlled on medication are eligible for entry
h) patients who currently receive medications (digitalis, beta-blockers, calcium channel-blockers, etc) that alter
cardiac conduction, if these medications are administered for cardiac arrhythmia, angina or congestive heart failure. If these medications are administered for other reasons (ie hypertension), the patient will be eligible.
9. Other serious illness or medical condition:
a) history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would
prohibit the understanding and giving of informed consent
b) active uncontrolled infection
c) active peptic ulcer, unstable diabetes mellitus
d) patients with symptomatic, intrinsic lung disease resulting in dyspnea
10. Past or current history of neoplasm other than breast carcinoma, except for:
a) curatively treated non-melanoma skin cancer
b) in situ carcinoma of the cervix
c) other cancer curatively treated and with no evidence of disease for at least 10 years
d) ipsilateral ductal carcinoma in-situ (DCIS) of the breast
e) lobular carcinoma in-situ (LCIS) of the breast
f) DCIS involving the contralateral breast removed by mastectomy
11. Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators
(SERMs), either for osteoporosis or prevention of breast cancer. Patients must have discontinued these agents prior to
randomization.
12. Chronic treatment with corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 20 mg
methylprednisolone or equivalent).
13. Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must be stopped prior to
randomization.
14. Definite contraindications for the use of corticosteroids.
15. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not
marketed drug within 30 days prior to study entry.
16. Concurrent treatment with any other anti-cancer therapy.
17. Male patients, as no clinical efficacy or safety data are available from phase I-II studies. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Disease-free survival (DFS) | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Calculated from the date of randomization up to the first date of local, regional, or distant relapse, second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) | |
| E.5.2 | Secondary end point(s) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | Measured from the date of randomization up to the date of death of any cause. | |
| 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 | Yes |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | |
| 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 | | Three arms : 1 comparator arm | |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 146 |
| 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 | Yes |
| 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 | | Argentina | | Australia | | Austria | | Belgium | | Bosnia and Herzegovina | | Brazil | | Bulgaria | | Canada | | Colombia | | Croatia | | Czech Republic | | Egypt | | Estonia | | France | | Germany | | Greece | | Hong Kong | | Hungary | | India | | Ireland | | Israel | | Italy | | Korea, Republic of | | Lebanon | | Mexico | | Poland | | Romania | | Russian Federation | | Slovakia | | Slovenia | | South Africa | | Spain | | Sweden | | Switzerland | | Taiwan | | Tunisia | | United Kingdom | | United States | | Uruguay | | Venezuela, Bolivarian Republic of | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| 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 | 13 |
