E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Investigate patients with operable, node-positive or high-risk node-negative HER2-positive Breast Carcinoma. |
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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 determine, separately in the treatment arms, the overall incidence of cardiac events (as defined in the protocol) or inability to administer trastuzumab during one year of planned treatment duration following randomization. Each patient can not contribute more than one event to the primary endpoint. The overall incidence is defined as: • cardiac toxicity (Level 1 or Level 2) or • inability of administering trastuzumab as planned during the 8 cycles of chemotherapy (Section 5.3.3.1) or • inability of administering trastuzumab as per package insert and planned for a total duration of one year (Section 5.4.3.2)
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E.2.2 | Secondary objectives of the trial |
Objective #1 To determine, separately in the treatment arms, the overall incidence of cardiac toxicity (Level 1 or Level 2) or inability of administering trastuzumab (as above) during the 8 cycles of chemotherapy. Each patient can not contribute more than one event to the secondary objective. Objective #2 To determine, separately in the treatment arms, during the 8 cycles of trial therapy: - incidence of Level 1 and Level 2 cardiotoxicity - frequency of patients not being able to initiate/continue trastuzumab after the first 4 cycles of chemotherapy Objective #3 To determine, separately in the treatment arms, during 1 year following randomization: - incidence of Level 1 and Level 2 cardiotoxicity - frequency of patients not being able to initiate / continue trastuzumab after 4 cycles of chemotherapy - frequency of patients requiring hold or suspension of trastuzumab therapy Objective #4 To evaluate separately in the treatment arms the rate of relapse free survival.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Subjects must demonstrate willingness to and be able to participate in the study and to adhere to dose and visit schedule; 2) Subjects must be of female gender and ≥18 years of age; 3) Subjects must have been diagnosed with operable, histological confirmed adenocarcinoma of the breast with no clinical or radiological evidence of metastatic disease but with otherwise high or intermediate risk tumor characteristics: - node-positive: T1-3, N1-2, M0; - node-negative AND at least one of the following features: tumor > 2 cm in diameter, OR tumor > 1cm and negative ER/PR, OR malignancy grade II/III, OR presence of peritumoral vascular invasion OR age < 35 Y 4) HER2-positive by FISH (with gene amplification) or 3+ using immunohistochemistry 5) Subjects must have had complete resection (R0) of the primary tumor and axillary lymph nodes (or must have negative sentinel node(s)). 6) Baseline LVEF by MUGA scan or echocardiogram (ECHO) ≥ 55%. 7) ECOG-performance status of 0-1; 8) Adequate postoperative bone marrow function with neutrophils ≥ 1.5 x 10exp9/l, platelets ≥ 100 x 10exp9/l and hemoglobin ≥ LLN; 9) Adequate renal function: calculated creatinine clearance ≥ 50 ml/min. 10) Adequate postoperative liver function with with a total bilirubin < ULN, alkaline phosphatase < 2.5 times the ULN and AST < 1.5 times the ULN; 11) Subjects must be free of any clinically relevant disease that would, in the principal investigator’s and/or sponsor’s opinion, interfere with the conduct of the study or study evaluations; 12) Subjects of childbearing potential (including women who are less than 1 year postmenopausal and will be sexually active during the study) must agree to use a medically accepted method of contraception, while receiving protocol-specified medication and for 30 days after stopping the medication or be surgically sterilized prior to screening. 13) Subjects must be able to provide written informed consent.
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E.4 | Principal exclusion criteria |
1) Clinical or radiological evidence of metastatic disease; 2) Prior radiotherapy, chemotherapy or biotherapy for the currently diagnosed breast cancer prior to randomization; 3) History of the following cancers: ►Ipsilateral breast cancer ►Invasive DCIS treated with any therapy other than excision ►Contralateral breast cancer ►History of non-breast malignancies witin the 5 years prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the previous 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin; 4) Clinically significant pericardial effusion; 5) Serious cardiac illness including, but not confined to ►History of documented congestive heart failure ►History of any form of cardiomyopathy or active treatment for any form of cardiomyopathy ►History of angina pectoris or documented transmural myocardial infarction, or active angina pectoris requiring medication ►Serious ventricular arrhythmias requiring medication or ICD therapy, uncontrolled supraventricular arrhythmias ►Clinically significant valvular disease ►Poorly controlled arterial hypertension (systolic BP > 180 mmHg, diastolic BP > 100 mmHg) 6) Sensory/motor neuropathy > grade 2 as defined by NCI-CTC; 7) Pregnancy or intending to become pregnant during the study; 8) Nursing (breastfeeding) or intending to be nursing during the study; 9) Any of the following clinical conditions: ►Chronic obstructive pulmonary disease, requiring chronic treatment ►Clinically significant active infections ►A history of a psychological illness of condition, preventing the subject to understand the requirements of the study. ►Unstable regulation of diabetes mellitus 10) A situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study; 11) Is on staff, affiliated with,or a family member of the staff personnel directly involved with this study; 12) Usage of any investigational product within 30 days prior to enrollment; 13) Participation in any other interventional clinical study involving drug, device or biological. This would not prohibit the patient from participating in a QOL, questionnaire, blood collection, or observational study; 14) Allergy to or sensitivity to the study drug or its excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to determine, separately in the treatment arms, the overall incidence of cardiac events or inability to administer trastuzumab during one year of planned treatment duration.
Each patient can not contribute more than one event to the primary endpoint. The overall incidence is defined as: • cardiac toxicity (Level 1 or Level 2) or • inability of administering trastuzumab as planned during the 8 cycles of chemotherapy (Section 5.3.3.1) or • inability of administering trastuzumab as per package insert and planned for a total duration of one year (Section 5.4.3.2).
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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) | 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) | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |