| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Investigar pacientes con carcinoma de mama positivo para HER2 operable, con ganglios positivos o con ganglios negativos de alto riesgo.
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 administering trastuzumab during one year following randomization. Each patient can not contribute more than one event to the primary endpoint:
• cardiac toxicity (Level 1 or Level 2) or
• inability of administering trastuzumab as planned during the courses 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 courses 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 courses 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 courses 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 courses 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 |
Subjects with operable, node-positive or high-risk node-negative (see #3 below) HER2-positive breast carcinoma are eligible for the study, provided they satisfy the following criteria.
1) Subjects must demonstrate willingness to and be able to participate in the study and to adhere to dose and visit schedules;
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 risk tumor characteristics:
- node-positive: T1-3, N1-2, M0;
- node-negative: tumor > 2 cm in diameter and positive ER or PR, or tumor > 1cm and negative ER/PR - or malignancy grade II/III
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).
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 109/l, platelets ≥ 100 x 109/l and hemoglobin ≥ 7.5 mmol/l;
9) Adequate renal function: calculated creatinine clearance ≥ 50 ml/min.
10) Adequate postoperative liver function 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 |
A subject who meets any of the following exclusion criteria will be disqualified from participation in the study:
1) Clinical or radiological evidence of metastatic disease;
2) Prior radiotherapy, chemotherapy or biotherapy for the currently diagnosed breast cancer prior to randomization;
3) Clinically significant pericardial effusion;
4) 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)
5) Sensory/motor neuropathy > grade 2 as defined by NCI-CTC;
6) Pregnancy, or intending to become pregnant during the study;
7) Nursing, or intending to be nursing during the study;
8) 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
9) A situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study;
10) Usage of any investigational product within 30 days prior to enrollment;
11) Participation in any other clinical study;
12) 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) |
There is no primary efficacy endpoint for this study. The primary objective of this study is to determine, separately in the treatment arms, the overall incidence during one year following randomization of
• cardiac toxicity (Level 1 or Level 2) or
• inability of administering trastuzumab as planned during the courses 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)
Each patient can not contribute more than one event to the primary endpoint
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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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
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