E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced, inflammatory or early stage HER2 positive breast cancer
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 make a preliminary assessment of the tolerability of neoadjuvant treatment with one of the following treatment regimens: Arm A FEC->T with trastuzumab and pertuzumab given from the start of the chemotherapy regimen (i.e. concurrently with the anthracycline) OR Arm B FEC->T with trastuzumab and pertuzumab given from the start of the taxane treatment (i.e. following the anthracycline) OR Arm C TCH with pertuzumab, with both antibodies being given from the start of the chemotherapy. The primary objective will be evaluated when all patients have received six cycles of neoadjuvant treatment, had their surgery and all necessary samples taken or withdrawn from the study whichever is earlier. |
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E.2.2 | Secondary objectives of the trial |
•To make a preliminary assessment of the activity associated with each regimen as indicated by the complete pathological response (pCR) rate. •To evaluate the safety profiles of each treatment regimen, including pre-operative (neoadjuvant) and post-operative (adjuvant) treatment. •To investigate the overall survival, the time to clinical response, time-to-response, disease free survival and progression free survival for each treatment arm. •To investigate the biomarkers that may be associated with primary and secondary efficacy endpoints in accordance with each treatment arm. •To investigate the rate of breast conservative surgery for all patients with T2-3 tumors for whom mastectomy was planned at diagnosis. An overall assessment of the risk and benefit of each regimen will be made.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female patients with locally inflammatory or early stage, unilateral and histologically confirmed invasive breast cancer. The initial breast cancer asessment should be performed by a physician with experience in surgery for breast cancer. Patients with inflammatory breast cancer must be able to have a core needle biopsy. 2. Primary tumor > 2cm in diameter. 3. HER-pos breast cancer confirmed by a central laboratory. Tumors must be HER2 3+ by IHC or FISH/CISH +(FISH/CISH pos mandatory for HER 2 2+ tumors). 4. Availability of FFPE tissue for central confirmation of HER2 eligibility. 5. Female patients, age>=18 years. 6. Baseline LVEF>=55%. 7. Performance status ECOG<=1. 8. At least 4 weeks since major unrelated surgery, with full recovery. 9. A negative pregnancy test must be available for pre-menopausal women and for women less than 12 months after the onset of menopause. 10. For women of childbearing potential agreement to use a "highly effective" , non-hormonal form of contraception or two "effective" forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment. 11. Signed informed consent.
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E.4 | Principal exclusion criteria |
1. Metastatic disease (Stage IV) or bilateral breast cancer. 2. Previous anticancer therapy or radiotherapy for any malignancy. 3. Other malignancy, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. 4. Inadequate bone marrow function (e.g. Absolute Neutrophil Count (ANC) < 1.5 x 109/L, Platelet count < 100 x 109/L and Hb < 9 g/dL). 5. Impaired liver function: (e.g. serum [total] bilirubin > 1.25 x ULN (with the exception of Gilbert’s syndrome), AST, ALT > 1.25 x ULN, albumin < 25 g/L. 6. Inadequate renal function, serum creatinine > 1.5 x ULN. 7. Uncontrolled hypertension (systolic >150 and/or diastolic > 100), unstable angina, CHF of any NYHA classification, serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment, or LVEF < 55%. 8. Dyspnea at rest or other diseases which require continuous oxygen therapy. 9. Severe uncontrolled systemic disease (e.g. hypertension, clinically significant cardiovascular, pulmonary, metabolic, wound-healing, ulcer, or bone fracture). 10. Patients with insulin-dependent diabetes. 11. Pregnant and/or lactating women. 12. Patients with reproductive potential not willing to use a ‘highly effective’ method of contraception or two ‘effective’ methods of contraception as described in General Inclusion Criterion number 10. 13. Received any investigational treatment within 4 weeks of study start. 14. Patients with known infection with HIV, HBV, HCV. 15. Current chronic daily treatment with corticosteroids (dose of >10 mg methylprednisolone, or equivalent [excluding inhaled steroids]) 16. Known hypersensitivity to any of the study drugs or excipients. 17. Patients assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of the study is to describe the tolerability of the treatment regimens in Arms A, B and C during neoadjuvant treatment. The primary endpoint of this study therefore does not relate to efficacy. The following safety endpoints are considered of primary importance for the evaluation of the primary objective: – Incidence of symptomatic cardiac events as assessed by the Investigator (Grade 3, 4 or 5 symptomatic LVSD) – LVEF measures over the course of the neoadjuvant period (LVEF decline of ≥10% from baseline and to a value of <50%)
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 | No |
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 study will be five years after randomization of the last patient or progressive disease experienced in all patients or the trial is terminated by the Sponsor, whichever is earlier. This data point will be considered LPLV (Last Patient Last Visit). |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 7 |