E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with previously untreated ErbB2-overexpressing Stage I - IIIA invasive breast cancer with primary tumour size > 1cm. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
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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 |
The primary objective of the study is to compare the rate of pathologic complete response (pCR) in the breast at the time of definitive surgery. |
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E.2.2 | Secondary objectives of the trial |
• The pCR rate in the breast and axilla at the time of definitive surgery in the study treatment regimen versus the reference regimen.
• Overall response rate (complete plus partial response) in the breast and axilla.
• The breast conservation rate. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent approved by an Independent Ethics Committee (IEC) and obtained prior to any study specific screening procedures. 2. Female patients aged ≥18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 –1. 4. Histologically confirmed, previously untreated, operable Stage I-IIIA invasive breast cancer: • Primary tumour greater than 1 cm in diameter measured by clinical examination and confirmed by at least one imaging study (mammography, breast ultrasound or MRI). • In the case of a multifocal tumour (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be >1 cm and is designated as the “target” lesion for all subsequent tumour evaluations. 5. Over expression and/or amplification of ErbB2 in the invasive component of the primary tumour according to one of the following definitions. Central laboratory confirmation is not required prior to randomization, but tumour samples must be available for banking and retrospective confirmation. • 3+ over expression by IHC (>30% of invasive tumour cells); • 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ hybridization (FISH/CISH) test demonstrating ErbB2 gene amplification; • ErbB2 gene amplification by FISH/CISH (>6 ErbB2 gene copies per nucleus, or a FISH ratio [ErbB2 gene copies to chromosome 17 signals] of >2.2.) Patients with a negative or equivocal overall result (FISH test ratio of ≤2.2, ≤6.0 ErbB2 gene copies per nucleus) and staining scores of 0,1+, 2+ or 3+ (in 30% or less neoplastic cells) by IHC are NOT eligible for participation in the trial. 6. Known ER and PgR hormone receptor status. 7. LVEF within institutional normal range (evaluated by multiple-gated acquisition [MUGA] or echocardiography). 8. Women of childbearing potential must have a negative serum pregnancy test within 14 days (preferably 7 days) of first dose of study treatment and agree to use effective contraception, as defined in Section 7.3.2, during the study and for 28 days following the last dose of study drug. 9. Adequate baseline organ function defined by: • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, • Hemoglobin ≥ 9 g/dL, • Platelet count ≥ 100 x 109/L, • Serum bilirubin ≤1.5 x ULN. In the case of known Gilbert´s syndrome, < 2x ULN is allowed, • ALT and AST ≤ 2.5 x ULN, • Alkaline phosphatase ≤ 2.5 x ULN, • Serum creatinine ≤ 1.6 mg/dL or calculated creatinine (Cockcroft and Gault ) clearance ≥50mL/m. 10. Patient agrees to make available tumour tissue samples for submission to the central laboratory for planned as well as future translational research. 11. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
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E.4 | Principal exclusion criteria |
1. Metastatic, locally advanced, or inflammatory breast cancer as defined by the AJCC (7th Edition). 2. Bilateral breast cancer. 3. Multicentric breast cancer (defined as the presence of two or more foci of cancer in different quadrants of the same breast). 4. Any prior treatment for primary breast cancer (other than excision of tumour in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy, all of which exclude the patient). 5. Concurrent participation in another clinical trial involving anti-cancer investigational drug or administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment. 6. History of any prior malignancy in previous 5 years (patients with a history of completely resected non-melanoma skin cancer or successfully treated carcinoma in situ of the cervix are eligible). 7. History of significant comorbidities that interfere with the conduct of the study, or evaluation of the results, or with informed consent. 8. Active infection. 9. Peptic ulcer or unstable diabetes mellitus within 8 weeks prior to study enrolment. 10. Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (≤6 months before enrolment), myocardial infarction (≤6 months before enrolment), unstable angina, New York Heart Association (NYHA) ≥ grade 2 congestive heart failure, serious cardiac arrhythmia requiring medication during the study and that might interfere with regularity of the study treatment, or not controlled by medication. 11. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment). 12. Lactating women. 13. Subjects unable to swallow and retain orally administered medication or with any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome, major resection of the stomach or bowels, or ulcerative colitis are also excluded. 14. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator. 15. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to any of the study drugs, active ingredients, or excipients that contraindicates their participation. 16. Concomitant use of CYP3A4 inhibitors or inducers (see Section 6.2 for list of prohibited medications). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is pathologic complete response (pCR) in the breast at the time of definitive surgery defined as the absence of invasive disease. |
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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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |
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 |