E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-POSITIVE, LOCALLY ADVANCED, INFLAMMATORY, OR EARLY-STAGE BREAST CANCER |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | 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 |
The primary objective of this study is to evaluate the cardiac safety of neoadjuvant treatment with the following regimens:
• ddAC-->T+ PH: Dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support as needed according to local guidelines, followed by weekly paclitaxel (T) for 12 weeks, with pertuzumab and trastuzumab (PH) given every 3 weeks from the start of paclitaxel (Cohort A).
• FEC-->D+ PH: 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) given every 3 weeks for four cycles, followed by docetaxel (D) given every 3 weeks for four cycles, with pertuzumab and trastuzumab (PH) given every 3 weeks from the start of docetaxel (Cohort B). |
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E.2.2 | Secondary objectives of the trial |
- Secondary safety objectives are to evaluate the safety profiles of the two treatment regimens during the pre-operative (neoadjuvant) and adjuvant treatment periods, including adverse events (graded according to NCI CTCAE Version 4.0), serious adverse events, laboratory abnormalities (graded according to NCI CTCAE Version 4.0), and serum levels of anti-therapeutic antibodies (ATAs) against pertuzumab.
- The efficacy objectives for this study are as follows:
• To make an assessment of the antitumor activity associated with each regimen, as indicated by the pCR rate (defined as eradication of invasive disease in the breast and axilla; i.e., ypT0/is ypN0, or tpCR rate)
• To investigate the clinical response, event-free survival (EFS), invasive disease-free survival (iDFS), and overall survival (OS) for each treatment regimen |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adult patients, ≥ 18 years of age
- HER2-positive breast cancer confirmed by a central laboratory
- Primary tumor > 2 cm in diameter, or > 5 mm in diameter and node-positive
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Baseline LVEF ≥ 55% (measured by ECHO or MUGA) |
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E.4 | Principal exclusion criteria |
- Any previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer
- Metastatic disease (Stage IV) or bilateral breast cancer
- Previous exposure to any investigational treatment within 4 weeks before the first dose of study treatment
- Prior breast or non-breast malignancy within 5 years prior to study
entry, except for carcinoma in situ and basal cell and squamous cell
carcinoma of the skin. Patients with malignancies occurring more than 5
years prior to study entry are permitted if curatively treated.
- Inadequate hematologic, renal or liver function
- Pregnant or lactating women
- History of congestive heart failure of any New York Heart Association (NYHA) criteria
- angina requiring anti-anginal medication
- history of myocardial infarction within 6 months of enrollment
- serious or uncontrolled cardiac arrhythmia requiring treatment
- History or evidence of poorly controlled hypertension
- Severe, uncontrolled systemic disease
- Positive for hepatitis B, hepatitis C or HIV infection |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cardiac safety: Incidence of left ventricular systolic dysfunction (symptomatic or asymptomatic). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary cardiac safety evaluation will occur after all patients have completed neoadjuvant therapy (or have withdrawn from the study or are lost to follow up).
Cardiac safety will continue to be assessed in all patients throughout the adjuvant and post-treatment period. Additional analyses of these parameters (and other safety and efficacy data) will be conducted after the primary analysis at the following timepoints:
• After all patients have completed adjuvant anti-HER2 therapy (or have withdrawn from the study or are lost to follow up)
• At the end of the study (5 years after the last patient was enrolled) |
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E.5.2 | Secondary end point(s) |
- To make an assessment of the antitumor activity associated with each regimen, as indicated by the pCR rate
- To investigate the clinical response, event-free survival (EFS), invasive disease-free survival (iDFS), and overall survival (OS) for each treatment regimen
- Safety: Incidence of adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be assessed at the time of the primary analysis and at other key timepoints:
• After all patients have completed adjuvant anti-HER2 therapy (or have withdrawn from the study or are lost to follow up)
• At the end of the study (5 years after the last patient was enrolled) |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 | No |
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 |
Brazil |
Canada |
Denmark |
France |
Germany |
Italy |
Norway |
Poland |
Portugal |
Spain |
United Kingdom |
United States |
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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 the study will be 5 years after enrollment of the last patient in the study (or when all patients have died or the trial is terminated by the Sponsor, whichever is earliest). This data point will be considered last patient, last visit (LPLV). |
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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 | 6 |
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 | 6 |