| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive operable primary breast cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 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) |
|
| 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 compare IDFS (Invasive Disease Free Survival) (1) in the node-positive subpopulation and (2) in the overall protocol–defined population of patients between the two treatment arms. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare IDFS plus second non-breast primary cancers, DFS(Disease Free Survival), and distant recurrence-free interval (DRFI) (1) in the node-positive subpopulation and (2) in the overall protocol defined population between the two treatment arms.
• To compare OS (1) in the node-positive subpopulation and (2) in the overall protocol-defined population between the two treatment arms.
Safety Objectives:
• To compare overall safety, cardiac safety, hepatic, and pulmonary safety between the two treatment arms.
Patient-reported Outcome (PRO) Objectives:
• To compare PROs of treatment-related symptoms, patient functioning, and health-related quality of life (HRQoL) between the two treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Adult patients, >/= 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status </= 1
- Non-metastatic histologically confirmed primary invasive breast carcinoma that was operable
- HER2-positive breast cancer
- Known hormone receptor status of the primary tumor
- Adequately excised: patients must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy
- Pathological tumor-node-metastasis staging (Union for International Cancer Control-American Joint Committee on Cancer [UICC/AJCC] 7th edition): Eligible patients must have either:
• Node-positive disease (pN >/= 1), any tumor size except T0, and any hormonal receptor status, or
• Node-negative disease (pN0) with pathologic tumor size >2.0 cm by standard local assessment AND negative for ER and PR determined by a central pathology laboratory
- Patients with synchronous bilateral invasive disease are eligible only if both lesions are HER2-positive
- No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the last surgery if additional resection required for breast cancer) and randomization
- Baseline LVEF </= 55% measured by echocardiogram (ECHO; preferred) or multiple-gated acquisition (MUGA) scans
- Female patients of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception. For male patients with partners of childbearing potential, one highly effective form of contraception or two effective forms of contraception must be used. Contraception must continue for the duration of study treatment and for 6 months after the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
- History of any prior (ipsi- and/or contralateral) invasive breast carcinoma
- History of non-breast malignancies within the 5 years prior to study entry, except for carcinoma in situ (CIS) of the cervix, CIS of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin
- Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC 7th edition, including inflammatory breast cancer
- For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment (e.g., neoadjuvant or adjuvant), including, but not limited to, chemotherapy, anti-HER2 therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or other tyrosine kinase inhibitors), hormonal therapy, OR anti-cancer radiation therapy (RT) (intraoperative radiotherapy as a boost at the time of primary surgery is acceptable)
- Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any malignancy
- History of DCIS and/or LCIS that was treated with any form of systemic chemotherapy, hormonal therapy, or RT to the ipsilateral breast where invasive cancer subsequently developed. Patients who had their DCIS/LCIS treated with surgery only and/or contralateral DCIS treated with radiation are allowed to enter the study
- Patients with contraindication to RT while adjuvant RT is clinically indicated
- Concurrent anti-cancer treatment in another investigational trial
- Cardiopulmonary dysfunction as defined by protocol
- Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
• Significant symptoms (Grade >/=2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia
• Myocardial infarction within 12 months prior to randomization
• Uncontrolled hypertension o
• Evidence of transmural infarction on ECG
• Requirement for oxygen therapy
- Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes, or known infection with HIV
- Any known active liver disease. For patients who are known carriers of HBV, active hepatitis B infection must be ruled out per local guidelines
- Inadequate hematologic, renal or liver function
- Pregnant or lactating women
- Hypersensitivity to any of the study medications or any of the ingredients or excipients of these medications, including hypersensitivity to benzyl alcohol
- Chronic immunosuppressive therapies, including systemic corticosteroids. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Invasive disease-free survival (IDFS), defined as time from randomization to occurrence of ipsilateral breast cancer recurrence, second primary invasive breast cancer, distant recurrence, or death of any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| up to approximately 10 years |
|
| E.5.2 | Secondary end point(s) |
• IDFSplus second primary non-breast cancer, excluding non-melanoma skin cancers and carcinoma in situ of any site
• Disease-free survival (DFS), defined as time between randomization and first occurrence of IDFS, second primary non-breast cancer and contralateral or ipsilateral ductal carcinoma in situ (DCIS)
• Distant recurrence-free interval (DRFI), defined as time between randomization and first occurrence of distant breast cancer recurrence
• Overall Survival (OS)
• Safety: Incidence of adverse events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| up to approximately 10 years |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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.8.2.4 | 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 154 |
| 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 |
| Belgium |
| Chile |
| Colombia |
| El Salvador |
| Georgia |
| Guatemala |
| Hong Kong |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Norway |
| Portugal |
| Spain |
| Sweden |
| Thailand |
| Israel |
| Mexico |
| Panama |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| South Africa |
| Switzerland |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
| Argentina |
| Australia |
| Bosnia and Herzegovina |
| Canada |
| Czech Republic |
| Brazil |
| France |
| Germany |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The study is planned to end after the last patient randomized into the study has undergone final follow up assessment. To enable long-term follow-up for survival and safety information, the study is planned to end approximately 10 years after the first patient is randomized. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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