E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with operable HER2-positive primary breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Newly diagnosed with primary breast cancer that is HER2-positive |
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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 | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER2 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 compare invasive disease-free survival (IDFS) in patients with HER2-positive breast cancer randomized to chemotherapy plus one year of trastuzumab plus placebo or chemotherapy plus one year of trastuzumab plus pertuzumab. |
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E.2.2 | Secondary objectives of the trial |
To compare invasive disease-free survival including second non-breast cancers, disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), cardiac safety, overall safety and health-related quality of life (HRQL) in the two treatment arms. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A subset of patients will participate in a substudy as detailed in a separate protocol.
Full title: A pharmacokinetic substudy in association with the phase III, randomized, multicenter, doubleblind, placebo-controlled trial APHINITY (BIG 4-11/BO25126/TOC4939G) to evaluate pharmacokinetics and potential drug-drug interactions in patients with early breast cancer.
Protocol identifiers: BIG 4-11 / BO25126 / TOC4939G (PK substudy
1)
Protocol date: 2011-06-20
Please refer to the substudy protocol for further information. |
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E.3 | Principal inclusion criteria |
- Adult patients. >/= 18 years of age
- Non-metastatic primary invasive HER2-positive carcinoma of the breast that is adequately excised, and that is either node-positive (except T0), or node-negative but with presence of at least one risk factor as defined by the protocol (the latter option only applies to protocol version A. Node-negative patients are NOT allowable under protocol version B.)
- Eastern Cooperative Oncology Group (ECOG) performance status </=1
- The interval between definitive surgery for breast cancer and the first dose of chemotherapy must be no more than 8 weeks (56 days). All procedures, including randomization, must occur during this period. The first cycle of chemotherapy must be administered within 7 days of randomization or on Day 56, whichever occurs first.
- Known hormone receptor status (estrogen receptor and progesterone receptor)
- Baseline LVEF >/= 55%
- Women of childbearing potential and male participants with partners of childbearing potential must agree to use effective contraception (as defined by the protocol) by the patient and/or partner for the duration of the study treatment and for at least 7 months after the last dose of study drug |
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E.4 | Principal exclusion criteria |
- History of any prior (ipsi- and/or contralateral) invasive breast cancer
- History of non-breast malignancies within the 5 years prior to study entry, except for carcinoma in situ of the cervix, carcinoma in situ of the
colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin
- Any "clinical" T4 tumor as defined by TNM, including inflammatory
breast cancer
- Any previous systemic chemotherapy for cancer or radiotherapy for cancer
- Prior use of anti-HER2 therapy for any reason or other prior biologic or immunotherapy for cancer
- Concurrent anti-cancer treatment in another investigational trial
- Serious cardiac or cardiovascular disease or condition
- Pregnant or lactating women |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the trial is Invasive Disease-Free Survival (IDFS). It is a composite endpoint which is defined as the time from randomization until the date of the first occurrence of one of the following events:
• Ipsilateral invasive breast tumor recurrence (ie, an invasive breast cancer involving the same breast parenchyma as the original primary lesion);
• Ipsilateral local-regional invasive breast cancer recurrence (ie, an invasive breast cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast);
• Distant recurrence (ie, evidence of breast cancer in any anatomic site – other than the two abovementioned sites – that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer);
• Contralateral invasive breast cancer;
• Death attributable to any cause including breast cancer, non-breast cancer or unknown cause (but cause of death should be specified if at all possible). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will take place when approximately 379 IDFS events have occurred.
In order to ensure sufficient data maturity (particularly in patients enrolled after the protocol amendment B), in the event that 379 IDFS events are reached sooner than 30 months after last patient enrolled (as is anticipated based on the revised IDFS assumptions), the primary analysis will be delayed until 30 months after last patient randomized. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of the present trial include OS (overall survival), DFS (disease-free survival), IDFS (invasive disease-free survival) including second primary non-breast cancer, RFI (recurrence-free interval) and DRFI (distant recurrence-free interval).
Additionally, cardiac and overall safety, as well as quality of life will be evaluated. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary variables will be analyzed in a similar manner as the primary endpoint to compare the two treatment arms, estimate 3-year event rates (5-year event rates for OS). An event driven OS analysis is planned when 640 deaths have occurred, estimated to be around nine and a half years after last patient randomized. Assuming the primary analysis for IDFS occurs after 379 events then the first interim OS analysis will be made available at this time (estimated to be 4 to 5 years after the first patient is randomized). Two subsequent interim analyses of OS will be performed approximately 2.5 and 5 years later, with the final event-driven OS analysis defined above. |
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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 | Yes |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 270 |
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 |
Argentina |
Chile |
Colombia |
El Salvador |
Guatemala |
New Zealand |
Panama |
Peru |
Philippines |
Switzerland |
Ukraine |
Hong Kong |
Taiwan |
Australia |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
South Africa |
Thailand |
United Kingdom |
United States |
Croatia |
European Union |
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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 will formally end approximately 15 years from the date the last patient is randomized into the study providing the study objectives have been met by this time.
This may or may not coincide with the time of the event-driven Overall Survival analysis, depending on the event rate. |
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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 | 17 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 17 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |