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    Summary
    EudraCT Number:2010-022902-41
    Sponsor's Protocol Code Number:BIG4-11/BO25126/TOC4939g
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-09-02
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2010-022902-41
    A.3Full title of the trial
    A randomized multicenter, double-blind, placebo-controlled
    comparison of chemotherapy plus trastuzumab plus placebo
    versus chemotherapy plus trastuzumab plus pertuzumab as
    adjuvant therapy in patients with operable HER2-positive
    primary breast cancer
    Randomizovaná, multicentrická, dvojitě zaslepená, placebem kontrolovaná
    studie porovnávající chemoterapii s trastuzumabem a placebem oproti
    chemoterapii s trastuzumabem a pertuzumabem jako podpůrnou léčbu u
    pacientů s operovatelným HER2-pozitivním primárním karcinomem prsu.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Pertuzumab in Addition to Chemotherapy and Herceptin (Trastuzumab) as Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer
    Studie s Pertuzumabem v kombinaci s chemoterapií a Herceptinem jako
    adjuvantní léčba u pacientů s HER2 pozitivním primárním karcinomem prsu
    A.3.2Name or abbreviated title of the trial where available
    APHINITY Adjuvant Pertuzumab and Herceptin IN IniTial therapY of breast cancer
    A.4.1Sponsor's protocol code numberBIG4-11/BO25126/TOC4939g
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Perjeta
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited, UK
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePertuzumab (rhuMAb 2C4)
    D.3.2Product code Ro 436-8451/F01
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPertuzumab
    D.3.9.1CAS number 380610-27-5
    D.3.9.2Current sponsor codeRO4368451
    D.3.9.3Other descriptive namerhuMAb 2C4
    D.3.9.4EV Substance CodeSUB16455MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number420 mg/14ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeHumanized monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with operable HER2-positive primary breast cancer
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed with primary breast cancer that is HER2-positive
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    E.3Principal 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
    E.4Principal 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
    E.5 End points
    E.5.1Primary 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).
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA270
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Chile
    China
    Colombia
    Croatia
    El Salvador
    European Union
    Guatemala
    Hong Kong
    Israel
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Panama
    Peru
    Philippines
    Russian Federation
    South Africa
    Switzerland
    Taiwan
    Thailand
    Ukraine
    United States
    E.8.7Trial 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 10 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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4080
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 720
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2540
    F.4.2.2In the whole clinical trial 4800
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will remain in follow up for ca. 10 yrs. after last patient is randomized or until death occurs. They should receive additional endocrine anticancer therapy if the tumor is shown to be hormone receptor positive (in accordance with the locally approved SmPC and nationally recognized guidelines). Disease-free patients will not require any specific additional anti cancer therapy.
    Patients with recurrent disease should be treated at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Breast International Group (BIG)
    G.4.3.4Network Country Belgium
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation BrEAST
    G.4.3.4Network Country Belgium
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Frontier Science And Technology Research Foundation, Inc
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 4
    G.4.1Name of Organisation Frontier Science (Scotland) Ltd
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-10-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-14
    P. End of Trial
    P.End of Trial StatusCompleted
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