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    Summary
    EudraCT Number:2007-002997-72
    Sponsor's Protocol Code Number:TOC4129g/WO20698
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-01-15
    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 ConcernedFrance - ANSM
    A.2EudraCT number2007-002997-72
    A.3Full title of the trial
    A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF PERTUZUMAB + TRASTUZUMAB + DOCETAXEL vs. PLACEBO + TRASTUZUMAB + DOCETAXEL IN PREVIOUSLY UNTREATED HER2-POSITIVE METASTATIC BREAST CANCER
    A.4.1Sponsor's protocol code numberTOC4129g/WO20698
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 No
    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 RO4368451/F01
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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.3.9.2Current sponsor codeRO4368451/F01
    D.3.9.3Other descriptive namerhuMAb 2C4
    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/14 ml
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Yes
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 No
    D.IMP: 2
    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 Herceptin®
    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.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNTrastuzumab
    D.3.9.1CAS number 180288-69-1
    D.3.9.2Current sponsor codeRo 45-2317/V03
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Yes
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 No
    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
    HER2 positive metastatic breast cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10006202
    E.1.2Term Breast cancer stage IV
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 positive breast cancer
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10021974
    E.1.2Term Inflammatory breast cancer
    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 progression-free survival (PFS) based on tumor assessments by an independent review facility (IRF) between patients in the two treatment arms.
    E.2.2Secondary objectives of the trial
    • To compare overall survival (OS) between the two treatment arms
    • To compare PFS between the two treatment arms based upon investigator assessment of progression
    • To compare the overall objective response rate between the two treatment arms
    • To compare the duration of objective response between the two treatment arms
    • To compare the safety profile between the two treatment arms
    • To compare time to symptom progression, as assessed by the FACT Trial Outcome Index - Physical Functional Breast (TOI-PFB)
    • To evaluate if biomarkers from tumor tissues or blood samples (e.g., HER3 expression, Fc gamma, and serum ECD/HER2 and/or HER ligands concentrations) correlate with clinical outcomes
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. DNA REPOSITORY SUBSTUDY IN ASSOCIATION WITH PERTUZUMAB STUDY TOC4129g/WO20698. Protcocol no. TOC4129g/WO20698 (Substudy 1), dated 7-Sep-07.
    The primary objective of this study is to perform exploratory analyses to generate hypotheses identifying genes associated with treatment response, toxicity, or disease risk. If such genetic hypotheses are identified, they may be tested in future clinical studies within this therapeutic area. This study is optional and a separate Informed Consent will be required.

    Biomarker Sample Repository ( optional), included in main protocol version B dated 2007-12-12:
    The collected blood samples may be used to develop and validate diagnostic assays and allow the generation of statistically meaningful biomarker data related to HER2-positive breast cancer disease or response to pertuzumab and/or trastuzumab.

    Metastatic tumor tissue samples for biomarker analysis ( optional), included in main protocol version B dated 2007-12-12:
    assessment of tumor tissue biomarkers for pertuzumab/trastuzumab response prediction.
    E.3Principal inclusion criteria
    Disease specific inclusion criteria:
    1. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Patients with measurable and nonmeasurable lesion are eligible. Locally recurrent disease must not be amenable to resection with curative intent.
    Note: Patients with de-novo Stage IV disease are eligible.
    2. HER2-positive (defined as 3+ IHC or FISH amplification ratio ≥ 2.0 ) MBC confirmed by a Sponsor-designated central laboratory. It is strongly recommended that a formalin-fixed paraffin-embedded (FFPE) tissue block from the primary tumor be
    submitted for central laboratory confirmation of HER2 eligibility; however, if that is not possible, 25 unstained and freshly cut slides will be submitted. (Tissue will subsequently be used for assessment of biomarkers.)

    General inclusion criteria:
    3. Age ≥ 18 years
    4. Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline (within 42 days of randomization) as determined by either ECHO or MUGA (ECHO is the preferred method. If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study, and to the extent possible, be obtained at the same institution) (see Section 7.4.2 of the protocol, page 98). All pre-study LVEF values during and post-trastuzumab adjuvant treatment for patients who received such adjuvant therapy prior to enrollment into the study will
    be collected.
    5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
    6. For women of childbearing potential, agreement to use an effective form of contraception (patient and/or partner, e.g., surgical sterilization, a reliable barrier method [condoms, diaphragm], intrauterine devices, or abstinence) and to continue its use for the duration of study treatment and for 6 months after the last dose of
    study treatment7. Signed, written informed consent (approved by the Institutional Review Board or Independent Ethics Committee) obtained prior to any study procedure.
    E.4Principal exclusion criteria
    Cancer Related Exclusion Criteria:
    1. History of anticancer therapy for MBC (with the exception of one prior hormonal regimen for MBC). This includes any EGFR or anti-HER2 agents or vaccines, cytotoxic chemotherapy, or more than one prior hormonal regimen for MBC.
    2. History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting
    3. History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of < 12 months
    4. History of persistent Grade ≥ 2 hematologic toxicity resulting from previous adjuvant therapy
    5. Current peripheral neuropathy of NCI-CTCAE, Version 3.0, Grade ≥ 3 at randomization
    6. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma
    7. Current clinical or radiographic evidence of central nervous system (CNS) metastases. CT or MRI scan of the brain is mandatory (within 28 days of randomization) in cases of clinical suspicion of brain metastases.
    8. History of exposure to the following cumulative doses of anthracyclines:
    •doxorubicin or liposomal doxorubicin > 360 mg/m2
    •epirubicin > 720 mg/m2
    •mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2
    •Other (e.g., liposomal doxorubicin or other anthracycline > the equivalent of 360 mg/m2 of doxorubicin)
    •If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
    Hematological, Biochemical, and Organ Function
    9. Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina
    10. History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia)
    11. History of myocardial infarction within 6 months of randomization
    12. History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy
    13. Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy

    General Exclusion Criteria
    14. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization:
    •Absolute neutrophil count < 1,500 cells/mm3
    •Platelet count < 100,000 cells/mm3
    •Hemoglobin < 9 g/dL
    •Total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert’s syndrome)
    •SGOT (AST) and SGPT (ALT) > 2.5 x ULN
    •SGOT (AST) or SGPT (ALT) > 1.5 x ULN with concurrent serum alkaline phosphatase > 2.5 x ULN (unless bone metastases are present)
    •Serum creatinine > 2.0 mg/dL or 177 μmol/L
    •International normalized ratio (INR) and activated partial thromboplastin time (aPTT) > 1.5 x ULN (unless on therapeutic coagulation)
    15. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
    16. Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
    17. Pregnant or lactating women
    18. History of receiving any investigational treatment within 28 days of randomization
    19. Current known infection with HIV, HBV, or HCV
    20. Receipt of IV antibiotics for infection within 14 days of randomization
    21. Current chronic daily treatment with corticosteroids (dose of > 10 mg/ day methylprednisolone equivalent) (excluding inhaled steroids)
    22. Known hypersensitivity to any of the study drugs
    23. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) based on Independent Review Facility (IRF) evaluations. PFS is defined as the time from randomization to the first documented radiographical progressive disease, as determined by the IRF using RECIST (Therasse et al. 2000), or death from any cause, whichever occurs first. Carcinomatous meningitis diagnosed by cytologic evaluation of cerebral spinal fluid will also define progressive disease.
    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 Yes
    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 No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Evaluation of biomarkers, Quality of Life, Antitherapeutic AntiBodies against Pertuzumab
    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.8.3 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.8.4.1Number of sites anticipated in Member State concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA64
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    See protocol section 3.1.1: The trial will end when approximately 385 deaths have been reported or the trial is terminated by the Sponsors.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 800
    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)
    See section 5.7: Patients who discontinue this study for progressive disease or other reasons will receive treatment according to the local standard of care. Any post-study cancer treatment will be recorded. Information on patient outcomes and information on post-progression anti-cancer therapies will be captured as far as reasonably possible on a post-progression follow-up form. Patients will not receive open-label pertuzumab after discontinuation from study treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-03-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-03-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-23
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