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    Summary
    EudraCT Number:2012-003554-83
    Sponsor's Protocol Code Number:BO25114
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-11-30
    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 ConcernedAustria - BASG
    A.2EudraCT number2012-003554-83
    A.3Full title of the trial
    A double-blind, placebo-controlled, randomized, multicenter phase III study evaluating the efficacy and safety of pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2-positive metastatic gastro-esophageal junction and gastric cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluating the efficacy and safety of pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2-positive metastatic gastro-esophageal junction and gastric cancer
    A.3.2Name or abbreviated title of the trial where available
    JACOB
    A.4.1Sponsor's protocol code numberBO25114
    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.3.9.3Other 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 / 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) 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.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 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 INNTRASTUZUMAB
    D.3.9.1CAS number 0180288-69-1
    D.3.9.2Current sponsor codeRO45-2317
    D.3.9.3Other descriptive nameTrastuzumab; rhuMAb HER2, Anti-HER
    D.3.9.4EV Substance CodeSUB12612MIG
    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) 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 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 advanced gastroesophageal junction/gastric cancer
    E.1.1.1Medical condition in easily understood language
    HER2-positive advanced gastroesophageal junction/gastric cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10066896
    E.1.2Term HER-2 positive gastric 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 overall survival (OS) in patients treated with pertuzumab in addition to Herceptin® (trastuzumab) plus fluoropyrimidine plus cisplatin (TFP) versus patients treated with placebo in addition to TFP
    E.2.2Secondary objectives of the trial
    • To compare investigator-assessed PFS, ORR, duration of objective response (DoR), and clinical benefit rate (CBR) between the two treatment arms
    • To compare the safety profile between the two treatment arms
    • To assess the pharmacokinetics of pertuzumab
    • To compare the patient-reported outcomes (PROs) of health-related quality of life (HRQoL), GC, and treatment-related symptoms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scale and
    its GC module, the QLQ-STO22, for patients in each treatment arm
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Disease-Specific Inclusion Criteria
    1. Histologically confirmed (by enrolling center) metastatic adenocarcinoma of the stomach or GEJ
    2. HER2-positive tumor defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed by a sponsor-designated central laboratory on a primary or metastatic tumor
    Note: ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 centromere (CEP17). For IHC scoring, the cutoffs as approved by the Food and Drug Administration (FDA) in the context of ToGA apply. Availability of formalin-fixed paraffin-embedded (FFPE)
    representative tumor tissue for central confirmation of HER2 is mandatory. (See Section 4.5.1.1 for further details.)
    3. Measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1; see Appendix 3.
    4. Eastern Cooperative Oncology Group (ECOG) PS 0 or 1
    5. Life expectancy ≥ 3 months

    General Inclusion Criteria
    6. Age≥ 18 years
    7. Ability to comply with requirements of the protocol, as assessed by the investigator
    8. Signed Informed Consent document
    E.4Principal exclusion criteria
    Cancer-Related Exclusion Criteria
    1. Previous systemic cytotoxic chemotherapy for advanced (metastatic) disease
    2. History of exposure to the following cumulative doses of anthracyclines:
    a. Epirubicin > 720 mg/m2
    b. Doxorubicin or liposomal doxorubicin > 360 mg/m2
    c. Mitoxantrone > 120 mg/m2 or idarubicin > 90 mg/m2
    d. Other (e.g., liposomal doxorubicin or other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)
    e. If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
    3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for gastric or GEJ adenocarcinoma
    4. Previous treatment with any HER2-directed therapy, at any time, for any duration
    5. Previous exposure to any investigational treatment within 30 days before the first dose of study treatment
    6. Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to bone metastases, if recovered from all toxicities)
    7. History or evidence of brain metastasis
    8. Clinically significant active GI bleeding (Grade ≥ 2 according to NCI CTCAE v4.03)
    9. Residual toxicity resulting from previous therapy (e.g., hematologic, cardiovascular, or neurologic toxicity that is Grade ≥ 2). Alopecia is permitted.
    10. Other malignancy (in addition to GC) occurring within 5 years before enrollment, except for carcinoma in situ of the uterine cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent Clinical Laboratory Exclusion Criteria (must be confirmed within 7 days before first dose of study treatment)
    11. Absolute neutrophil count (ANC) < 1.5 × 109/L
    12. Platelet count < 75 × 109/L
    13. Hemoglobin < 9.0 g/dL
    14. Creatinine CL< 60 mL/min (Cockcroft-Gault Formula, see Appendix 6)
    15. Serum bilirubin (total) > 1.5 × upper limit of normal (ULN) of laboratory normal range; in case of known Gilbert disease a total bilirubin of up to 2 × ULN is permitted.
    16. AST, ALT, and alkaline phosphatase (ALP) parameters:
    a) In patients with no liver and no bone metastases
    i. AST or ALT > 1.5 × ULN, and ALP > 2.5 ×ULN
    ii. AST or ALT > 2.5 ×ULN
    b) In patients with liver metastases and no bone metastases
    i. AST or ALT > 5 × ULN, and ALP > 2.5 ×ULN
    c) In patients with liver metastases and bone metastases
    i. AST or ALT > 5 × ULN, and ALP > 10×ULN
    d) In patients with bone metastases and no liver metastases
    i. AST or ALT > 1.5 × ULN, and ALP > 10 ×ULN
    17. Serum albumin < 25 g/L
    18. Serum pregnancy test positive in a female patient of childbearing potential
    General Exclusion Criteria
    19. Documented history of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria (see Appendix 5)
    20. Angina pectoris requiring treatment
    21. Myocardial infarction within the past 6 months before the first dose of study treatment
    22. Clinically significant valvular heart disease or uncontrollable high-risk cardiac arrhythmia (i.e., atrial tachycardia with a heart rate >100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular-block
    (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
    23. History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure >100 mmHg)
    24. Baseline LVEF value < 55%, assessed by echocardiogram [ECHO], multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan
    25. Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy
    26. Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus)
    27. Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered
    28. Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment
    29. Ongoing chronic treatment or high-dose treatment with corticosteroids. Inhaled steroids, topical steroids and clinically indicated short courses of oral steroids are permitted.
    30. Known dihydropyrimidine dehydrogenase (DPD) deficiency
    31. Known hypersensitivity to any component of study treatment
    32. Current use of antiviral drug sorivudine or its chemically related analogs, such as brivudine
    33. Lactating female patient
    34. Any patient unwilling or unable to use adequate contraceptive measures (as described in Section 5.2.3) during study treatment and for at least 7 months after the last dose of pertuzumab or trastuzumab, except for a patient with documented surgical sterilization or a postmenopausal female
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable, OS, is the time from the date of randomization to the date of death from any cause. For patients who are still alive on the date of clinical data cutoff for the OS analysis, the last date when the patient is known to be alive on or prior to the clinical cut-off date will be used to determine the censoring date. Patients who do not have any postbaseline data (e.g., dosing records, imaging dates, visit dates) will be censored at the date of randomization plus 1 day.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be assessed approx. 50 months after FPI when 502 deaths will have occurred – which is expected to happen in approx. JUL2017. However, if the interim efficacy analysis (351 deaths) provided significant and meaningful treatment benefit and an acceptable safety profile can be seen, then the study could be stopped early. The interim analysis is expected to take place in approx. AUG2016
    E.5.2Secondary end point(s)
    Investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of objective response (DoR), and clinical benefit rate (CBR).
    E.5.2.1Timepoint(s) of evaluation of this end point
    These will be analysed together with the primary endpoint.
    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 Yes
    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
    Quality of Life, exploratory biomarker assessments
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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
    Australia
    Brazil
    Canada
    China
    Croatia
    El Salvador
    European Union
    Guatemala
    Japan
    Kazakhstan
    Korea, Republic of
    Macedonia, the former Yugoslav Republic of
    Malaysia
    Mexico
    Panama
    Peru
    Russian Federation
    Switzerland
    Taiwan
    Thailand
    Turkey
    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
    This study will end when the targeted number of events for the final analysis of OS (n = 502) is reached and the last patient who received study treatment has completed 5 years of cardiac safety follow up thereafter or when the study is terminated by the
    Sponsor, whichever occurs first.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months10
    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: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 280
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 326
    F.4.2.2In the whole clinical trial 780
    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)
    The clinical management of patients after they conclude study treatment will be at the discretion of the investigator, but the patient should not receive pertuzumab after PD. However, neither the patient nor the investigator will be unblinded during survival follow up as to whether the patient received pertuzumab or placebo during treatment in this study.
    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 Decision2013-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-13
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