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    Summary
    EudraCT Number:2010-020998-16
    Sponsor's Protocol Code Number:MO22998
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-10-28
    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 ConcernedGermany - PEI
    A.2EudraCT number2010-020998-16
    A.3Full title of the trial
    A Phase III randomized study evaluating the efficacy and safety of continued and re-induced bevacizumab in combination with chemotherapy for patients with locally recurrent or metastatic breast cancer after first-line chemotherapy and bevacizumab treatment.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    not applicable
    A.3.2Name or abbreviated title of the trial where available
    TANIA
    A.4.1Sponsor's protocol code numberMO22998
    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 organisationRoche Pharma AG
    B.5.2Functional name of contact pointCountry Study Manager
    B.5.3 Address:
    B.5.3.1Street AddressEmil-Barell-Strasse 1
    B.5.3.2Town/ cityGrenzach-Whylen
    B.5.3.3Post code79369
    B.5.3.4CountryGermany
    B.5.4Telephone number00497624142655
    B.5.5Fax number00497624143185
    B.5.6E-maildagmar.moench@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 Avastin
    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 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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMAb VEGF, anti-VEGF
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 typeRecombinant humanised monoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally recurrent (LR) or metastatic breast cancer (mBC) progressing after first-line chemotherapy and bevacizumab treatment.
    E.1.1.1Medical condition in easily understood language
    recurrence or spreading of breast cancer after the first chemotherapy and bevacizumab treatment
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10055113
    E.1.2Term Breast cancer metastatic
    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 determine the clinical benefit of continued or re-induced bevacizumab treatment in combination with second-line chemotherapy for patients with LR or mBC who have progressed after treatment with first-line chemotherapy combined with bevacizumab, as measured by second-line progression-free survival (PFS).
    E.2.2Secondary objectives of the trial
    To further evaluate the efficacy and characterize the safety of continued treatment with bevacizumab in combination with second and subsequent lines of chemotherapy as measured by the following:
    • Third-line PFS
    • Second- and third-line PFS
    • Second-line PFS in stratified subgroups
    • Overall survival (OS)
    • One-year survival
    • Second-line Overall response rate (ORR) in patients with measurable disease at baseline
    • Quality of life (QoL)
    • Safety profile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient’s awareness and willingness to comply with the study requirements
    2. Female patients ≥18 years of age
    3. Histologically confirmed HER2-negative adenocarcinoma of the breast with documented progression of disease following or during first-line treatment with bevacizumab in combination with chemotherapy for LR or mBC; patients can have measurable or non-measurable disease.
    4. A minimum of 4 cycles of bevacizumab 15 mg/kg or 6 cycles 10 mg/kg received in the first-line setting.
    5. Patients must have received bevacizumab in combination with chemotherapy. Patients may have received:
    • Bevacizumab monotherapy
    • Bevacizumab in combination with endocrine treatment
    • Endocrine treatment
    • Nothing
    as part of their maintenance treatment.
    6. ECOG performance status (PS) of 0-2
    7. At least 28 days since prior radiation therapy or surgery and recovery from treatment
    8. Estimated life expectancy of ≥12 weeks
    E.4Principal exclusion criteria
    Disease-specific exclusions
    1. Patients who have received anti-angiogenic therapy or anti-vascular endothelial growth factors other than bevacizumab for the first-line treatment of LR/mBC
    2. Patients who have exclusively received endocrine treatment in combination with bevacizumab until the first progression
    3. Positive or unknown HER2/neu status or for whom determination of HER2 status is not possible.
    4. Current, recent (within 4 weeks or 2 half-lives before day of cycle 1) or planned participation in an experimental drug study - other than a bevacizumab breast cancer study.
    5. Active malignancy, other than superficial basal cell and superficial squamous cell, or carcinoma in situ of the cervix or breast within the last 5 years
    6. Any laboratory values at baseline as follows:
    Hematology:
    ANC <1.5x10E9/L or 1500/mm3
    Platelet count <75x10E9/L
    Hemoglobin <8 g/dL
    Coagulation:
    INR >1.5 except for patients on stable anticoagulant therapy
    aPTT ≥1.5 times upper limit of normal (ULN) or greater than the lower limit of the therapeutic range
    Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of Day 1, Cycle 1.
    Serum chemistry:
    Total bilirubin >1.5 times ULN
    AST or ALT >2 times ULN
    ALP >2 times ULN
    7. Inadequate renal function, defined as:
    Creatinine clearance <50 mL/min
    Urine dipstick for proteinuria ≥2+ unless a 24-hour protein ≤1 g is demonstrated
    8. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would prevent the patient from meeting the study requirements
    9. Serious active infection requiring i.v. antibiotics and/or hospitalization at study entry
    10. Patients who are treated with any medicinal product that contraindicates the use of any of the study drugs, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications
    Bevacizumab-specific exclusions
    11. Inadequately controlled hypertension while receiving anti-hypertensive medication
    12. Prior history of hypertensive crisis or hypertensive encephalopathy
    13. Prior history of nephrotic syndrome
    14. New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF). For those patients where it is indicated an ECHO/MUGA must be performed. The LVEF must be above the institutional lower limit of normal in order for the patient to be eligible.
    15. History of myocardial infarction or unstable angina within 6 months prior to day 1 of cycle 1.
    16. History of stroke or transient ischemic attack (TIA) within 6 months prior to day 1 of cycle 1.
    17. Known CNS disease, except for treated brain metastases. Treated brain metastases are defined as: having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging during the screening period. Anticonvulsants are allowed. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are excluded. A brain or MRI scan is required within 28 days prior to day 1 of cycle 1 if the presence of untreated brain metastases is suspected.
    18. Significant vascular disease within 6 months prior to day 1 of cycle 1
    19. Any previous venous thromboembolism > NCI-CTCAE Grade 3
    20. History of hemoptysis within 1 month prior to day 1 of cycle 1
    21. Evidence of bleeding diathesis or significant coagulopathy.
    22. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 of cycle 1, or anticipation of need for major surgical procedure during the course of the study
    23. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1 of cycle 1
    24. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to day 1 of cycle 1
    25. Serious, non-healing wound, active ulcer, or untreated bone fracture
    26. Known hypersensitivity to any component of bevacizumab or any of the study drugs
    27. Pregnant or lactating females.
    28. Chronic, daily treatment with high-dose aspirin or clopidogrel
    29. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of bevacizumab or any of the study drugs that may affect the interpretation of the results or render the patient at high risk for treatment complications.

    E.5 End points
    E.5.1Primary end point(s)
    To determine the clinical benefit of continued or re-induced bevacizumab treatment in combination with second-line chemotherapy for patients with LR or mBC who have progressed after treatment with first-line chemotherapy combined with bevacizumab, as measured by second-line progression-free survival (PFS).
    Primary study endpoint: Second-line PFS
    E.5.1.1Timepoint(s) of evaluation of this end point
    the first docuemented disease progression or death from any cause, whichever occurs first
    E.5.2Secondary end point(s)
    To further evaluate the efficacy and characterize the safety of continued treatment with bevacizumab in combination with second and subsequent lines of chemotherapy.

    Secondary study endpoints: Third-line PFS, Second- and third-line PFS, Second-line PFS in stratified subgroups, Second-line Overall Response Rate (ORR) in patients with measurable disease at baseline, One-year survival, Overall survival (OS), Quality of Life (QoL), Safety Profile
    E.5.2.1Timepoint(s) of evaluation of this end point
    not applicable
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Dynamic biomarkers; Quality of life
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    chemotherapy
    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 concerned27
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA104
    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
    Brazil
    European Union
    Israel
    Switzerland
    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
    End of study will occur when all patients have been followed up for at
    least 24 months after randomization, unless they have been lost to
    follow-up, withdrawn consent, or died, or if the trial is prematurely
    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 years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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.1.1Number of subjects for this age range: 0
    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: 288
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 355
    F.4.2.2In the whole clinical trial 488
    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)
    At the end of study, patients without progression and still receiving
    treatment can continue to receive bevacizumab until disease
    progression or unacceptable toxicity by consenting to be rolled over
    into separate protocol(s) designed to allow treatment continuation of
    bevacizumab until progression.
    Patients, who don't consent to be rolled over into separate protocol,
    will receive post-study treatment for MBC at the investigator's
    discretion.
    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 Decision2011-02-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-30
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