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    Summary
    EudraCT Number:2015-000535-33
    Sponsor's Protocol Code Number:BCII_2015
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-09-29
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-000535-33
    A.3Full title of the trial
    Phase II, Open-Label Study to Evaluate Safety and Explore Efficacy of Escalating Doses of Bevacizumab-IRDye800CW as an Optical Imaging Agent to Detect Cancer Tissue Delineation During Tumor Resection Surgery in Patients with Breast Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Is it possible to make breast cancer visible during surgery by using a fluorescent tumor-specific dye during breast cancer surgery?
    Kan borstkanker zichtbaar gemaakt worden met een fluorescerende stof zodat de chirurg tijdens de operatie de tumor beter kan onderscheiden van gezond weefsel.
    A.3.2Name or abbreviated title of the trial where available
    Breast-cancer Fluorescence Guided Surgery
    A.4.1Sponsor's protocol code numberBCII_2015
    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 SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDutch Cancer Foundation
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointDepartment of Surgery
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9700 RB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number315-3612283
    B.5.5Fax number31503614873
    B.5.6E-mailg.m.van.dam@umcg.nl
    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 nameBevacizumab-800Cw
    D.3.4Pharmaceutical form Solution for injection/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 coden/a
    D.3.9.3Other descriptive namen/a
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 No
    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 typethe tracer consists of an antibody-based fluorescent agent. The targeting moiety is a therapeutic antibody directed against VEG-A (i.e. bevacizumab-IRDye800CW)
    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
    Patients with breast cancer eligible for surgery
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    Borstkanker
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    This is an interventional exploratory open label dose escalation trial to be conducted in two trial centers. Studying the fluorescence signal in breast cancer tissue after administration of increasing doses of Bevacizumab-IRDye 800CW 1:2 conjugate (second generation tracer) in patients with confirmed breast cancer who are scheduled for tumor resection surgery or mastectomy. The aim of this study is to define the optimal dose of the tracer for the visualisation of intra operative tumor delineation.
    E.2.2Secondary objectives of the trial
    Asses the safety of the second generation conjugate at all doses tested.
    Compare conventional histo-pathological margin assessment with margin assessment using the fluorescent signal
    Confirm if fluorescent signal corresponds to tumor tissue
    Explore fluorescence intensity ex vivo in tumor and surrounding tissue
    Relate TBRs to plasma concentrations of complete tracer and fractions of unbound tracer components.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or Female, aged ≥ 18 years.
    2. Confirmed diagnosis of breast cancer by means of histology or cytology and eligible for tumor resection surgery.
    3. Tumor size ≥ 5 mm (0, 5 cm) diameter according to anatomical imaging data.
    4. WHO performance score 0-2.
    5. Life expectancy greater than 12 weeks
    6. Written informed consent has been obtained
    7. In the Investigator’s opinion, patient is able and willing to comply with all trial requirements.
    For female subjects who are of childbearing potential, are premenopausal with intact reproductive organs or are less than 2 years post menopausal
    8. A negative serum pregnancy test within 2 weeks prior to receiving the second generation tracer
    9. Willing to ensure that she or her partner uses effective contraception during the trial and for 3 months thereafter.
    E.4Principal exclusion criteria
    1. Non palpable breast tumor
    2. Breast prosthesis in the target breast
    3. History of infusion reactions to Bevacizumab or other monocolonal antibody therapies
    4. Concurrent anticancer therapy (chemotherapy, radiotherapy, vaccines, immunotherapy) delivered within the last 6 weeks prior to the start of the treatment
    5. Unresolved chronic non-hematological toxicity higher than NCI-CTC grade 2
    6. Participation in a clinical study involving an investigational drug or device within 30 days prior to the start of treatment
    7. Significant renal or hepatic impairment.
    8. Scheduled elective surgery, with the exception of the breast surgical procedure, or other procedures requiring general anaesthesia during the trial.
    9. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
    10. Inadequately controlled hypertension with or without current antihypertensive medications.
    11. History of MI, TIA, CVA, pulmonary embolism, uncontrolled CHF, significant liver disease, unstable angina within 6 months prior to enrolment.
    12. Patients receiving anticoagulant therapy with vitamin K antagonists.
    13. Patients receiving Class IA or Class III antiarrhythmic agents.
    14. Evidence of QT prolongation on pre treatment ECG (males >440ms, females>450 ms)
    15. Magnesium, potassium and calcium levels below LLN which is regarded clinically relevant with regards to study participation.
    E.5 End points
    E.5.1Primary end point(s)
    • Tumor to Background Ratio (TBR) calculated from images taken intra-operatively
    • Tumor to Background Ratio (TBR) calculated from the bread loaf sliced excised specimen
    TBR is defined as the mean fluorescence intensity measured in the fluorescent region (tumor area) divided by the mean fluorescence intensity in the same image outside fluorescent region (non tumor area).

    Selection of endpoints
    To assess the success of intra operative tumor tissue delineation, the tumor to background ratios (TBR) will be calculated from images taken intra-operatively. A second ex vivo TBR will be calculated from bread loaf slices of the excised specimen. Microscopic histopathology and fluorescence microscopy will be done to confirm if the fluorescent signal corresponds to actual tumor tissue as a secondary endpoint parameter.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This end-point will be evaluated after surgery - post-hoc analyses of both the intraoperative required images of the wound bed and at the Dept of Pathology in-depth by fluorescence imaging
    E.5.2Secondary end point(s)
    • Safety variables will be any observed or reported adverse event from signing informed consent till the last study assessment.
    • Presence of positive margins as assessed by the surgeon intra operatively based on fluorescent images.
    • Presence of positive margins based on lump examination using the fluorescent signal
    • Tumor margins as obtained following standard histopathological practice
    • TBR calculated in microscopic slices in which tumor delineation is confirmed on adjacent H&E stained slides (Odyssey scanner, LICOR Inc, USA)
    • Fluorescence intensity in tumor and surrounding tissue is measured in fluorescent units (FU). Tumor-to-background ratios (TBR) are calculated post operatively in defined regions of interest (ROI) in the bread loaf specimens and histological slices. The variation in the signal at various increments distance of the tumor margin (0, 0.5, 1.0, 1.5, 2.0, and 2.5 up to 5 cm) will be expressed as percentage of the maximal fluorescence measured in the specimen.
    • Plasma concentration of the conjugate
    • Percentages of complete conjugate, free Bevacizumab and free IRDye 800 CW
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time-points:

    screening visit (-7 +/-3 days)
    pre-surgery visit: injection of the tracer (-3 days)
    day-of-surgery: (day 0 )
    post-surgery (12 +/-3 days)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    dose-escalation study of 4 cohorts
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 27
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state27
    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)
    None
    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 Decision2015-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-17
    P. End of Trial
    P.End of Trial StatusOngoing
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