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    Summary
    EudraCT Number:2005-005666-36
    Sponsor's Protocol Code Number:IBCSG 22-00
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2009-07-08
    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 ConcernedSweden - MPA
    A.2EudraCT number2005-005666-36
    A.3Full title of the trial
    Low-dose Cytotoxics as “Anti-angiogenesis Treatment” following Adjuvant
    Induction Chemotherapy for Patients with ER-negative and PgR-negative
    Breast Cancer

    Maintenance Chemotherapy in Hormone Non- Responsive Breast Cancer
    A.3.2Name or abbreviated title of the trial where available
    Maintenance Chemotherapy in Hormone Non-Responsive Breast Cancer
    A.4.1Sponsor's protocol code numberIBCSG 22-00
    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 SponsorInternational Breast Cancer Study Group
    B.1.3.4CountrySwitzerland
    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 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 Yes
    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 nameCyclophosphamide
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyclophosphamide
    D.3.9.1CAS number 50-18-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.2.5The 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 nameMethotrexate
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMethotrexate
    D.3.9.1CAS number 59-05-2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Histologically proven ER-negative and PgRnegative breast cancer with either a total mastectomy with axillary clearance or a lesser procedure with axillary lymph node dissection or sentinel node procedure, and classified as T1a,b,c, T2, T3, or pT4 with minimal dermal invasion, Nx, pN0, pSentN0, pN1, or pN2, and M0. Patients with disease defined as SNB positive are eligible only if they have undergone an axillary dissection, OR are SNB micrometastatic and are randomized to IBCSG Trial 23-01.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10006190
    E.1.2Term Breast cancer invasive NOS
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of a low-dose chemotherapy regimen, hypothesized to have antiangiogenic activity, administered following a standard chemotherapy program, in patients whose tumors are not endocrine therapy-responsive.
    Treatment comparisons will be based upon the following endpoint:
    - Disease-free survival
    E.2.2Secondary objectives of the trial
    - Overall survival
    - Systemic relapse
    - Systemic disease-free survival
    - Quality of Life.
    - Sites of first recurrence
    - Incidence of second (non-breast) malignancies
    - Causes of deaths without relapse of breast cancer
    - Toxicity
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Serum Substudy: Assessment of Vascular Endothelial Growth Factor (VEGF), Soluble Her2 Protein (NRP, HER2-ECD) and Vascular Cellular Adhesion Molecule-1 (VCAM-1) in Serum Samples

    Protocol Amendment 2, Version 3.0, 01.11.2005

    Main objectives:
    To evaluate differences from baseline (after completion of induction chemotherapy but before commencement of CM Maintenance for patients rando-mized to CM Maintenance) to 18 months after the start of induction chemotherapy in serum VEGF, VCAM-1 and NRP protein values between patients in the Observation Group and those in the low dose Cyclophosphamide Methotrexate (CM) Maintenance Group.

    Secondary objectives:
    To compare the differences from baseline to 12 and 36 months after the start of
    induction chemotherapy of serum VEGF, VCAM-1 and NRP values in the two randomized groups.
    To compare VEGF, VCAM-1 and NRP values before and after progression in the two
    randomized groups.
    E.3Principal inclusion criteria
    Premenopausal or postmenopausal patients with histologically proven primary breast cancer.

    The primary tumor must be classified as T1a,b,c, T2, T3, or pT4 with minimal dermal invasion, Nx, pN0, pSentN0, pN1, or pN2, and M0. Patients with disease defined as SNB positive are eligible only if they have undergone an axillary dissection, OR are SNB micrometastatic and are randomized to IBCSG Trial 23-01. The tumor must be confined to the breast, without detected metastases elsewhere.

    Estrogen and progesterone receptor status must be known by immunohistochemistry, before randomization, and both must be negative, which is defined as < 10% of the tumor cells positive by immunohistochemical evaluation.

    HER2 status must be known and determined by either immunohistochemistry or FISH before randomization.

    The induction chemotherapy must be approved by the IBCSG Scientific Committee and must begin (or have begun) within 8 weeks of definitive surgery.

    Patients must have had either:
    • a total mastectomy. Radiotherapy is optional after mastectomy. OR
    • a breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomy with negative margins) with radiotherapy planned. Radiation therapy to the conserved breast is required.

    Patient must have had pathological axillary staging performed on a specimen from axillary clearance or sentinel node biopsy. In order to be classified as pN0, patients who receive axillary clearance must have a minimum of 6 lymph nodes available for pathological examination.

    Patients must have completed pre-randomization Quality of Life (QL) Forms. The only
    exceptions are cognitive or physical impairment that interferes with QL assessment or inability to read any of the languages available on IBCSG QL forms.

    The patient must be in adequate health to begin or continue with induction chemotherapy or start maintenance chemotherapy:
    • WBC greater than 3.0x109/l
    • Platelets greater than 100x109/l
    • Serum creatinine below 120 µmol/l, adequate liver values
    • Serum bilirubin below 20 µmol/l
    • No cystitis
    • No evidence of any toxicity grade 2 or worse (CTC), in particular: nausea, vomiting,
    diarrhea, mucositis (stomatitis or any other mucousal inflammation), or epigastric pain.

    Written informed consent dated and signed by both patient and investigator.

    Must be geographically accessible for follow-up.

    Patients must be informed of, and agree to, data and material transfer and handling, in accordance with national data protection guidelines and Swiss data protection law (as IBCSG is a foundation under Swiss law).
    E.4Principal exclusion criteria
    Patients with T4 carcinoma with ulceration of skin, infiltration of skin (except pathologically minimal dermal involvement), peau d'orange or inflammatory breast cancer, or with distant metastases. Any suspicious manifestation requires appropriate investigation to exclude metastasis.

    Patients with bilateral malignancies (except in situ carcinoma), or with a suspicious mass in the opposite breast, unless that mass has been proven by biopsy to be benign.

    Patients, who, before start of induction chemotherapy, had a skeletal pain of unknown cause, elevated alkaline phosphatase, or a bone scan showing hot spots for which metastases cannot be ruled out by X-ray, MRI and/or CT.

    Patients in whom the margins of the resected specimen (whether mastectomy or local excision) contained invasive tumor. Patients who have local excision with a positive margin may become eligible if within 8 weeks from first surgery they undergo adequate resection or mastectomy with clear margins.

    Patients with previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix, or contra- or ipsilateral in situ breast carcinoma.

    Patients who have received prior therapy for breast cancer other than primary irradiation, approved induction regimen, or trastuzumab. Prior endocrine therapy for breast cancer or prevention is not permitted.

    Patients with non-malignant systemic diseases that would prevent them from undergoing any of the treatment options, or would prevent prolonged follow-up.

    Patients with psychiatric or addictive disorders that would prevent them from giving informed consent to therapy and randomization.

    Patients who either have been pregnant or who have lactated within 6 months of diagnosis.

    Patients with a history of noncompliance to medical regimens and patients who are considered potentially unreliable.
    E.5 End points
    E.5.1Primary end point(s)
    First confirmation of recurrence (local, regional or distant) or metastatic disease, second primary (non-breast) tumor, and/or death.

    Disease-free survival (DFS) is defined as the time from randomization to local, regional or distant recurrence (including recurrence restricted to the breast after breast conserving treatment), appearance of a second primary tumor, or death from any cause, whichever occurs first. An in situ recurrence either in the ipsilateral or in the contralateral breast is not considered a recurrence.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    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
    Nil (no CM Maintenance)
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Expected completion of trial in 6.5 years (2 years to complete pt recruitment, 1 year until treatment completion and additional 3.5 years of follow-up to achieve the targeted number of events for the final analysis).
    Follow-up will take place every 6 months during years 1-5 and yearly thereafter
    lifelong.
    The interim analyses are planned after 133 (presented to DSMC in April 2009) and 215 (70%), the final analysis after 307 events have been observed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years14
    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 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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 924
    F.4.2.2In the whole clinical trial 1080
    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 Decision2009-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-12-07
    P. End of Trial
    P.End of Trial StatusOngoing
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