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    Summary
    EudraCT Number:2016-003459-31
    Sponsor's Protocol Code Number:2016/816
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2016-08-22
    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 ConcernedNorway - NOMA
    A.2EudraCT number2016-003459-31
    A.3Full title of the trial
    Treatment of patients with advanced breast cancer harboring TP53 mutations with dose-dense cyclophosphamide - the p53 trial
    Behandling av pasienter med metastatisk brystkreft med TP53 mutasjoner med dose-dense
    (dose-tett) cyclofosfamid
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cyclophosphamide chemotherapy for breast cancers harboring TP53 gene mutations
    Cycklofosfamid cellegiftbehandling ved brystkreft med TP53 genfeil
    A.3.2Name or abbreviated title of the trial where available
    p53 trial
    p53 studien
    A.4.1Sponsor's protocol code number2016/816
    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 SponsorHelse Bergen, Haukeland University Hospital
    B.1.3.4CountryNorway
    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 supportWestern Norway Regional Health Authority
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHelse Bergen, Haukeland University Hospital
    B.5.2Functional name of contact pointReseach and development dept
    B.5.3 Address:
    B.5.3.1Street AddressHaukelandsveien 22
    B.5.3.2Town/ cityBergen
    B.5.3.3Post code5021
    B.5.3.4CountryNorway
    B.5.6E-mailstian.knappskog@helse-bergen.no
    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 Sendoxan
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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 Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) 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 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
    Locally advanced breast cancer and metastatic breast cancer
    Lokalavansert brystkreft og metastatisk brystkreft
    E.1.1.1Medical condition in easily understood language
    Breast cancer with large tumors or breast cancer that has spread to inner organs
    Brystkreft med store svulster eller brystkreft som har spredd seg til indre organer
    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
    The primary objectives of this trial is to prospectively evaluate the objective response rate (ORR) of dose dense cyclophosphamide in patients with TP53 mutated breast cancer or TP53 wt breast cancer.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this trial are;
    - Identify molecular markers of therapy response/resistance and survival outcome, beyond TP53 mutations.
    - Percentage of patients with locally advanced breast cancer with pathological complete response (pCR).
    - Clinical benefit rate (CBR), in patients with metastatic breast cancer.
    - Recurrence-free and overall survival, compared to historical data.
    - Safety and tolerability of the study treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Primary (T2 tumors or Locally advanced breast cancers; LABC) in need of pre-surgical chemotherapy or metastatic breast cancer in need of chemotherapy.
    - Resistance to endocrine therapy:
    Either i) estrogen and progesterone negative tumor, or ii) harboring an estrogen and / or progesterone positive tumor where regular endocrine therapies have failed or where the treating physician finds endocrine therapy not indicated.
    - Prior cancer therapy:
    Metastatic disease:
    First line treatment:
    No prior chemotherapy*. Prior endocrine therapy +/- CDK4/6 inhibitor or mTOR inhibitors is allowed if hormone receptor positive, HER2 negative disease.
    * Only for patients with TP53 mutated disease. Previous adjuvant chemotherapy, including alkylating agents (cyclophosphamide a.o.) and/or platinum, is allowed if completed >12 months prior to inclusion in the trial.
    Late-stage disease (approved protocol):
    i) Prior exposure to and resistance to a taxane regimen**.
    ii) Prior exposure to and resistance to an anthracycline regimen*** -
    iii) Previous adjuvant chemotherapy, including alkylating agents (cyclophosphamide a.o.) and/or platinum, is allowed if completed >12 months prior to inclusion in the trial.

    Primary breast cancer (T2 tumors or LABC):
    i) Prior exposure to and lack of response to a taxane regimen**.
    ii) Prior exposure to and lack of response to an anthracycline regimen***
    *** Mandatory only for patients with TP53 wt tumors.
    ** For HER2 positive breast cancer, previous taxane + anti-HER2 treatment is required.
    In metastatic breast cancer resistance to taxanes/anthracyclines is defined as progressive disease (PD). In primary breast tumors lack of response is defined as stable disease (SD) after 4 courses of chemotherapy or PD, or SD/PD after initial response, or further taxane/anthracyclines is not possible due to toxicity. Breast cancer relapsing within 12 months subsequent to adjuvant taxanes or anthracyclines is considered resistant and re-exposure is not required prior to inclusion in the trial. This relates also to patients who could not receive proper taxane or anthracycline therapy due to side effects or other medical reasons.
    - The primary tumor or at least one metastatic lesion must be available for biopsy collection at protocol inclusion. Notably; for patients with primary metastatic breast cancer, TP53 status should be determined in a metastatic deposit; tissue from the primary tumor may not substitute (this relates both to patients with synchronous and metachronous metastatic disease).
    - Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST.
    - WHO performance status 0-1
    - Known tumor ER, PGR and HER2 status in the current situation, i.e. archival and historic breast cancer tissue can not be used for patients with relapse of the disease. However, patients can be included regardless of hormone receptor and HER2 status; in case such information lacks at inclusion, it may be analysed on the biopsy retrospectively.
    - Age >18 years
    - Radiology studies for tumor measurements and ecco cor for cardiac function must be performed within 28 days of commencing treatment per protocol (MRI breast for primary breast cancer and CT thorax/abdomen/pelvis and/or MRI + bone scintigraphy/bone scan for metastatic disease).
    - Before patient registration, written informed consent must be given according to national and local regulations.
    - Blood test requirements:
    - Neutrophils > 1.0 x 109/L
    - Platelets > 75 x 109/L
    - Bilirubin < 20 µmol/L.
    - Serum creatinine < 1.5 x ULN
    E.4Principal exclusion criteria
    - Co-morbidity that, based on the assessment of the treating physician, may preclude the use of cyclophosphamide at actual doses.
    - Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    - Pregnant or lactating patients.
    - Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist.
    - Active cystitis (to be treated upfront)
    - Active bacterial infections
    - Urinary obstruction
    - Known hypersensitivity towards cyclophosphamide or pegfilgrastim, their metabolites and other ingredients in the drug administration formulation.
    - Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.
    - Patients with HER2 positive, metastatic breast cancer in the first line setting (Arm C).
    - Amendment 2021: Previous platinum or cyclophosphamide chemotherapy
    (incl. EC90) if completed less than 12 months prior to inclusion in the trial.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate (ORR), TP53 mutated breast cancer
    Objective response rate (ORR), TP53 wt breast cancer
    E.5.1.1Timepoint(s) of evaluation of this end point
    Annually
    E.5.2Secondary end point(s)
    Identify molecular markers of therapy response/resistance and survival outcome, beyond TP53 mutations.
    Assess whether responses are recorded among patients harbouring TP53 mutations belonging to one of the following mutation subgroups
    Percentage of patients with locally advanced breast cancer with pathological complete response (pCR).
    Clinical benefit rate (CBR), in patients with metastatic breast cancer
    Recurrence-free and overall survival, compared to historical data.
    Safety and tolerability of the study treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Side effects: continously.
    Efficacy of treatment: interim analysis after first 12 patients, estimated
    to be after 1 yr
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 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 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 No
    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 trial is 10 years after the inclusion of last subject on trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state190
    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)
    After completing chemotherapy within the trial the patients will receive treatment and care based on standard national guidelines.
    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 Decision2016-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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