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    Summary
    EudraCT Number:2016-003752-79
    Sponsor's Protocol Code Number:PIONEER
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-05-03
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-003752-79
    A.3Full title of the trial
    Randomised Phase II clinical trial PIONEER- A Pre-operative wIndOw study of letrozole plus PR agonist (Megestrol Acetate) versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PIONEER- A pre-surgical window study of letrozole plus megestrol acetate versus letrozole alone in post-menopausal patients with ER-positive breast cancer
    A.3.2Name or abbreviated title of the trial where available
    PIONEER
    A.4.1Sponsor's protocol code numberPIONEER
    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 SponsorCambridge University Hospitals NHS Foundation Trust and University of Cambridge
    B.1.3.4Country
    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 supportAntiCancer Fund
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCCTU
    B.5.2Functional name of contact pointCarrie Bayliss
    B.5.3 Address:
    B.5.3.1Street AddressCambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
    B.5.3.2Town/ cityLevel 6, Coton House, Box 401
    B.5.3.3Post codeCB2 0QQ
    B.5.4Telephone number01223 596474
    B.5.5Fax number01223 256763
    B.5.6E-mailcctu@addenbrookes.nhs.uk
    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 Megestrol Acetate
    D.2.1.1.2Name of the Marketing Authorisation holderPar Pharmaceutical Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameMegestrol Acetate
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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 INNMegestrol Acetate 40mg
    D.3.9.1CAS number 595-33-5
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.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 nameLetrozole
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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 INNLetrozole
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeAS3
    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) 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.IMP: 3
    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 nameMegestrol Acetate 160mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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 INNMegestrol Acetate
    D.3.9.1CAS number 595-33-5
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ER-positive, HER2-negative, invasive primary breast cancer of at least 1 cm size
    E.1.1.1Medical condition in easily understood language
    Early Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10070577
    E.1.2Term Oestrogen receptor positive breast 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 determine if the addition of megestrol acetate (a progesterone receptor activator) in combination with letrozole (an anti-oestrogen) results in a decrease of tumour activity/growth given 15 days of treatment before surgery in patients with early-stage, ER-positive breast cancer, as measured by changes in Ki-67 (The Ki-67 protein is a cellular marker for proliferation/growth) between baseline and day 15.
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    • To compare and correlate the biological effects of Letrozole alone compared to Letrozole plus Megestrol Acetate using other immunohistochemical markers of tumour response: Caspase 3, Aurora kinase A, change in expression of the androgen and progesterone receptors, and the absolute value of Ki67 at Day 15
    • To compare and correlate the change in Ki67 and the biological effects of low dose Megestrol Acetate compared to high dose Megestrol Acetate using other immunohistochemical markers of tumour response: Caspase 3, Aurora kinase A, change in expression of the androgen and progesterone receptors, and the absolute value of Ki67 at Day 15
    • To assess the safety and tolerability of the combination of Letrozole +/- Megestrol Acetate by recording and assessing adverse and serious adverse events.

    Exploratory Objectives:
    • To assess progestin-induced ER reprogramming following treatment with Letrozole and Megestrol Acetate, using transcription factor mapping (ChIP-seq)
    E.2.3Trial contains a sub-study No
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PIONEER – Pharmokinetic Blood samples (optional). Patient Sheet 2.
    E.3Principal inclusion criteria
    Inclusion Criteria
    To be included in the trial the patient must:

    • Histologically confirmed breast adenocarcinoma
    • Postmenopausal women, defined as having experienced:
    - 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. ≥50 years, history of vasomotor symptoms) or
    - six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or
    - surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.
    • Core biopsy confirmation of ER positive (Allred≥3) and HER2 negative invasive carcinoma on core biopsy, >=T1c, either cN0 or N+
    • Patients whose cancers have been deemed to be operable by the MDT
    • Surgery planned within the next 2-6 weeks
    • ECOG performance status of 0, 1 or 2
    • Adequate Liver, Renal and Bone marrow function, defined as:
    - Adequate liver function where bilirubin is ≤1.5 x ULN
    - Adequate renal function with estimated creatinine clearance of ≥60 ml/min
    - Adequate bone marrow function with ANC ≥1.0 x 109/L and Platelet count ≥100 x 109/L
    • Written informed consent to participate in the trial and to donation of tissue
    E.4Principal exclusion criteria
    Exclusion Criteria
    The presence of any of the following will preclude patient inclusion:

    • History of hormone replacement therapy in the last 6 months
    • Previous treatment with tamoxifen or an aromatase inhibitor in the last six months
    • Known hypersensitivity or contraindications to aromatase inhibitors or megestrol acetate
    • Known allergy to lactose
    • Known to have a progestogen-containing intrauterine system in situ, unless removed prior to randomisation
    • Known metastatic disease on presentation
    • Recurrent breast cancer (patients with a new primary invasive breast cancer will be eligible to participate)
    • Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator
    • Treatment with an investigational drug within 4 weeks before randomization
    • Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication
    • Inability to give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    Change in tumour proliferation measured by Ki67 immuno-histochemical (IHC) assessment (%) between baseline and day 15 (+≤4 Days).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The effect on tumour proliferation will be assessed after a 15 day course of treatment with letrozole (either alone or in combination with megestrol acetate).
    E.5.2Secondary end point(s)
    • Change in tumour apoptosis between baseline and Day 15 (+≤4 Days), measured by Caspase 3 (IHC)
    • Change in expression of AR and PR (IHC) between baseline and Day 15 (+≤4 Days)
    • Change in proliferation by Aurora Kinase A (IHC) between baseline and Day 15 (+≤4 Days)
    • Absolute value of Ki67 at Day 15 (+≤4 Days)
    Safety Endpoints
    • Incidence of serious adverse events
    • Incidence of adverse events of all grades (CTCAE Version 4.03)

    Exploratory outcome measure:
    • Transcription factor mapping (ChIP-seq) of ER
    • Differences in response to treatments within METABRIC-defined subtypes of ER-positive breast cancer


    E.5.2.1Timepoint(s) of evaluation of this end point
    The incidence and severity of adverse events will be recorded from the point of informed consent, regardless of whether a patient has yet received a medicinal product, to follow up. However, if the patient has any ongoing adverse drug-reactions at follow up, these will be followed up until resolved.

    Preliminary evidence of tumour response will be assessed after a 15 day course of letrozole treatment (either alone or in combination with megestrol acetate)
    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 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 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    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
    The end of trial will be the date 12 months after the last patient’s last visit which will allow sufficient time for the translational endpoints to be investigated and the data cleaned for analyses and reports
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days1
    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.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 114
    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 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 state189
    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)
    Once the study treatment has finished patients will continue on the standard treatment pathway to have surgery and receive standard post-operative treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-24
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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