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    Summary
    EudraCT Number:2013-003947-51
    Sponsor's Protocol Code Number:M14POS
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-21
    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 number2013-003947-51
    A.3Full title of the trial
    Phase I/prospective randomized phase II trial Of the Safety and Efficacy of tamoxifen in combination with the Isoform selective Pi3K inhibitor GDC-0032 compared with tamoxifen alONe in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment (POSEIDON trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An early-stage clinical trial to evaluate the safety and effectiveness of GDC-0032 when given alongside Tamoxifen to patients with HER2 negative advanced breast cancer, who have previously received hormone treatment
    A.3.2Name or abbreviated title of the trial where available
    Poseidon
    A.4.1Sponsor's protocol code numberM14POS
    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 SponsorNKI-AVL
    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 supportGenentech
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportEurocan
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportRather
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNKI-AVL
    B.5.2Functional name of contact pointProf. Dr. S. Linn
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31205122591
    B.5.5Fax number31205122572
    B.5.6E-mails.linn@nki.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 nameGDC-0032/ Taselisib ®/ RG 7604
    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 INNTaselisib ®
    D.3.9.1CAS number 1282512484
    D.3.9.2Current sponsor codeGDC-0032
    D.3.9.3Other descriptive nameGDC-0032 (RO5537381)
    D.3.9.4EV Substance CodeSUB61505
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 RoleComparator
    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 tamoxifen
    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 nametamoxifen
    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 INNTAMOXIFEN
    D.3.9.1CAS number 10540-29-1
    D.3.9.4EV Substance CodeSUB10825MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hormone receptor positive metastatic breast cancer
    E.1.1.1Medical condition in easily understood language
    Advanced staged breast cancer patients who previously received hormone treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Dose escalation (phase Ib):
    • To determine the recommended phase II dose (RPTD) of GDC-0032 in combination with tamoxifen in hormone receptor positive metastatic breast cancer patients who have progressed after prior endocrine treatment
    Randomized phase II:
    • To compare progression free survival (PFS) in hormone receptor positive, HER2 negative, metastatic breast cancer patients (both lobular and non-lobular) with prior exposure to endocrine therapy, randomized to treatment with (tamoxifen and placebo) versus (tamoxifen and GDC-0032) at the recommended phase II dose defined in the phase 1b study
    E.2.2Secondary objectives of the trial
    phase Ib:
    •safety and tolerability using CTCAE v. 4.03 criteria
    •pharmacokinetics of GDC-0032 in combination with tamoxifen
    •investigate the possibility of major drug-drug interactions (PK)
    •obtain proof of target inhibition by selected pharmacodynamic measurements
    •look for preliminary evidence of anti-tumour activity
    •assess the status of potential biomarkers for drug response
    •assess germline DNA sequence for pharmacogenetics studies
    Randomized phase II:
    •compare OS, ORR, CBR in both treatment arms
    •compare PFS, ORR, CBR and OS in patients randomised to tamoxifen and placebo versus tamoxifen in combination with GDC-0032 in lobular breast cancer patients and in prespecified subgroups
    •compare toxicity profiles in each treatment arm using CTCAE v. 4.03 criteria
    •compare differences in tamoxifen and tamoxifen metabolite levels between treatment arms
    •assess potential biomarkers of drug response
    •assess germline DNA sequence for pharmacogenetic studies
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Phase Ib (dose escalation)
    • Minimum age for inclusion 18 years
    • Breast cancer patients with ER and/or PR positive tumours, or patients with other cancer types whom the investigator considers might benefit from endocrine therapy combined with PI3K inhibition (for example ovarian cancer and cancer of the uterus).
    • Patients with WHO performance status ≤ 2
    • Adequate organ and marrow function
    • Fasting glucose ≤ 120 mg/dL (=6.66 mmol/L) and HbA1c ≤ ULN.

    Randomized phase II:
    • Pre- and Postmenopausal patients with histology-/cytology- proven ER and/or PR positive*, HER2 negative breast cancer with recurrent or metastatic disease which has progressed on prior endocrine therapy
    Premenopausal patients should also receive LHRH agonist.
    • Patient with WHO performance status ≤ 2
    • Adequate organ and marrow function
    • Fasting glucose ≤ 120 mg/dL (=6.66 mmol/L) and HbA1c ≤ ULN.
    • Patients must have either measurable or evaluable disease by RECIST criteria.
    • Availability of a representative tumour tissue specimen
    E.4Principal exclusion criteria
    Exclusion Criteria
    • Patients with premenopausal follicle stimulating hormone (FSH) and/or plasma estradiol levels who are not treated with a LHRH agonist
    • More than 5 prior chemotherapeutic regimens for metastatic breast cancer
    • Endocrine therapies or small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 5 half-lives of the compund or active metabolites with a maximum of 4 weeks..
    • Cytotoxic chemotherapy within 3 weeks, or nitrosoureas or mitomycin C within 6 weeks before the first dose of the study treatment
    • Antibody therapy within 4 weeks before the first dose of the study treatment
    • Radiation therapy within 2 weeks before the first dose of study treatment
    • Untreated, symptomatic, or progressive brain metastases.
    • PT/ INR (PTT) test results at screening > 1.3 x the laboratory upper limit of normal.
    • Corticosteroid use equivalent to more than 10mg prednisone daily
    • Patients with a history of
    - Thrombo-embolic disease or is currently receiving therapeutic doses of warfarin
    - Crohn’s disease or ulcerative colitis or other forms of autoimmune colitis
    - Clinically significant cardiac or pulmonary dysfunction
    - Type 1 or 2 diabetes requiring daily anti-hyperglycaemic medication
    E.5 End points
    E.5.1Primary end point(s)
    Dose escalation (phase Ib):
    • The recommended phase II dose of GDC-0032 in combination with tamoxifen

    Randomized phase II:
    • Progression free survival in hormone receptor positive, HER2 negative, metastatic breast cancer patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Dose escalation (phase Ib): • 28 days after treatment start of the last patient Randomized phase II: • to be assessed every 3 months after end of treatment, until death
    E.5.2Secondary end point(s)
    Dose escalation (phase Ib):
    • Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03
    • Pharmacokinetic measurements for GDC-0032 and tamoxifen
    • Pharmacodynamic measurements of PI3K inhibition like: p-AKT, p-mTOR, p-p70S6K, p-S6RP, p-4EBP1; changes in markers of glucose metabolism; and treatment induced cellular responses such as inhibition of proliferation in tumour biopsies
    • Assessment of objective response measured by RECIST criteria.
    • Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response
    • Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype)

    Randomized phase II:
    • Differences in ORR, CBR and OS between both treatment arms
    • PFS, ORR, CBR and OS in patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032) in the predefined subgroups.
    • Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03) in both treatment arms (including PRO-CTCAE criteria in a subgroup of patients)
    • Differences in tamoxifen and tamoxifen metabolite levels between both arms
    • Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response
    • Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype) in relation to tamoxifen and GDC-0032 pharmacokinetics / toxicity
    E.5.2.1Timepoint(s) of evaluation of this end point
    Dose escalation (phase Ib): • 6 months after end of treatment Randomized phase II: • to be assesses every 3 months after end of treatment, until death
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    To evaluate safety and tolerability of escalating doses of GDC-0032 in combination with tamoxifen
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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 years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In 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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 322
    F.4.2.2In the whole clinical trial 322
    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 Decision2014-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-06
    P. End of Trial
    P.End of Trial StatusOngoing
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