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    Summary
    EudraCT Number:2012-005036-28
    Sponsor's Protocol Code Number:2012/41
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-04-19
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2012-005036-28
    A.3Full title of the trial
    Pharmacogenetic study in castration-resistant prostate cancer patients treated with abiraterone acetate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pharmacogenetic study in castration-resistant prostate cancer patients treated with abiraterone acetate
    A.3.2Name or abbreviated title of the trial where available
    ABIGENE
    A.4.1Sponsor's protocol code number2012/41
    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 SponsorCENTRE ANTOINE LACASSAGNE
    B.1.3.4CountryFrance
    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 supportJANSSEN CILAG
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCENTRE ANTOINE LACASSAGNE
    B.5.2Functional name of contact pointLOVERA Christine
    B.5.3 Address:
    B.5.3.1Street Address33 avenue de valombrose
    B.5.3.2Town/ citynice
    B.5.3.3Post code06189
    B.5.3.4CountryFrance
    B.5.4Telephone number+33492031618
    B.5.5Fax number+33492031030
    B.5.6E-mailchristine.lovera@nice.unicancer.fr
    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 ZYTIGA
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN CILAG
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameABIRATERONE ACETATE
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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
    Prostate cancer metastatic
    E.1.1.1Medical condition in easily understood language
    prostate cancer metastatic
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    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
    The primary objective will be to investigate the relationships between candidate-gene polymorphisms specifically related to AA pharmacology: CYP17A1, SLCO2B1 and SLCO2B3 (13 single nucleotide polymorphisms) and the clinical efficacy of AA in terms of progression-free survival. Such relationships will take into account relevant histo-prognostic factors of metastatic CRPC cancers (clinical staging, pre-treatment PSA, Gleason score) and treatment compliance.
    E.2.2Secondary objectives of the trial
    - To investigate relationships between the above-cited candidate-gene polymorphisms specifically related to AA pharmacology (13 single nucleotide polymorphisms) and the following pharmacological effects of AA: Biological response on PSA, Overall survival, Time-to-PSA progression, Symptomatic or clinical progression-free survival, Toxicity.
    To investigate the relationship between clinical end-points and genetic profile from pan-genome SNPs analyses.
    To investigate the link between CYP17A1 gene polymorphisms and CYP17A1 tumoral expression.
    To examine the possible link between the evolution of sDHEA and androstenedione circulating levels and AA pharmacodynamics.
    To document the frequency of potentially relevant polymorphisms of cabazitaxel (CYP3A4 and CYP3A5).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The purpose of this optional ancillary study will be to re-examine the variability of AA pharmacokinetic (PK) as well as to evaluate the hypothetic links between PK and pharmacodynamics of AA. Thus, relationships between AA pharmacokinetics variability and the variability of treatment response and toxicity will be examined. To this end, residual steady state plasma concentrations of abiraterone will be measured at different periods of treatment. In addition, we will investigate whether the circulating levels of sDHEA and androstenedione, which may reflect the intensity of CYP17A1 inhibition, could be used as surrogate markers of the AA pharmacokinetic variability.
    E.3Principal inclusion criteria
    1.Age > 18 years.
    2.Histologically confirmed prostate adenocarcinoma.
    3.ECOG ≤ 2.
    4.Evidence of metastatic disease by the presence of documented locoregional or distant metastases on CT scan of the abdomen and/or pelvis, or bone scintigraphy.
    5.Patients who have had disease progression during or after prior docetaxel chemotherapy regimen, defined as:
    a.Progressive measurable disease : At least a 20% increase in the sum of the longest diameters of measurable lesions over the smallest sum observed –or- the appearance of one or more new measurable lesions as assessed by CT scan. Soft tissue disease progression defined by modified RECIST 1.1 criteria (baseline lymph node size must be ≥ 2.0 cm to be considered target or evaluable lesion).
    OR
    b.Bone Scan Progression: appearance of 2 or more new lesions on bone scan.
    OR
    c.Increasing serum PSA level: Two consecutive increases in PSA levels documented over a previous reference value obtained at least one week apart are required. If the third PSA value is less than the second, an additional fourth test to confirm a rising PSA is acceptable. A minimum starting value of 2.0 ng/mL is required for study entry.
    NOTE: Androgen ablative therapy may have included either medical or surgical castration.
    6.At least one prior chemotherapy regimen of docetaxel.
    7.At least 28 days had to have elapsed between the withdrawal of antiandrogens and enrolment, except LH-RH agonist therapy that must be continued throughout this study for patients who were already treated by it.
    8.Hormonal castration confirmed biologically (testosterone < 0.5 ng/ml).
    9.Patient with adequate organ function
    E.4Principal exclusion criteria
    1.Patients already treated with abiraterone acetate.
    2.Known hypersensitivity or allergy to abiraterone or any of the excipients (see attachment 9).
    3.Patients suffering from severe liver or renal impairment.
    4.Any radiation within 28 days prior to study entry.
    5.Patient with central nervous system (CNS) metastasis or with history of CNS metastasis.
    6.Patient treated for a cancer other than prostate cancer, with the exception of basal cell carcinoma, within the past 5 years.
    7.Treatment on another therapeutic clinical trial within 28 days before enrolment
    8.Prior treatment with novel hormonal agents including enzalutamide, orteronel, ARN509, EPI100 and novel non hormonal treatments including cabozantinib, alpharadin.
    9.Uncontrolled medical conditions such as heart failure, myocardial infarction, uncontrolled hypertension, stroke or treatment of a major active infection within 3 months of randomization, as well as any significant concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy.
    10.Permanent contraindication to corticosteroids.
    11.Patient with history of poor compliance or current or past psychiatric conditions or severe acute or chronic medical conditions that would interfere with the ability to comply with the study protocol.
    12.Patient enables to give informed consent.
    13.People particularly vulnerable as defined in Articles L.1121-5 to -8 of the French Healthcare Code
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival will be defined as the time elapsed between treatment initiation and disease progression.
    Disease progression will be defined as radiographic progression in soft tissue or bone, or as PSA progression plus symptomatic progression.
    Radiographic progression disease assessment will be based on the use of computed tomography (CT) or magnetic resonance imaging (MRI) for Soft-tissue lesion and defined according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria or based on bone scan according to criteria adapted from the PCWG2 (Scher 2008).

    Biological response on PSA will be defined as a decrease of 50% in the PSA concentration from pre-treatment baseline PSA value, confirmed after 4 weeks by an additional PSA evaluation.

    Overall survival will be defined as the time from start of therapy to death from any cause.

    Time to PSA progression will be defined as the time elapsed between treatment initiation and PSA progression.
    PCWG2 defines PSA progression as the first date that a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir, which has to be confirmed by a second value, obtained 3 to 4 weeks later.

    Symptomatic or clinical progression will be defined as the time from start of therapy to the first sign of progression defined by one of the following:
    Pain progression - Worsening of pain due to metastatic bone disease feel by the patient, and according the investigator’s physical examination,
    Development of a skeletal related event (SRE) defined as pathologic fracture, spinal cord compression, palliative radiation to bone, or surgery to bone,
    General physical health deterioration
    Any increase in prednisone or prednisolone dose or a change to a more potent glucocorticoid such as dexamethasone, to treat prostate cancer related signs and symptoms, such as fatigue and pain are considered a disease progression event.

    Toxicity: All adverse events and serious adverse events will be recorded.
    The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 will be used (Appendix 3) to grade clinical and laboratory AEs.

    Histo-prognostic factors and treatment compliance:
    - Histo-prognostic factors of metastatic CRPC cancers including clinical staging, pre-treatment PSA, Gleason score will be collected at screening visit.
    - Treatment compliance will be evaluated by using a logbook: patients will be asked to keep track of their drug intake every day through it.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every months during 3 months then every 2 months during 15 months
    E.5.2Secondary end point(s)
    Pharmacogenetic analysis

    •Candidate-gene approach
    The candidate gene approach will include 13 SNPs potentially related to the pharmacodynamics of AA and 2 SNPs potentially related to cabazitaxel pharmacokinetics, all analyzed by pyrosequencing or by PCR-RFLP methods.
    The 13 SNPs potentially related to the pharmacodynamics of AA will concern 9 functional SNPs of the CYP17A gene (allele frequency of the rare alleles > 12%), along with 4 functional SNPs of genes involved in the membrane-transport of testosterone and dehydroepiandrosterone, SLCO2B1 and SLCO1B3 (allele frequency of the rare alleles > 20%):
    - Nine SNPs of CYP17A1 gene: -34 T>C (rs 743572), -362 T>C (rs 2486758), 35 T>C (rs 1004467), 137 G>A (rs 6162), 195 C>A (rs 6163), 11994 C>A (rs 4919683), 13871 A>G (rs 10883782), 15831 G>T (rs 619824) and 1243+113 T>A (rs 10883783).
    - Three SNPs of SLCO2B1 gene: 312Arg>Gln (rs 12422149), 3551 A>T (rs 1789693) and A>G (rs 1077858)
    - One SNP of SLCO1B3 gene: 112Ser>Ala (rs 4149117).

    The two SNPs potentially related to the variability of cabazitaxel effects will be:
    - One SNP of CYP3A4: variant *1B (rs 2740574), rare allele frequency = 4%
    - One SNP of CYP3A5: variant *3 (rs 776746), rare allele frequency = 30%.

    •Genome-wide approach
    DNA samples will also be analyzed using a genome-wide approach. However, the choice of the beadchip that will be used for this additional analysis will be defined at the end of the recruitment period, based on the most recent technological advancements. Indeed, this field presents rapid changes in technology and cost, and we need to ensure optimum utilization of the genetic material regarding analytical strategies (pan genome data quality) as well as statistical analysis (choice of the partner providing bioinformatics analysis).

    Analysis of circulating hormone levels
    The circulating levels of DHEA and androstenedione will be studied by using radioimmunoassay from a specific blood sample drawn at the inclusion and either every month or every 15 days (optional) during the first 3 months, and the day after last drug intake.

    Pharmacokinetic analysis (optional)
    A specific blood sample will be taken at the inclusion, and then every two weeks during the first 3 months of treatment, as well as the day after last drug intake when feasible. These blood samples will correspond to minimal steady-state concentration (Css min) of abiraterone. Abiraterone will be analyzed by means of high-performance liquid chromatography tandem mass spectrometry (HPLC-MS-MS).

    Immunohistochemical (IHC) analyses of primary tumors
    CYP17A1 tumoral expression level will be evaluated before initiation of treatment by immunohistochemical (IHC) analysis on retrospectively-collected paraffin blocks of primary tumors.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every months during 3 months then every 3 months during 15 months
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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
    translationnal study
    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 concerned13
    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
    according to the investigator's choice among the available standard therapies
    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 months36
    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: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 170
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    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 state330
    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)
    Patients should be taken in charge according to investigator's choice
    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 Decision2013-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-12
    P. End of Trial
    P.End of Trial StatusCompleted
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