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    Summary
    EudraCT Number:2014-005684-32
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-10-23
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-005684-32
    A.3Full title of the trial
    [18F] DIHYDRO-TESTOSTERONE PET IMAGING IN PATIENTS WITH PROGRESSIVE PROSTATE CANCER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    [18F] Dihyro-testosterone(FDHT) PET/CT- A novel Imaging technique in Patients with Porgressive Prostate Cancer
    A.3.2Name or abbreviated title of the trial where available
    FDHT - version 1, 9 March 2015
    A.4.1Sponsor's protocol code number
    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 SponsorThe Royal Marsden NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    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 supportMovember Foundation
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Royal Marsden NHS foudation Trust
    B.5.2Functional name of contact pointChua
    B.5.3 Address:
    B.5.3.1Street AddressDowns Road
    B.5.3.2Town/ citySutton
    B.5.3.3Post codeSM25PT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0208 661 3544
    B.5.6E-mailsue.chua@rmh.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 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 nameFluorinated dihydrotestosterone
    D.3.2Product code FDHT
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN18F-fluorodihydrotestosterone
    D.3.9.3Other descriptive name18F- fluorodihydrotestosterone
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mCi/ml millicurie(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.7 to 1
    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 Yes
    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
    Progressive Prostate cancer
    E.1.1.1Medical condition in easily understood language
    Prostate Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 objectives of this study are:

    1 - To study the accumulation and biodistribution of 18F-FDHT in patients with progressive prostate cancer.

    2 - The accumulation and location of 18F-FDHT activity will be assessed on a site by site basis and correlated with radionuclide bone scan, Computed Tomography (CT) and Magnetic Resonance Imaging (MRI).

    3 - The kinetics, metabolism, and bio-distribution will be assessed.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:

    1 - To define the relationship between 18F-FDHT uptake and tumour diffusivity as assessed by MRI.

    2 - To study changes in 18F-FDHT accumulation over time in patients treated
    with:
    • Abiraterone acetate
    • Castration and other hormones
    • Chemotherapy.

    The tertiary objective:

    1 - To preliminarily determine the relationship between 18F-FDHT uptake and tissue analyses of AR expression (tissue will not be acquired under this protocol at RM).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1 Patients with histologically confirmed prostate cancer (Male ≥18 years old, no upper limit)

    2 Progressive disease manifest by either:
    2.1 Imaging modalities:
    Bone Imaging: New osseous lesions on bone imaging (bone scintigraphy or NaF PET scan) and/or
    MRI or CT: An increase in measurable soft tissue disease, or the appearance of new sites of disease.
    Or
    2.2. Biochemical progression:
    A minimum of three rising PSA values from a baseline that are obtained 1 week or more apart, or 2 measurements 2 or more weeks apart.

    3 Visible lesions by CT, bone imaging or MRI, consistent with disease.

    4 Informed consent: able and willing to give written informed consent and to comply with the study protocol procedures.
    E.4Principal exclusion criteria
    1. Previous anaphylactic reaction to 18F-FDHT.

    2. Hepatic: Bilirubin > 1.5 x upper limit of normal (ULN), AST/ALT >2.5 x ULN, albumin <2 g/dl, and GGT > 2.5 x ULN IF Alkaline phosphatase >2.5 x ULN.

    3. Renal: Creatinine > 1.5 x ULN or creatinine clearance <60mL/min.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints:(this analysis is based on the total trial data collected from the 105 patients recruited across sites)

    For each patient in cohort 1 (30 patients) and each lesion imaged within the field of view of a dynamic 18F-FDHT PET scan, we will fit a 2-compartment, first-order model and determine k3 values (a measure of androgen receptor density) using a metabolite corrected, venous blood-sample-scaled, population-based input function. Historically, we have seen an average of 18 lesions per patient for mCRPC patients. The general estimating equation approach, based on an ordinal regression model, will be used to determine at the lesion level the relationship between k3 and the concentration of AR within the lesion as determined from subsequently acquired biopsy samples of these same lesions. The general estimating equation approach is used to account for the multiple time points (15, 30, 45, 60, 90, and 120 minutes from 18F-FDHT injection) imaging is obtained. It is noted that the measure of AR concentration is semi-quantitative, and is recorded using the ordinal scores. The ordinal regression model may be represented as ωj = exp(αj + βk3), where ωj is odds the androgen receptor concentration is less than or equal to j, and αj, β are the ordinal regression parameters to be estimated. A test of association for this model is carried out using the score test for β=0, which indicates that a change in the k3 measure has no effect on androgen receptor concentration.
    A total of 75 patients will be used to explore the reproducibility of the 18F-FDHT SQM measure. This part of the study design will consist of three patient cohorts that are described as cohorts 2-4. The analyses will be undertaken at the patient and lesion level using the SQM measure. The primary analysis is at the patient level and the primary endpoint is the relative difference in the maximum SQM at baseline and post-baseline. For a given patient, if the relative difference is ≤ 0.15, then the measure is stable. The post-baseline time points are day 2 (cohort 2), day 8 (cohort 3), and day 22 (cohort 4).
    Initially 25 patients will be studied in cohort 2, where 18F-FDHT PET scans will be recorded at baseline and at day two. If unstable scans (a relative difference > 0.15) are recorded in 5 or more patients at any time during accrual, then the study will proceed to cohort 3; otherwise, an additional 50 patients will be studied in cohort 2. The probability of proceeding to cohort 3 is 0.10 when the true stability rate in the population is 0.10. This probability increases to 0.90 when the true stability rate in this cohort population is 0.30. If necessary, this algorithm will be used for the decision to continue accrual in cohort 3 (25 patients in the first stage and if the scans are stable 25 additional patients will be accrued to this cohort) or to proceed to cohort 4. If the study reaches cohort 4, 25 patients will studied in this final group.
    The concordance correlation coefficient measure of reproducibility will be computed in the cohort with 25 or more patients. To calculate reproducibility, the baseline and post-baseline data pair for each subject are plotted and the concordance correlation coefficient measures the variation of the points around a 45-degree line through the origin. The statistic for the concordance correlation coefficient ranges between zero and one, with the value one representing perfect reproducibility of the 18F-FDHT SQM measures. We will look at reproducibility at the patient and lesion levels. For each 18F-FDHT measure, a 95% confidence interval for the concordance correlation coefficient will be computed. If for a given measure the lower confidence bound exceeds 0.80, it will be concluded that this measure is reproducible. To account for the correlation of the 18F-FDHT measure between lesions within patient, a bootstrap estimate of the standard error of the concordance correlation coefficient estimate will be computed using the subject as the re-sampling unit. This bootstrap approach provides flexibility in estimating the standard error when the number of lesions varies between patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please see above.
    E.5.2Secondary end point(s)
    Secondary endpoints:
    Areas of abnormal 18F-FDHT uptake on PET will be visually correlated on WB-MRI for the presence of abnormal MR signal intensity (on T1 and fat/water sequences), diffusion (on DW-MR images and ADC maps) or perfusion (raw DCE images and parametric maps). Quantitative MRI measurements from diffusion-weighted imaging (ADC) and DCE-MRI (Ktrans, kep, ve) will be calculated and correlated to quantitative and semi-quantitative PET metrics obtained from areas of abnormal 18F-FDHT uptake. Lesions detected on MRI without corresponding 18F-FDHT accumulation on PET will also be recorded.
    For expansion cohorts 2-4 patients (at least 30 patients) will be treated with abiraterone acetate for 28 days after the second scan. At the conclusion of the treatment a third scan is proposed and an initial examination of the prognostic value of the change in18F-FDHT PET and MRI from the second to the third scan will be undertaken. The two other endpoints will be PSA progression free survival time and radiographic progression free survival time. The Cox proportional hazards model will be employed to study the prognostic value of the change in 18F-FDHT and MRI parameters. A landmark analysis, starting after the completion of the abiraterone acetate treatment, will be performed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see above.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.6.13.1Other scope of the trial description
    comparison of imaging modalities
    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
    This Pharmacokinetic study is performed in patients with metastatic CRPC
    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 No
    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.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number 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 EEA1
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Netherlands
    United Kingdom
    United States
    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 defined as: One year after the first scan on the last patient recruited.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days6
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 105
    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)
    This study will have no influence on the therapy management of the patients. The patients included in the study will be treated according to the standard procedures/guidelines followed in the urology or oncology departments of the site.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation The Institute of Cancer Research
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-09-15
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