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    Summary
    EudraCT Number:2017-000155-21
    Sponsor's Protocol Code Number:UC-0160/1702
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-31
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-000155-21
    A.3Full title of the trial
    An open label, randomized, phase III study, evaluating the efficacy of a Combination of Apalutamide with Radiotherapy and LHRH Agonist in high-risk postprostatectomy biochemically relapsed prostate cancer patients.
    Essai de phase III, randomisé, en ouvert, évaluant l’efficacité de l’association apalutamide avec une
    radiothérapie et un agoniste de la LHRH chez des patients atteints d’un cancer de la prostate à haut
    risque de récidive biochimique après prostatectomie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open label, randomized, phase III study, evaluating the efficacy of a Combination of Apalutamide with Radiotherapy and LHRH Agonist in high-risk postprostatectomy biochemically relapsed prostate cancer patients.
    A.3.2Name or abbreviated title of the trial where available
    CARLHA- 2
    A.4.1Sponsor's protocol code numberUC-0160/1702
    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 SponsorUNICANCER
    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 support JANSSEN Pharmaceutica NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUNICANCER
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address101, rue de Tolbiac
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75654
    B.5.3.4CountryFrance
    B.5.4Telephone number33173 77 55 43
    B.5.6E-mailgetug-afu33@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 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 nameApalutamide
    D.3.2Product code JNJ-56021927
    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 INNAPALUTAMIDE
    D.3.9.1CAS number 204420
    D.3.9.4EV Substance CodeSUB189031
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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
    High-risk biochemically-relapsed prostate adenocarcinoma following radical prostatectomy.
    E.1.1.1Medical condition in easily understood language
    High-risk biochemically-relapsed prostate adenocarcinoma following radical prostatectomy.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10060862
    E.1.2Term Prostate 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 evaluate the clinical benefit of adding the androgen receptor competitive inhibitor apalutamide in combination with a Luteinizing Hormone Releasing Hormone (LHRH) agonist concomitantly to salvage radiotherapy (SRT) after biochemical progression following radical prostatectomy in patients with high-risk prostate adenocarcinoma. The clinical benefit will be evaluated using the progression-free survival (PFS) rate at 5 years.
    E.2.2Secondary objectives of the trial
    1. To evaluate the prostate-cancer specific survival rate
    2. To evaluate the overall survival rate at 10 years
    3. To evaluate the biochemical relapse rate
    4. To evaluate the time to castration resistant prostate cancer
    5. To evaluate safety
    6. To assess patients’ quality of life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have signed a written informed consent form prior to any trial specific procedures
    2. Age ≥ 18 years old and ≤ 80 years old
    3. Histologically confirmed diagnosis of prostate adenocarcinoma treated primarily with radical prostatectomy
    4. Pathologically proven to be lymph node negative by pelvic lymphadenectomy (N0) or lymph node status pathologically unknown (undissected pelvic lymph nodes [Nx])
    5. Tumor stage pT2, pT3 or pT4* (*only in case of bladder neck involvement)
    6. Patients should have no clinical and radiological signs (18FCH-PET CT-scan or 68Ga-PSMA-PET) of metastatic disease. Patients with a local relapse detected on PET scan be randomized
    7. ECOG performance status ≤ 1
    8. PSA ≤ 0.1 ng/mL after radical prostatectomy (dosage performed within 3 months after surgery)
    9. PSA ≥ 0.2 ng/mL and ≤ 2 ng/mL at the time of randomization with an elevation of PSA over three consecutive assays
    10. At least 6 months between radical prostatectomy and biochemical relapse
    11. High-risk features as defined by at least one of these characteristics: PSA at relapse > 0.5 ng/mL or Gleason score > 7 or tumor stage pT3b or resection margins R0 or PSA doubling time ≤ 6 months
    12. Adequate renal function: serum creatinine < 1.5 x upper limit of normal (ULN) or a calculated corrected creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula, creatinemia < 2 ULN
    13. Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (unless documented Gilbert’s syndrome), AST and ALT ≤ 2.5 x ULN
    14. Patients with female partners of reproductive potential should agree to use effective contraceptive method during treatement period and for 3 months after the last dose of apalutamide or for 6 months after the last fraction of radiotherapy
    15. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
    16. Patients must be affiliated to the Social Security System
    E.4Principal exclusion criteria
    1. Histologically proven lymph nodes involvement at initial lymphadenectomy: pN1,pN2, pN3
    2. Previous treatment with hormone therapy for prostate cancer
    3. Histology other than adenocarcinoma
    4. Surgical or chemical castration
    5. Other malignancy except adequately treated basal cell carcinoma of the skin or other malignancy from which the patient has been cured for at least 5 years
    6. Previous pelvic radiotherapy
    7. History of Inflammatory bowel disease or any malabsorption syndrome or conditions that would interfere with enteral absorption
    8. Uncontrolled hypertension (defined as systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
    9. Clinically significant history of liver disease consistent with Child-Pugh class B or C
    10. History of seizure or condition that may pre-dispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness ≤ 1 year prior to randomization; brain arteriovenous malformation or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
    11. Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
    12. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g pulmonary embolism, cerebrovascular accident including transient ischemic attacks) or clinically significant ventricular arrhythmias within 6 months prior to randomization
    13. Known hypersensitivity to apalutamide or to any of its components
    14. Galactosemia, Glucose-galactose malabsorption or lactase deficiency
    15. Inability or willingness to swallow oral medication
    16. Individual deprived of liberty or placed under the authority of a tutor
    17. Patients already included in another therapeutic trial with an experimental drug or having been given an experimental drug within the 30 days before inclusion
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the 5-year-progression free survival (PFS).
    PFS is defined as the time from the date of randomization to the date of first evidence of loco-regional recurrences, or distant metastases, or death from any cause whichever occurs first, or the date of last known follow-up alive without any such events.
    Evidence of loco-regional recurrences is evaluated on PET CT (18FCH-PET CT-scan or 68Ga-PSMA PET)
    Evidence of distant metastases is evaluated on PET CT (18FCH-PET CT-scan or 68Ga- PSMA PET)
    Relapse at a distant metastatic site is defined as the occurrence of PET CT defined bone or soft tissue distant metastasis.
    E.5.2Secondary end point(s)
    Efficacy:
    1. Cancer-specific overall survival is defined as the time from the date of randomization to the date of death related to prostate cancer or the date of last known follow-up alive.
    2. Overall survival (OS) will be assessed at 10 years. OS is defined as the time from the date of randomization to the date of death from any cause or the date of last known follow-up alive.
    3. Biochemical relapse-free survival will be retrospectively defined by the interval between the date of randomization and the date of the first PSA elevation following the 6-months treatment in both arms (PSA ≥ 0.5 ng/mL confirmed by two consecutive PSA increases over a 2-months interval).
    If no biochemical relapse is observed, the PSA concentration will be measured every 6 months for 5 years and every year thereafter.
    In order to compare PSA values, PSA assays must always be performed for each patient in the same laboratory.
    Following biochemical relapse, clinical staging (18FCH-PET CT-scan or 68Ga-PSMA PET) will be repeated every 6 months until local or metastatic progression is detected.
    4. The time to castration resistance is defined as the time from the date of randomization to the date of appearance of castration resistance defined in the EAU guidelines (Cornford Eur Urol 2017). Castration-resistant prostate cancer (CRPC) is defined as castrate serum testosterone <50 ng/dl or 1.7 nmol/l plus one of the following types of progression:
    - Biochemical progression: Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml
    - Radiologic progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using the Response Evaluation Criteria in Solid Tumours
    Safety:
    Frequency, nature and severity of adverses events will be assessed according to the NCI CTCAE version 5.0 (see Appendix 4)
    Acute toxicity related to radiotherapy is defined as occurring during radiotherapy and up to 3 months after completion of radiotherapy.
    Late toxicity related to radiotherapy is defined as occurring later than 3 months after end of radiotherapy.
    The tolerance will be evaluated up until 10 years.

    Patient-reported outcomes:
    Quality of life will be assessed at baseline, at end of SRT, at end of treatment visit and at every follow up visit until disease progression by using:
    - EORTC QLQ-C30 questionnaire
    - EORTC QLQ-PR25 questionnaire
    - IIEF-5 questionnaire
    - IADL scale for patients ≥ 75 years old
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    Salvage Radiotherapy + 6-months of LHRH agonist
    E.8.2.4Number of treatment arms in the trial2
    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 concerned20
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years14
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years14
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 290
    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 state490
    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 Decision2018-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-04
    P. End of Trial
    P.End of Trial StatusOngoing
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