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    Summary
    EudraCT Number:2018-004329-10
    Sponsor's Protocol Code Number:UKM17_0018
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-21
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-004329-10
    A.3Full title of the trial
    A Randomized, open-label, Phase 2 Study of Adjuvant Apalutamide or Standard of Care in Subjects with High-risk, Localized or Locally Advanced Prostate Cancer After Radical Prostatectomy
    Randomisierte, offene Phase II Studie mit adjuvantem Apalutamid oder einer Standardbehandlung bei Hochrisikopatienten mit lokal begrenztem oder lokal fortgeschrittenem Prostatakarzinom nach radikaler Prostatektomie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study with apalutamide in patients with prostate cancer in whom the prostate has been removed who are at high risk of disease recurrence
    Studie mit Apalutamid bei Patienten mit Prostatakrebs, bei denen die Prostata entfernt wurde und bei denen ein hohes Risiko für ein Wiederauftreten der Erkrankung besteht
    A.3.2Name or abbreviated title of the trial where available
    ADAM
    A.4.1Sponsor's protocol code numberUKM17_0018
    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 SponsorWestfälische Wilhelms-Universität Münster c/o Universitätsklinikum Münster, Geschäftsbereich Recht u. Drittmittel
    B.1.3.4CountryGermany
    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 Pharmaceutica NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinik für Urologie und Kinderurologie am UKM Münster
    B.5.2Functional name of contact pointUniv.-Prof. Dr. med Martin Bögemann
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Schweitzer Campus 1, Gebäude A1
    B.5.3.2Town/ cityMünster
    B.5.3.3Post code48149
    B.5.3.4CountryGermany
    B.5.4Telephone number00492518344600
    B.5.5Fax number00492518348310
    B.5.6E-mailmartin.boegemann@ukmuenster.de
    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 Erleada
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Film-coated 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 956104-40-8
    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 adenocarcinoma of the prostate after radical prostatectomy (RPE)
    E.1.1.1Medical condition in easily understood language
    Patients who were treated with radical prostatectomy for prostate cancer and who are at righ risk for metastasis
    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 determine if adjuvant apalutamide in prostate cancer patients at high risk of developing subsequent metastatic disease results in prolonged biochemically recurrence-free survival after radical prostatectomy (RPE) in comparison to standard of care (SOC).
    E.2.2Secondary objectives of the trial
    1. To characterize the safety and tolerability of apalutamide in subjects with high-risk, localized or locally advanced prostate cancer having received RPE

    2. To determine if apalutamide in subjects with high-risk, localized or locally advanced prostate cancer having received RPE results in an improvement of PSADT, i.e. increased PSADT in case of BCR
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent form (ICF)
    2. Men ≥ 18 years of age
    3. Patients with histologically confirmed adenocarcinoma of the prostate after radical prostatectomy
    4. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
    5. Exclusion of metastatic disease by CT-scan of abdomen (MRI of abdomen is possible)
    and bone scan prior to study inclusion. A PSMA PET-CT/MRI is possible. In this case it has to be done with a diagnostic CT/MRI with contrast media and not with a low dose CT-scan only. In case PSMA-PET imaging has been done, a bone scan can be omitted. CT/MRI, and bone-scan imaging or PSMA PET-CT/MRI administered ≤12 weeks before RPE may be used for screening
    6. Patients after RPE must meet the d’Amico criteria for high risk of disease recurrence (T-stage and Gleason-score determined after radical prostatectomy) i.e. 1 of the following after RPE: 1) Gleason score ≥8, any T-stage, any iPSA or 2) Gleason score 6 or 7, any iPSA and ≥pT3 or 3) iPSA >20 ng/ml, any Gleason score, any T-stage.
    7. Patients have to have recovered from radical prostatectomy within eight weeks to be able to take part in the study
    8. PSA must have declined below 0.2 ng/ml prior to randomization
    9. Adequate hematologic, hepatic, and renal function:
    • Hematologic
    i) Haemoglobin ≥ 9.0 g/dL independent of transfusions
    ii) Neutrophils ≥ 1.5 Ths./µL
    • Hepatic
    i) Total Bilirubin =< 1.5X upper limit of normal (ULN) [except for subjects with documented Gilbert’s disease in which case total bilirubin not to exceed 10X ULN]
    ii) Alanine (ALT) and aspartate (AST) aminotransferase =< 2.5X ULN
    • Renal:
    i) Serum creatinine <1.5X ULN or calculated creatinine clearance ≥ 50 mL/min
    ii) Serum potassium ≥ 3.5 mM
    iii) Serum albumin ≥ 3.0 g/dL
    10. Ability to swallow study medication tablets
    11. In case of apalutamide treatment: Agrees to use a condom and another highly effective method of birth control if he is having sex with a woman of childbearing potential or to use a condom if he is having sex with a woman who is pregnant
    E.4Principal exclusion criteria
    1. Any chronic medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone q.d.
    2. Prior cytotoxic chemotherapy or biologic therapy for the treatment of prostate cancer
    3. Prior or current treatment of prostate cancer with apalutamide, enzalutamide, darolutamide, or other investigational agents targeting the androgen receptor
    4. Prior therapy with Sipuleucel-T or other vaccination or immunogenic therapy for the treatment of prostate cancer
    5. Prior treatment with abiraterone acetate or other androgen synthesis inhibitors (e. g. ketoconazole, TAK700, TOK001)
    6. Use of 5-α reductase inhibitors (eg, dutasteride, finasteride) ≤4 weeks prior to randomization
    7. Prior surgical castration or medical castration using LHRH-Agonists or GnRH-Antagonists
    8. Prior or current radiation or radionuclide (including radium-223 dichloride) therapy for treatment of prostate cancer (adjuvant radiation of the prostate bed without involvement of the regional lymph node template as by standard of care in case of positive surgical margins (R1) is allowed)
    9. Prior or current systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1
    10. Any lymph node or distant metastasis
    11. History of seizures or condition that may predispose 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).
    12. Current or prior treatment with anti-epileptic medications for the treatment of seizures
    13. Management of cardiovascular risk factors, such as hypertension, diabetes or dyslipidaemia should be optimised as per standard of care before treatment with apalutamide will be initiated
    13.1. Uncontrolled hypertension (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg. For patients with relevant comorbidities (e.g. diabetes) systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg). Patients with a history of hypertension are allowed provided that blood pressure is controlled by anti-hypertensive treatment
    13.2. Patients with uncontrolled diabetes defined as HbA1c ≥7.5%
    13.3. Patients with a dyslipidemia defined as LDL cholesterol >100 mg/dl. For patients with a dyslipidemia defined as LDL cholesterol >100 mg/dl and SCORE-value of 1-5%: In case of a SCORE-value of <1% a LDL cholesterol level of up to 115 mg/dl is acceptable. In case of increased LDL cholesterol above these values a statin-therapy can be initiated and a rescreening within 4 weeks is possible
    13.4. Cardiovascular risk assessment via an appropriate score (e.g. the SCORE-Chart for the European high/low risk score from the European Society of Cardiology) and ≥ borderline risk i.e. 10% of developing cardiovascular events within 10 years without prior cardiovascular disease
    14. Active or symptomatic viral hepatitis or chronic liver disease or HIV
    15. History of pituitary or adrenal dysfunction
    16. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 12 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of <50% at baseline, or clinically relevant pelvic lymphocele after radical prostatectomy as evaluated by clinical examination and/or pelvic ultrasound (if a risk is present, patients may be allowed to be enrolled after adaptive risk management).
    17. Any condition that requires treatment with digoxin, digitoxin, and other digitalis drugs
    18. Long QT Syndrome
    19. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy
    20. Other malignancy with a ≥30% probability of recurrence within 24 months, except non-melanoma skin cancer
    21. Any condition, which, in the opinion of the investigator, would preclude participation in this trial.
    22. Gastrointestinal conditions affecting absorption
    23. Hypersensitivity to the active substance, or to any of the excipients of the study medication
    24. Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator’s opinion, compromises the patient’s ability to understand the patient information, to give informed consent or to comply with the study protocol.
    25. Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. There may be exceptions at the discretion of the (coordinating) investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS). This endpoint is defined as time interval from randomization until BCR, metastases, or death from any cause, whichever occurs first. BCR is defined as a PSA ≥ 0.2 ng/ml that has risen on at least two separate occasions at least four weeks ± 3 days apart and measured by the central PSA-lab. The time of BCR is then backdated to the time of the first increased PSA measurement.
    Metastatic disease will be defined as the presence of bone metastases visualized on bone scan prostate cancer working group 3 (PCWG3)-criteria; and/or visceral (e.g. liver, lung, brain) or extra-pelvic nodal metastases visualized on CT scan (or MRI scan) (RECIST 1.1-criteria). If deemed indicated by the study physician a PSMA-PET-CT/MRI can be done instead. Evaluations will be performed every 6 months once BCR occurred or sooner if clinically indicated.
    For a patient with none of these events before the end of follow-up, observation of PFS will be censored at the date of his last follow-up examination.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At every study visit.
    E.5.2Secondary end point(s)
    1) Safety and tolerability assessed on the basis of adverse events, more precisely adverse events, serious adverse events, adverse reactions, and serious adverse reactions
    2) PSA doubling time (PSADT). In case of an BCR, PSA kinetics as the PSADT are calculated based on the monthly PSA measurements during the first six months after the BCR. The values used to determine the BCR are included in the calculation of PSA kinetics as well. In case of a sudden incline of PSA to values close to 0.5 ng/ml, a follow-up (radiation) therapy or next generation imaging diagnostics in search for potential metastasis that may lead to subsequent therapy might be started before the 6 months since BCR have passed. In this case, PSA kinetics will be calculated based on all PSA measurements available since BCR but at least based on 3 PSA measurements with at least 4 weeks in-between each measurement.
    PSADT is calculated according to Pound et al. by the natural log of 2 (0.693) divided by the slope of the relationship between the log of PSA and time of PSA measurement (i.e. time from BCR) for each patient. PSADT can also be assessed using the MSKCC PSADT calculator
    (https://www.mskcc.org/nomograms/prostate/psa_doubling_time) using the above definitions.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Ongoing basis from signed informed consent form until BCR occurred and PSADT was calculated or when distant metatstasis occurred (both with or without BCR)
    2) If BCR occurs up to 6 months later
    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) 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 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
    SOC (observation only or an optional adjuvant radiation of the prostate bed in case of R1 status)
    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 concerned19
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 years8
    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 years8
    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: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state130
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 190
    F.4.2.2In the whole clinical trial 190
    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)
    Whenever a subject completes the Treatment Phase and the End-of-Treatment Visit (apalutamide group only), suffers BCR or metastasis (whichever occurs first) or has been followed-up for a maximum of 5 years after the last patient is randomized, it will be continued to be treated according to standard of care based on investigator/patient decision.
    Keine
    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 Decision2020-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-09
    P. End of Trial
    P.End of Trial StatusOngoing
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