E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High risk adenocarcinoma of the prostate after radical prostatectomy (RPE) |
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E.1.1.1 | Medical condition in easily understood language |
Patients who were treated with radical prostatectomy for prostate cancer and who are at righ risk for metastasis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060862 |
E.1.2 | Term | Prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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). |
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E.2.2 | Secondary 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 thorax and abdomen (MRI of abdomen is possible) and bone scan prior to radical prostatectomy. 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. 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 |
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E.4 | Principal 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 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 6 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
SOC (observation only or an optional adjuvant radiation of the prostate bed in case of R1 status) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |