E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intermediate and Limited High Risk Localized Prostate Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
intermediate or favorable (or limited) high risk prostate cancer |
|
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 the combination of apalutamide with 6 months of androgen deprivation therapy by LHRH agonists in patients with
intermediate and limited high-risk, localized prostate cancer receiving primary radiation therapy results in an improvement of disease-free
survival evaluated by the treating physician, in comparison to the combination of radiation and androgen deprivation therapy without the addition of apalutamide. |
|
E.2.2 | Secondary objectives of the trial |
•to characterize the safety profile of the combination treatment by radiation with LHRH agonists and apalutamide in patients
•To characterize the early effect of addition of apalutamide to treatment with androgen deprivation therapy (ADT) and radiation (RT) on the PSA
values on treatment assessed by the value measured at 6 months and by the lowest value achieved on treatment (PSA nadir)
•To determine if the combination of apalutamide with 6 months of ADT and RT improves
- the biochemical progression-free survival with biochemical relapse defined according to the Phoenix criteria of these patients
- the metastasis-free survival of these patients
- the overall survival and prostate-cancer specific survival of these patients
•To assess the impact of the addition of apalutamide to the combined RT and ADT on the health related quality of life of the patients measured by
mean hormone-treatment related symptoms scale of the QLQ PR25, and by the IPSS score. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Histologically confirmed diagnosis of prostate adenocarcinoma diagnosed by ultrasound guided biopsy of the prostate containing 10-12 cores showing no neuroendocrine component at local institution. (An MRI-fusion biopsy is allowed if taken because a previous biopsy was negative.)
•PSA<or= and either of :
- Favorable intermediate risk :
- Only one of the following intermediate risk factors: PSA 10-20 ng/mL, or Gleason score 7 (3+4) (international society of urological pathology-ISUP Grade 2), or cT2b
- Unfavorable intermediate risk :
- either PSA 10-20 ng/mL and cT2b,
- or Gleason score 7 (4+3) (ISUP Grade 3)
- Limited high risk: <T2c, and PSA > 20 ng/mL or Gleason score >7 (ISUP Grade 4/5)
•M0 by standard imaging work-up
•Scheduled to be treated with primary prostate RT
•ECOG/WHO Performance Status ≤ 2
•The following laboratory values done within 4 weeks before randomization:
- aspartate aminotransferase (AST), alanine aminotransferase (ALT), <2.5 x upper limit of normal (ULN)
- total bilirubin <1.5 x upper limit of normal (ULN)
[NOTE: in subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible]
- creatinine level < 2 x ULN
- serum albumin ≥ 3.0 g/dL
- serum potassium ≥ 3.5 mmol/L
- hemoglobin ≥ 10.0 g/dL (independent of transfusion and/or growth factors within 3 months prior to randomization)
- platelet count ≥ 100 x 109/L (independent of transfusion and/or growth factors within 3 months prior to randomization)
•Age ≥ 18 years and ≤ 80 years
•Be able to swallow whole study drug tablets
•Patients with partners of childbearing / reproductive potential should agree to use a condom plus a highly effective method of birth control while on study drug and for at least 3 months following the last dose of study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Patients must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study treatment.
•Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
•Central pathology review on slides obtained at diagnosis for quality assurance purpose will be done. |
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E.4 | Principal exclusion criteria |
•cT2c, T3, T4 or pelvic lymph nodes involvement, as assessed by CT scan or MRI (cN1) or pelvic lymph node dissection (pN1)
•Previous pelvic irradiation or radical prostatectomy.
•Bilateral orchiectomy
•Prior systemic (e.g., chemotherapy) or procedural (e.g., prostatectomy, cryotherapy) treatment for prostate cancer
•Prior treatment with 5-alpha reductase inhibitors for benign prostatic hypertrophy not discontinued 4 weeks prior to randomization
•Prior treatment with any LHRH agonist or antagonist, bicalutamide, flutamide or nilutamide, enzalutamide, abiraterone acetate, orteronel, galeterone, ketoconazole, aminoglutethimide, estrogens, megestrol acetate, and progestational agents for prostate cancer
•Prior treatment with radiopharmaceutical agents (e.g., strontium-89) or immunotherapy for prostate cancer
•Other malignancy except adequately treated basal cell carcinoma of the skin or other malignancy from which the patient has no evidence of disease for at least 5 years.
•History of Ulcerative Colitis, Crohn's Disease, Ataxia Telangiectasia, systemic lupus erythematosus or Fanconi anemia
•History of seizure or condition that may predispose to seizure (including but not limited to: a) prior stroke, transient ischemic attack or loss of consciousness, any of which occurred ≤ 1 year prior to randomization; b) brain arteriovenous malformation; or c) intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
•Medications known to lower the seizure threshold (see list under prohibited medication, section 5.4.4) must be discontinued or substituted at least 4 weeks prior to study entry
•Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (e.g., heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval > 450 ms at baseline
•Uncontrolled hypertension (systolic 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
•Bilateral hip prostheses
•Prior treatment with systemic glucocorticoids ≤ 4 weeks prior to randomization or is expected to require long-term use of corticosteroids during the study
•Use of any investigational agent ≤ 4 weeks prior to randomization
•Current chronic use of opioid analgesics for ≥3 weeks for oral or ≥ 7 days for non-oral formulations
•Major surgery ≤ 4 weeks prior to randomization
•Known or suspected contraindications or hypersensitivity to apalutamide, bicalutamide or LHRH agonists or any of the components of the formulations
•Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary trial endpoint is disease-free survival . Disease-free survival (DFS) is defined as the interval from the date of randomization to the date of first evidence of loco-regional recurrences, distant metastases, initiation of other anticancer treatment for prostate cancer or death from any cause, whichever occurs first, or the date of last known follow-up alive without any of these events. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary trial analysis ("final analysis") is planned to take place when 87 events of DFS have been observed. |
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E.5.2 | Secondary end point(s) |
•Progression-free survival that includes first events of biochemical
failure by Phoenix criteria in addition to the events listed in the primary
endpoint DFS.
•Metastasis-free survival
•Overall survival
•Prostate cancer specific survival
•PSA value at the end of the 6 months of treatment
•PSA nadir observed on treatment
•Health-related quality of life evaluated using self-administered EORTC QLQ-C30 questionnaire and EORTC QLQ-PR25 instruments.
•Adverse events graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Radiotherapy, Biobanking, quality of life |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | No |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Denmark |
France |
Germany |
Italy |
Poland |
Spain |
Switzerland |
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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
|
End of study occurs when all of the following criteria have been
satisfied:
1. At least thirty days after the end of the protocol treatment of the last patient
and
2. Provided all patients have finished protocol specific procedures, not being otherwise part of the standard clinical practice.
and
3. Provided the trial is mature for the analysis of the primary endpoint as defined in the protocol
and
4. The database has been fully cleaned and frozen for this analysis. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 18 |