| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prostate cancer |
| Cancer de la prostate |
|
| E.1.1.1 | Medical condition in easily understood language |
| Intermediate unfavorable risk prostate cancer |
| Cancer de la prostate à risque intermédiaire défavorable |
|
| 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 | LLT |
| E.1.2 | Classification code | 10036910 |
| E.1.2 | Term | Prostate cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 assess the preliminary signs of antitumor activitity of darolutamide when prescribed for 6 months in association with radiotherapy in patients with unfavorable intermediate risk prostate cancer. Activity will be measured in terms of biological response defined as PSA ≤0.1ng/ml and measured 6 months after randomization.
|
Evaluer les signes préliminaires de l’activité antitumorale du darolutamide prescrit pendant 6 mois en association avec la radiothérapie externe conformationnelle chez les patients présentant un cancer de la prostate à risque intermédiaire défavorable. L’activité antitumorale sera mesurée en termes de réponse biologique définie par un taux de PSA ≤ 0.1 ng/ml évalué 6 mois après la randomisation
|
|
| E.2.2 | Secondary objectives of the trial |
Independently for each treatment strategy: assessment of antitumor activity in terms of :
o Biological response (PSA ≤0.1ng/ml) measured
o at the end of darolutamide or ADT,
o 2 months following randomization,
o 3, 6, and 9 months post-radiotherapy,
o 2, 3 and 5 years following randomization
o Biolochemical Progression-free survival,
o Metastases-free survival,
o Disease-free survival,
o Prostate cancer-specific survival,
o Overall-survival,
o Time to testosterone recovery
• Independently for each treatment strategy: Assessment of the safety profile of the therapeutic strategy and assessment of the quality of life before, during and after treatment |
Indépendamment pour chaque stratégie de traitement : évaluation de l’activité antitumorale en termes de :
o Réponse biochimique (PSA ≤ 0.1 ng/ml) mesurée :
- A la fin du traitement par Darolutamide ou à la suppression androgénique,
- 2 mois après la randomisation,
- 3, 6 et 9 mois après la radiothérapie,
- 2,3 et 5 ans après la randomisation.
o Survie sans progression biochimique,
o Survie sans métastases,
o Survie sans maladie,
o Survie spécifique au cancer de la prostate,
o Survie globale,
o Temps de récupération de la testostérone.
• Indépendamment pour chaque stratégie de traitement : évaluation du profil de toxicité de la stratégie thérapeutique, évaluation de la qualité de vie avant, pendant et après traitement |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18,
2. Histological diagnosis of prostate malignancy
3. Cancer without loco-regional or distant metastasis (tumor assessment must comprise at least Pelvic MRI AND thoraco-abdomino-pelvic contrast-enhanced CT-Scan AND Bone Scintigraphy. (Note that additional assessment by PET-Scan is allowed as per investigator judgement),
4. Unfavorable intermediate risk prostate cancer diagnosis defined by the NCCN Guidelines.
One of the following criteria is sufficient to define an unfavorable intermediate risk prostate cancer:
- Gleason = 7 (4+3)
- ≥ 50% of thecore of biopsies need to be positive for adenocarcinoma
If these criteria are not being identified, two or three of the following criteria are necessary to define unfavorable intermediate risk prostate cancer:
- PSA value between 10-20 ng/ml
- Gleason 7 (3+4) or 6
- T2b (clinical or radiological)
Note: patients with iT3a (extraprostatic extension) can be included only if gleason score is 6 and PSA less than 20 [22].
5. Patients newly diagnosed with an unfavorable intermediate risk prostate cancer according to the protocol criteria or previously diagnosed with low risk (Gleason score < 6, clinical stage < T2a, and PSA< 10) prostate cancer progressing to eligible risk disease according to the protocol criteria within 30 days before registration
6. Patients must have a life expectancy of at least 5 years,
7. Performance status ECOG ≤ 2,
8. Patients without contra-indications to EBRT as per physician judgement,
9. Patients with adequate organ function defined by all the following laboratory values (< ULN (Upper Limit of Normal)) :
a) Hemoglobin ≥ 9 g/dL,
b) Neutrophils ≥ 1.5 G/L
c) Platelets ≥ 80 G/L
d) Total bilirubin < 2X ULN
e) AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
f) Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula).
10. Available archived paraffin-embedded tumor sample for research purpose,
11. Patients with a social security in compliance with the french law,
12. Voluntary signed and dated written informed consent prior to any study specific procedure,
13. Men must agree to use an effective method of contraception throughout the treatment period and for one week after discontinuation of treatment. |
|
| E.4 | Principal exclusion criteria |
1. Stage T3b-T4 prostate cancer by clinical examination or radiologic evaluation,
2. Patients with Gleason score ≥8,
3. Patients with PSA > 20 ng/ml,
4. Presence of loco-regional or distant metastasis (MRI/CT-Scan and Bone Scintigraphy),
5. Contra-indications to MRI and to contrast-enhanced CT-scan,
6. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone less than 50 ng/dL or below the normal range for the institution.
7. Previous prostate cancer treated by androgen deprivation, chemotherapy, surgery, or radiotherapy,
8. Patients with previous orchiectomy
9. Patients actively receiving or having received within 6 months prior enrollment any concurrent androgens, anti-androgens, estrogens, or progestational agents,
10. Patients having received ketoconazole, finasteride or dutasteride within 30 days of inclusion,
11. Previous and current malignancies other than prostate cancer within the last 5 years with the exception of adequately treated basal cell or squamous cell carcinoma of the skin, acute lymphoblastic leukemia, non-muscle invasive bladder cancer,
12. Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection),
13. History of cerebrovascular accident (within the last 6 months)
14. Impaired cardiac function including any one of the following:
a) Clinically documented myocardial infarction (within the last 6 months)
b) History of severe/unstable angina (within the last 6 months)
c) History of peripheral artery/coronary bypass surgery (within the last 6 months)
d) History of or presence of congestive heart failure according to the New York Heart Association (NYHA) class 3 or 4 with LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram or multi-gated acquisition scan performed in the last 6 months
e) History of or prensece of risk factors for QT interval prolongation
f) History of or presence of clinically significant ventricular or atrial tachy-arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
g) Clinically significant resting bradycardia (< 50 beats per minute)
h) History of Mobitz II second degree or third degree heart block without use of ventricular-paced pacemaker
i) History of or presence of clinically significant hypotension (e.g. systolic blood pressure < 86 mmHg on 2 consecutive measurements)
j) ECG demonstrating equal to or greater than grade III toxicity according the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
15. Uncontrolled hypertension
16. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery),
17. Major surgery within 4 weeks prior enrolment except pelvic lymph-nodes dissection (extended or limited),
18. Known hypersensitivity to any involved study drug or of its formulation components, to natural gonadotrophin releasing hormone (GnRH) or its analogues
19. Galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome
20. Men who are not using an effective method of contraception as previously described
21. Use of herbal or alternative remedies that may affect hormonal status such as Prostasol or PC-SPES,
22. History of non-compliance to medical regimens or inability to grant consent,
23. Patient unable to follow and comply with the study procedures because of any geographical, social or psychpsychological reasons,
24. Individuals under judicial protection or deprived of liberty.
25. Inability to swallow or to give subcutaneous or intramuscular injections.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy will be assessed in terms of biological response defined as a PSA concentration ≤0.1ng/ml at 6 months post-randomization |
| L’activité anti tumorale sera mesurée en termes de réponse biologique définie par un taux de PSA ≤ 0.1 ng/ml évalué 6 mois après la randomisation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Biochemical response at 6 months post-randomization will be reported. |
| la réponse biologique à 6 mois post-randomisation sera reportée |
|
| E.5.2 | Secondary end point(s) |
1. Biochemical disease progression is defined asa PSA level higher than PSA nadir + 2 ng/mL according to Phoenix’s criteria.
2. Biochemical progression-free survival is defined as the delay between the date of randomization and the date of biochemical disease progression or death, whichever comes first. Median bPFS, as well as 2-, 3-, and 5-year bPFS will be reported.
3. Metastasis Free Survival is defined as the delay between the date of randomization and the date of metastasis diagnosis (imaging and/or biopsy). Median MFS, as well as 2-, 3- and 5-year MFS will be reported.
4. Disease Free Survival (DFS) is defined as the delay between randomization and the first of the following events:
o biological PSA progression defined as level higher than PSA nadir + 2 ng/mL according to Phoenix’s criteria
o progression (local, regional, distant)
o death (any cause).
Median DFS, as well as 2-, 3- and 5-year DFS will be reported.
5. Prostate cancer-specific Survival (PCSS) is defined as the delay between the date of randomization and the date of prostate cancer-related death. Median PCSS, as well as 2-, 3- and 5-year PCSS will be reported.
6. Overall survival is defined as the delay between the date of randomization and the date of death (all cause). Median OS, as well as 2-, 3- and 5-year OS will be reported.
7. Time to testosterone recovery defined as the time from randomization to the time when serum of total testosterone level increases to above the lower limit of the normal range.
8. The safety profile (acute, i.e. < 3 months and late 2-, 3- and 5-year) of each treatment strategy will be graded using NCI CTCAE v5. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
9. Quality of life will be assessed as follows (M0, M3, M6, M12, M24, M60):
oAs per the EORTC QLQ-C30 questionnaire and prostate cancer module PR-25
oAssessment of erectile dysfunction, as per IIEF5
oAssessement of symptoms of benign prostatic hyperplasia as per IPSS questionnaire |
•La progression biochimique de la maladie est définie par une concentration de PSA supérieure au nadir de PSA + 2 ng/mL, tel que définie par les critères de Phoenix.
•La survie sans progression biochimique (bPFS) est définie par le délai entre la date de randomisation et le premier des évènements suivants : date de progression biochimique de la maladie ou décès. La bPFS médiane, ainsi que les taux de bPFS à 2, 3 et 5 ans seront rapportés.
• La survie sans métastase (MFS) est définie par le délai entre la date de randomisation et la date de diagnostic de la métastase (imagerie et/ou biopsie). La MFS médiane, ainsi que les taux de MFS à 2, 3 et 5 ans seront rapportés.
• La survie sans maladie (DFS) est définie par le délai entre la randomisation et le premier des événements suivants :
o Progression biologique selon les critères de Phoenix
o Progression (locale, régionale, distante),
o décès (toute cause).
La SSM médiane, ainsi que les taux de SSM à 2, 3 et 5 ans seront rapportés.
• La survie spécifique au cancer de la prostate (PCSS) est définie par le délai entre la date de randomisation et la date de décès lié au cancer de la prostate. La PCSS médiane, ainsi que les taux de PCSS à 2, 3 et 5 ans seront rapportés.
• La survie globale (OS) est définie par le délai entre la date de randomisation et la date de décès (toutes causes). La SG médiane, ainsi que les taux d’OS à 2, 3 et 5 ans seront rapportés.
• Le temps de récupération de la testostérone est défini par le délai entre la date de randomisation et le moment où le taux sérique total de testostérone augmente au-dessus de la limite inférieure de la valeur normale.
• Le profil de toxicité (aigüe, c'est-à-dire < 3 mois et tardive à 2, 3 et 5 ans) de chaque stratégie de traitement sera évalué à l'aide de la classification du NCI CTCAE v5. Les EI et SAE seront codés selon la terminologie médicale normalisée MedDRA.
• La qualité de vie sera évaluée (M0, M2, M6, M12, M24, M60) :
o Selon le questionnaire EORTC QLQ-C30 et le module PR-25 spécifique au cancer de la prostate
o Évaluation de la dysfonction érectile, selon l’IIEF5,
o Évaluation des symptômes de l'hyperplasie bénigne de la prostate selon le questionnaire IPSS.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The biochemical disease progression will be assessed across the study period.
2. Median biochemical progression-free survival, as well as 2-, 3-, and 5-year bPFS will be reported.
3. Median metastasis Free Survival and 2-, 3- and 5-year MFS will be reported
4. Median disease Free Survival (DFS) 2-, 3- and 5-year DFS will be reported
5. Median prostate cancer-specific Survival (PCSS) 2-, 3- and 5-year PCSS will be reported
6. Median Overall survival as well as 2-, 3- and 5-year OS will be reported.
7. Time to testosterone recovery will be reported once all the data for the patient is known.
8. Safety will be assessed across the treatment period
9. Quality of life will be assessed at M0, M3, M6, M12, M24 and M60 |
|
| 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 |
| quality of life |
| qualité de vie |
|
| 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 |
| combinaison de la radiothérapie externe conformationnelle avec suppression androgénique courte (6 mo |
| combination of external beam radiotherapy (EBRT) and 6 months ADT (androgen deprivation therapy) |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
| LVLS |
| Dernière visite du dernier patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 84 |
| E.8.9.1 | In the Member State concerned days | |
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