| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| oligometastatic hormone sensitive prostate cancer |
| cancer de la prostate oligométastatique, hormonosensible |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic prostate cancer |
| cancer de la prostate métastatique |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| 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 | 10007463 |
| E.1.2 | Term | Carcinoma prostatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Two-years Progression-free survival. |
| Survie sans progression à 2 ans |
|
| E.2.2 | Secondary objectives of the trial |
a) Quality of life scoring using the EORTC QLQ-C30 supplemented with QLQ-PR25 and pain with BPI + EVA.
b) Androgen deprivation therapy free survival : ADT will be started in both arms at time of polymetastatic disease, local progression of metastases (defined above) or symptoms. In case of a metachronous oligometastatic recurrence, a retreatment with radiotherapy or surgery is allowed. Calculation will start from randomization until ADT is started.
c) Prostate cancer specific survival will be calculated from randomization until Prostate cancer death.
d) Overall survival will be calculated from randomization until death from any cause.
e) Time to first symptomatic event will be calculated from randomization until the event of symptoms due to metastatic disease.
f) Acute and late toxicity due to radiotherapy will be scored using the Common toxicity criteria version 4.0.
g) Sphingolipids measurements
h) Immune response monitoring
|
a) Qualité de vie et douleur
b) Survie sans traitement anti-andogénique
c) Survie spécifique au cancer de la prostate
d) Survie globale
e) Temps jusqu’aux premiers symptomes
f) Toxicité aigue et tardive liée à la radiothérapie
g) Dosage des sphingolipides
h) Monitoring de la réponse immunitaire
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
2. Age > or = 18 years at time of study entry
3. Histologically proven diagnosis of prostate cancer (PCa)
4. PCa patients with a biochemical recurrence
following treatment with curative intent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines.
5. A maximum of 5 bone or lymphnode metastases diagnosed on FCH or Ga-PSMA PET CT.
6. WHO performance state 0-1
7. Controlled primary tumor.
8. If ADT has been previously administered to the patient, a minimum of 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study. For this category of patients, serum testosterone has to be higher than 6 nmol/l prior to inclusion.
9. Adequate normal organ and marrow function as defined [in protocol]
10. Body weight > 30kg
11. Life expectancy of > 24 months
|
1. Consentement éclairé signé avant toute procédure liée au protocole, y compris les évaluations de dépistage
2. Âge > ou = 18 ans au moment de la randomisation
3. Diagnostic histologiquement prouvé du cancer de la prostate
4. Patients présentant une récidive biochimique de leur cancer de la prostate, après un traitement à visée curative (prostatectomie radicale, radiothérapie primaire ou une combinaison des deux) selon les recommandations de l'EAU.
5. Maximum 5 métastases osseuses ou ganglions lymphatiques, diagnostiqués à l'aide d'un scanner TEP FCH ou TEP Ga-PSMA.
6. OMS 0-1
7. Tumeur primaire contrôlée.
8. Si un traitement anti-androgénique a déjà été administré au patient, un minimum de 12 mois doit s'être écoulé entre la durée prévue de la dernière injection et l'inclusion du patient dans l'étude. Pour cette catégorie de patients, la testostérone sérique doit être supérieure à 6 nmol / l avant l'inclusion.
9. Fonction normale appropriée d'organe et de moelle comme définie [au protocole]
10. Poids > 30 kg
11. Espérance de vie > 24 mois.
|
|
| E.4 | Principal exclusion criteria |
1. Serum testosterone level < 50 ng/ml
2. Vertebral metastases with a minimum distance inferior to 5 mm between GTV and spinal cord
3. Spinal cord compression
4. Any unresolved toxicity NCI CTCAE (v4.03) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
5. PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, oestrogen)
6. Lung, Brain, Liver or other visceral metastases
7. Relapsed primary tumor
8. Perihilar lymphnode metastases
9. Previous irradiation of the oligometastatic site using a dose > 20 Gy less than 5 years ago.
10. Previous treatment with a cytotoxic agent for PCa
11. Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids...)
13. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
14. Any prior immune therapy (CTLA-4, PD1 or PD-L1 inhibitor, including durvalumab)
15. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
16. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
17. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Durvalumab.
19. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
Patients with vitiligo or alopecia
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included but only after consultation with the study physician
Patients with celiac disease controlled by diet alone
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement
21. History of another primary malignancy except for
Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
22. History of leptomeningeal carcinomatosis
23. History of active primary immunodeficiency
24. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
25. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
26. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
27. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
28. Male patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period |
1. Taux de testostérone sérique <50 ng / ml
2. Métastases vertébrales avec une distance minimale inférieure à 5 mm entre GTV et la moelle épinière
3. Compression de la moelle épinière
4. Toute toxicité non résolue NCI CTCAE (v4.03) Grade > ou = 2 d'un traitement anticancéreux antérieur, à l'exception de l'alopécie, du vitiligo et des valeurs de laboratoire définies dans les critères d'inclusion
5. Augmentation du PSA survenu au cours d’un traitement actif (agoniste de la LHRH, antagoniste de la LHRH, anti-androgène, blocage maximal des androgènes, œstrogène)
6. Métastases au poumon, cerveau, foie ou autres métastases viscérales
7. Tumeur primaire récidivante
8. Métastases ganglionnaires périhilaires
9. Irradiation antérieure du site oligométastatique en utilisant une dose > 20 Gy au cours des 5 dernières années.
10. Traitement antérieur avec un agent cytotoxique pour le cancer de la prostate
11. Traitement au cours du mois passé avec des produits connus pour influer sur le taux de PSA (par exemple le fluconazole, le finastéride, les corticostéroïdes ...)
12. Participation à une autre étude clinique avec un produit expérimental au cours des 4 dernières semaines
14. Toute immunothérapie antérieure (inhibiteur de CTLA-4, PD1 ou PD-L1, incluant le durvalumab
15. Utilisation actuelle de médicaments immunosuppresseurs, ou dans les 14 jours avant la première dose de durvalumab, à l'exception des corticostéroïdes intranasaux et inhalés ou des corticostéroïdes systémiques à doses physiologiques qui ne doivent pas être administrés dépasser 10 mg / jour de prednisone ou un corticostéroïde équivalent.
16. Traitement par radiothérapie à plus de 30% de la moelle osseuse ou avec un large champ de radiation dans les 4 semaines suivant la première dose du médicament à l'étude
17. Intervention chirurgicale majeure (telle que définie par l'investigateur) dans les 28 jours précédant la première dose de Durvalumab.
19. Troubles auto-immuns ou inflammatoires documentés, actifs ou antérieurs (y compris maladie intestinale inflammatoire [par exemple colite ou maladie de Crohn], diverticulite [à l'exception de diverticulose], lupus érythémateux disséminé, syndrome de Sarcoïdose ou syndrome de Wegener [granulomatose avec polyangéite, Graves ' maladie, polyarthrite rhumatoïde
20. Maladie intercurrente incontrôlée, notamment une infection continue ou active, insuffisance cardiaque congestive symptomatique, hypertension incontrôlée, angine de poitrine instable, arythmie cardiaque, maladie pulmonaire interstitielle, troubles gastro-intestinaux chroniques graves associés à la diarrhée, ou maladie psychiatrique
21. Antécédents d' autre affection maligne primaire
22. Antécédents de carcinomatose leptoméningée
23. Antécédents d'immunodéficience primaire active
24. Infection active, y compris la tuberculose
29. Hommes potentiellement fertiles qui ne sont pas disposés à utiliser un moyen contraceptif efficace jusqu’à 90 jours après la dernière dose de durvalumab. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression : Two types of progression are defined and definitions of progression are used and registered according to the recommendations of the prostate cancer clinical trials working group.
- PSA or biochemical progression
- local progression : response with the iRECIST criteria
- distant recurrences
If a patient meets any of the progression criteria or death from any causes, the patient will be considered to have progressive disease.
Calculation will start from randomization until progression or death.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Quality of life and pain: QLQ-C30 + QLQ-PR25 + BPI + EVA.
b) Survival without anti-androgen therapy: ADT will be started in both arms at the time of polymetastatic disease, local progression of metastases (defined above) or symptoms. In the case of metachronic oligometastatic recurrence, radiotherapy or surgery may be reprocessed. The calculation will start from the inclusion randomization until the ADT is started.
c) Prostate cancer-specific survival: calculated from inclusion randomization to death by prostate cancer.
d) Overall survival: calculated from randomization to death of any cause
e) Time to first symptoms: calculated from the inclusion of randomization until the onset of symptoms due to metastatic disease.
f) Acute and late toxicity related to radiotherapy: CTC AE version 4.03
g) Determination of sphingolipids
h) Monitoring the immune response |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| see above for each 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| radiothérapie stéréotaxique seule |
| single Stereotactic Body Radiation Therapy (SBRT) |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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