E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
very high risk localized or locally advanced prostate cancer |
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E.1.1.1 | Medical condition in easily understood language |
very high risk localized or locally advanced prostate cancer |
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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 assess if GnRH antagonists improve progression free survival (progression that can be biological, clinical, or death) compared to GnRH agonists in combination with external beam radiation therapy in patients with high-risk localized or locally-advanced cancer who receive this treatment after initial radical prostatectomy or as primary therapy
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E.2.2 | Secondary objectives of the trial |
- documentation of effect of GnRH antagonists on clinically significant cardiovascular events in the subgroup of patients at high risk of such events at baseline; - documentation of side effects and quality of life, I-PSS and urinary tract infections; - assessment of relative treatment effect on secondary efficacy endpoints (clinical progression, time to next systemic therapy, time on therapy, overall and cancer specific survival) and on PSA at 6 months after end of RT |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients may enter the trial once in either of two clinical settings where a combination therapy involving irradiation combined with androgen deprivation therapy is envisaged: a) patients who are scheduled for primary treatment by irradiation combined with minimum 18 months of androgen deprivation therapy or b) patients who were operated within the EORTC SPECTA 1553 study and who are scheduled to receive adjuvant or early salvage irradiation.
Entry criteria for patients planned for primary radiotherapy: ♦ Histologically confirmed diagnosis of prostate adenocarcinoma diagnosed on a systematic ultrasound guided biopsy of the prostate containing at least 8 cores. An MRI-fusion biopsy is allowed if taken because a previous biopsy was negative. A TURP specimen pathology is allowed. Two of the following 4 risk factors for relapse: ♦ PSA ≥20 ng/ml, ♦ Gleason sum ≥8, ♦ cN1 (regional LN with a short axis length >10mm by CT scan or MRI) or pathologically confirmed lymph nodes (pN1), ♦ cT3-T4 (by MRI or core biopsy) (ie. If PSA≥20 ng/ml then only one of the other 3 risk factors is needed) Entry criteria for patients previously enrolled in EORTC SPECTA 1553, treated by radical prostatectomy: ♦ Radical prostatectomy in EORTC SPECTA 1553performed within 1 year ♦ Scheduled to receive irradiation combined with 6 months of androgen deprivation therapy in the following cases: ♦ In the adjuvant setting with PSA ≥ 0.1 ng/mL at 12 weeks post-surgery and/or ≥ 2 pathologically confirmed positive nodes after radical prostatectomy ♦ For a biochemical recurrence (BCR) ≤ 1 year after radical prostatectomy (defined as per guidelines as two consecutive rising serum PSA values greater than or equal to 0.2 ng/mL) Entry criteria for all patients Either of ♦M0 according to standard imaging methods (i.e. bone scan and conventional CT/MR image) or M0 according to modern imaging methods (i.e. whole-body MRI, PET/CT) ♦ M0 according to bone scan and conventional CT/MR image and M1a and M1b only with ≤ 3 lesions detected by modern imaging methods are also allowed, called "Oligometastatic disease". Patients with oligometastatic disease will undergo metastasis targeted therapy Testosterone ≥ 200 ng/dL ♦ Adequate bone marrow function (absolute neutrophil count (ANC) 1.5 109/L; hemoglobin ≥ 10.0 g/dl; platelets 100 109/L) ♦ Adequate hepatic function: Bilirubin: total bilirubin 1.5 upper limit of normal (ULN). AST and/or ALT ≤ 2.5 ULN. ♦ Adequate renal function: calculated creatinine clearance ≥ 50 mL/min ♦ Magnesium and potassium within normal limits of at the institution ♦ WHO Performance status 0-1 ♦ Age ≥ 18 and ≤ 80 years ♦ Participants who have partners of childbearing potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after 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 ♦ Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
♦ M1c, confirmed by any imaging method or biopsy ♦ Previous use of androgen deprivation therapy, antiandrogens if not interrupted for more than 6 months prior to entering the study ♦ History of severe untreated asthma, anaphylactic reactions or severe urticaria and/or angiodema. ♦ Hypersensitivity towards any of the active substances, the excipients used and synthetic GnRH or GnRH derivatives ♦ No severe hepatic impairment (Child Pugh C) ♦ Uncontrolled diabetes mellitus ♦ Coronary revascularization (PCI or multivessel CABG), carotid artery or iliofemoral artery revascularizaton (percutaneous or surgical procedure) within the last 30 days prior to entering the trial ♦ Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (eg, heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval >450 ms ♦ Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin), or the patient has been free of malignancy for a period of 3 years prior to first dose of study drug(s). Prior history of bladder cancer (except appropriately treated Tis or T1a) excludes the patient ♦ Any contraindication to external beam radiotherapy ♦ Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition which, in the opinion of the investigator, would preclude participation in this trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
progression-free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
progression-free survival defined as the time in days from randomization to death, clinical or biochemical progression (Phoenix definition, whichever comes first (see chapter 7.2)) |
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E.5.2 | Secondary end point(s) |
1. Clinical progression-free survival 2. Time to next systemic anticancer therapy 3. Time to next systemic anticancer therapy other than ADT 4.Proportion of patients switching from GnRH antagonists to GnRH agonists and total effective duration of treatment with the originally allocated drug. 5. Overall survival 6. Prostate Cancer specific survival 7. PSA 6. The incidence of clinical cardiovascular events – CCE (i.e. arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease) in patients who had cardiovascular events before entering the trial and in those without such events. 9. The incidence of urinary tract infection 10. Patient reported outcomes - International Prostate Symptoms Score (I-PSS) (urinary symptoms) - Quality of Life (HRQoL) measured with EORTC QLQ-C30 and PR25 instruments with the overall health related quality of life scale as primary scale - EQ-5L (to enable a future health economics analysis) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.time from randomization (RD) to the first event among: death, clinical progression or the start of another line of systemic anti-neoplastic therapy 2.interval of time between RD and first day of initiation of a next line of systemic anti-neoplastic therapy 3. time between RD and the first event of -initiation of any new anti-neoplastic therapy other than ADT -or death due to PCa 4.at switch time 5.from RD to death dates 6. PCa-specific survival will be measured from the date RD to the date of death related to prostate cancer. 7. at 6 months after completion of RT 8. from the day of RD to the first documentation of CCE or death 9. from the RD to the first documentation of urinary tract infection 10. at baseline and duration FU for all patients in the study. |
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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 | No |
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 | Yes |
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) | 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 | 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) | Yes |
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
| 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 |
Germany |
Italy |
Spain |
Switzerland |
United Kingdom |
France |
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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
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End of study occurs when all of the following criteria have been satisfied: 1. Thirty days after all patients have stopped all protocol treatment and protocol specific interventions 2. The trial is mature for the analysis of the primary endpoint as defined in the present protocol (see section 8.1) 3. The database has been fully cleaned and locked for this analysis |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |