| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| very high risk localized or locally advanced 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) |
|
| 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
|
|
| 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 line of systemic therapy, time on therapy, overall and cancer specific survival) and on PSA at 6 months after end of RT |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
♦ 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. PSA ≥ 10 ng/ml and 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) (see Appendix H),
♦ cT3-T4 (by MRI or core biopsy)
(ie. If PSA≥20 ng/ml then only one of the other 3 risk factors is needed)
♦ M0 by standard imaging work-up (see chapter 6 for specification of standard work-up)
♦ Testosterone ≥ 200 ng/dl
♦ Adequate renal function: calculated creatinine clearance ≥ 50 mL/min (Appendix D)
♦ Magnesium and potassium within normal limits of the institution or corrected to within normal limits prior to the first dose of treatment.
♦ Patients with prolonged QT-intervals due to prescribed Class IA (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmic medication must be carefully evaluated for GnRH-agonist or GnRH antagonist use, because these drugs may prolong the QT-interval.
♦ Clinically normal cardiac function for-left ventricular ejection fraction (≥ 50%) as assessed either by multi-gated acquisition scan or cardiac ultrasound, triplicate 12 lead ECG without clinically relevant abnormalities. WHO Performance status 0-1 (see Appendix C)
♦ Age ≥ 18 years 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. |
|
| E.4 | Principal exclusion criteria |
♦ Previous use of androgen deprivation therapy, antiandrogens. 5-alpha reductase inhibitors are allowed if 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 the investigational drug
♦ The following biological parameters :AST, ALT, total bilirubin, prothrombin time, serum albumin above upper level of normal range No severe hepatic impairment (Child Pugh C)
♦ History of gastro-intestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the protocol treatment.
♦ History of pituitary or adrenal dysfunction
♦ Uncontrolled diabetes mellitus
♦ History of ulcerative colitis, Crohn's Disease, ataxia, telangiectasia, systemic lupus erythematosus, or Fanconi anemia.
♦ Clinically significant heart disease as evidence myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50 % at baseline
♦ 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 at baseline, or intake of medications that prolong the QT/QTc interval
♦ Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
♦ 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 excludes the patient
♦ Prior radical prostatectomy (TURP or suprapubic adenomectomy for benign prostatic hyperplasia is allowed)
♦ 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression-free survival |
|
| 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)) |
|
| E.5.2 | Secondary end point(s) |
1. Clinical progression-free survival
2. Time to next systemic anticancer therapy (including secondary hormonal manipulation)
3. Proportion of patients switching from GnRH antagonists to GnRH agonists and total effective duration of treatment with the originally allocated drug.
4. Overall survival
5. Prostate Cancer specific survival
6. PSA
7. 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.
8. The incidence of urinary tract infection
9. 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. at the time in days from randomization to the first event among: death, a clinical progression or the start of another line of systemic anti-neoplastic therapy
2. interval of time between randomization and the first day of initiation of a next line of systemic anti-neoplastic therapy
3. at switch time
4. from the date of randomization to the date of death
5. Prostate cancer-specific survival will be measured from the date of randomization to the date of death related to prostate cancer.
6. at six months after completion of RT
7. from the day of randomization to the first documentation of CCE or death
8. from the day of randomization to the first documentation of urinary tract infection
9. at baseline and duration follow-up for all patients in the study. |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Austria |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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. 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 8.1)
3. The database has been fully cleaned and locked for this analysis |
|
| 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 |
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