| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Localised prostate cancer at high risk of recurrence |
|
| E.1.1.1 | Medical condition in easily understood language |
| Localised prostate cancer at high risk of recurrence |
|
| 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 determine effects on:
1) Metastasis-free survival (metastasis or death from any cause, MFS) |
|
| E.2.2 | Secondary objectives of the trial |
To determine effects on:
2) Overall survival (death from any cause, OS)
3) Prostate cancer specific survival (death from prostate cancer)
4) PSA progression-free survival (Phoenix criteria, or death from any cause, PSA-PFS)
5) Clinical progression-free survival (imaging, symptoms, signs, initiation of other anti-cancer treatment, or death from any cause, clinical-PFS)
6) Time to subsequent hormonal therapy (restarting ADT)
7) Time to castration-resistant disease (PCWG2 criteria)
8) Safety (adverse events - CTCAE v4.03)
9) Health related quality of life (EORTC QLQC-30 & PR-25, EQ-5D-5L)
10) Health outcomes relative to costs (incremental cost effectiveness ratio) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) To identify biomarkers that are prognostic and/or predictive of
response to treatment, safety and resistance to study treatment
(associations of biomarkers with clinical outcomes). |
|
| E.3 | Principal inclusion criteria |
1. Pathological diagnosis of adenocarcinoma of the prostate, judged to be at high risk for recurrence based on any of the following (in accordance with the ISUP Consensus 2005 (13) see Appendix 3):
Gleason score 8-10
OR
Gleason score of 4+3 AND clinical T2b-4 AND PSA >20ng/mL OR
N1 disease (involvement of lymph nodes at or below the bifurcation of the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or biopsy proven
2. Age ≥18 yrs
3. Adequate bone marrow function Hb ≥100g/L and WCC ≥ 4.0 x 109/L and platelets ≥100 x 109/L
4. Adequate liver function: ALT < 2 x ULN and bilirubin < 1.5 x ULN, (or if bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin).
5. Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockroft-Gault)
6. ECOG performance status of 0-1
7. Study treatment both planned and able to start within 7 days of randomisation.
8. Willing and able to comply with all study requirements, including treatment, and attending required assessments
9. Has completed the baseline HRQOL questionnaires UNLESS is unable to complete because of literacy or limited vision
10. Signed, written, informed consent
|
|
| E.4 | Principal exclusion criteria |
1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
2. Involvement of lymph nodes superior to the common iliac bifurcation, and/or outside the pelvis (distant lymph nodes). Lymph node involvement is defined by histopathological confirmation, or by a short axis measurement >10mm on standard imaging (CT or MRI, but not PET).
3. Any contraindication to external beam radiotherapy
4. History of
a. seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma).
b. loss of consciousness or transient ischemic attack within 12 months of randomization
c. significant cardiovascular disease within the last 3 months:
including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater, see Appendix 4), ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.03) , thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
5. Evidence of metastatic disease: minimum imaging required is a CT and/or MRI of the abdomen and pelvis, and a whole body bone scan (WBBS). If equivocal bone scan, follow-up plain films are required to show NO evidence of cancer if not covered by CT/MRI
6. PSA > 100 ng/mL
7. History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours).
8. Concurrent illness, including severe infection that might jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
a. HIV-infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant enzalutamide.
9. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
10. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.
11. Use of hormonal therapy or androgen deprivation therapy, including enzalutamide, except in the following setting:
a. Use of LHRHA (with or without anti-androgens) for less than 30 days prior to randomisation in the trial.
12. Bilateral orchidectomy or radical prostatectomy
13. Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields
14. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.
15. Major surgery within 21 days prior to randomisation
16. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of enzalutamide, including difficulty swallowing tablets
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine effects on:
1) Metastasis-free survival (metastasis or death from any cause, MFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assuming the study is not terminated early, the final analysis is planned to be undertaken after the required number of MFS events have occurred. |
|
| E.5.2 | Secondary end point(s) |
To determine effects on:
2) Overall survival (death from any cause, OS)
3) Prostate cancer-specific survival (death from prostate cancer)
4) PSA progression-free survival (Phoenix criteria or death from any cause, PSA-PFS)
5) Clinical progression-free survival (imaging, symptoms, signs, initiation of other anti-cancer treatment, or death from any cause, clinical-PFS)
6) Time to subsequent hormonal therapy (restarting ADT)
7) Time to castration-resistant disease (PCWG2 criteria)
8) Safety (adverse events - CTCAE v4.03)
9) Health related quality of life (EORTC QLQC-30, PR-25 & EQ-5D-5L)
10) Health outcomes relative to costs (incremental cost effectiveness ratio) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assuming the study is not terminated early, the final analysis is planned to be undertaken after the required number of MFS events have occurred. |
|
| 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 | 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 | 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) | 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
| 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 | 34 |
| 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 |
| Australia |
| New Zealand |
| United States |
| Austria |
| Belgium |
| Ireland |
| Italy |
| Slovenia |
| Spain |
| 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 protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. 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 | 7 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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