| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer that started in the prostate and has spread to other parts of the body |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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) Overall survival (death from any cause)
|
|
| E.2.2 | Secondary objectives of the trial |
To determine effects on:
2) Prostate specific antigen progression free survival (PCGW2)
3) Clinical progression free survival (imaging, symptoms, signs)
4) Adverse events (CTCAE v4.03)
5) Health related quality of life (EORTC QLQ C-30, PR-25 and EQ-5D-5L)
6) 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 |
| 7) 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). Version 1, 11 Nov 2013 |
|
| E.3 | Principal inclusion criteria |
1. Male aged 18 or older with metastatic adenocarcinoma of the prostate defined by
Documented histopathology or cytopathology of prostate adenocarcinoma from a biopsy of a metastatic site
OR
Documented histopathology of prostate adenocarcinoma from a TRUS biopsy, radical prostatectomy, or TURP and metastatic disease consistent with prostate cancer.
OR
Metastatic disease typical of prostate cancer (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA that is rising and >20ng/mL
2. Target or non-target lesions according to RECIST 1.1
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 1.5-2x ULN, they must have a normal conjugated bilirubin). If liver metastases are present ALT must be < 5xULN
5. Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockroft-Gault, See Appendix 7)
6. ECOG performance status of 0-2. Patients with performance status 2 are only eligible if the decline in performance status is due to metastatic prostate cancer.
7. Study treatment both planned and able to start within 7 days after randomisation.
8. Willing and able to comply with all study requirements, including treatment and required assessments
9. Has completed baseline HRQL questionnaires UNLESS is unable to complete because of limited literacy or 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. 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 functional capacity class II or greater, Refer to Appendix 6), 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.
3. Life expectancy of less than 12 months.
4. History of another malignancy within 5 years prior to randomisation, except for either non-melanomatous carcinoma of the skin or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta and low grade T1 tumours).
5. 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.
6. 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;
7. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.
8. Prior ADT for prostate cancer (including bilateral orchidectomy), except in the following settings:
a. Started less than 12 weeks prior to randomisation AND PSA is stable or falling. The 12 weeks starts from whichever of the following occurs earliest: first dose of oral anti-androgen, LHRHA, or surgical castration.
b. In the adjuvant setting, where the completion of adjuvant hormonal therapy was more than 12 months prior to randomisation AND the total duration of hormonal treatment did not exceed 24 months. For depot preparations, hormonal therapy is deemed to have started with the first dose and to have been completed when the next dose would otherwise have been due, e.g. 12 weeks after the last dose of depot goserelin 10.8mg.
9. Prior cytotoxic chemotherapy for prostate cancer, but up to 2 cycles of docetaxel chemotherapy for metastatic disease is permitted as per section 5.3.2.4 is allowed.
10. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine effects on:
1) Overall survival (death from any cause)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Versions 1 and 2 of the ENZAMET protocol specified an interim analysis on OS would be performed at 67% of the required events (i.e. 470 deaths, see Section 11.1). Following simultaneous publication in June 2017 of two randomized controlled trials, LATITUDE24 and STAMPEDE25, the ENZAMET Trial Management Committee decided to add two extra interim analyses at 50% and 80% of required events. No interim efficacy data from ENZAMET was considered or used to reach this decision. The Lan-DeMets O’Brien-Fleming spending function approach will be used, and remains the appropriate technique for evaluating these analysis results
Interim analyses will be conducted at 50%, 67%, and 80% of the required events. |
|
| E.5.2 | Secondary end point(s) |
To determine effects on:
2) Prostate specific antigen progression free survival (PCGW2)
3) Clinical progression free survival (imaging, symptoms, signs)
4) Adverse events (CTCAE v4.03)
5) Health related quality of life (EORTC QLQ C-30, PR-25 and EQ-5D-5L)
6) Health outcomes relative to costs (incremental cost effectiveness ratio)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Versions 1 and 2 of the ENZAMET protocol specified an interim analysis on OS would be performed at 67% of the required events (i.e. 470 deaths, see Section 11.1). Following simultaneous publication in June 2017 of two randomized controlled trials, LATITUDE24 and STAMPEDE25, the ENZAMET Trial Management Committee decided to add two extra interim analyses at 50% and 80% of required events. No interim efficacy data from ENZAMET was considered or used to reach this decision. The Lan-DeMets O’Brien-Fleming spending function approach will be used, and remains the appropriate technique for evaluating these analysis results
Interim analyses will be conducted at 50%, 67%, and 80% of the required events. |
|
| 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
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| New Zealand |
| Australia |
| Canada |
| United Kingdom |
| United States |
| Ireland |
|
| 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 trial when required number of deaths have occurred = 470 deaths. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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