| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with high-risk nonmetastatic prostate cancer progressing after definitive therapy (radical prostatectomy or radiotherapy or both). |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.0 |
| 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 evaluate efficacy, as measured by metastasis-free survival (MFS) |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate efficacy, as measured by the following:
– Key protected secondary endpoints:
* Overall survival
* Proportion of patients per group who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable prostate-specific antigen (PSA)
* Time to castration resistance
– Proportion of patients per group with undetectable PSA 2 years after suspension of study drug treatment at week 37 due to undetectable PSA
– Proportion of patients per group with undetectable PSA at 36 weeks on study drug
– Prostate cancer-specific survival
– Time to resumption of any hormonal therapy following suspension at week 37 due to undetectable PSA
– Time to first symptomatic skeletal event
– Time to metastasis
– Time to clinically relevant pain
– Quality of life
● To evaluate safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18 years or older and willing and able to provide informed consent.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate at initial biopsy, without neuroendocrine differentiation, signet cell, or small cell features.
3. Prostate cancer initially treated by radical prostatectomy or radiotherapy (including brachytherapy) or both, with curative intent.
4. PSA doubling time ≤ 9 months as calculated by the sponsor.
5. Screening PSA ≥ 2.0 ng/mL for patients who had radical prostatectomy as primary treatment for prostate cancer or ≥ 5.0 ng/mL and greater than or equal to the nadir + 2 ng/mL for patients who had radiotherapy as primary treatment for prostate cancer.
6. Serum testosterone ≥ 150 ng/dL (5.2 nmol/L) at screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
8. Estimated life expectancy of ≥ 12 months.
9. Able to swallow the study drug and comply with study requirements including independently completing study questionnaires.
10. Throughout study, the patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) from screening through 3 months after the last dose of study drug or per local guidelines where these require additional description of contraceptive methods. Two acceptable methods of birth control thus include the following:
● Condom (barrier method is required)
AND
● One of the following is required:
– Established and ongoing use of oral, injected, or implanted hormonal method of contraception by the female partner
– Placement of an intrauterine device or intrauterine system by the female partner
– Additional barrier method including contraceptive sponge and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner
– Tubal ligation in the female partner performed at least 6 months before screening
– Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), performed at least 6 months before screening
11. Throughout the study, the patient must use a condom if having sex with a pregnant woman.
12. Must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Prior or present evidence of distant metastatic disease as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) or chest x-ray for soft tissue disease and whole-body radionuclide bone scan for bone disease. Patients with soft tissue pelvic disease may be eligible if lesions do not qualify as target lesions (eg, lymph nodes below aortic bifurcation are permissible if the short axis of the largest lymph node is < 15 mm). If the screening bone scan shows a lesion suggestive of metastatic disease, the patient will be eligible only if a second imaging modality (plain film, CT, or MRI) does not show bone metastasis. If the imaging results are equivocal or consistent with metastasis, the patient is not eligible for enrollment.
2. Prior hormonal therapy other than neoadjuvant/adjuvant therapy to treat prostate cancer ≤ 36 months in duration and ≥ 9 months before randomization.
3. Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for prostate cancer.
4. Prior systemic biologic therapy, including immunotherapy, for prostate cancer.
5. Major surgery within 4 weeks before randomization date.
6. Treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks of randomization.
7. For patients who had a prior prostatectomy, a suitable candidate for salvage radiotherapy as determined by the investigator in consideration of appropriate guidelines (eg, American Society for Radiation Oncology / American Urological Association [ASTRO/AUA]; European Association of Urology [EAU]).
8. Participation in a clinical study of an investigational agent that inhibits the androgen receptor or androgen synthesis (eg, TAK-700, ARN-509, ODM-201); patients who received placebo are allowed.
9. Use of any other investigational agent within 4 weeks before randomization date.
10. Known or suspected brain metastasis or active leptomeningeal disease.
11. History of another invasive cancer within 3 years before screening, with the exception of fully treated cancers with a remote probability of recurrence. The medical monitor and investigator must agree that the possibility of recurrence is remote.
12. Absolute neutrophil count < 1500/μL, platelet count < 100,000/μL, or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received any growth factors or blood transfusions within 7 days before the hematology values obtained at screening.
13. Total bilirubin ≥ 1.5-times the upper limit of normal (except patients with documented Gilbert’s disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5-times the upper limit of normal at screening.
14. Creatinine > 2 mg/dL (177 μmol/L) at screening.
15. Albumin < 3.0 g/dL (30 g/L) at screening.
16. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months before randomization.
17. Clinically significant cardiovascular disease including the following:
- Myocardial infarction within 6 months before screening
- Unstable angina within 3 months before screening
- New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction ≥ 45%
- History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
- History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
- Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening
- Bradycardia as indicated by a heart rate of ≤ 45 beats per minute on the screening electrocardiogram (ECG)
- Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening
18. Gastrointestinal disorder affecting absorption.
19. Hypersensitivity reaction to enzalutamide or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
20. Contraindication to the use of leuprolide, such as a previous hypersensitivity reaction to an LHRH analogue or any of the excipients in the leuprolide injection.
21. Ongoing drug or alcohol abuse as per investigator judgment.
22. Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the study, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Metastasis free survival (MFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death on study (death within 168 days after permanent treatment discontinuation), whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
● Overall survival
● Proportion of patients who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA
● Time to castration resistance |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
● Overall survival: the time between randomization and death due to any cause.
● Proportion of patients who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA: no specific timepoint
● Time to castration resistance: the time from randomization to the date of the first PSA increase while on study drug treatment that is ≥ 25% and ≥ 2 μg/L (2 ng/mL) above the nadir or screening value, whichever is lower, and that is confirmed by a second consecutive value obtained at least 3 weeks later. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double blind with the exception that enzalutamide monotherapy and leuprolide are open label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 91 |
| 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 |
| Austria |
| Brazil |
| Canada |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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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| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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