| 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 | 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 evaluate efficacy, as measured by metastasis-free survival (MFS) |
|
| E.2.2 | Secondary objectives of the trial |
| ● To evaluate efficacy, as measured by the secondary and exploratory endpoints |
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| 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 |
Title: An Endocrine and Metabolic Substudy of Protocol MDV3100-13: EMBARK, a Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy
Objectives:
To evaluate endocrine and metabolic function, as assessed by the following:
– Glycated hemoglobin A1c (HbA1c) and fasting glucose, insulin, and lipids
– Bone mineral density and lean/fat body mass |
|
| 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. Prostate cryoablation is not considered definitive therapy for this study, but its prior use is not exclusionary.
4. PSA doubling time ≤ 9 months as calculated by the sponsor.
5. Screening PSA by the central laboratory ≥ 1 ng/mL for patients who had radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer and at least 2 ng/mL above the nadir for patients who had radiotherapy only 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.
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 the short axis of the largest lymph node is < 20 mm for lymph nodes below aortic bifurcation. 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, MRI) does not show bone metastasis. If the imaging results are equivocal or consistent with metastasis by central radiology review, the patient is not eligible for enrollment. Positron-emission tomography (PET) is not an evaluable imaging modality for this study.
2. Prior hormonal therapy.Neoadjuvant/adjuvant therapy to treat prostate cancer ≤ 36 months in duration and ≥ 9 months before randomization, or a single dose or a short course (≤ 6 months) of hormonal therapy given for rising PSA ≥ 9 months before randomization is allowed.
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 (TBili) ≥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 (unless of cardiac origin) 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
- 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) between enzalutamide plus leuprolide and placebo plus leuprolide. |
|
| 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) |
To evaluate efficacy, as measured by the following:
* MFS between enzalutamide monotherapy versus placebo plus leuprolide.
* Time to prostate-specific antigen (PSA) progression;
* Time to first use of new antineoplastic therapy;
* Overall survival
Other Secondary Endpoints:
* Time to distant metastasis
* Proportion of patients per group who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable
* 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
*Time to resumption of any hormonal therapy following suspension at week 37 due to undetectable PSA
*Time to castration resistance
*Time to symptomatic progression
*Time to first symptomatic skeletal event
*Time to clinically relevant pain
*Quality of life
*Safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
● Overall survival: is defined as the time between randomization and death of any cause. Long term follow up data (survival status, skeletal related events and new prostate cancer therapies) will be collected every 12 weeks up until the final analysis of OS.
● 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
| 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 | 148 |
| 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 |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Denmark |
| Finland |
| France |
| Italy |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Sweden |
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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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| 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 | |
| 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 |
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