| 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 |
| Metastatic 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| 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 the PFS of MDV3100 as compared to bicalutamide |
|
| E.2.2 | Secondary objectives of the trial |
To determine the safety of treatment with MDV3100 as compared to bicalutamide;
To determine the PSA response of MDV3100 at week 13 as compared to bicalutamide;
To determine the time to PSA progression of MDV3100 as compared to bicalutamide. |
|
| 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 |
Optional Pharmacogenomics Sub-Study is included into main protocol under Appendix 6.
Objective: to comprehensively analyze suspected disease-related genes and genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, etc. |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Double Blind Period:
1. IRB/IEC approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA for U.S. sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
3. Ongoing androgen deprivation therapy with a LHRH agonist or antagonist at a stable dose and schedule within 4 weeks of randomization or bilateral orchiectomy (i.e., surgical or medical castration).
4. Serum testosterone level ≤ 1.7 nmol/L (50 ng/dL) at Screening.
5. Metastatic disease documented at screening by one of the following:
At least two bone lesions on bone scan, or
Soft tissue disease documented by CT/MRI, or
Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by CT/MRI.
6. Progressive disease at study entry defined as one or more of the following three criteria occurring in the setting of castrate levels of testosterone:
PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 μg/L (2 ng/mL);
Soft tissue disease progression defined by RECIST 1.1.;
Bone disease progression defined by two or more new lesions on bone scan.
7. Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on BPI-SF Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization.
8. ECOG performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer.
9. Estimated life expectancy of ≥ 12 months.
10. Able to swallow the study drug and comply with study requirements.
11. A male subject and his female spouse/partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:
1. Condom (barrier method of contraception), AND
2. In addition to a condom, one of the following acceptable forms of contraception is required:
- Established use of oral, injected or implanted hormonal methods of contraception.
- Placement of an intrauterine device (IUD) or intrauterine system (IUS).
- Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
- Tubal ligation for at least 6 months prior to Screening
- Vasectomy or other surgical castration at least 6 months prior to Screening
Inclusion Criteria for Open Label Period:
Subjects must meet the following inclusion criteria:
1. IRB/IEC approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA for U.S. sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Received double-blind study treatment during the study. If treated with enzalutamide during double-blind period, treatment must be ongoing at time of Open Label enrollment.
3. Ongoing androgen deprivation therapy with a LHRH agonist or antagonist at a stable dose and schedule unless already had a bilateral orchiectomy.
4. Able to swallow the study drug and comply with study requirements.
5. A male subject and his female spouse/partner who is of childbearing potential must continue to use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) throughout the Open-Label Period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:
1. Condom (barrier method of contraception), AND
2. In addition to a condom, one of the following acceptable forms of contraception is required:
•Established use of oral, injected or implanted hormonal methods of contraception.
•Placement of an intrauterine device (IUD) or intrauterine system (IUS).
•Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
•Tubal ligation for at least 6 months prior to initial double-blind screening
•Vasectomy or other surgical castration at least 6 months prior to initial double blind screening
6. Agrees to avoid sperm donation while taking enzalutamide. |
|
| E.4 | Principal exclusion criteria |
Double-Blind period:
1. Prior cytotoxic chemotherapy for prostate cancer.
2. Severe concurrent disease, infection, or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment.
3. Known or suspected brain and/or skull metastasis or active epidural disease.
4. Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, and hemoglobin < 5.6 mmol/L (9 g/dL) at Screening; (NOTE: subjects must not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at Screening).
5. Total bilirubin > 1.5 times the upper limit of normal (ULN) at Screening. This will not apply to subjects with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic
pathology), who will be allowed in consultation with the sponsor.
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times ULN at Screening.
7. Creatinine > 177 μmol/L (2 mg/dL) at Screening.
8. Albumin ≤ 30 g/L (3.0 g/dL) at Screening.
9. History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer.
10. Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/day, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization.
11. Current or prior use of ketoconazole for the treatment of prostate cancer.
12. Use of antiandrogens within 6 weeks prior to randomization.
13. Documented prior disease progression while receiving antiandrogens. Disease progression defined as PSA progression, radiographic progression and/or clinical deterioration.
14. Current or prior treatment with 5-α reductase inhibitors or anabolic steroids within 6 months prior to randomization.
15. Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone) within 3 months prior to randomization or expectation of their use during the study.
16. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to randomization
17. Major surgery within 2 months prior to randomization.
18. History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with antiepileptic
medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization.
19. Clinically significant cardiovascular disease including:
Myocardial infarction within six months prior to Screening;
Uncontrolled angina within three months prior to Screening;
Congestive heart failure NYHA class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or MUGA scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%;
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at Screening.
20. Prior use or participation in a clinical trial of an investigational agent that blocks androgen synthesis and/or androgen receptor activity.
21. Participation in a previous clinical trial of MDV3100.
22. Use of an investigational agent within four weeks prior to randomization.
23. Gastrointestinal disorder affecting absorption
Open Label Period: Only apply to subjects starting treatment with enzalutamide after receiving bicalutamide in double-blind period.
1.Has taken commercially available enzalutamide (Xtandi)
2.Severe concurrent disease, infection, or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment
3.Has current or previously treated brain metastasis or active leptomeningeal disease
4.Has a history of seizure or a condition that may increase the risk of seizure
5.Has any of the following: total bilirubin ≥ 1.5 times the ULN (except patients with a diagnosis of Gilbert’s disease), ALT or AST ≥ 2.5 times ULN at enrollment into open-label period. For patients with documented liver metastases, ALT and AST exclusion is > 5 times ULN;
6.Has creatinine > 2 mg/dL (177 µmol/L) at enrollment into Open-label period
7.Met one or more discontinuation criteria in the double-blind period >30 days prior to enrollment in Open-Label Period
8.Use of another anti androgen, cytotoxic chemotherapy or other investigational drug within 4 weeks prior to Open-Label enrollment |
|
| 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 |
| The duration of progression-free survival (PFS) will be calculated from the date of randomization to the date of first objective evidence of radiographic disease progression, skeletal-related event, initiation of new anti-neoplastic therapy, or death by any cause, whichever occurs first. Subjects must be assessed with CT/MRI and bone scan within 28 days prior to randomization (Day 1). Scans should be scheduled in such a way that the scan results are available at the regularly scheduled visits at week 13, 25 and every subsequent 12 weeks. |
|
| E.5.2 | Secondary end point(s) |
1)To determine the safety of treatment with MDV3100 as compared to bicalutamide
2)To determine the prostate specific antigen (PSA) response of MDV3100 at week 13 as compared to bicalutamide
3)To determine the time to PSA progression of MDV3100 as compared to bicalutamide
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) at every visit
2) at week 13
3) week, 13, 25 and every subsequent 12 weeks, 30 days from date of last dose, 60 days from date of last dose, Every 12 weeks from date of last dose
|
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 |
| OPEN-label period begins when unblinding of the double-blind period occurs |
|
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 11 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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