| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate Cancer that has spread despite testosterone-lowering treatments |
|
| 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 | 21.1 |
| 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 compare the efficacy of continuing treatment with enzalutamide after adding docetaxel and prednisolone versus placebo plus docetaxel and prednisolone, as measured by progression-free survival (PFS) in subjects with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with progression during treatment with enzalutamide alone |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of continuing treatment with enzalutamide after adding docetaxel and prednisolone versus placebo plus docetaxel and prednisolone, as measured by the following in subjects with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with progression during treatment with enzalutamide alone:
- Time to prostate-specific antigen (PSA) progression;
- PSA response;
- Objective response rate;
- Time to pain progression;
- Time to opiate use for cancer-related pain;
- Time to first skeletal-related event;
- Quality of life.
Safety profile including cumulative dose of docetaxel and Health Resource Use will be described for these subjects. |
|
| 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 |
Biomarker Sub-study:
- Subjects in a subset of countries and sites will be invited to participate
in a voluntary, exploratory, biomarker sub-study. For subjects who have
consented to provide samples for this sub-study, blood samples for
circulating biomarker analysis will be taken at the following timepoints:
- Period 1: Week 1/Day 1 (pre dosing with enzalutamide), Week 5, Week
13, and when subjects progress clinically (4 samples).
- Period 2: Week 1/Day 1 (pre study drug in Period 2), Cycle 2 (Week 4),
Cycle 5 (Week 13), Cycle 9 (Week 25), when subjects progress clinically
or reach another endpoint in the study and at Follow-Up (30 days after
last dose of IMP) (6 samples).
- Any subject who consents to participate in the biomarker sub-study,
but fails to provide a valid baseline sample for Period 1, may still
participate in Period 2 of the biomarker sub-study. In this case, the last
sample of Period 1 (the sample taken when they progress clinically)
should be taken as part of the baseline for Period 2. Informed Consent
for the biomarker samples must be taken before any samples are
collected. Samples are to be handled according to the laboratory manual,
and shipped to a central laboratory for processing. |
|
| E.3 | Principal inclusion criteria |
1. Age 18 or older;
2. Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable);
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features;
4. Ongoing ADT with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of initiation of IMP, or bilateral orchiectomy (i.e., surgical or medical castration);
5. Serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL);
6. Metastatic (M1) disease documented by at least 2 bone lesions on bone scan, or soft tissue disease documented by CT/MRI;
7. Progressive disease at study entry defined as the following 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 Screening should be ≥ 2 μg/L (≥ 2 ng/mL). In the event of prior androgen receptor inhibitor use, the most recent local PSA and the Screening PSA assessed by the central laboratory (central PSA) must be obtained at least 4 weeks after the last dose of androgen receptor inhibitor;
8. Asymptomatic or minimally symptomatic prostate cancer (BPI SF question 3 score of < 4) at Screening;
9. ECOG performance score of 0-1 at Screening;
10. Estimated life expectancy of ≥ 12 months from Screening;
11. Be suitable and willing to receive chemotherapy as part of the trial;
12. Able to swallow the IMP and comply with study requirements;
13. Subjects and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control* (one of which must be a condom) starting at Screening and continue throughout the study period and for 3 months after the final IMP administration;
14. Subjects must not donate sperm starting at Screening and throughout the study period and for 3 months after the final IMP administration. A condom is required throughout the study period and for 3 months after the final IMP administration if the subject is engaged in sexual activity with a pregnant woman;
15. Subject agrees not to participate in another interventional study
while on treatment. Subjects who are participating in a control arm of an
interventional study which includes only standard of care, or in an
observational phase following an interventional study, may be eligible
for this study, providing they meet all the other entry criteria. |
|
| E.4 | Principal exclusion criteria |
1. Absolute neutrophil count (ANC) < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 6.2 mmol/L (< 10 g/dL)
(NOTE: subjects must not have received any growth factors or blood transfusions within seven days prior to the hematologic laboratory values obtained at Screening);
2. Total bilirubin > upper limit of normal (ULN); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 times ULN; Child-Pugh B and C hepatic impairment;
3. Creatinine > 177 μmol/L (> 2 mg/dL);
4. Albumin ≤ 30 g/L (≤ 3.0 g/dL;
5. Prior treatment with the following agents for the treatment of prostate cancer: Aminoglutethimide; Ketoconazole; Abiraterone; Enzalutamide or participation in a clinical trial of enzalutamide; 223Ra, 89Sr, 153Sm, 186Re/188Re; Immunomodulatory therapies (e.g. Sipuleucel-T, DCVAC); Cytotoxic chemotherapy (e.g. docetaxel, cabazitaxel, mitoxantrone, estramustine); Participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (e.g. ARN-509, ODM-201, VT-464; unless the treatment was placebo);
6. Current or prior treatment within 4 weeks prior to initiation of IMP with the following agents for the treatment of prostate cancer: Antiandrogens (e.g., bicalutamide, nilutamide, flutamide); 5-α reductase inhibitors (e.g., finasteride, dutasteride); Estrogens; Anabolic steroids; Drugs with antiandrogenic properties such as spironolactone > 50 mg/kg; Progestational agents;
7. Subject has received investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to initiation of IMP;
8. Use of opiate analgesia for pain from prostate cancer within 4 weeks prior to initiation of IMP;
9. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to initiation of IMP;
10. Major surgery within 4 weeks prior to initiation of IMP;
11. History of seizure or any condition that may predispose to seizures at any time in the past (e.g., prior cortical stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). History of loss of consciousness or transient ischemic attack within 12 months prior to Screening;
12. Known or suspected brain metastasis or active leptomeningeal disease;
13. History of another malignancy within the previous 5 years other than non-melanoma skin cancer;
14. Clinically significant cardiovascular disease including: Myocardial infarction within six months prior to Screening; Uncontrolled angina within three months prior to Screening; Congestive heart failure New York Heart Association (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 multi-gated acquisition scan (MUGA) 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; Bradycardia as indicated by a heart rate < 45 beats per minute on the screening ECG or physical examination; Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at Screening;
15. Gastrointestinal disorders affecting absorption (e.g., extensive small bowel resection, active inflammatory bowel disease);
16. Medical contraindications to the use of prednisolone or docetaxel;
17. Allergies to any of the active ingredients or excipients in the study drugs;
18. Any condition which, in the Investigator’s opinion, makes the subject unsuitable for study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is PFS with progression defined as radiographic progression, unequivocal clinical progression, or death.
PFS is defined as the time from randomization to the earliest objective evidence of radiographic progression, unequivocal clinical progression, or death on study, whichever occurs first.
- Radiographic disease progression is defined for bone disease by the appearance of 2 or more new lesions on whole-body radionuclide bone scan per PCWG2 criteria or for soft tissue disease by RECIST 1.1;
- Unequivocal clinical progression is defined as any of the following:
- new onset cancer pain requiring chronic administration of opiate analgesic medication;
- deterioration from prostate cancer of ECOG performance status score to 3 or higher;
- initiation of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression. Radiotherapy for palliative management of symptoms due to prostate cancer will not be considered unequivocal clinical progression;
- Death on study is defined as death within 112 days of treatment discontinuation without objective evidence of radiographic progression. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to the earliest objective evidence of radiographic progression, unequivocal clinical progression, or death on study, whichever occurs first.
- Imaging is assessed every 12 weeks
- Clinical progression endpoints will be assessed at each clinical visit (every 3 weeks during docetaxel dosing, every 12 weeks thereafter) |
|
| E.5.2 | Secondary end point(s) |
- Time to PSA progression, defined as the time from randomization to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later;
- PSA response, defined as the percentage change in PSA from randomization to Week 13 (or earlier for those that discontinue therapy), as well as the maximum decline in PSA that occurs at any point after treatment;
- Objective response rate, defined as the best overall radiographic response after randomization as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in subjects who have a measurable tumor;
- Time to pain progression, defined as the time to an increase of ≥ 30% from randomization in the mean of BPI-SF pain intensity item scores (items 3, 4, 5, and 6);
- Time to opiate use for cancer-related pain, defined as the time to initiation of chronic administration of opiate analgesia;
- Time to first SRE, defined as the time from randomization to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain;
- Quality of life, as assessed using FACT-P and EQ-5D-5L.
Other Endpoints:
- Cumulative dose of docetaxel.
- Health resource use (hospitalization and duration thereof; number and types of visits to a health
professional) in Period 1 and Period 2
Exploratory Endpoints:
- To analyze candidate biomarkers in circulation for association with
response or progression and for identifying mechanisms of resistance.
Safety Endpoints:
- Safety in both Periods will be assessed by AEs, clinically significant changes in physical examination, vital signs, laboratory values, and ECGs.
- Deaths, defined as deaths due to any cause, will be summarized descriptively. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Imaging is assessed every 12 weeks
- Clinical endpoints will be assessed at each clinical visit (every 3 weeks during docetaxel dosing, every 12 weeks thereafter)
- Quality of Life endpoints will be assessed every 12 weeks |
|
| 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 | No |
| 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 | Yes |
| 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 | 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 |
| Two Periods; Period 1 open-label active treatment; Period 2 double-blind randomized treatment |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 83 |
| 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 |
| Austria |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| 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
|
|
| 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 | |
| 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 | 6 |
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