| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castrate-resistant prostate cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic castrate-resistant prostate cancer |
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| 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) |
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| 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 |
Primary Objective:
To determine the safety and tolerability of Radium-223 when administered in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer. Toxicities will be recorded and graded according to the NCI - CTCAE criteria, version 4. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
1. To examine the objective time to clinical/radiological progression of patients treated with Radium-223 in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer.
2. To examine the objective time to PSA progression of patients treated with Radium-223 in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer.
3. To assess PSA response (50% reduction from baseline).
4. To assess Change in alkaline phosphatase
5. To measure the time to first skeletal-related event.
6. To assess pain (Brief Pain Inventory-Short Form)
7. To measure overall survival.
8. Translational sub-study: To examine potential biomarkers of enzalutamide resistance in circulating tumour cells, whole blood, plasma & Serum.
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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 |
To examine potential biomarkers of enzalutamide resistance in circulating tumour cells.
Version 2, dated 25-Apr-2014.
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| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Written informed consent obtained prior to any study-related procedures
2. Age ≥ 18 years and male.
3. ECOG performance status ≤ 2.
4. Histologically/cytologically confirmed adenocarcinoma of the prostate, and without neuroendocrine differentiation or small cell histology.
5. Metastatic disease as confirmed by CT/MRI or bone scan
6. Patients must have documented Progressive disease (PD) either by radiological or PSA criteria as defined in a) and b) below:
a) For the radiological PD assessment, 2 sets of scans using the same imaging modality (ie CT/MRI or bone scan) and taken at separate time points are required to document radiological disease progression during or following the patient’s most recent anti-neoplastic therapy, (note: the 1st bone scan can be from before most recent therapy but the 2nd scan must show disease progression during or after the most recent therapy).
For patients with bone disease, progression will be assessed following recommendations by the Prostate Cancer Working Group (PCWG2): appearance of 2 or more new lesions on bone scan, confirmed, if necessary, by other imaging modalities (such as CT scan or MRI), if results of the bone scans are ambiguous).
For patients with soft tissue lesions progression will be assessed using RECIST 1.1 criteria. Patients may have measurable or non-measurable disease according to RECIST criteria version 1.1.
b) PSA progression is defined as an increase in PSA, as determined by 2 separate measurements taken at least 1 week apart and confirmed by a third. If the third measurement is not greater than the second measurement, then a fourth measurement must be taken and must be greater than the second measurement for the patient to be eligible for the study. Furthermore, the confirmatory PSA measurement (i.e. the third or, if applicable, fourth PSA measurement) must be defined. If a patient has received prior anti-androgen therapy (e.g. bicalutamide), PSA progression must be evident and documented after discontinuation of anti-androgen therapy, (note: The 1st PSA reading taken to document disease progression when the patient presents can be while the patient is on Casodex or other ADT).
7. Prior surgical castration or concurrent use of an agent for medical castration (e.g. GnRH analogue) with testosterone at screening less than 50ng/dL.
8. Screening PSA ≥ 2ng/mL.
9. Patients, even if surgically sterilized (i.e. status post-vasectomy), who:
- will abstain from intercourse
- or must agree to use barrier contraception during and for 6 months after discontinuation of study treatment.
- If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 6 months after treatment.
10. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 28 days prior to registration.
11. Life expectancy of 12 months or more based on general health and prostate cancer disease status as judged by the investigator.
12. Documented presence of osseous metastases with or without visceral involvement / lymph nodes.
13. Able to swallow study drug as whole tablet.
14. Adequate haematological, hepatic, and renal function.
• Haemoglobin ≥ 10g/dL.
• Neutrophils (ANC/AGC) ≥1500/mm³ (1.5 x 10^9/L).
• Platelets ≥ (100 x 10^9/L).
• Total bilirubin ≤ 1.5mg/dL (25.65 μmol/L) with the exception of Gilberts syndrome.
• Both ALT (SGPT) and AST (SGOT) ≤ 3 x ULN with or without liver Metastasis.
• Serum creatinine ≤1.5 ULN or calculated creatinine clearance (CrCl) ≥ 50mL/min according to the Cockcroft and Gault formula.
15. Continuous daily use of oral prednisone, oral dexamethasone, or other systemic corticosteroids is allowed prior to study entry but must be discontinued a minimum of 2 weeks prior to start of study treatment.
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| E.4 | Principal exclusion criteria |
Exclusion criteria:
1. Patients receiving any other investigational agents (within 30 days prior to registration).
2. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis).
3. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).
4. Prior therapy with orteronel, ketoconazole, aminoglutethimide, abiraterone or enzalutamide.
5. All anti-androgen therapy (including bicalutamide) is excluded within 6 weeks prior to first dose of study drug. Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5-alpha reductase inhibitors (eg, finasteride or dutasteride), must be discontinued 2 weeks before the first dose of study drug. [bisphosphonates and Denosumab are allowed concomitant medications].
6. Prior chemotherapy for prostate cancer, with the exception of:
- neoadjuvant/ adjuvant therapy as part of initial primary treatment for local disease that was completed 2 or more years prior to screening.
-Patients who received prior docetaxol for castrate sensitive metastatic prostate cancer commencing within 120 days of ADT initiation where total dose received did not exceed 450mg/m2
7. Prior exposure to radioisotope therapy; Prior exposure to bone directed radioisotope therapy, eg samarium 153, strontium 90.
8. Exposure to external beam radiation within 4 weeks prior to receiving the first dose of study drug. Patients must also have recovered from all treatment-related toxicities.
In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting treatment with Ra-223 dichloride (Xofigo®).
9. Diagnosis of or treatment for another systemic malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma
in situ of any type are not excluded if they have undergone complete resection.
10.History of myocardial infarction, unstable symptomatic ischemic heart disease/ unstable angina, uncontrolled on-going arrhythmias of Grade >2 (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4), pulmonary embolism, or any other cardiac condition (e.g. pericardial effusion restrictive cardiomyopathy) within 6 months prior to first dose of study drug. Patients with long QT, QTcF >470ms or uncontrolled hypertension are excluded.
11.New York Heart Association Class III or IV heart failure (see Appendix L).
12.History of seizure, underlying brain injury with loss of consciousness, stroke, Transient Ischaemic attack (TIA), cerebral vascular accident , primary brain tumours or brain metastases, brain arteriovenous malformation, alcoholism, or the use of concomitant medications that may lower the seizure threshold.
13. Known human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any ongoing serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with participation in this study. Patients will be tested for hepatitis B or C or HIV infection during screening if they are considered by the investigator to be at higher risk for these infections and have not been previously tested, or if testing is required by the independent ethics committee or institutional review board.
14. Prohibited medications, including drugs that may affect exposure to enzalutamide i.e. study drugs that induce or inhibit CYP3A4, CYP2C8, and CYP2C9 (See section 6.4.3 and also Appendix H).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
• The incidence of grade 3 or higher adverse events during the period of combination therapy will be recorded and graded according to the NCI - CTCAE criteria, version 4.
The grade 3/4 toxicity rate will be presented as the percentage of patients in the safety population who experienced a grade 3 or higher toxicity, together with the accompanying two-sided 90% confidence interval using normal approximation.
The primary analysis will be performed for the safety population, defined as all registered patients who received at least one dose of study treatment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will be performed for the safety population, defined as all registered patients who received at least one dose of study treatment. |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Time to clinical/radiological progression (as measured according to the PCWG2 and RECIST 1.1 criteria);
• Time to PSA progression (as measured according to the PCWG2 criteria);
• PSA response (50% reduction from baseline);
• Change in alkaline phosphatase;
• Time to first skeletal-related event;
• Pain assessment (Brief Pain Inventory-Short Form);
• Overall survival;
• Translational sub-study: To examine potential biomarkers of enzalutamide resistance in circulating tumour cells, whole blood, plasma and serum.
Efficacy endpoints will be analysed for the intention-to-treat population, defined as all registered patients regardless of whether they received study treatment or not.
Clinical and PSA progression-free survival probabilities over time will be estimated using the Kaplan-Meier method, presenting estimates of median PFS with 95% confidence intervals (CIs), also estimates of PFS and 95% CIs at 12 months.
Overall survival and time to first skeletal-related event will be analysed similarly to radiological and PSA progression-free survival.
Descriptive statistics will be presented for pain as assessed by the Brief Pain Inventory-Short Form.
Regarding the translational sub-study, the statistical analysis of the data will employ an evaluation of the clinical sensitivity and specificity of the studied biomarkers to predict favourable response to therapy. Confidence intervals will be prepared for each statistic. As exact biomarker levels are not known, the study has assumed that biomarker (mutation) positivity may be up to 0.5% in Enzalutamide sensitive patients but should increase to approximately 1.0% or greater when detected in CTCs or cfDNA.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A median of 16.5 months for radiological progression free survival would indicate efficacy of treatment, and less than 8 months would indicate futility. A median of 11 months for PSA progression free survival would indicate efficacy, and less than 5.6 months would indicate futility. The planned sample size of 44 patients would be sufficient to provide 90% power (at a 5% significance level) to distinguish between an unacceptable median of 8 months for radiological PFS and an acceptable median of 16.5 months, assuming an accrual period of 12 months and a statistical analysis time point of 12 months after the last patient enters the study. This sample size would also provide 90% power to distinguish between an unacceptable median of 5.6 mnths for PSA PFS and an acceptable median of 11 mnths. |
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| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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The end of the study is defined as when all enrolled patients have completed either a treatment and/or study withdrawal visit.
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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 | |
| E.8.9.1 | In the Member State concerned days | |
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