| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer. |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the prostate gland |
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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 | 14.1 |
| 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) |
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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 |
| To compare the clinical benefit of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic. |
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| E.2.2 | Secondary objectives of the trial |
To establish additional clinically relevant improvements in prostate cancer patients treated with abiraterone acetate in comparison to placebo.
To characterize the safety profile of abiraterone acetate in this patient population.
To characterize the pharmacokinetics of abiraterone acetate when administered concurrently with prednisolone.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet the following criteria to be enrolled in this study.
1. Willing and able to provide written informed consent
2. Written Authorization for Use and Release of Health and Research Study information (US sites only) or Data Protection Consent (European sites only) has been obtained
3. Male aged 18 years and above
4. Histologically or cytologically confirmed adenocarcinoma of the prostate
5. Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in diameter
6. Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria
7. Asymptomatic or mildly symptomatic from prostate cancer. A score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic.
8. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study.
9. Previous anti-androgen therapy and progression after withdrawal. Patients who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment (≥ 4 weeks since last flutamide, ≥ 6 weeks since last bicalutamide or nilutamide).
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
11. Hemoglobin ≥ 10.0 g/dL independent of transfusion
12. Platelet count ≥100,000/μL
13. Serum albumin ≥ 3.5 g/dL
14. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min
15. Serum potassium ≥ 3.5 mmol/L
16. Liver function:
i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert’s disease)
ii. AST or ALT < 2.5 x ULN
17. Able to swallow the study drug whole as a tablet
18. Life expectancy of at least 6 months
19. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration.
Eligibility Criteria for Patients Formerly on Placebo who Crossover to Abiraterone Acetate from Long-term Follow-up
1. Previous participation in the placebo arm of Study COU-AA-302 and currently in long term follow-up.
2. Patient is willing and able to provide written informed consent to receive abiraterone acetate therapy.
3. Investigator's assessment that abiraterone acetate therapy will be safe and beneficial.
4. If subject received therapy with mitoxantrone, MUGA/ECHO must be ≥50%.
5. Not currently receiving prostate cancer treatment other than LHRH analogues. Patients who have received chemotherapy should have received the last dose of chemotherapy at least 4 weeks before Cycle 1 Day 1 of crossover.
6. The safety of concomitant cytotoxic chemotherapy and abiraterone acetate treatment has not been established. No cytoxtoxic chemotherapy should be administered while the patient is receiving abiraterone acetate treatment.
7. ECOG performance status of 0,1, or 2. Treatment will be continued until the investigator determines that the patient is not receiving benefit from continued treatment with abiraterone acetate, the patient needs to start other anti-cancer treatment, the patient withdraws consent, or the study is terminated by the sponsor. If the study has not been terminated or the patient did not withdraw consent, the patient will re enter the long-term follow-up phase as described in the main protocol. |
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study:
1. Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated.
2. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid.
3. Pathological finding consistent with small cell carcinoma of the prostate.
4. Liver or visceral organ metastasis.
5. Known brain metastasis.
6. Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1.
7. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC.
8. Radiation therapy for treatment of the primary tumor within 6 weeks of Cycle 1, Day 1.
9. Radiation or radionuclide therapy for treatment of metastatic CRPC.
10. Previously treated with ketoconazole for prostate cancer for greater than 7 days.
11. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1.
12. Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1).
13. Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1).
14. Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
15. Active or symptomatic viral hepatitis or chronic liver disease.
16. History of pituitary or adrenal dysfunction.
17. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline.
18. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy.
19. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months.
20. Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1.
21. Any condition which, in the opinion of the investigator, would preclude participation in this trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary efficacy endpoints:
• Overall survival
• Radiographic progression-free survival
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At day 1 of cycles 3, 5, 7, 10, 13, 16, 19 etc... of treatment (each cycle being 28 days) |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy assessments:
- time to opiate use for cancer-related pain and time to administration of cytoxic chemotherapy for metastatic prostate cancer will be prospectively assessed.
- EOCG performance status will be evaluated throughtout the study to assess time to first deterioration
- PSA values will be collected throughout the study to assess time to PSA progression |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| ECOG status - at day 1 of cycles 1, 2, 3, 4, 5, 6 etc...... of treatment (each cycle being 28 days) |
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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 | Yes |
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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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
|
| Follow-up will continue for 60 months (5 years) or until patient dies, is lost to follow-up, or withdraws informed consent. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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