| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Castration-Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer with rapidly rising PSA not responsive to hormonal treatment. |
|
| 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 demonstrate superiority in the metastasis-free survival (MFS) of men with high risk NM-CRPC treated with Apalutamide versus placebo |
|
| E.2.2 | Secondary objectives of the trial |
To compare the overall survival (OS) of men with high risk NM-CRPC treated with Apalutamide versus placebo and:
To compare the time to symptomatic progression in men with high risk NM-CRPC treated with Apalutamide versus placebo
To compare the time to initiation of cytotoxic chemotherapy in men with high risk NM-CRPC treated with Apalutamide versus placebo
To compare the progression-free survival (PFS) of men with high risk NM-CRPC treated with Apalutamide versus placebo
To compare the time to metastasis (TTM) in men with high risk NM-CRPC treated with Apalutamide versus placebo
To evaluate the safety and tolerability of Apalutamide |
|
| 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 |
VENTRICULAR REPOLARIZATION SUB-STUDY: (Appendix 8, Protocol Version 3.0 08 May 2013)
To evaluate the effect of Apalutamide on ventricular repolarization in a subset of patients from selected clinical sites. The effect of Apalutamide on ventricular repolarization will be centrally analyzed by a third-party cardiac safety laboratory in a subset of 100 patients enrolled at selected sites that will be participating in the main protocol. Both Apalutamide and placebo patients will be enrolled in a blinded manner as per the main protocol randomization criteria.
-The primary objective of this sub-study is to evaluate whether Apalutamide has a threshold pharmacological effect on cardiac repolarization, as detected by changes in electrocardiogram (ECG) QT intervals corrected for heart rate by Fridericia’s correction method (QTcF)
-The secondary objectives of this study sub-study are as follows:
-To investigate the effect of Apalutamide on the following ECG parameters: PR, RR, QRS, QT, QTcB (Bazett’s correction method), and T-Wave morphology
-To further characterize the pharmacokinetic (PK) profile of Apalutamide and to assess the exposure-effect relationships (if any) between Apalutamide plasma concentrations and ECG interval change |
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with high risk for development of metastases, defined as PSADT ≤ 10 months. PSADT is calculated using at least 3 PSA values obtained during continuous ADT (see Section 5.1).
2. Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA > 2 ng/mL
3. Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study to maintain castrate levels of testosterone.
4.Patients receiving bone loss prevention treatment with bone-sparing agents indicated for the treatment of osteoporosis at doses and dosing schedule appropriate for the treatment of osteoporosis (e.g., denosumab [Prolia®], zoledronic acid [Reclast®]) must be on stable doses for at least 4 weeks prior to randomization.
5. Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) must have at least a 4-week washout prior to randomization AND must show continuing disease (PSA) progression (an increase in PSA) after washout.
6. At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (e.g., dutasteride, finasteride), estrogens (irrespective of dose used), and any other anti-cancer therapy prior to randomization, including chemotherapy given in the adjuvant/neoadjuvant setting (e.g., clinical trial)
7. At least 4 weeks must have elapsed from major surgery or radiation therapy prior to randomization
8. Age ≥ 18 years
9. Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1
10. Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade 1 or baseline prior to randomization
11. Adequate organ function as defined by the following criteria:
-Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN)
-Total serum bilirubin ≤1.5 x ULN. Total serum bilirubin >1.5 x ULN is allowed if Gilbert’s disease is documented prior to end of screening procedures
-Serum creatinine ≤ 2 x ULN
-Absolute neutrophil count (ANC) ≥ 1500/μL
-Platelets ≥ 100,000/μL
-Hemoglobin ≥ 9.0 g/dL
-Administration of growth factors or blood transfusions will not be allowed within 4 weeks of the hematology labs required to confirm eligibility
12. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to randomization
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory and radiographic assessments, and other study procedures, including ability to swallow study drug tablets, the completion of patient reported outcomes questionnaires and long-term follow-up visits
Eligibility Criteria for Placebo Subjects to Crossover to Open Label
Apalutamide:
1a. Subject is willing and able to provide written informed consent to
crossover to open-label apalutamide
2a. Subject has adequate organ function as defined by the following
criteria:
-Serum aspartate transaminase (AST; serum glutamic oxaloacetic
transaminase [SGOT]) and serum alanine transaminase (ALT; serum
glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal
(ULN)
-Total serum bilirubin ≤1.5 x ULN
-Total serum bilirubin >1.5 x ULN is allowed if Gilbert's disease has been
previously documented
-Serum creatinine ≤ 2 x ULN
-Absolute neutrophil count (ANC) ≥ 1500/L
-Platelets ≥ 100,000/L
-Hemoglobin ≥ 9.0 g/dL
3a. Subject has not received any other systemic therapy for
nonmetastastic
castrate resistant prostate cancer other than blinded study
drug and androgen deprivation therapy.
4a. Subjects who have previously had an end of treatment visit and
evidence of distant metastasis from the blinded independent central
reviewer will not be eligible for open label apalutamide.
5a. Subjects who had study treatment withheld for ≥28 consecutive days
at the time of unblinding will need approval from the medical monitor to
be eligible for crossover. |
|
| E.4 | Principal exclusion criteria |
1.Presence of distant metastases confirmed by blinded independent central review (BICR), including CNS and vertebral or meningeal involvement, or history of distant metastases. Exception: Pelvic lymph nodes <2 cm in short axis (N1) located below the iliac bifurcation are allowed
2. Symptomatic loco-regional disease requiring medical intervention, such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor (e.g., tumor obstruction of bladder trigone)
3. Prior treatment with second generation anti-androgens (e.g., enzalutamide)
4. Prior treatment with CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galerterone, ketoconazole, aminoglutethimide)
5. Prior treatment with radiopharmaceutical agents (e.g., Strontium-89), immunotherapy (e.g., sipuleucel-T), or any other investigational agent for NM-CRPC
6. Prior chemotherapy for prostate cancer except if administered in the adjuvant/neoadjuvant setting
7. History of seizure or condition that may pre-dispose to seizure (e.g., stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
8. Concurrent therapy with any of the following (all must have been
discontinued or substituted for at least 4 weeks prior to randomization):
Medications known to lower the seizure threshold (for a complete list please see Appendix 5)
Herbal (e.g. saw palmetto) and non-herbal (e.g. pomegranate) products that may decrease PSA levels
Systemic (oral/IV/IM) corticosteroids. Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated, but it should be tapered off as soon as possible
Any other experimental treatment on another clinical trial
Agents indicated for the prevention of skeletal-related events in patients with solid tumors (e.g., denosumab [Xgeva®])
9. History or evidence of any of the following conditions:
Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization
Any of the following within 6 months prior to randomization: Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias
Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP≥100 mmHg). Patients with a history of uncontrolled hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
Gastrointestinal disorder affecting absorption
Active infection, such as human immunodeficiency virus (HIV)
Any other condition that, in the opinion of the Investigator, would impair the patient’s ability to comply with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Metastasis-Free Survival (MFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
MFS data for patients without metastasis or death will be censored on the date of the last tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the date of randomization + 1 day).
Tumor assessments will be performed at baseline and at 16-week intervals from randomization. Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan. |
|
| E.5.2 | Secondary end point(s) |
For the secondary endpoints, a hierarchical testing will be performed in
the following order:
-Time to Metastasis (TTM)
-Progression-Free Survival (PFS)
-Time to symptomatic progression
-Overall Survival (OS)
-Time to initiation of cytotoxic chemotherapy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS (every 4 months via clinic visit or telephone contact) |
|
| 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 | 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 | Yes |
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 185 |
| 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 |
| New Zealand |
| Taiwan |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Norway |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
Patients will remain on study until BICR-confirmed disease progression, development of unacceptable toxicity, or withdrawal of consent.
If the study is not terminated beforehand per the recommendation of the DMC, the end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met. |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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