| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or Following Docetaxel-based Therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.1 |
| 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) |
|
| 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 if orteronel plus prednisone improves overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
To determine if orteronel plus prednisone improves radiographic progression-free survival (rPFS)
To determine if orteronel plus prednisone improves 50% prostate-specific antigen (PSA) response rate at 12 weeks
To evaluate if orteronel plus prednisone improves pain response at 12 weeks
|
|
| 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 |
| One sub study CTC biomarker profiling will be conducted at selected sites, however Germany has not be chosen to participate in these sub-studies. The objective of the CTC biomarker profiling to assess candidate biomarkers predictive of orteronel antitumor activity including, but not limited to, the TMPRSS2:ERG fusion gene, the AR gene and the PTEN gene and the other clinical endpoints such as OS and time to disease progression. Details of the sub study is provided in the protocol C21005, dated 13th May 2011. |
|
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1.Male patients 18 years or older.
2. Voluntary written consent, given before performance of any studyrelated procedure not part of standard medical care, and with the
understanding that consent may be withdrawn at any time without
prejudice to future medical care.
3. Adenocarcinoma of the prostate histologically or cytologically
confirmed.
4. Metastatic disease radiographically documented by CT/MRI or bone
scan.
5. Progressive disease based on PSA and/or radiographic criteria,
defined as 1 or more of the following:
•Radiographic disease progression based on RECIST 1.1 in patients with measurable soft tissue lesions. 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.
•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 subject to be eligible for
randomization in the study. Furthermore, the confirmatory PSA
measurement (ie, the third or, if applicable, fourth PSA measurement)
must be ≥ 2 ng/mL. Notes: Determination of PSA progression can be
based on results from a local laboratory. The PSA value obtained from
the central laboratory during the screening process does not have to be used in the determination of PSA progression, but that value should be at least greater than the first PSA used for determination of PSA progression. If a patient has received prior antiandrogen therapy (eg, bicalutamide, MDV-3100), PSA progression must be evident and documented after discontinuation of antiandrogen therapy.
6. Prior surgical castration or concurrent use of an agent for medical
castration (eg, GnRH analogue) with testosterone at screening <50
ng/dL.
7. Screening PSA ≥ 2 ng/mL. (Screening PSA value must be obtained
from the central laboratory.)
8. Must have received prior docetaxel therapy:
•Must have received ≥ 360 mg/m2 of docetaxel within a 6-month
period. Patients who were clearly intolerant to docetaxel or develop
progressive disease before receiving ≥ 360 mg/m2 are also eligible if
they have received at least 225 mg/m2 of docetaxel within a 6-month
period and meet the other study entry criteria.
•Have progressive disease during or following 1 or 2 regimens of
cytotoxic chemotherapy, 1 of which must have included docetaxel. (A
regimen is when docetaxel is administered either as a single agent or in
combination with other therapies.)
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 2.
10. Screening clinical laboratory values as specified below:
•Serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) must be ≤3 x the upper limit of normal (ULN).
•Total bilirubin ≤1.5 x ULN.
•Estimated creatinine clearance using the Cockcroft-Gault formula must
be
> 40 mL/minute (see Section 15.4).
•Absolute neutrophil count (ANC) ≥ 1500/ μL and platelet count ≥
100,000/μL.
11. Patients, even if surgically sterilized (ie, status postvasectomy),
who:
•Agree to practice effective barrier contraception during the entire study
treatment period and for 4months after the last dose of study drug, or
•Agree to completely abstain from heterosexual intercourse.
12. Screening calculated ejection fraction of ≥ 50% by multiple gated
acquisition (MUGA) scan, or by echocardiogram (ECHO). (The same
modality should be used for a patient throughout the study.)
13. Stable medical condition, including the absence of acute
exacerbations of chronic illnesses, serious infections, or major surgery
within 28 days prior to randomization, and otherwise noted in other
inclusion/exclusion criteria.
14. Life expectancy of 6 months or more based on general health and
prostate cancer disease status as judged by the investigator |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be
enrolled in the study:
1. Prior therapy with orteronel, ketoconazole, abiraterone, or
aminoglutethimide.
2. Known hypersensitivity to compounds related to orteronel, orteronel
excipients, prednisone, or GnRH analogue.
3. Any other therapies for prostate cancer, except for 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.
4. Exposure to radioisotope therapy within 4 weeks of receiving the first
dose of study drug; exposure to external beam radiation within 4 weeks
of receiving the first dose of study drug.
5. Documented central nervous system metastases.
6. Treatment with any investigational compound within 30 days prior to
the first dose of study drug or ongoing active participation in another
experimental trial related to the treatment of PC. (Patients who are in
long-term follow-up following active treatment in other trials are
eligible.)
7. Current spinal cord compression, current bilateral hydronephrosis, or
current bladder neck outlet obstruction. Note: Patients with definitive
local therapy for urinary tract obstruction, eg, with stents, may be
eligible after a review by the study medical monitor.
8. 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 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.
9. History of myocardial infarction, unstable symptomatic ischemic heart
disease, ongoing arrhythmias of Grade > 2 (NCI CTCAE, version
4.02),(81) or thromboembolic events (eg, deep vein thrombosis,
pulmonary embolism, or symptomatic cerebrovascular events) or any
other cardiac condition (eg, pericardial effusion restrictive
cardiomyopathy) within 6 months prior to first dose of study drug.
Chronic stable atrial fibrillation on stable anticoagulant therapy is
allowed.
10. New York Heart Association Class III or IV heart failure.
11. ECG abnormalities of:
•Q-wave infarction, unless identified 6 or more months prior to
screening
•QTc interval > 460 msec
12. Uncontrolled hypertension despite appropriate medical therapy
(blood pressure [BP] of greater than 160 mmHg systolic and 90 mmHg
diastolic at 2 separate measurements no more than 60 minutes apart
during the Screening visit). Note: Patients may be rescreened after
adjustment of antihypertensive medications.
13. Known human immunodeficiency virus (HIV) infection, active chronic
hepatitis B or C, life-threatening illness unrelated to cancer, or any
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. Likely inability to comply with the protocol or cooperate fully with
the investigator and site personnel.
15. Known gastrointestinal (GI) disease or GI procedure that could
interfere with the GI absorption or tolerance of orteronel, including
difficulty swallowing tablets.
16. Uncontrolled nausea, vomiting, or diarrhea despite appropriate
medical therapy.
17. Those patients whose prostate cancer is confined to just the prostate bed or immediate adjacent tissue. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival. Time from randomization to death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall survival: Time from randomization to death/lost to follow up.
|
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints are:
• rPFS
• 50% PSA response at 12 weeks
• Pain response rate at 12 weeks
Other Secondary Endpoints
The other secondary endpoints are:
• AEs, physical examinations, vital signs, weight, ECOG performance
status, cardiac assessments, and clinical laboratory evaluations
• 50% PSA response at any time during the study, 90% PSA response at
12 weeks and at any time during the study, and best PSA response at
any time during the study
• Time to PSA progression
• Changes in CTC counts
• Changes in target lesions in patients with measurable tumors by
RECIST 1.1 criteria
• Time to pain progression, time to pain response, best pain response,
and duration of pain response
• HRQOL response rate as measured by the 2-item global QOL index of
the EORTC QLQ-C30
• Population pharmacokinetics of orteronel using sparse sampling time
points |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• 50% PSA response at 12 weeks
• Pain response rate at 12 weeks
• 50% PSA response at any time during the study, 90% PSA response at 12 weeks and at any time during the study, and best PSA response at
any time during the study |
|
| 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 | Yes |
| 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) | 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 | 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 167 |
| 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 |
| Belgium |
| Bulgaria |
| Canada |
| China |
| France |
| Greece |
| Ireland |
| Italy |
| Japan |
| Austria |
| Croatia |
| Netherlands |
| Portugal |
| Romania |
| Slovakia |
| Sweden |
| European Union |
| Argentina |
| Australia |
| Belarus |
| Brazil |
| Chile |
| Colombia |
| Estonia |
| Finland |
| Germany |
| Hungary |
| Korea, Republic of |
| Lithuania |
| Spain |
| Israel |
| Mexico |
| Peru |
| Poland |
| Singapore |
| Switzerland |
| Taiwan |
| Turkey |
| 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 be followed for survival until 80% of patients have died or are lost to follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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