| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy-naive Metastatic Castration-resisitant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| 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 determine if orteronel plus prednisone improves Radiographic Progression-Free Survival (rPFS)
To determine if orteronel plus prednisone improves Overall Survival (OS)
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| E.2.2 | Secondary objectives of the trial |
To determine if orteronel plus prednisone improves 50% Prostate-Specific Antigen (PSA) response at 12 weeks
To evaluate changes in Circulating Tumor Cell (CTC) counts
To evaluate whether orteronel improves time to pain progression
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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 |
| Two sub studies, bone biomarker and CTC biomarker profiling will be conducted at selected sites, however the United Kingdom has not been chosen to participate in these sub-studies. The objective of the bone biomarker sub study is to evaluate changes in markers of bone turnover, such as serum N-telopeptide and serum bone-specific alkalinephosphatase, in approximately 240 patients within the overall study population. The objective of the CTC biomarker profiling is 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 these sub studies are provided in the protocol C21004, dated 21st July 2010. |
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| 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 study related 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 either 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 (refer to Section 15.1 of protocol) 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; refer to Section 15.1); 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 patient 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. Either absence of pain or pain, regardless of cause, not requiring use of any opioid or narcotic analgesia in the 2 weeks prior to randomization.
8. Screening PSA ≥ 2 ng/mL. (Screening PSA value must be obtained from the central laboratory.)
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Section 15.2.2).
10. Screening clinical laboratory values as specified below:
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤2.5 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 4 months after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g, calandar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.
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 12 months or more based on general health and prostate cancer disease status as judged by the investigator. |
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| 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, aminoglutethimide, or abiraterone.
2. Known hypersensitivity to compounds related to orteronel, orteronel excipients, prednisone, or GnRH analogue.
3. All antiandrogen therapy (including bicalutamide) is excluded within 4 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.
4. Continuous daily use of oral prednisone, oral dexamethasone, or other systemic corticosteroids for more than 14 days within 3 months prior to screening (inhaled, nasal, and local steroids are allowed [eg, joint injection]).
5. Prior chemotherapy for PC, 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.
6. 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.
7. Documented central nervous system metastases.
8. 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.)
9. 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 project clinician.
10. 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.
11. History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.02)(77), 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.
12. New York Heart Association Class III or IV heart failure (see Section 15.5 of protocol).
13. ECG abnormalities of:
• Q-wave infarction, unless identified 6 or more months prior to screening
• QTc interval > 460 msec
14. 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 adjustments of antihypertensive medications.
15. 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.
16. Uncontrolled nausea, vomiting, or diarrhea despite appropriate medical therapy.
17. Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of orteronel, including difficulty swallowing tablets.
18. Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel.
19. Those patients whose prostate cancer is confined to just the prostate bed or immediate adjacent tissue.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are:
•Radiographic progression-free survival, defined as time from randomization to radiographic disease progression or death from any cause, whichever occurs first.
•overall survival (OS)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint: Radiographic progression-free survival. Timepoint: Time from Randomization to radiographic progression or death, whatever comes first.
Overall survival: Time from randomization to death/lost to follow up.
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| E.5.2 | Secondary end point(s) |
The key secondary endpoints are:
•50% PSA response at 12 weeks
•Favorable changes in CTC levels at 12 weeks
•Time to pain progression as measured by worst pain item in the BPI-SF and changes in opioid analgesic use, if any.
Other Secondary Endpoints
The other secondary endpoints are:
• Safety, including the incidence of TEAEs, severity and type of AEs, and by changes from baseline in the patient’s vital signs, weight, Eastern Cooperative Oncology Group (ECOG) performance status, electrocardiogram (ECG), cardiac ejection fraction test results, dual energy X-ray absorptiometry (DXA), and clinical laboratory results
• SRE rate and time to SRE
• 50% PSA response at any time during the study beginning 4 weeks following the start of study drug; 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
• Time to docetaxel chemotherapy
• Time to subsequent antineoplastic therapy
• Tumor responses in target lesions in patients with measurable tumor by RECIST criteria
• Time to deterioration in global health status as measured by the 2-item global QOL index of the EORTC-QLQ-C30
• Population pharmacokinetics of orteronel using sparse sampling time points
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• 50% PSA response at 12 weeks
• Favorable changes in CTC levels at 12 weeks
• 50% PSA response at any time during the study beginning 4 weeks following the start of study drug; 90% PSA response at 12 weeks and at any time during the study, and best PSA response at any time during the study
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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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 198 |
| 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 |
| New Zealand |
| Portugal |
| Romania |
| Slovakia |
| Sweden |
| European Union |
| Argentina |
| Australia |
| Belarus |
| Brazil |
| Chile |
| Colombia |
| Czech Republic |
| Estonia |
| Finland |
| Germany |
| Hong Kong |
| Hungary |
| Latvia |
| Lithuania |
| Spain |
| Israel |
| Mexico |
| Peru |
| Poland |
| Serbia |
| Singapore |
| South Africa |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| 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
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| All patients will be followed for survival (long-term follow-up) after discontinuing the treatment/short-term follow-up portion of the study. Long-term follow-up will continue until death or termination of the study by the sponsor. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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