E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with High Risk Invasive Urothelial Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Subjects who have undergone radical resection of Invasive urothelial carcinoma originating in the bladder or upper urinary tract (renal pelvis or ureter) and are at high risk of recurrence. |
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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 | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 disease free survival (DFS) for nivolumab versus placebo in: - subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and -all randomized subjects |
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E.2.2 | Secondary objectives of the trial |
-To compare the overall survival (OS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects -To evaluate non-urothelial tract recurrence free survival (NUTRFS) in each randomized treatment group (nivolumab versus placebo) in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects -To evaluate disease specific survival (DSS) in each randomized treatment group (nivolumab and placebo) in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. All subjects must be status post radical surgical resection (R0) for Invasive Urothelial Carcinoma performed within 120 days prior to randomization. Subjects with carcinoma in situ in surgical margins are not eligible for study entry. 2. All subjects must have pathologic evidence of urothelial carcinoma (originating in bladder, ureter, or renal pelvis) at high risk of recurrence based on pathologic staging of radical surgery tissue (see protocol for more details) 3. Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (eg. minor variants) are accepted 4. All subjects must have disease-free status defined as no clinical or radiographic evidence of recurrence of disease documented by a complete physical examination and imaging studies within 4 weeks of randomization. Subjects with equivocal nodes less than 15 mm in short axis may be eligible after discussion with BMS Medical Monitor. All suspect lesions identified during screening radiographic procedures should be discussed with the Medical Monitor prior to randomization. Imaging studies must include CT of chest and CT or MRI of abdomen, pelvis, and all known sites of resected disease including cystoscopy in subjects with upper GU primaries who still have bladder intact. Brain imaging (MRI except where contraindicated in which CT scan is acceptable) must be completed within 4 weeks prior to randomization for subjects with clinical suspicion of CNS disease. Subjects who are found to have high-risk NMIBC at the time of screening are not eligible for study entry. Patients with low-risk papillary lesions may enter the study if rendered free of disease at cystoscopy. Subjects with intermediate-risk NMIBC may enter the study if intravesical chemotherapy or BCG is not required. Screening cystoscopy may occur within 60 days of randomization and is encouraged to be done prior to other imaging. Any suspect lesions seen on cystoscopy should be biopsied to rule-out the possibility of high-risk lesions. 5. Tumor tissue from the most recently resected site of disease (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis must be provided for biomarker analyses. In order to be randomized, a subject must have a PD-L1 expression level classification (>=1%, < 1%, indeterminate) as determined by the central lab. 6. Life expectancy >= 6 months 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Subjects who have not received cisplatin based neoadjuvant chemotherapy and are considered ineligible for cisplatin adjuvant chemotherapy, may enter the study with ECOG PS 2 (see Appendix 2) 8. Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration. TURBT must be completed 14 days before randomization.
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E.4 | Principal exclusion criteria |
1. Partial cystectomy in the setting of bladder cancer primary tumor or partial nephrectomy in the setting of renal pelvis primary tumor. 2. Adjuvant systemic or radiation therapy for urothelial or prostatic carcinoma following radical surgical resection of urothelial carcinoma. 3. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. 4. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer with evidence of undetectable Prostate Specific Antigen (PSA) or carcinoma in situ of the prostate, cervix or breast. Patients with known history of recent metastatic urothelial carcinoma will be excluded. 5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 6. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 7. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after adrenal crisis). 8. All toxicities attributed to prior anti-cancer therapy other than nephropathy, neuropathy, hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll. See protocol inclusion criterion 2) i) (5) for renal function eligibility. Neuropathy must have resolved to Grade 2 (NCI CTCAE version 4). 9. Treatment with any chemotherapy, radiation therapy, biologics for cancer, intravesical therapy, or investigational therapy within 28 days of first administration of study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease Free Survival - This endpoint will be analyzed in two different populations (co-primary): Subjects with PD-L1 expression level >=1% and all randomized subjects. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 5 years after the first subject is randomized. |
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E.5.2 | Secondary end point(s) |
-To compare Non-Urothelial Tract Recurrence Free Survival (NUTRFS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>= 1% membranous staining in tumor cells) and all randomized subjects -To compare the Disease Specific Survival (DSS) for nivolumab and placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects -To compare the Overall Survival (OS) for nivolumab versus placebo in subjects with tumors expressing PD-L1 (>=1% membranous staining in tumor cells) and all randomized subjects. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For all secondary endpoints: approximately 5 years after the first subject is randomized. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Outcomes Research Assessments, Immunogenicity Assessments |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Denmark |
France |
Germany |
Greece |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Peru |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
Switzerland |
Taiwan |
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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Last follow-up visit of the last subject |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
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 | 25 |