Clinical Trials List
Protocol NumberONO-4538-33/CA209274
2016-02-01 - 2020-07-31
Phase III
Terminated2
Study ended1
ICD-10C66.2
Malignant neoplasm of left ureter
ICD-9198.1
Secondary malignant neoplasm of other urinary organs
A Phase 3 Randomized, Double-blind, Multi-center Study of Adjuvant Nivolumab versus Placebo in Subjects with High Risk Invasive Urothelial Carcinoma
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Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
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Sponsor
ONO Pharmaceutical Co., Ltd. /Bristol-Myers Squibb Company
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Yeong-Shiau Pu Division of Hematology & Oncology
- YU-CHUAN LU Division of Urology
- - - Division of Urology
- JHE-CYUAN GUO Division of Hematology & Oncology
- - - Division of Urology
- Ying-Chun Shen Division of Hematology & Oncology
- CHUNG-HSIN CHEN Division of Urology
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Che-Hung Lin Division of Hematology & Oncology
- Wei-Ching Lin Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- Sheng-Chen Wen Division of Urology
- 黃俊農 Division of Urology
- Hung-Lung Ke Division of Urology
- Ching-Chia Li Division of Urology
The Actual Total Number of Participants Enrolled
0 Study ended
Condition/Disease
高風險侵襲性泌尿上皮細胞癌
Objectives
Primary Objectives
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
Secondary Objectives
-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.
Test Drug
Nivolumab
Active Ingredient
Nivolumab
Dosage Form
Solution for Infusion
Dosage
10mg/mL, 10mL/vial
Endpoints
The purpose of this study is to test the efficacy (how well the drug works), safety and tolerability of the experimental drug nivolumab (also known as ONO-4538/BMS-936558). Nivolumab is an antibody (a type of human protein) that is tested to see if the drug can make the body's immune system work on tumor cells. The effect of Nivolumab on bladder cancer and other parts of the urinary tract system (ureter and renal pelvis) will be evaluated by measuring disease-free survival.
Inclution Criteria
1. All subjects must be status post radical surgical resection (R0) for IUC performed within 90 days prior to randomization.
2. All subjects must have pathologic evidence of urothelial carcinoma (originating in bladder, ureter, or renal
pelvis) at high risk of recurrence as described in one of the two below scenarios (i or ii):
(i) Subjects who have not received neo-adjuvant cisplatin chemotherapy: any pT3-pT4a or pT0/x-pT4a/N+ and are not eligible for or refusing adjuvant cisplatin chemotherapy
(1). Subjects ineligible for cisplatin due to any of the following criteria:
a. Creatinine Clearance (using the Cockcroft-Gault formula): < 60 mL/min
b. CTCAE version 4, grade 2 or above audiometric hearing loss
c. CTCAE version 4, grade 2 peripheral neuropathy
d. ECOG PS 2
(2). Subjects that are eligible for cisplatin may be candidates if they refuse available adjuvant chemotherapy, despite being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly documented.
ii) Subjects who received cisplatin based neo-adjuvant chemotherapy: any pT2-pT4a or pT0/x-pT4a/N+
3. Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (e.g. minor variants) are accepted.
4. All subjects must have disease-free status defined as no measurable disease by RECIST 1.1 documented by a complete physical examination and imaging studies within 4 weeks 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 at screening.
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. If insufficient tumor tissue content is provided for analysis (eg, unevaluable), acquisition of additional archived tumor tissue from the most recent resection (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis is required.
6. Life expectancy ≥ 6 months
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Per inclusion 2 i) (1), ECOG PS 2 is listed as part of cisplatin ineligibility criteria. 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
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
2. All subjects must have pathologic evidence of urothelial carcinoma (originating in bladder, ureter, or renal
pelvis) at high risk of recurrence as described in one of the two below scenarios (i or ii):
(i) Subjects who have not received neo-adjuvant cisplatin chemotherapy: any pT3-pT4a or pT0/x-pT4a/N+ and are not eligible for or refusing adjuvant cisplatin chemotherapy
(1). Subjects ineligible for cisplatin due to any of the following criteria:
a. Creatinine Clearance (using the Cockcroft-Gault formula): < 60 mL/min
b. CTCAE version 4, grade 2 or above audiometric hearing loss
c. CTCAE version 4, grade 2 peripheral neuropathy
d. ECOG PS 2
(2). Subjects that are eligible for cisplatin may be candidates if they refuse available adjuvant chemotherapy, despite being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly documented.
ii) Subjects who received cisplatin based neo-adjuvant chemotherapy: any pT2-pT4a or pT0/x-pT4a/N+
3. Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (e.g. minor variants) are accepted.
4. All subjects must have disease-free status defined as no measurable disease by RECIST 1.1 documented by a complete physical examination and imaging studies within 4 weeks 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 at screening.
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. If insufficient tumor tissue content is provided for analysis (eg, unevaluable), acquisition of additional archived tumor tissue from the most recent resection (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis is required.
6. Life expectancy ≥ 6 months
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Per inclusion 2 i) (1), ECOG PS 2 is listed as part of cisplatin ineligibility criteria. 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
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
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.
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-PD1/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 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. 2) i) (5) for renal function eligibility. Neuropathy must have resolved to Grade 2.
9. Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 28
days of first administration of study treatment.
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.
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-PD1/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 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. 2) i) (5) for renal function eligibility. Neuropathy must have resolved to Grade 2.
9. Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 28
days of first administration of study treatment.
The Estimated Number of Participants
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Taiwan
12 participants
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Global
700 participants
