A Phase 3 Randomized, Double-blind, Multi-center Study of Adjuvant Nivolumab versus Placebo in Subjects with High Risk Invasive Urothelial Carcinoma
- Trial ID
- 2022-500630-29-00
- Protocol
- CA209-274
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is 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. This is clinically relevant as it aims to determine the efficacy of nivolumab in preventing disease recurrence in patients with high-risk invasive urothelial carcinoma, potentially offering a new therapeutic option for improving patient outcomes.
Secondary objectives include: - Comparing 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. - Evaluating 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. - Evaluating 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.
Participants
The clinical trial involves a total of **202 participants** diagnosed with **high-risk invasive urothelial carcinoma**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on their status post-radical surgical resection for invasive urothelial carcinoma, performed within 120 days prior to randomization. All subjects must have a disease-free status, defined as no clinical or radiographic evidence of recurrence, confirmed by a complete physical examination and imaging studies. The trial includes individuals with a life expectancy of at least six months and an Eastern Cooperative Oncology Group (ECOG) performance status of 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 an ECOG PS of 2. The trial population is characterized by a high-risk of recurrence based on pathologic staging, and the dominant component of histology must be urothelial carcinoma or transitional cell carcinoma. Both male and female subjects are included, and the trial considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **Phase 3 randomized, double-blind, multi-center study** designed to evaluate the efficacy of **nivolumab** compared to placebo in subjects with high-risk invasive **urothelial carcinoma**. The primary objective is to compare disease-free survival (DFS) in subjects with tumors expressing PD-L1 (≥1% membranous staining in tumor cells) and all randomized subjects. Secondary endpoints include Non-Urothelial Tract Recurrence Free Survival (NUTRFS), Disease Specific Survival (DSS), and Overall Survival (OS) for nivolumab versus placebo. The trial is expected to conclude by May 29, 2026, with recruitment having started on June 23, 2022.
Participants will be involved in the study for a maximum treatment period of 12 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health status and treatment efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have undergone radical surgical resection for invasive urothelial carcinoma within 120 days prior to randomization, with no clinical or radiographic evidence of disease recurrence. Exclusion criteria include the presence of carcinoma in situ in surgical margins and high-risk non-muscle invasive bladder cancer (NMIBC) at screening.
Participants will be randomly assigned to receive either nivolumab or placebo, administered intravenously. The study is double-blind, meaning neither the participants nor the investigators will know which treatment the participants are receiving. The expected length of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **Nivolumab**, marketed under the name OPDIVO, which is provided as a 10 mg/mL concentrate for solution for infusion. This pharmaceutical form is a **solution for infusion** and is administered **intravenously**. The maximum daily dose is 240 mg, with a total maximum dose of 6240 mg over a treatment period of up to 12 months. The active substance, Nivolumab, is a protein of other origin, and the product is manufactured by Bristol-Myers Squibb Pharma EEIG. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
Another experimental treatment in the study is MDX1106 ONO-4538, also containing **Nivolumab** as the active substance. This product is a **solution for injection** and is similarly administered **intravenously**. The dosing parameters are consistent with those of OPDIVO, with a maximum daily dose of 240 mg and a total maximum dose of 6240 mg over a 12-month period. This product is also developed by Bristol-Myers Squibb International Corporation, and participant compliance is closely monitored throughout the trial.
The study includes a **placebo** group, which receives a 0.9% sodium chloride injection, a standard **solution for injection**. This placebo is used to maintain the double-blind nature of the trial, ensuring unbiased results. The placebo is administered in a manner consistent with the experimental treatments, although specific dosing details are not provided.
Additionally, a 5% Dextrose injection is utilized as a **placebo** in the study. This solution is administered to participants in the placebo group to mimic the administration of the experimental treatments. The use of this placebo helps to maintain the integrity of the study's blinding process. The administration schedule for the placebo is aligned with that of the active treatments to ensure consistency across all participant groups.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **Disease Free Survival (DFS)** as the primary endpoint. This will be analyzed in two distinct populations: subjects with PD-L1 expression levels of 1% or greater and all randomized subjects. Secondary endpoints include the comparison of Non-Urothelial Tract Recurrence Free Survival (NUTRFS), Disease Specific Survival (DSS), and Overall Survival (OS) between the treatment group receiving nivolumab and the placebo group. These endpoints will also be evaluated in subjects with tumors expressing PD-L1 at levels of 1% or greater and across all randomized subjects.
The trial is designed as a Phase 3, randomized, double-blind, multi-center study. The main objective is to compare the DFS for nivolumab versus placebo in subjects with high-risk invasive urothelial carcinoma. The trial will involve subjects who have undergone radical surgical resection and are at high risk of recurrence. The efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, with the estimated end date set for May 29, 2026.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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)
- Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (eg. minor variants) are accepted
- 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. 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
- 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.
- Life expectancy >= 6 months
- 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
- 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
Exclusion Criteria
- Partial cystectomy in the setting of bladder cancer primary tumor or partial nephrectomy in the setting of renal pelvis primary tumor
- Adjuvant systemic or radiation therapy for urothelial or prostatic carcinoma following radical surgical resection of urothelial carcinoma
- 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
- 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.
- 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 enrol
- 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
- 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)
- 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)
- Treatment with any chemotherapy, radiation therapy, biologics for cancer, intravesical therapy, or investigational therapy within 28 days of first administration of study treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 23 Jun 2022 | 22 |
 Belgium | Not Recruiting | 23 Jun 2022 | 4 |
 Denmark | Not Recruiting | 23 Jun 2022 | 7 |
 France | Not Recruiting | 23 Jun 2022 | 17 |
 Germany | Not Recruiting | 23 Jun 2022 | 21 |
 Greece | Not Recruiting | 23 Jun 2022 | 9 |
 Ireland | Not Recruiting | 23 Jun 2022 | 10 |
 Italy | Not Recruiting | 23 Jun 2022 | 11 |
 The Netherlands | Not Recruiting | 23 Jun 2022 | — |
 Poland | Not Recruiting | 23 Jun 2022 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MDX1106 ONO-4538 | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 240 | 12 | PRD260416 |
5% Dextrose injection | Placebo | N/A | — | — | — | N/A |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 240 | 12 | PRD2941375 |
0.9% sodium chloride injection. Solution for injection. | Placebo | N/A | — | — | — | N/A |