Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
- Registration Number
- NCT03532451
- Lead Sponsor
- PrECOG, LLC.
- Brief Summary
Patients with muscle-invasive bladder cancer (MIBC) who can not receive cisplatin or refuse cisplatin therapy will receive nivolumab or nivolumab/lirilumab before a planned surgical procedure called a radical cystectomy (RC) to remove the bladder.
Nivolumab works by attaching to and blocking a molecule called Programmed Death-1 (PD-1). Lirilumab attaches to and blocks a group of molecules called Killer Cell Immunoglobulin-Like Receptor (KIR). PD-1 and KIR are proteins present mainly on immune system cells, and each controls part of the immune system by shutting it down. It is hoped that by binding to and inactivating these proteins, these drugs can enhance the body's ability to detect, attack and destroy cancer cells.
The purpose of this research study is to see whether nivolumab alone or combination of nivolumab and lirilumab given before surgery is effective in treating people who have bladder cancer, and to examine the side effects, good and bad, associated with nivolumab and lirilumab.
- Detailed Description
Bladder cancer (BC) is the 6th most common malignancy in the United States with an estimated 79,030 new cases and 16,870 deaths in 2017. It is the 4th most common cancer in men and there are presently \>500,000 BC patients alive in the US. It accounts for about 5% of all new cancers in the US. It is also the most expensive cancer to treat from diagnosis to death. Almost a third of BC patients present with MIBC.
This is a Phase Ib open-label clinical trial for patients that are either cisplatin-ineligible or refuse cisplatin-based chemotherapy and have MIBC (T2-T4a, N0-N1, M0).Neoadjuvant treatment must start within 10 weeks of transurethral resection of the most recent transurethral resection of bladder tumor (TURBT) that showed muscularis propria invasion.
Patients must have sufficient baseline tumor tissue. Tumor tissue content for CD8+ T-cell density assessment must be qualified as sufficient (≥ 20% tumor content in the specimen) for analysis and must be documented by the local pathologist prior to registration.
The first 12 patients will be enrolled into Cohort 1 and treated with nivolumab before a planned RC (Completed November 20, 2019).
In the absence of the occurrence of high rate of treatment related Adverse Events (AEs) with nivolumab, the study will proceed with enrollment into Cohort 2 with the combination of nivolumab/lirilumab before a planned RC.
Each group will receive a total of 2 doses (week 0 and 4) of nivolumab (Cohort 1) or nivolumab/lirilumab (Cohort 2) therapy followed by RC with bilateral (standard or extended) pelvic lymph node dissection (PLND).
Mandatory tumor tissue at Screening (archived tumor tissue from Transurethral Resection of Bladder Tumor \[TURBT\] may be used) and at time of RC. Peripheral blood and urine samples are also required.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 43
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1: Nivolumab Nivolumab Nivolumab 480 mg IV on week 0 and week 4 Cohort 2: Nivolumab/Lirilumab Nivolumab/Lirilumab Nivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4
- Primary Outcome Measures
Name Time Method Grade 3 or Higher Treatment Related Adverse Events as Assessed by CTCAE V5.0 16 months To assess safety of treatment according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) manifested as the rate of Grade 3 or higher treatment related adverse events in patients treated with nivolumab (Cohort 1) or combination of nivolumab/lirilumab (Cohort 2). The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. Toxicity graded by CTCAE v5.0 scaling from 1-5 (mild to death). Grade 3 or higher events are those that are graded '3- severe or medically significant', 4- life-threatening consequences; urgent intervention indicated' or '5-Death related to AE'.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Pathologic Complete and Partial Response Responses was assessed at baseline and time of radical cystectomy (within 6 weeks after the last treatment), up to 6 months. Measured by pathologic complete (pT0N0) and partial (\<pT2N0) response rate at time of RC in the two cohorts
Two Year Recurrence-free Survival 24 months Measured by recurrence rate after 2 years following the RC in the two cohorts.
Rate of no RC Due to TRAEs from completion of neoadjuvant treatment to 6 weeks after the rate of patients in each cohort who do not get RC within 6 weeks after completion of neoadjuvant treatment specifically and directly related to treatment-related adverse events (AEs)
Change in CD8+ TIL Density From pre-treatment Transurethral Resection of Bladder Tumor (TURBT) which happens 10 weeks (at most) before treatment to post-treatment Radical Cystectomy (RC), up to 6 months. RC was scheduled within 6 weeks after the last neoadjuvant infusion CD8+ TIL density was measured at baseline(TURBT) and radical cystectomy after treatment. Change in CD8+ TIL density from pre-treatment Transurethral Resection of Bladder Tumor (TURBT) to post-treatment Radical Cystectomy (RC) tissues separately in patients treated with nivolumab or combination of nivolumab/lirilumab. Each individual patient's CD8+ TIL density change was defined as number of CD8+ cells / the annotated tissue area in mm2
Percentage Change in CD8+ TIL Density The outcome was measured from pre-treatment Transurethral Resection of Bladder Tumor (TURBT) to Radical Cystectomy (RC), up to 6 months.TURBT was scheduled 10 weeks at most before the treatment. RC was scheduled within 6 weeks after the last treatment. CD8+ TIL density was measured at baseline(TURBT) and radical cystectomy after treatment. The change in CD8+ TIL density from pre-treatment Transurethral Resection of Bladder Tumor (TURBT) to post-treatment Radical Cystectomy (RC) tissues separately in patients treated with nivolumab or combination of nivolumab/liriluma. Each individual patient's percent change was defined as \[(Cystectomy TIL Density)-(TURBT TIL Density)\] / (TURBT TIL Density) x 100
Trial Locations
- Locations (8)
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
University of TX Southwestern
🇺🇸Dallas, Texas, United States
University of Washington
🇺🇸Seattle, Washington, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States