Bladder Cancer
Conditions
Keywords
Muscle-Invasive, Cisplatin-Ineligible, Nivolumab, Lirilumab
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.
Interventions
DRUGNivolumab
Nivolumab 480 mg intravenously (IV) over approximately 30 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion.
DRUGNivolumab/Lirilumab
Nivolumab 480 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) with at least a 30 minute rest between infusions followed by lirilumab 240 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion.
Sponsors
Bristol-Myers Squibb
PrECOG, LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cohort 1: Nivolumab alone (Completed November 20, 2019). In the absence of the occurrence of high rate of treatment related adverse events, the study will proceed with enrollment into Cohort 2: Nivolumab/Lirilumab.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed MIBC (T2-T4a, N0-N1, M0 per American Joint Commission on Cancer \[AJCC\]) pure or mixed histology urothelial carcinoma. Clinical node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined to the true pelvis and are within the planned surgical LN dissection template. * The most recent TURBT that showed muscularis propria invasion should be within 10 weeks prior to beginning study therapy. Patients must have sufficient baseline tumor tissue from either initial or repeat TURBTs. The local site pathologist will be asked to estimate and record the rough approximate percentage of viable tumor in the TURBT sample (initial or repeat TURBT with highest tumor content) to document at least 20% viable tumor content prior to registration. * Patients must be ineligible for cisplatin-based chemotherapy due to any of the following below OR refused cisplatin-based chemotherapy: * Creatinine clearance(CrCl) \<60 mL/min with Easter Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 * Creatinine clearance(CrCl) ≥ 60 mL/min with ECOG PS 2 (if patient fit for RC) * Hearing impaired ≥ Grade 2 by CTCAE criteria * Neuropathy ≥ Grade 2 by CTCAE criteria * Patient refused cisplatin-based chemotherapy? * Patients must be medically fit for TURBT and RC. * Age ≥ 18 years. * Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent. * Willing to provide tumor tissue, blood, and urine samples for research. * Adequate organ function as measured by the following criteria, obtained ≤ 4 weeks prior to registration: * Absolute Neutrophil Count (ANC) ≥ 1000/mm³ (stable off growth factor within 4 weeks of first study drug administration) * Platelets ≥ 100,000/mm³ * Hemoglobin ≥ 8 g/dL * Serum Creatinine Clearance ≥ 30 mL/min using the Cockcroft-Gault formula * Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x Upper Limit of Normal (ULN) * Total Bilirubin ≤ 1.5x ULN (in the absence of previously diagnosed Gilbert's disease) * Women must not be pregnant or breastfeeding since we do not know the effects of nivolumab and lirilumab on the fetus or breastfeeding child. * Sexually active women of child-bearing potential with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 5 months for women and 7 months for men following last dose of study drugs. * Active or prior documented autoimmune disease within the past 2 years prior to Screening or other immunosuppressive agent within 14 days of study treatment. * Patients may not have locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration. * Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible. * Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances: * Not currently active and diagnosed at least 3 years prior to the date of registration. * Non-invasive diseases such as low risk cervical cancer or any cancer in situ. * Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no systemic chemotherapy was indicated.(e.g. low/intermediate risk prostate cancer, etc.). * Patients may not have received any prior immune checkpoint inhibitor (i.e. anti-KIR, anti-PD-1, anti-PD-L1, or other). * Patients may not have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury. * Patients must not have clinically significant cardiac disease. * Patients may not have chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV). * Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion. * Patients may not have known diagnosis of any condition (e.g. post-hematopoietic or solid visceral organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. * Patients with any serious and/or uncontrolled concurrent medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that could, in the investigator's opinion, cause unacceptable safety risks or potentially interfere with the completion of the treatment according to the protocol are not eligible. * Patients may not have any live viral vaccine used for prevention of infectious diseases within 4 weeks prior to study drug(s). * Patients unwilling or unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Nivolumab Nivolumab 480 mg IV on week 0 and week 4
Nivolumab: Nivolumab 480 mg intravenously (IV) over approximately 30 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion. | 13 |
| Cohort 2: Nivolumab/Lirilumab Nivolumab 480 mg IV and Lirilumab 240 mg on week 0 and week 4
Nivolumab/Lirilumab: Nivolumab 480 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) with at least a 30 minute rest between infusions followed by lirilumab 240 mg IV over approximately 60 minutes every 4 weeks for 2 neo-adjuvant doses (week 0 and 4) followed by RC with bilateral (standard or extended) PLND as soon as possible but within 6 weeks after the last neoadjuvant infusion. | 29 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not undergo surgery | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 2: Nivolumab/Lirilumab | Total | Cohort 1: Nivolumab |
|---|---|---|---|
| Age, Continuous | 75 years | 75 years | 76 years |
| Clinical Stage cT2-4a N1 | 1 Participants | 2 Participants | 1 Participants |
| Clinical Stage cT2-4a Nx | 3 Participants | 3 Participants | 0 Participants |
| Clinical Stage cT2 N0 | 23 Participants | 33 Participants | 10 Participants |
| Clinical Stage cT3 N0 | 0 Participants | 1 Participants | 1 Participants |
| Clinical Stage cT4 N0 | 2 Participants | 3 Participants | 1 Participants |
| ECOG Performance Status 0 | 18 Participants | 28 Participants | 10 Participants |
| ECOG Performance Status 1 | 11 Participants | 13 Participants | 2 Participants |
| ECOG Performance Status 2 | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 38 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Prior Chemotherapy | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 40 Participants | 13 Participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 3 Participants |
| Sex: Female, Male Male | 18 Participants | 28 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 13 | 6 / 29 |
| other Total, other adverse events | 12 / 13 | 28 / 29 |
| serious Total, serious adverse events | 3 / 13 | 6 / 29 |
Outcome results
Primary
Grade 3 or Higher Treatment Related Adverse Events as Assessed by CTCAE V5.0
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'.
Time frame: 16 months
Population: Patients who received any treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab | Grade 3 or Higher Treatment Related Adverse Events as Assessed by CTCAE V5.0 | 0 proportion of participants |
| Cohort 2: Nivolumab/Lirilumab | Grade 3 or Higher Treatment Related Adverse Events as Assessed by CTCAE V5.0 | 0.07 proportion of participants |
Secondary
Change in CD8+ TIL Density
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
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab | Change in CD8+ TIL Density | 120.5 percent of CD8+ cells |
| Cohort 2: Nivolumab/Lirilumab | Change in CD8+ TIL Density | 126.9 percent of CD8+ cells |
Comparison: Null hypothesis is the change in CD8+ cell density is not significantly different from zero.p-value: 0.08Wilcoxon Signed-Rank Test
p-value: 0.002Wilcoxon Signed-Rank Test
Secondary
Percentage Change in CD8+ TIL Density
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
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab | Percentage Change in CD8+ TIL Density | 0.8 percentage of change |
| Cohort 2: Nivolumab/Lirilumab | Percentage Change in CD8+ TIL Density | 1.1 percentage of change |
p-value: 0.88Wilcoxon rank sum test
Secondary
Percentage of Participants With Pathologic Complete and Partial Response
Measured by pathologic complete (pT0N0) and partial (\<pT2N0) response rate at time of RC in the two cohorts
Time frame: Responses was assessed at baseline and time of radical cystectomy (within 6 weeks after the last treatment), up to 6 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Nivolumab | Percentage of Participants With Pathologic Complete and Partial Response | ypT0N0 | 16.7 percentage of participants |
| Cohort 1: Nivolumab | Percentage of Participants With Pathologic Complete and Partial Response | <ypT2N0 | 25.0 percentage of participants |
| Cohort 2: Nivolumab/Lirilumab | Percentage of Participants With Pathologic Complete and Partial Response | ypT0N0 | 21.4 percentage of participants |
| Cohort 2: Nivolumab/Lirilumab | Percentage of Participants With Pathologic Complete and Partial Response | <ypT2N0 | 32.1 percentage of participants |
Secondary
Rate of no RC Due to TRAEs
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)
Time frame: from completion of neoadjuvant treatment to 6 weeks after
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Nivolumab | Rate of no RC Due to TRAEs | 0 Participants |
| Cohort 2: Nivolumab/Lirilumab | Rate of no RC Due to TRAEs | 0 Participants |
Secondary
Two Year Recurrence-free Survival
Measured by recurrence rate after 2 years following the RC in the two cohorts.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab | Two Year Recurrence-free Survival | 82 percentage of RFS patients |
| Cohort 2: Nivolumab/Lirilumab | Two Year Recurrence-free Survival | 89 percentage of RFS patients |