Nivolumab with or without Ipilimumab before Surgery in Treating Patients with Muscle Invasive Bladder Cancer or High Grade Urothelial Cancer of the Upper Urinary Tract
- Histologically confirmed diagnosis of urothelial carcinoma. Variant histology is acceptable if there is a predominant urothelial component.
- For MUSCLE-INVASIVE UROTHELIAL CANCER OF THE BLADDER (Cohorts 1 – 3): Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease. Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.
- For UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (URETER OR RENAL PELVIS) (Cohort U): Histologically confirmed high grade urothelial carcinoma of the upper tract and/or radiographically visible tumor stage T2-T4a N0/x M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. (Variant histology is acceptable if there is a predominant urothelial component).
- Patients ineligible for cisplatin based on any of the following criteria: * Estimated or calculated creatinine clearance >= 30 ml/min but < 60 ml/min. * Grade 2 or above audiometric hearing loss (per CTCAE v4.0). * Grade 2 or above peripheral neuropathy (per CTCAE v4.0).
- Availability of tumor specimen block or 30 unstained slides from diagnosis of muscle-invasive disease. Patients with fewer than 30 slides available may be enrolled after discussion with the principal investigator.
- Karnofsky performance status >= 70%.
- Medically appropriate candidate for radical cystectomy, as per Memorial Sloan Kettering (MSK) Attending Urologic Oncologist
- Absolute neutrophil count >= 1.5 x 10^9/L.
- Platelets >= 100 x 10^9/L.
- Bilirubin =< 1.5 times the upper limit of normal (x ULN).
- Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3 x ULN.
- Partial thromboplastin time (PTT) / prothrombin time (PT) =< 1.5 x ULN or international normalized ratio (INR) < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.
- Prior treatment with systemic chemotherapy for urothelial cancer, including immune checkpoint inhibitors for non-muscle invasive bladder cancer. (Prior intravesical treatment such as Bacillus Calmette-Guerin [BCG] is allowed.)
- Prior bladder-directed radiotherapy (exclusion applies only to MIBC Cohorts 1 – 3).
- Presence of active autoimmune disease, symptoms, or conditions, with the following exceptions: * Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, asymptomatic laboratory evidence of autoimmune disease (e.g.: positive anti-nuclear antibody [+ANA], positive rheumatoid factor [+RF], antithyroglobulin antibodies), or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.
- Unstable angina.
- New York Heart Association (NYHA) grade II or greater congestive heart failure.
- History of myocardial infarction within 6 months.
- History of stroke within 6 months.
- Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose.
- Major surgical procedure within 28 days prior to the study. (Transurethral resection of bladder tumor is permitted)
- Serious, non-healing wound, ulcer, or bone fracture.
- Other prior malignancy active within the previous 2 years except for local or organ-confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study.
- Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other medicines specifically targeting T cells are prohibited. Prior IL-2 is permitted.
- Prior therapy with intravesical Bacillus Calmette-Guerin (BCG) within 6 weeks of treatment.
- Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- History of allergy to study drug component or history of severe hypersensitivity reaction to any monoclonal antibody.
- Women who are breastfeeding or pregnant as evidenced by a positive pregnancy test within 14 days of first dose.
- Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover).
- Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle). * WOCBP are defined as those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopausal is defined as: ** Amenorrhea >= 12 consecutive months without another cause, or ** For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
- Inability to comply with study and/or follow-up procedures.
I. To determine the proportion of patients who proceed to radical cystectomy and pelvic lymph node dissection (RC-PLND) within 60 days after completion of neoadjuvant nivolumab or nivolumab in combination with ipilimumab for cisplatin-ineligible muscle invasive bladder cancer (MIBC), without delays due to treatment-related toxicities or progressive disease. (MIBC Cohorts)
II. To determine the proportion of patients who achieve pathologic complete response, i.e. the absence of residual disease on pathologic evaluation on surgical specimen following neoadjuvant nivolumab plus ipilimumab for cisplatin-ineligible urothelial carcinoma of the upper tract (UTUC). (UTUC Cohort)
I. To evaluate the preliminary clinical activity of nivolumab and nivolumab in combination with ipilimumab in cisplatin-ineligible patients with MIBC. (MIBC Cohorts)
II. To describe the rate of grade 3-4 treatment-related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) version [v] 4.0. (MIBC Cohorts)
III. To describe the rate of grade 3-5 post-surgical complications according to Clavien-Dindo classification system. (MIBC Cohorts)
IV. To evaluate the clinical activity of nivolumab and ipilimumab cisplatin-ineligible patients with UTUC. (UTUC Cohort)
V. To describe the rate of grade 3-4 treatment-related toxicities according to CTCAE v4.0. (UTUC Cohort)
VI. To describe the rate of grade 3-5 post-surgical complications according to Clavien-Dindo classification system. (UTUC Cohort)
VII. To describe the proportion of patients who proceed to radical surgery within 60 days after the completion of nivolumab and ipilimumab. (UTUC Cohort)
I. Examine the correlation between pathologic response rate and genomic alterations, including deoxyribonucleic acid (DNA) damage response and repair gene alteration status, FGFR3 mutation status, and other genomic alterations.
II. Correlation between baseline and changes in plasma and urinary cell-free DNA, and pathologic responses.
I. Changes in tumor characteristics (mutation burden, neo-antigen score, PD-L1 expression, T-cell receptor [TCR] repertoire, DNA damage repair gene alteration status).
II. Treatment-related effects on the peripheral blood immune populations.
IIa. Evaluate the immunologic effects on peripheral blood T-cell phenotypes and TCR repertoire during therapy and after completion of therapy.
IIb. Evaluate the presence of predicted neo-antigen specific T-cells.
III. Mechanisms of immune- and non-immune-mediated resistance in residual tumor.
IV. Investigate the influence of therapy on tumor-infiltrating immune cells with CD8+ lymphocytes in particular.
V. Baseline functional status and changes in functional status following neoadjuvant immune checkpoint inhibitor(s).
OUTLINE: MIBC patients are assigned to 1 of 3 cohorts, and UTUC patients are assigned to cohort U.
COHORT I: Patients receive nivolumab intravenously (IV) day 1. Treatment repeats every 2 weeks for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 10, patients undergo radical cystectomy.
COHORT II: Patients receive nivolumab IV on days 1 and 22, and ipilimumab IV on day 1. Treatment repeats every 6 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 11, patients undergo radical cystectomy.
COHORT III: Patients receive nivolumab IV and ipilimumab IV on day 1. Treatment repeats every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 9, patients undergo radical cystectomy.
COHORT U: Patients receive nivolumab IV on days 1, 22, and 45, and ipilimumab IV on days 1 and 45 in the absence of disease progression or unacceptable toxicity. Beginning week 9, patients undergo radical cystectomy.
After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 2 years.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Min Yuen Teo
- Primary ID 18-042
- Secondary IDs NCI-2018-00923
- Clinicaltrials.gov ID NCT03520491