A Pilot Study to Evaluate the Safety of Neoadjuvant Nivolumab Alone or in Combination With Ipilimumab for Cisplatin-Ineligible Patients With Muscle Invasive Bladder Cancer (CA209-9DJ)
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Bladder Cancer
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 52
- Locations
- 7
- Primary Endpoint
- number of patients who proceed to radical cystectomy and pelvic lymph node dissection (RC-PLND)
- Status
- Active, Not Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
The purpose of this study is to test if immunotherapy with nivolumab alone or in combination with ipilimumab is safe and does not delay the planned bladder cancer surgery. The investigators want to see if treatment with these drugs prior to surgery may decrease the size of the bladder cancer and thus could help make the surgery more successful.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of urothelial carcinoma of the bladder. 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 ≥ 30ml/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.
Exclusion Criteria
- •Prior treatment with systemic chemotherapy for urothelial cancer, including immune checkpoint inhibitors for non-muscle invasive bladder cancer. (Prior intravesical treatment such as 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.: +ANA, +RF, anti-thyroglobulin 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.
Arms & Interventions
Cohort 1
Nivolumab 3 mg/kg on day 1 of each cycle for a total of 5 cycles. Each cycle will be two weeks long and treatment will occur during weeks 0, 2, 4, 6, and 8.
Intervention: Nivolumab
Cohort 1
Nivolumab 3 mg/kg on day 1 of each cycle for a total of 5 cycles. Each cycle will be two weeks long and treatment will occur during weeks 0, 2, 4, 6, and 8.
Intervention: Radical cystectomy
Cohort 2
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1 of each cycle, followed by Nivolumab 3 mg/kg on day 22 of each cycle for a total of 2 cycles. Each cycle will be six weeks long. Ipilimumab and Nivolumab will occur on weeks 0 and 6 while Nivolumab alone will occur on weeks 3 and 9.
Intervention: Nivolumab
Cohort 2
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1 of each cycle, followed by Nivolumab 3 mg/kg on day 22 of each cycle for a total of 2 cycles. Each cycle will be six weeks long. Ipilimumab and Nivolumab will occur on weeks 0 and 6 while Nivolumab alone will occur on weeks 3 and 9.
Intervention: Ipilimumab
Cohort 2
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1 of each cycle, followed by Nivolumab 3 mg/kg on day 22 of each cycle for a total of 2 cycles. Each cycle will be six weeks long. Ipilimumab and Nivolumab will occur on weeks 0 and 6 while Nivolumab alone will occur on weeks 3 and 9.
Intervention: Radical cystectomy
Cohort 3
Ipilimumab 3 mg/kg on day 1 each cycle and Nivolumab 1 mg/kg on day 1 of each cycle for a total of 3 cycles. Each cycle will be three weeks long and treatment will occur during weeks 0, 3, and 6.
Intervention: Nivolumab
Cohort 3
Ipilimumab 3 mg/kg on day 1 each cycle and Nivolumab 1 mg/kg on day 1 of each cycle for a total of 3 cycles. Each cycle will be three weeks long and treatment will occur during weeks 0, 3, and 6.
Intervention: Ipilimumab
Cohort 3
Ipilimumab 3 mg/kg on day 1 each cycle and Nivolumab 1 mg/kg on day 1 of each cycle for a total of 3 cycles. Each cycle will be three weeks long and treatment will occur during weeks 0, 3, and 6.
Intervention: Radical cystectomy
Cohort U (UTUC patients) is independent from Cohorts 1 - 3. ( who are cisplatin-ineligible)
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1, of each cycle, followed by Nivolumab 3 mg/kg on day 22 and Ipilimumab 3mg/kg and Nivolumab 1mg/kg on day 45.
Intervention: Nivolumab
Cohort U (UTUC patients) is independent from Cohorts 1 - 3. ( who are cisplatin-ineligible)
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1, of each cycle, followed by Nivolumab 3 mg/kg on day 22 and Ipilimumab 3mg/kg and Nivolumab 1mg/kg on day 45.
Intervention: Ipilimumab
Cohort U (UTUC patients) is independent from Cohorts 1 - 3. ( who are cisplatin-ineligible)
Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1, of each cycle, followed by Nivolumab 3 mg/kg on day 22 and Ipilimumab 3mg/kg and Nivolumab 1mg/kg on day 45.
Intervention: Radical cystectomy
Outcomes
Primary Outcomes
number of patients who proceed to radical cystectomy and pelvic lymph node dissection (RC-PLND)
Time Frame: within 60 days after completion of neoadjuvant nivolumab or nivolumab in combination with ipilimumab for cisplatin-ineligible MIBC, without delays due to treatment-related toxicities or progressive disease