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A Study to Test the Safety of Immunotherapy With Nivolumab Alone or With Ipilimumab Before Surgery for Bladder Cancer Patients Who Are Not Suitable for Chemotherapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03520491
Recruitment Status : Recruiting
First Posted : May 9, 2018
Last Update Posted : February 2, 2023
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Study Description
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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.

Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Nivolumab Drug: Ipilimumab Procedure: Radical cystectomy Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This is a pilot study designed to evaluate neoadjuvant nivolumab and nivolumab in combination with ipilimumab in patients with muscle-invasive bladder cancer (MIBC) or urothelial cancers of the upper urinary tract (ureter or renal pelvis) [UTUC], who are ineligible for treatment with cisplatin-based chemotherapy. The study is designed with three sequential 15-patient cohorts.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 25, 2018
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: 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.
 Drug: Nivolumab
Nivolumab 3 mg/kg or Nivolumab 1 mg/kg

Procedure: Radical cystectomy
RC-PLND is to take place within 60 days from the last dose of treatment.(After week 10 for cohort 1, after week 11 for cohort 2, and after week 9 for cohort 3.)
Experimental: 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.
 Drug: Nivolumab
Nivolumab 3 mg/kg or Nivolumab 1 mg/kg

Drug: Ipilimumab
Ipilimumab 3 mg/kg

Procedure: Radical cystectomy
RC-PLND is to take place within 60 days from the last dose of treatment.(After week 10 for cohort 1, after week 11 for cohort 2, and after week 9 for cohort 3.)
Experimental: 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.
 Drug: Nivolumab
Nivolumab 3 mg/kg or Nivolumab 1 mg/kg

Drug: Ipilimumab
Ipilimumab 3 mg/kg

Procedure: Radical cystectomy
RC-PLND is to take place within 60 days from the last dose of treatment.(After week 10 for cohort 1, after week 11 for cohort 2, and after week 9 for cohort 3.)
Experimental: 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.
 Drug: Nivolumab
Nivolumab 3 mg/kg or Nivolumab 1 mg/kg

Drug: Ipilimumab
Ipilimumab 3 mg/kg

Procedure: Radical cystectomy
RC-PLND is to take place within 60 days from the last dose of treatment.(After week 10 for cohort 1, after week 11 for cohort 2, and after week 9 for cohort 3.)


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • Karnofsky performance status ≥ 70%.
  • Medically appropriate candidate for radical cystectomy, as per MSK Attending Urologic Oncologist
  • Age ≥ 18 years.

  • Required initial laboratory values:

    • 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
    • PTT/PT ≤1.5 x ULN or INR < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.

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.
  • 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 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. Post-menopausal 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03520491


Contacts
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Contact: Min Yuen Teo, MD 646-888-4867 teom@mskcc.org
Contact: Jonathon Rosenberg, MD 646-888-4741

Locations
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United States, New Jersey
Memorial Sloan Kettering Basking Ridge (All Protocol Activities) Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Min Yuen Teo, MD    646-888-4867      
Memorial Sloan Kettering Monmouth (All Protocol Activities) Recruiting
Middletown, New Jersey, United States, 07748
Contact: Min Yuen Teo, MD    646-888-4867      
Memorial Sloan Kettering Bergen (All Protocol Activities) Recruiting
Montvale, New Jersey, United States, 07645
Contact: Min Yuen Teo, MD    646-888-4867      
United States, New York
Memorial Sloan Kettering Commack (All protocol activities) Recruiting
Commack, New York, United States, 11725
Contact: Min Yuen Teo, MD    646-888-4867      
Memorial Sloan Kettering Westchester (All Protocol Activities) Recruiting
Harrison, New York, United States, 10604
Contact: Min Yuen Teo, MD    646-888-4867      
Memorial Sloan Kettering Cancer Center (All Protocol Activities) Recruiting
New York, New York, United States, 10065
Contact: Min Yuen Teo, MD    646-888-4867      
Contact: Jonathan Rosenberg, MD    646-888-4741      
Memorial Sloan Kettering Nassau (All protocol activities) Recruiting
Uniondale, New York, United States, 11553
Contact: Min Yuen Teo, MD    646-888-4867      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: Min Yuen Teo, MD Memorial Sloan Kettering Cancer Center
More Information
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Additional Information:

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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03520491    
Other Study ID Numbers: 18-042
First Posted: May 9, 2018    Key Record Dates
Last Update Posted: February 2, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
Immunotherapy
Nivolumab
Ipilimumab
18-042
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
 Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action