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Intermittent Checkpoint Inhibitor Therapy for the Treatment of Advanced or Metastatic Urothelial Cancer

Trial Status: Active

This phase II trial studies how well intermittent checkpoint inhibitor therapy works in treating patients with urothelial cancer that has spread to other places in the body (advanced or metastatic). Checkpoint inhibitors, such as pembrolizumab, atezolizumab, durvalumab, nivolumab, and avelumab, are drugs that work by helping the immune system recognize and kill cancer cells. This study is being done to find out whether intermittent checkpoint inhibitor therapy works the same, better, or worse than continued checkpoint inhibitor therapy in treating patients with urothelial cancer.

Inclusion Criteria

  • Histological confirmation of urothelial carcinoma (any histology)
  • Advanced or metastatic urothelial carcinoma
  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Has received at least 24 weeks (+/- 4 weeks) on CPI therapy per standard of care (SOC) for advanced urothelial carcinoma
  • Karnofsky performance score (KPS) >= 70%
  • Willing and able to provide informed consent
  • Serum creatinine =< 2 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 30 mL/min (measured or calculated using the Cockcroft-Gault formula)
  • Hemoglobin (Hb) >= 8.0 g/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
  • Bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

Exclusion Criteria

  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Patients are excluded if they have known human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)
  • Major surgery (e.g., cystectomy) less than 28 days prior to the first dose of study drug
  • Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 7 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
  • Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
  • Pregnant women are excluded from this study because animal studies have demonstrated that PD-1/PD-L1 inhibitors can cause fetal harm when administered to pregnant women. Breastfeeding women are excluded from this study because PD-1/PD-L1 inhibitors may be excreted in human milk and the potential for serious adverse reactions in nursing infants


Case Comprehensive Cancer Center
Status: ACTIVE
Contact: Moshe C. Ornstein
Phone: 216-445-6592


I. To assess the efficacy of intermittent checkpoint inhibitor (CPI) therapy, defined as the proportion of patients who remain off therapy for at least 36 weeks.


I. To determine the clinical outcome (treatment free interval [TFI], overall response rate [ORR], progression free survival [PFS], overall survival [OS]) in advanced urothelial carcinoma with intermittent CPI therapy.

II. To assess response to re-initiation of CPI therapy.


I. Investigate the genomic and immunologic markers of response and resistance to therapy.

II. Investigate the immunomodulatory cell makeup (specifically, lymphocyte PD1 occupancy, myeloid-derived suppressor cells [MDSC], regulatory T cells [Treg], CD4 and CD8 T Cells, TCR repertoire) at the start of treatment, during the intermittent phase and off treatment.


Patients receive pembrolizumab intravenously (IV) over 30 minutes, atezolizumab IV over 30 or 60 minutes, durvalumab IV over 60 minutes, nivolumab IV over 30 minutes, or avelumab IV over 60 minutes on day 1. Cycles repeat every 14 days for durvalumab and avelumab, every 21 days for pembrolizumab and atezolizumab, and every 28 days for nivolumab in the absence of disease progression or unacceptable toxicity. After 24 weeks of CPI treatment, patients with tumor burden reduction of 10% or greater suspend CPI treatment.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Moshe C. Ornstein

  • Primary ID CASE6819
  • Secondary IDs NCI-2020-02423
  • ID NCT04322643