A Study to Evaluate Gemcitabine and MK-3475 (Pembrolizumab) to Treat Patients with BCG-Unresponsive Non-Muscle Invasive Bladder Cancer


About this study

The purpose of this study is to assess the effect of adding pembrolizumab to gemcitabine in treating patients with non-muscle invasive bladder cancer whose cancer does not respond to Bacillus Calmette-Guerin (BCG) treatment. Drugs used in chemotherapy, such as gemcitabine, work in different ways by stopping the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the patient's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding pembrolizumab to gemcitabine may delay the return of BCG-unresponsive bladder cancer for longer period compared to gemcitabine alone.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • High grade Ta, T1 or CIS urothelial carcinoma. Accrual of patients with Ta or T1 disease may be closed to ensure adequate patients enrollment to meet the primary endpoint.
  • Persistent disease after completing therapy with at least induction BCG (≥ 5 doses) and the first round of maintenance or second induction course (≥ 2 doses).
  • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above.
  • High grade T1 after completing therapy with at least induction BCG (≥ 5 doses) or after completing therapy with at least induction BCG (≥ 5 doses) and first round of maintenance or second induction course (≥ 2 doses).
  • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above.
  • Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible.
  • Patients who are disease free at 6 months after starting BCG but have high grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible.
  • The recurrence must be within 6 months of the last BCG dose.
  • Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy.
  • All visible tumor must be completely resected 60 days prior to registration (residual pure CIS is permitted).
  • All patients must have histologically confirmed urothelial cancer of the bladder within 60 days prior to registration. All patients must have had a cystoscopy without papillary tumor and negative urinary cytology within 21 days of registration. (positive cytology is allowed in patients with pure CIS).
  • All patients with T1 tumors must undergo a re-staging transurethral resection of bladder tumor (TURBT) within 60 days of registration. There must be uninvolved muscularis propria present in the re-staging TURBT. The initial TURBT prior to re-staging TURBT may be greater than 60 days prior to registration.
  • Patients must have had imaging with computed tomography (CT) or magnetic resonance imaging (MRI) abdomen/pelvis within 90 days of registration demonstrating no evidence of metastasis.
  • Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.
  • Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3.
  • Platelet count ≥ 100,000/mm^3.
  • Hemoglobin ≥ 9.0 g/dL.
  • Creatinine ≤ 1.5 x upper limit of normal (ULN).
  • In patients with creatinine > 1.5 x ULN, if measured or calculated creatinine clearance > 30 mL/min, then patient is eligible.
  • Total Bilirubin ≤ 1.5 x ULN.
  • In patients with a total bilirubin > 1.5 x ULN, if direct bilirubin < 1.0 X ULN, then patient is eligible.
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5 x ULN.
  • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN.
  • Unless patient is receiving anticoagulant therapy, then PT or partial thromboplastin time (PTT) must be within the therapeutic range of intended use of the anticoagulant(s).
  • Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
  • Unless patient is receiving anticoagulant therapy, then PT or PTT must be within the therapeutic range of intended use of the anticoagulant(s).
  • Patients with human immunodeficiency virus (HIV) are eligible with the following:
    • On stable regimen of anti-retroviral therapy (highly active anti-retroviral therapy [HAART]);
    • No requirement for antibiotic or antifungal for prevention of opportunistic infections;
    • A CD4 count about 250 cells/mcl and undetectable HIV viral load by PCR.
  • Has no known additional malignancy that has had progression or has required active treatment in the last three years. Exceptions include basal or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent is allowed, provided that the prostate-specific antigen (PSA) is undetectable for at least 1 year while off androgen deprivation therapy.
  • No live vaccines or BCG within 30 days prior to registration.
  • Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable:
    • Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).

Exclusion Criteria:

  • Patients cannot have had a history of urothelial carcinoma in the ureters or prostatic urethra 24 months prior to registration.
  • Patients must not have received any prior or concurrent systemic chemotherapy or immunotherapy (prior intravesical chemotherapy and interferon is permitted). Single dose chemotherapy post TURBT is permitted.
  • Patients must not have received any prior bladder radiation.
  • Patients must not have had an active autoimmune disease requiring systemic treatment within 24 months prior to registration. Autoimmune diseases include, but not limited to, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.
  • Patients must not have undergone prior organ or bone marrow transplant.
  • Patients must not have active tuberculosis.
  • Patients must not have been treated with antibiotics for an active infection within 14 days prior to registration. Prophylactic antibiotics are permitted.
  • Patients must not have a history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or active pneumonitis.
  • Patients must not have active hepatitis B or C (resolved disease with positive anti-hepatitis B core [HBc] antibody or negative polymerase chain reaction [PCR] for hepatitis C [HCV] RNA permitted).
  • Glucocorticoids for any purpose other than to modulate symptoms from an adverse event of suspected immunologic etiology. Physiologic doses of corticosteroids are allowed.
  • Physicians should consider whether any of the following may render the patient inappropriate for this protocol:
    • Psychiatric illness which would prevent the patient from giving informed consent;
    • Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mark Tyson, M.D., M.P.H.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information


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Additional contact information

Cancer-related trials contact form

Phone: 855-776-0015 (toll-free)

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