Pembrolizumab (MK-3475) and Bacillus Calmette-Guérin (BCG) as First-Line Treatment for High-Risk T1 Non-Muscle-Invasive Bladder Cancer (NMIBC) and High-Grade Non-Muscle-Invasive Upper Tract Urothelial Carcinoma (NMI-UTUC)]

  • End date
    Apr 25, 2024
  • participants needed
  • sponsor
    Memorial Sloan Kettering Cancer Center
Updated on 4 October 2022
radical cystectomy
neutrophil count
carcinoma in situ
bladder cancer
invasive bladder cancer
transurethral resection
bladder tumor
intravesical bcg


The purpose of this study is to find out the effectiveness of pembrolizumab in combination with BCG as a first line therapy for participants with high grade T1 bladder cancer who are at "high risk" for BCG alone to be ineffective and are seeking an alternative treatment option to radical cystectomy. There is biologic rationale for combining pembrolizumab and BCG as two distinct immunotherapies with possible additive or synergistic activity in urothelial cancer. The combination of pembrolizumab with BCG will also be evaluated in an exploratory cohort of patients with upper tract urothelial cancer.


Patients will receive pembrolizumab (MK-3475) administered after TUR in combination with BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as a 400 mg IV infusion at 6-week intervals (Q6W) for 9 doses over a 48 week period, unless there is unacceptable toxicity or other reasons that would warrant the discontinuation of treatment. Patients will receive once-weekly BCG therapy (TICE strain, 50 mg) for 6 consecutive weeks as a standard induction course, given as intravesical BCG for patients with T1 bladder cancer, and administered through a percutaneous nephrostomy tube in antegrade fashion for patients with high-grade NMI-UTUC, consistent with standard clinical practice. BCG will start on week 3 after the first infusion of pembrolizumab (400 mg) to allow for initial priming of T cells to further enhance the effects of BCG treatment. Initiation of induction BCG may be delayed (up to 14 days) if deemed clinically indicated by the treating physician due to side effects from TURBT or ureteroscopy and with permission from the Principal Investigator (PI).

Condition Bladder Cancer
Treatment pembrolizumab (MK-3475), Bacillus Calmette-Guérin (BCG)
Clinical Study IdentifierNCT03504163
SponsorMemorial Sloan Kettering Cancer Center
Last Modified on4 October 2022


Yes No Not Sure

Inclusion Criteria

Be willing and able to provide written informed consent/assent for the trial
Histologically confirmed urothelial cancer by TURBT performed at MSK for patients in the T1 bladder cancer cohort or by high-grade cytology/biopsy by ureteroscopy performed at MSK for patients in the NMI-UTUC cohort
TURBT within 6 weeks of protocol entry with complete resection of all papillary lesions for patients in the T1 bladder cancer cohort and ureteroscopy within 6 weeks of protocol entry with complete ablation of all papillary lesions with ureteroscopy or through antegrade percutaneous access for patients in the NMI-UTUC cohort
Patients in the T1 bladder cancer cohort must have high risk, BCG-naïve non-muscle-invasive urothelial cancer defined as having one of the following disease
T1 on restaging biopsy, plus CIS
Multiple (≥ 1) T1 recurrences, plus CIS
Multifocal T1 plus CIS
T1b (extensive/deep invasion into lamina propria) plus CIS
Lymphovascular invasion plus CIS
T1 with variant histology: including micropapillary, nested variant, poorly differentiated, squamous, and glandular differentiation (the presence of variant histology will be based on MSKCC review), plus CIS
T1 with urothelial carcinoma of prostatic urethra (Ta, Tis, or T1 within prostatic urethra), plus CIS
Large (≥3 cm) T1 tumor, plus CIS
Patients in the NMI-UTUC cohort must have high risk, BCG naïve NMI-UTUC, defined by
having one of the following disease states
Histologic confirmed ureteroscopic biopsy with clinical stage Tis (also known as CIS), Ta, or T1 disease in the renal pelvis. Concomitant ureteral disease will be allowed if completely treated endoscopically
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
Clinical stage Tis confirmed by a positive high-grade selective cytology, coupled with ureteroscopic evaluation, confirming only flat eryethematous lesions and the absence of papillary tumors
Patients must have cross sectional imaging (CT or MRI urogram) within 3 months of
protocol entry demonstrating no evidence of metastasis or radiographic
evidence of muscle invasive disease
Patient refusal of cystectomy and bilateral pelvic lymphadenectomy for the T1 bladder cancer cohort, or refusal of radical nephroureterectomy for NMI-UTUC cohort
Hemoglobin ≥ 9 g/dL
Bilirubin ≤ 1.5 times the upper limit of normal (x ULN)
No prior intravesical BCG therapy for patients in the T1 bladder cancer cohort
No prior radiation therapy for bladder cancer for patients in the T1 bladder cancer cohort. Prior radiation therapy for prostate cancer is allowed
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN
Calculated creatinine clearance ≥ 30 using the CKD-Epi formula
ECOG performance status of 0 or 1
Age ≥ 18 years
Female subjects of childbearing potential must be willing to use 2 methods of birth control, be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of the study medication (reference section 9.5.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year
Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, localized prostate cancer, and CIS of the cervix)
Required initial laboratory values
Absolute neutrophil count ≥ 1.5 x 10^9/L
Platelets ≥ 100 x 10^9/L

Exclusion Criteria

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
Pregnant (positive pregnancy test) or lactating
Serious, non-healing wound, ulcer, or bone fracture
Inability to comply with study and/or follow-up procedures
Prior therapy with an anti-PD-1 agent, anti-PD-L1 agent, or other inhibitory or stimulatory agent oriented towards a T-cell receptor
Current or History of muscle invasive bladder cancer or prostatic stromal invasion
Active infection requiring systemic therapy
Known history of human immunodeficiency virus (HIV)
Known active Hepatitis B or Hepatitis C
Received live attenuated vaccines within 30 days prior to start of study treatment. Patients must also agree to avoid live attenuated vaccines during study treatment
Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren's syndrome will not be excluded from the study
Presence of any systemic metastases (i.e, nodal, visceral, or central nervous system)
Major surgical procedure (other than TURBT or ureteroscopy) within 28 days prior to the study
Known contraindications to BCG, defined as one of the following
History of systemic hypersensitivity reaction or history of febrile systemic BCG reaction
Febrile illness or persistent gross hematuria
Active tuberculosis
Immunosuppression due to congenital or acquired immune deficiency, concurrent immune suppressive disease, systemic cancer therapy, or chronic immunosuppressive therapy other than topical or inhaled corticosteroids
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