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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)]

Primary Purpose

Bladder Cancer

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab (MK-3475)
Bacillus Calmette-Guérin (BCG)
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bladder Cancer focused on measuring Pembrolizumab (MK-3475), Bacillus Calmette-Guérin (BCG), 17-602

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 states:

    • 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.
    • 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.
  • 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.
  • 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.
  • 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.
  • 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
    • Hemoglobin ≥ 9 g/dL
    • Bilirubin ≤ 1.5 times the upper limit of normal (x ULN)
    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN
    • Calculated creatinine clearance ≥ 30 using the CKD-Epi formula

Exclusion Criteria:

  • Current or History of muscle invasive bladder cancer or prostatic stromal invasion.
  • 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
  • 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
  • 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
  • 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.
  • 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

Sites / Locations

  • Memorial Sloan Kettering Basking Ridge (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Monmouth (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Bergen (All protocol activities)Recruiting
  • Memorial Sloan Kettering Commack (All protocol activities)Recruiting
  • Memorial Sloan Kettering West Harrison (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Cancer Center (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Nassau (All Protocol Activities)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

High Risk T1 Bladder Cancer Cohort

Exploratory cohort for high-grade non-muscle-invasive upper tract urothelial carcinoma

Arm Description

Pts will receive pembrolizumab/MK-3475 after transurethral resection of bladder tumor/TURBT in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as a 400 mg IV infusion at 6-wk intervals for 9 doses over a 48-wk period, unless there is unacceptable toxicity or other reasons to discontinue treatment occur. Intravesical BCG therapy (TICE strain, 50 mg) will be given 1x-weekly for 6 consecutive wks as a standard induction course, followed by maintenance BCG consistent w/standard clinical practice. BCG will start on wk 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.

Pts will receive pembrolizumab (MK-3475) administered after ureteroscopy/laser ablation in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as 400 mg IV infusion at 6-week intervals for 9 doses over a 48-week period, unless there is unacceptable toxicity or other reasons that would warrant the discontinuation of treatment. Pts will receive once-weekly BCG therapy (TICE strain, 50 mg) for 6 consecutive wks as a standard induction course 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 wk 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.

Outcomes

Primary Outcome Measures

The proportion of patients who are disease-free
The primary objective for the high-risk T1 bladder cohort is to estimate the proportion of patients who remain free from high-grade recurrence (by urine cytology, cystoscopy ± biopsy) at 6 months from the start of treatment with pembrolizumab (MK-3475) and BCG

Secondary Outcome Measures

The proportion of patients who remain free from high-grade recurrence
Determine the proportion of patients who remain free from high-grade recurrence (by urine cytology, cystoscopy ± biopsy) at 12 months from the start of treatment with pembrolizumab (MK-3475) and BCG

Full Information

First Posted
April 11, 2018
Last Updated
September 25, 2023
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03504163
Brief Title
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)]
Official Title
Phase II Study of 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 Cell Carcinoma (NMI-UTUCC)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 27, 2018 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

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

5. Study Description

Brief Summary
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.
Detailed Description
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bladder Cancer
Keywords
Pembrolizumab (MK-3475), Bacillus Calmette-Guérin (BCG), 17-602

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This is a phase II trial of Pembrolizumab (MK-3475) in combination with Bacillus Calmette-Guérin (BCG) as first-line therapy in patients with high-risk T1 bladder cancer and also in an exploratory cohort of patients with high-grade NMI-UTUC.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
37 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
High Risk T1 Bladder Cancer Cohort
Arm Type
Experimental
Arm Description
Pts will receive pembrolizumab/MK-3475 after transurethral resection of bladder tumor/TURBT in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as a 400 mg IV infusion at 6-wk intervals for 9 doses over a 48-wk period, unless there is unacceptable toxicity or other reasons to discontinue treatment occur. Intravesical BCG therapy (TICE strain, 50 mg) will be given 1x-weekly for 6 consecutive wks as a standard induction course, followed by maintenance BCG consistent w/standard clinical practice. BCG will start on wk 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.
Arm Title
Exploratory cohort for high-grade non-muscle-invasive upper tract urothelial carcinoma
Arm Type
Experimental
Arm Description
Pts will receive pembrolizumab (MK-3475) administered after ureteroscopy/laser ablation in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as 400 mg IV infusion at 6-week intervals for 9 doses over a 48-week period, unless there is unacceptable toxicity or other reasons that would warrant the discontinuation of treatment. Pts will receive once-weekly BCG therapy (TICE strain, 50 mg) for 6 consecutive wks as a standard induction course 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 wk 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.
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab (MK-3475)
Intervention Description
Pembrolizumab (MK-3475) will be administered as a 400 mg intravenous (IV) infusion at 6- week intervals for 9 doses over a 48-week.
Intervention Type
Drug
Intervention Name(s)
Bacillus Calmette-Guérin (BCG)
Intervention Description
Intravesical BCG will be administrated once per week over a 6-week period as induction therapy, followed by maintenance BCG consistent with standard clinical practice
Primary Outcome Measure Information:
Title
The proportion of patients who are disease-free
Description
The primary objective for the high-risk T1 bladder cohort is to estimate the proportion of patients who remain free from high-grade recurrence (by urine cytology, cystoscopy ± biopsy) at 6 months from the start of treatment with pembrolizumab (MK-3475) and BCG
Time Frame
6 months
Secondary Outcome Measure Information:
Title
The proportion of patients who remain free from high-grade recurrence
Description
Determine the proportion of patients who remain free from high-grade recurrence (by urine cytology, cystoscopy ± biopsy) at 12 months from the start of treatment with pembrolizumab (MK-3475) and BCG
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 8 weeks of protocol entry with complete resection of all papillary lesions for patients in the T1 bladder cancer cohort and ureteroscopy within 8 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 states: 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. 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. 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. 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. 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. 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 Hemoglobin ≥ 9 g/dL Bilirubin ≤ 1.5 times the upper limit of normal (x ULN) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN Calculated creatinine clearance ≥ 30 using the CKD-Epi formula Exclusion Criteria: Current or History of muscle invasive bladder cancer or prostatic stromal invasion. 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 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 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 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. 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dean Bajorin, MD
Phone
646-888-4700
Email
bajorind@mskcc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Eugene Pietzak, MD
Phone
6464224781
Email
pietzake@mskcc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Basking Ridge (All Protocol Activities)
City
Basking Ridge
State/Province
New Jersey
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
Facility Name
Memorial Sloan Kettering Monmouth (All Protocol Activities)
City
Middletown
State/Province
New Jersey
ZIP/Postal Code
07748
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
Facility Name
Memorial Sloan Kettering Bergen (All protocol activities)
City
Montvale
State/Province
New Jersey
ZIP/Postal Code
07645
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
Facility Name
Memorial Sloan Kettering Commack (All protocol activities)
City
Commack
State/Province
New York
ZIP/Postal Code
11725
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
Facility Name
Memorial Sloan Kettering West Harrison (All Protocol Activities)
City
Harrison
State/Province
New York
ZIP/Postal Code
10604
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
Facility Name
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700
First Name & Middle Initial & Last Name & Degree
Eugene Pietzak, MD
Phone
6464224781
Email
pietzake@mskcc.org
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Facility Name
Memorial Sloan Kettering Nassau (All Protocol Activities)
City
Uniondale
State/Province
New York
ZIP/Postal Code
11553
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dean Bajorin, MD
Phone
646-888-4700

12. IPD Sharing Statement

Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center

Learn more about this trial

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)]

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