Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma
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| ClinicalTrials.gov Identifier: NCT03513952 |
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Recruitment Status :
Active, not recruiting
First Posted : May 2, 2018
Last Update Posted : January 4, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Advanced Bladder Urothelial Carcinoma Advanced Ureter Urothelial Carcinoma Metastatic Bladder Urothelial Carcinoma Metastatic Renal Pelvis Urothelial Carcinoma Metastatic Ureter Urothelial Carcinoma Metastatic Urethral Urothelial Carcinoma Metastatic Urothelial Carcinoma Recurrent Bladder Urothelial Carcinoma Recurrent Renal Pelvis Urothelial Carcinoma Recurrent Ureter Urothelial Carcinoma Recurrent Urethral Urothelial Carcinoma Stage III Bladder Cancer AJCC v8 Stage III Renal Pelvis Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage III Urethral Cancer AJCC v8 Stage IV Bladder Cancer AJCC v8 Stage IV Renal Pelvis Cancer AJCC v8 Stage IV Ureter Cancer AJCC v8 Stage IV Urethral Cancer AJCC v8 Stage IVA Bladder Cancer AJCC v8 Stage IVB Bladder Cancer AJCC v8 Unresectable Bladder Urothelial Carcinoma Unresectable Renal Pelvis Urothelial Carcinoma Unresectable Ureter Urothelial Carcinoma | Drug: Atezolizumab Procedure: Biopsy Procedure: Biospecimen Collection Procedure: Computed Tomography Biological: Glycosylated Recombinant Human Interleukin-7 Other: Laboratory Biomarker Analysis Procedure: Magnetic Resonance Imaging Procedure: Positron Emission Tomography and Computed Tomography Scan | Phase 2 |
PRIMARY OBJECTIVE:
I. To determine the clinical efficacy of the investigational treatment combination.
SECONDARY OBJECTIVES:
I. To determine the clinical activity and toxicity of the investigational treatment combination.
II. The clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related (ir) RECIST, and overall survival (OS).
III. The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression levels in the tumor microenvironment.
IV. The safety and toxicity of addition of CYT107 to atezolizumab.
EXPLORATORY OBJECTIVES:
I. To determine the immune correlates of the clinical activity of the investigational treatment combination.
II. Explore the effect of the investigational treatment combination on the number and phenotype of tumor-specific T cells in the peripheral blood.
III. Investigate for evidence that the investigational treatment combination increases the exposure of bladder cancer-specific antigens (e.g., cancer/testis antigens or neoantigens).
IV. Investigate changes in tumor microenvironment that correlate with response or provide information on potential actionable causes for lack of clinical benefit.
V. Investigate the potential that administration of atezolizumab with CYT107 may perturb the pharmacokinetics and immunogenicity of CYT107.
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP 1: Patients receive CYT107 intramuscularly (IM) on days 1, 8, 15, and 22, and atezolizumab intravenously (IV) over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
GROUP 2: Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 2 years.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 54 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Phase II Study of Atezolizumab (MPDL3280A) Plus Recombinant Human IL7 (CYT107) in Patients With Locally Advanced or Metastatic Urothelial Carcinoma |
| Actual Study Start Date : | September 28, 2018 |
| Estimated Primary Completion Date : | December 31, 2023 |
| Estimated Study Completion Date : | December 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Group 1 (CYT107, atezolizumab)
Patients receive CYT107 IM on days 1, 8, 15, and 22, and atezolizumab IV over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
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Drug: Atezolizumab
Given IV
Other Names:
Procedure: Biopsy Undergo biopsy of tumor
Other Names:
Procedure: Biospecimen Collection Undergo collection of blood and stool samples
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Biological: Glycosylated Recombinant Human Interleukin-7 Given IM
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography and Computed Tomography Scan Undergo PET/CT
Other Names:
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Experimental: Group 2 (atezolizumab)
Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
|
Drug: Atezolizumab
Given IV
Other Names:
Procedure: Biopsy Undergo biopsy of tumor
Other Names:
Procedure: Biospecimen Collection Undergo collection of blood and stool samples
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography and Computed Tomography Scan Undergo PET/CT
Other Names:
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- Objective response rate (ORR) [ Time Frame: Up to 2 years ]ORR to be defined by complete response (CR) or partial response (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1. The Cochran Mantel Haenszel test will be conducted to compare ORR in the experimental arm (atezolizumab + CYT107) to the ORR in the control arm (atezolizumab monotherapy). A one-sided significance level of 0.10 will be considered for the test.
- Clinical benefit rate (CBR) measured by RECIST version (v.) 1.1 and immune-related (ir) RECIST [ Time Frame: Up to 2 years ]CBR is defined as the percentage of patients with advanced or metastatic cancer who have achieved CR, PR, and stable disease (SD) to a therapeutic intervention in clinical trials of anticancer agents. A two-sided test for a difference in proportions will be conducted to compare the CBR in the experimental arm to the CBR in the control arm. A two-sided significance level of 0.05 will be considered for the test. Will also assess CBR in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
- Progression-free survival (PFS) [ Time Frame: Up to 2 years ]PFS to be measured by RECIST v1.1 and irRECIST. PFS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for overall survival (OS) and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess PFS in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
- Duration of response (DOR) [ Time Frame: Up to 2 years ]DOR is measured by RECIST v1.1 and irRECIST. DOR will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess DOR in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
- Overall survival [ Time Frame: Up to 2 years ]OS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess OS in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
- Assessment of investigation treatment combination on the immune-bias of the tumor microenvironment [ Time Frame: Up to 2 years ]The evaluation of the effect of the investigation treatment combination on the immune-bias of the tumor microenvironment, based upon baseline and post-baseline tumor biopsy comparisons of number, distribution, and phenotype of tumor-infiltrating cells; PD-L1 expression, and expression of Interferon gamma (IFN-gamma) and associated proinflammatory gene expression in the tumor microenvironment.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Patients must have histologically or cytologically documented locally advanced/inoperable or metastatic urothelial bladder carcinoma (UBC), including renal pelvis, ureters, urinary bladder, and urethra
- Note: Mixed histology tumors allowed if predominant histology is urothelial carcinoma
- Note: Small cell or neuroendocrine carcinoma is not allowed if predominant
- Patients must have recurrent disease after any prior platinum-based chemotherapy regimen
- Patients must have measurable disease per RECIST 1.1 assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI)
- ECOG performance status =< 2 (Karnofsky >= 60%)
- Patients must have a life expectancy of greater or equal to 12 weeks
- Leukocytes >= 2,500/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 8 g/dL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert's disease who have serum bilirubin level =< 3 x ULN may be enrolled)
- Aspartate aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT=< 5 x ULN for patients with liver involvement)
- Alkaline phosphatase =< 2.5 x ULN (=< 5 +/- ULN for patients with documented liver involvement or bone metastases)
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Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault
- At the discretion of the treating physician, a 24-hour urine creatinine clearance could be obtained and utilized as the gold standard if creatinine clearance by Cockcroft-Gault is < 30, and prevents patient enrollment on the trial
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
- Patients must provide tissue from an archival tumor sample (obtained within 2 years from screening visit) or newly obtained core, punch, or excisional biopsy of a tumor lesion if deemed relatively safe and technically feasible
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Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours before receiving the first dose of study agent(s); if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
- Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; CYT107 has not been tested for reproductive toxicity yet and may expose to the same risk; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Patients must have the ability to understand and the willingness to sign a written informed consent document
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Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
- A stable regimen of highly active antiretroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or systemic mitomycin C) before the initiation of study treatment
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Patients who have received more than 2 systemic cytotoxic chemotherapy regimens for metastatic urothelial carcinoma
- Note: Prior perioperative chemotherapy is allowed and is not counted as a line of therapy if patient relapsed >= 12 months later and received additional platinum-based chemotherapy for metastatic disease
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Patients who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier (i.e., have residual toxicities > grade 1); however, the following therapies are allowed:
- Hormone-replacement therapy or oral contraceptives
- Herbal therapy >= 1 week before initiation of study treatment (herbal therapy intended as anticancer therapy must be discontinued at least 1 week before initiation of study treatment)
- Palliative radiotherapy for bone metastases > 2 weeks before initiation of study treatment
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Patients who have received prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody, or pathway -targeting agents
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Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met:
- Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose
- No history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
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- Patients who have received treatment with any other investigational agent within 4 weeks before initiation of study treatment
- Patients who have received treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks before initiation of study treatment
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Patients who have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone ( > 10 mg/day or equivalent), cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti TNF] agents) within 2 weeks before initiation of study treatment
- Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
- The use of inhaled corticosteroids, and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
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Patients taking bisphosphonate therapy for symptomatic hypercalcemia
- Note: Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
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Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
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Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
- Evaluable or measurable disease outside the CNS
- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
- No neurosurgical resection or brain biopsy within 28 days before initiation of study treatment
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Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
- Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
- No stereotactic radiation or whole-brain radiation within 28 days before initiation of study treatment
- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
- Note: Patients with CNS metastases enrolled on trial must also have a brain MRI imaging at all standard radiologic evaluation timepoints
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- Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- Patients who have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
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Patients with known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver/nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); and inherited liver disease
- Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Patients with active underlying autoimmune disease requiring systemic immunosuppressive medication (oral prednisone > 10 mg/day or equivalent). Topical, inhaled, or intra-articular steroids or physiologic endocrine replacement (insulin, levothyroxine, etc.) are permitted. Patients with a history of autoimmune disease that is not currently active require consultation with the protocol principal investigator (PI) and/or Cancer Immunotherapy Trials Network (CITN) Coordinating Center
- Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Patients who have known additional malignancies other than UBC within 2 years before initiation of study treatment; exceptions include malignancies with a negligible risk of metastasis or death and treated with expected curative outcome (e.g., non-melanomatous skin cancers), or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer
- Patients with active tuberculosis (TB)
- Patients who have leptomeningeal disease
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Patients who have severe infections within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia;
- Exception: Uncomplicated urinary tract infection will not be considered as a severe infection in these patients
- Patients who have signs or symptoms of infection within 2 weeks before initiation of study treatment
- Patients who have received oral or IV antibiotics within 2 weeks before initiation of study treatment; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Patients who have major surgical procedure, other than for diagnosis, within 28 days before initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
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Patients who have had a live, attenuated vaccine within 4 weeks before initiation of study treatment or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab.
- Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks before initiation of study treatment or at any time during the study
- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina pectoris, cardiac arrhythmia, recent myocardial infarction (within the last 6 months), or psychiatric illness/social situations that would limit compliance with study requirements
- Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or medical (e.g., infectious) illness
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): NCT03513952
| United States, California | |
| Kaiser Permanente-Riverside | |
| Riverside, California, United States, 92505 | |
| United States, Florida | |
| Moffitt Cancer Center | |
| Tampa, Florida, United States, 33612 | |
| United States, Hawaii | |
| Straub Clinic and Hospital | |
| Honolulu, Hawaii, United States, 96813 | |
| University of Hawaii Cancer Center | |
| Honolulu, Hawaii, United States, 96813 | |
| United States, Illinois | |
| University of Chicago Comprehensive Cancer Center | |
| Chicago, Illinois, United States, 60637 | |
| United States, Louisiana | |
| East Jefferson General Hospital | |
| Metairie, Louisiana, United States, 70006 | |
| United States, Missouri | |
| Washington University School of Medicine | |
| Saint Louis, Missouri, United States, 63110 | |
| United States, New York | |
| Roswell Park Cancer Institute | |
| Buffalo, New York, United States, 14263 | |
| United States, Washington | |
| FHCC South Lake Union | |
| Seattle, Washington, United States, 98109 | |
| Principal Investigator: | Evan Y Yu | Cancer Immunotherapy Trials Network |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03513952 |
| Other Study ID Numbers: |
NCI-2018-00684 NCI-2018-00684 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CITN-14 ( Other Identifier: Cancer Immunotherapy Trials Network ) CITN-14 ( Other Identifier: CTEP ) P30CA015704 ( U.S. NIH Grant/Contract ) U01CA154967 ( U.S. NIH Grant/Contract ) |
| First Posted: | May 2, 2018 Key Record Dates |
| Last Update Posted: | January 4, 2023 |
| Last Verified: | January 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Carcinoma Urinary Bladder Neoplasms Carcinoma, Transitional Cell Urethral Neoplasms Ureteral Neoplasms Kidney Neoplasms Pelvic Neoplasms Recurrence Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Disease Attributes Pathologic Processes |
Urologic Neoplasms Urogenital Neoplasms Neoplasms by Site Urinary Bladder Diseases Urologic Diseases Urethral Diseases Ureteral Diseases Kidney Diseases Atezolizumab Antibodies, Monoclonal Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs |