A Study of Chemotherapy and Radiation Therapy Compared to Chemotherapy and Radiation Therapy Plus MEDI4736 (Durvalumab) Immunotherapy for Bladder Cancer Which Has Spread to the Lymph Nodes (The INSPIRE Study)

Bladder Urothelial Carcinoma Clinical Trial

Official title:

Phase II Study of Bladder-SparIng ChemoradiatioN With Durvalumab in Clinical Stage III, Node PosItive BladdeR CancEr (INSPIRE)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04216290
• Other study ID #: NCI-2019-08628
• Secondary ID: NCI-2019-08628EA
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 17, 2021
• Est. completion date: June 30, 2026

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the benefit of adding an immunotherapy drug called MEDI4736 (durvalumab) to standard chemotherapy and radiation therapy in treating bladder cancer which has spread to the lymph nodes. Drugs used in standard chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone. Patients with limited regional lymph node involvement may benefit from attempt at bladder preservation, and use of immunotherapy and systemic chemotherapy.

Description:

PRIMARY OBJECTIVE: I. To compare the clinical complete response rate (cCR) after chemoradiotherapy (chemoRT) with or without durvalumab in node-positive bladder cancer patients. SECONDARY OBJECTIVES: I. To compare the toxicity profile in both arms using the Common Terminology Criteria for Adverse Events (CTCAE). II. To estimate the progression-free survival (PFS) in both arms. III. To estimate overall survival (OS) post randomization in both arms. IV. To estimate the bladder intact event free survival (BIEFS) in both arms. V. To estimate the metastasis free survival (MFS) in both arms. VI. To estimate bladder cancer specific survival in both arms. VII. To estimate the complete clinical response duration in both arms. VIII. To estimate salvage cystectomy rates in both arms. EXPLORATORY OBJECTIVE: I. Planned subgroup analyses for clinical outcome (clinical complete response [CR] rate post chemoRT +/- durvalumab, MFS, OS, PFS) based on stratification factors. TRANSLATIONAL OBJECTIVE: I. To collect and bank tumor tissue and blood specimens at pre-and post-treatment with chemoRT +/- durvalumab to determine predictive or prognostic markers. OUTLINE: STEP 1 - Randomization: Patients are randomized to 1 of 2 arms. ARM C: Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice a week (BIW) for 6 weeks; cisplatin IV over 30-60 minutes once a week (QW) for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV continuous infusion on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy, cystoscopy, and computed tomography (CT) or magnetic resonance imaging (MRI) on study. Patients may also undergo tumor tissue and blood sample collection on study. ARM D: Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes BIW for 6 weeks; cisplatin IV over 30-60 minutes QW for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV continuous infusion on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy, cystoscopy, and CT or MRI on study. Patients may also undergo tumor tissue and blood sample collection on study. STEP 2 - Registration: Patients are assigned to 1 of 2 arms. ARM E: Patients previously randomized to Arm C (chemoradiation and durvalumab) who achieve clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy, cystoscopy, and CT or MRI on study. Patients may also undergo tumor tissue and blood sample collection on study. ARM F: Patients previously randomized to Arm D (chemoradiation) who achieve clinical CR or clinical benefit, or patients previously randomized to Arm C with no clinical CR or clinical benefit undergo observation. Patients also undergo bladder biopsy, cystoscopy, and CT or MRI on study. Patients may also undergo tumor tissue and blood sample collection on study. After completion of study treatment, patients are followed up every 12 weeks for 1 year, every 6 months for year 2, and then annually for years 3-4.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 95
• Est. completion date: June 30, 2026
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Step 1 (Randomization) Inclusion
• Patient must be >= 18 years of age
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of step 1 randomization
• Patient must have histologically proven pure or mixed urothelial cancer of the bladder
• NOTE: Small cell carcinoma is excluded, however other variant histologies are permitted provided a component of urothelial carcinoma is present
• Patient must have documented node-positive and non-metastatic disease (any T, any N, M0). Node positivity must have been defined prior to receiving and systemic chemotherapy or induction chemotherapy. Node positivity can fall into either of the following categories and will be defined by

imaging and/or biopsy:

• A lymph node >= 1.0 cm in short axis on imaging (i.e., CT or MRI or positron emission tomography [PET]/CT)
• A lymph node that is < 1 cm on imaging with either a biopsy confirming involvement with cancer
• For patients who have received induction chemotherapy (any type of systemic chemotherapy) for node positive bladder cancer prior to enrollment, there must be no signs of disease progression (CR/PR or stable disease [SD]) based on restaging

imaging and cystoscopy, which consists of:

• CT chest, abdomen, and pelvis obtained after completion of induction chemotherapy and within 8 weeks prior to step 1 randomization
• NOTE: MRI can be used instead of CT per treating physician discretion
• Cystoscopic evaluation and attempt to perform maximal TURBT performed by the participating urologist after completion of induction chemotherapy and within 12 weeks prior to step 1 randomization. If maximal TURBT is not possible for medical reasons, the enrollment must be discussed and approved with the study chair. Documentation of correspondences with the study chair must be kept on file
• Patients who achieve CR upon cystoscopy per urologist with no visible tumor (i.e., no need for additional TURBT), are allowed to proceed in the study as adequate resection with no residual disease in bladder
• For patients who did not receive induction chemotherapy (any type of systemic chemotherapy) for node positive bladder cancer prior to enrollment, the following

must be obtained:

• CT chest, abdomen, and pelvis completed within 8 weeks prior to step 1 randomization.
• NOTE: MRI can be used instead of CT per treating physician discretion
• Cystoscopic evaluation and attempt to perform maximal TURBT performed by the participating urologist within 12 weeks prior to Step 1 randomization. If maximal TURBT is not possible for medical reasons, the enrollment must be discussed and approved with the study chair. Documentation of correspondences with the study chair must be kept on file.
• For patients who may need repeat TURBT if their old TURBT has fallen out of window: If urologist determine no visible tumor (i.e., no need for additional resection) upon cystoscopy, they are allowed to proceed in the study as complete resection
• Patient must agree to undergo CT simulation and treatment planning. If this is the first case registered at the site, then a pre-treatment RT review will be required and will take up to 3 business days. The patient cannot start radiation treatment prior to successful completion of this pre-treatment review. Therefore, careful planning is necessary to meet the deadline of starting radiation within 20 business days of Step 1 randomization
• Patients with previous exposure to immune checkpoint inhibitor for non-muscle invasive disease are eligible. If given for NMIBC, the last dose must have been completed > 12 months prior to step 1 randomization
• Leukocytes >= 3,000/mcL (obtained < 14 days prior to step 1 randomization)
• Absolute neutrophil count (ANC) >= 1,500/mcL (obtained < 14 days prior to step 1 randomization)
• Hemoglobin >= 9 g/dL (obtained < 14 days prior to step 1 randomization)
• Platelets >= 100,000/mcL (obtained < 14 days prior to step 1 randomization)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days prior to step 1 randomization)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained < 14 days prior to step 1 randomization)
• Adequate renal function as evidenced by calculated (Cockcroft's formula) creatinine clearance or 24 hours actual creatinine clearance >= 30mL/min. The creatinine used to calculate the clearance result must have been obtained within 14 days prior to step 1 randomization. Actual body weight, not ideal body weight, must be used in the calculation
• Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months of step 1 randomization are eligible for this trial
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Site is encouraged to discuss with the study chair if needed prior to enrollment
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better
• Step 2 (Registration: Adjuvant Durvalumab vs. Observation) Inclusion
• Patient must have evaluation to determine clinical outcome post step 1 treatment (chemoRT+/- durvalumab) with imaging (CT chest, abdomen, and pelvis)(preferably contrast with urogram, if not contraindicated) and cystoscopy with biopsy confirmation to ensure no progression and absence of >= T2 disease in the bladder. Patient should be registered to step 2 within 28 days from the determination of primary response to step 1 treatment. However, for patients previously on Arm C, an additional 4 week delay to step 2 registration is allowed
• Patient on the chemoRT+ durvalumab (Arm C) must meet the following:
• Patient must have achieved either complete clinical response OR have demonstrated clinical benefit prior to continuing onto adjuvant durvalumab
• Patients who are to go on the adjuvant durvalumab (Arm E) must have recovered to at least grade 2 or less immune related AE prior to starting treatment except for immune related alopecia, clinically asymptomatic endocrinopathies. For patients who may have gotten immune related AEs during chemoRT+ durvalumab (Arm C), step 2 registration could be delayed up to additional 4 weeks to ensure recovery to at least grade 2 or lower prior to starting adjuvant therapy. However patients with durvalumab related AEs that require permanent discontinuation of durvalumab will not continue on the adjuvant treatment regardless of the response
• Patient must not have experienced immune related neurological disorder described as Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, or meningoencephalitis during chemoRT+ durvalumab treatment
• Patient must not have experienced immune related myocarditis or immune related pericarditis during chemoRT+ durvalumab treatment
• ANC >= 1,000 mcL (must be obtained < 28 days prior to step 2 registration)
• Hemoglobin >= 8g/dL (must be obtained < 28 days prior to step 2 registration)
• Platelets >= 70,000 mcL (must be obtained < 28 days prior to step 2 registration)
• NOTE: If recovery is not achieved, blood counts could be repeated weekly and step 2 registration could be delayed up to additional 4 weeks
• Patient on the chemoRT arm (Arm D) must have achieved either complete clinical response OR have demonstrated clinical benefit prior to be placed on the observation alone arm (Arm F)

Exclusion Criteria:

• Step 1 (Randomization) Exclusion
• Patient must not have received any previous radiation therapy to the pelvic area
• Patient must not have presence of concomitant active upper tract tumors or urethra tumors. History of previously adequately treated non-muscle invasive bladder cancer (NMIBC) are eligible; previously treated urothelial cancer or histological variant at any site outside of the urinary bladder are allowed, provided they have been Ta/T1/carcinoma in situ (CIS) and post treatment follow up imaging and endoscopic evaluation shows no evidence of disease
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to step 1 randomization to rule out pregnancy. A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patients must not expect to conceive or father children by using accepted and effected method(s) of contraception or by abstaining from sexual intercourse from the time of Step 1 randomization for the duration of their participation in the study and continue for at least 3 months after the last dose of protocol treatment
• For patients with autoimmune conditions, patient must not have history of prior documented autoimmune disease within 2 years prior to step 1 randomization
• NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring systemic treatment within 2 years prior to step 1 randomization) are not excluded. Patients with history of completely resolved childhood asthma or atopy are not excluded. Patients with asthma not requiring more than 10 mg/d or equivalent of prednisone are not excluded. Patients with well-controlled hypothyroidism on thyroxine replacement will be eligible as well. Patients with known history of hypoadrenalism on maintenance steroids will be eligible. Patients with type I diabetes mellitus will be eligible, provided their disease is well controlled. History of autoimmune related alopecia is also not an exclusion criteria
• Patient with active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) are not eligible
• Patient with a history of and/or confirmed pneumonitis are not eligible
• Patient with a history of primary immunodeficiency are not eligible
• Patient with history of allogeneic organ transplant are not eligible
• Patient must not have an active infection, including:
• Tuberculosis (based on clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice)
• Hepatitis B (HBV) (known positive HBV surface antigen [HBsAg] result). Past or resolved HBV infection (defined as the presence of hepatitis b core antibody [anti-HBc] and absence of HBsAg) are eligible
• Hepatitis C Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction test is negative for HCV ribonucleic acid (RNA)
• Patient must not have clinically significant liver disease that precludes patient from treatment regimens prescribed on the study (including, but not limited to, active viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease)
• Patient must not have received live attenuated vaccine within 30 days prior to the first dose of durvalumab
• NOTE: Patient, if enrolled, must not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab
• NOTE: Patient is permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily in order to minimize an overlap of adverse events)
• Patient must not have current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this

criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Patient must not have any unresolved toxicity (National Cancer Institute [NCI] CTCAE grade >= 2) from previous anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values
• NOTE: Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study chair
• NOTE: Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study chair. Documentation of correspondences with the study chair must be kept on file

Related Conditions & MeSH terms

• Bladder Urothelial Carcinoma
• Stage III Bladder Cancer AJCC v8
• Urinary Bladder Neoplasms

Intervention

Procedure:
• Biopsy of Bladder
Undergo bladder biopsy
• Biospecimen Collection
Undergo tumor tissue and blood sample collection

Drug:
• Cisplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT
• Cystoscopy
Undergo cystoscopy

Biological:
• Durvalumab
Given IV

Drug:
• Fluorouracil
Given IV
• Gemcitabine Hydrochloride
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Mitomycin
Given IV

Other:
• Patient Observation
Undergo observation

Radiation:
• Radiation Therapy
Undergo radiation therapy

Locations

Country	Name	City	State
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Oncology and Hematology LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Associates in Radiation Medicine	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Northwest Wisconsin Cancer Center	Ashland	Wisconsin
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Saint Louis Cancer and Breast Institute-Ballwin	Ballwin	Missouri
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Saint Charles Health System	Bend	Oregon
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Highline Medical Center-Main Campus	Burien	Washington
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Memorial Hospital of Carbondale	Carbondale	Illinois
United States	SIH Cancer Institute	Carterville	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Northwestern University	Chicago	Illinois
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Bay Area Hospital	Coos Bay	Oregon
United States	Greater Regional Medical Center	Creston	Iowa
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Porter Adventist Hospital	Denver	Colorado
United States	Broadlawns Medical Center	Des Moines	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Mercy Hospital Fort Smith	Fort Smith	Arkansas
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Unity Hospital	Fridley	Minnesota
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Nebraska Cancer Specialists/Oncology Hematology West PC	Grand Island	Nebraska
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	Edward Hines Jr VA Hospital	Hines	Illinois
United States	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	MU Health Care Goldschmidt Cancer Center	Jefferson City	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Longmont United Hospital	Longmont	Colorado
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Baptist Health Louisville	Louisville	Kentucky
United States	Jewish Hospital	Louisville	Kentucky
United States	UofL Health Medical Center Northeast	Louisville	Kentucky
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Sovah Health Martinsville	Martinsville	Virginia
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Loyola University Medical Center	Maywood	Illinois
United States	Idaho Urologic Institute-Meridian	Meridian	Idaho
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	East Jefferson General Hospital	Metairie	Louisiana
United States	LSU Healthcare Network / Metairie Multi-Specialty Clinic	Metairie	Louisiana
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Center	Missoula	Montana
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Louisiana State University Health Science Center	New Orleans	Louisiana
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Parker Adventist Hospital	Parker	Colorado
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	OSF Saint Francis Radiation Oncology at Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Valley Radiation Oncology	Peru	Illinois
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Mercy Hospital South	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	PeaceHealth United General Medical Center	Sedro-Woolley	Washington
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Saint Michael Cancer Center	Silverdale	Washington
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical complete response (CR)		Up to 4 years
Secondary	Metastasis-free survival	Will be estimated by the Kaplan-Meier method.	From randomization to first evidence of metastatic disease or death from any cause, assessed up to 4 years
Secondary	Bladder-intact event-free survival (BI-EFS)	Will be estimated by the Kaplan-Meier method.	From randomization to the first BI-EFS event, assessed up to 4 years
Secondary	Bladder cancer specific survival	Will be estimated by the Kaplan-Meier method.	From randomization to death from bladder cancer, assessed up to 4 years
Secondary	Overall survival	Will be estimated by the Kaplan-Meier method.	From randomization to death from any cause, assessed up to 4 years
Secondary	Progression-free survival	Will be estimated by the Kaplan-Meier method.	From randomization to first of local progression, nodal or distant metastasis, or death from any cause, assessed up to 4 years
Secondary	Complete response duration	Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.	From the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause, assessed up to 4 years
Secondary	Salvage cystectomy rate	Rate will be reported as a proportion of patients who do not experience clinical benefit after chemoradiotherapy (chemoRT) +/- MEDI4736 (durvalumab) along with a 90% confidence interval. Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.	Up to 4 years
Secondary	Incidence of adverse events	Assessed using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be evaluated in all treated patients, regardless of eligibility.	Up to 1 year