The Phase III Adaptive Radiation and Chemotherapy for Muscle Invasive Bladder Cancer Trial (ARCHER)
Summary
This phase III trial compares the effect of decreased number of radiation (ultra-hypofractionated) treatments to the usual radiation number of treatments (hypofractionation) with standard of care chemotherapy, with cisplatin, gemcitabine or mitomycin and 5-fluorouracil for the treatment of patients with muscle invasive bladder cancer. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a short period of time. Ultra-hypofractionated radiation therapy delivers radiation over an even shorter period of time than hypofractionated radiation therapy. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Chemotherapy drugs, such as mitomycin-C and 5-fluorouracil (5-FU), 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. Giving ultra-hypofractionated radiation may be equally effective as hypofractionated therapy for patients with muscle invasive bladder cancer.
Detailed description
PRIMARY OBJECTIVE: I. Demonstrate non-inferiority of ultra-hypofractionated (stereotactic body radiation therapy \[SBRT\]) compared to hypofractionated radiation therapy (RT) with a 10% non-inferiority margin (from 50% to 40%) in the rate of bladder-intact event-free survival (BI-EFS) at 3 years (corresponding to a hazard ratio \< 1.32). SECONDARY OBJECTIVES: I. Compare the rates of urinary and bowel toxicity, patient-reported outcomes (PRO), event-free survival (EFS), metastasis-free survival (MFS), and overall survival (OS) between the two treatment arms. II. Compare and evaluate symptomatic adverse events and quality of life measures that are most meaningful to patients. III. Evaluate circulating tumor deoxyribonucleic acid (ctDNA) as a biomarker to determine whether it is predictive of disease recurrence and as a secondary outcome variable. EXPLORATORY OBJECTIVES: I. Evaluate ctDNA, tissue-free minimal residual disease (tfMRD) and urine tumor DNA (utDNA) as biomarkers for predicting recurrence. II. Evaluate tfMRD, obtained at the time of progression, to determine if it captures the presence of disease. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive hypofractionated radiation therapy (RT) once daily (QD), Monday to Friday, for 20 treatments in the absence of disease progression or unacceptable toxicity. Patients also receive one of 3 systemic chemotherapy regimens per treating physician's choice: 1) cisplatin intravenously (IV) weekly for 4 weeks; 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22 and 25 or weekly for 4 weeks; or 3) mitomycin-C IV on day 1 and fluorouracil (5 FU), over 120 hours on days 1-5 and 22-26. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan and/or magnetic resonance imaging (MRI) or fluorodeoxyglucose (FDG) positron emission tomography (PET) throughout the study. In addition, patients may undergo optional blood and urine sample collection throughout the study, as well as an optional biopsy during cystoscopy during follow up. ARM II: Patients receive ultra-hypofractionated RT QD, no more than twice weekly, for 5 treatments in the absence of disease progression or unacceptable toxicity. Patients also receive one of 3 systemic chemotherapy regimens per treating physician's choice: 1) cisplatin IV weekly for 4 weeks; 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22 and 25 or weekly for 4 weeks; or 3) mitomycin-C IV on day 1 and 5 FU, over 120 hours on days 1-5 and 22-26. Treatment given in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI or FDG PET throughout the study. In addition, patients may undergo optional blood and urine sample collection throughout the study, as well as an optional biopsy during cystoscopy during follow up. After completion of study treatment, patients are followed up at week 16, every 3 months for 3 years then every 6 months to year 5.
Arms & interventions
- ProcedureBiospecimen Collection
Undergo blood, tissue, and urine sample collection
- DrugCisplatin
Given IV
- ProcedureComputed Tomography
Undergo CT scan
- DrugFluorouracil
Given IV
- DrugGemcitabine
Given IV
- RadiationHypofractionated Radiation Therapy
Undergo hypofractionated radiation therapy
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- DrugMitomycin
Given IV
- ProcedurePositron Emission Tomography
Undergo PET scan
- OtherSurvey Administration
Ancillary studies
- RadiationUltrahypofractionated Radiation Therapy
Undergo ultrahypofractionated radiation therapy.
Outcome measures
Primary
Bladder-intact event-free survival (BI-EFS)
Defined as histologically proven presence of muscle invasive bladder cancer (MIBC), radiographic evidence of nodal or metastatic disease, performance of radical cystectomy, or death from any cause. Time to event will be calculated from the date of randomization. BI-EFS will be estimated in the two treatment groups using the Kaplan-Meier method and the hazard ratio between ultra-hypofractionation and hypofractionation estimated by fitting a Cox proportional hazards regression model, including a treatment arm indicator variable and adjusting for the three stratification factors employed in the randomization.
Time frame: Up to 3 years
Secondary
Incidence of urinary adverse events
Time frame: Up to year 2
Incidence of bowel adverse events
Time frame: Up to year 2
Quality of life
Time frame: At baseline, 4 weeks, 16 weeks, 13 months, 25 months, and 37 months
Event free survival
Time frame: From randomization to histologically proven presence of MIBC, radiographic evidence of nodal or metastatic disease, or death from any cause, up to 5 years
Metastasis-free survival
Time frame: From randomization to radiographic evidence of metastatic disease or death due to any cause, up to 5 years
Overall survival
Time frame: From randomization to death from any cause, up to 5 years
Incidence of adverse events (AE)
Time frame: Up to year 2
Circulating tumor deoxyribonucleic acid (ctDNA)
Time frame: At baseline, end of treatment (week 4), weeks 16, 28, 40, 56, and at disease progression or last follow-up visit
Eligibility criteria
Study locations (211)
Mercy Hospital Fort Smith
Fort Smith, Arkansas, 72903
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
UC San Diego Moores Cancer Center
La Jolla, California, 92093
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045
UCHealth - Cherry Creek
Denver, Colorado, 80206
UCHealth Highlands Ranch Hospital
Highlands Ranch, Colorado, 80129
UCHealth Lone Tree Health Center
Lone Tree, Colorado, 80124
Beebe Medical Center
Lewes, Delaware, 19958
Beebe South Coastal Health Campus
Millville, Delaware, 19967
Helen F Graham Cancer Center
Newark, Delaware, 19713
Medical Oncology Hematology Consultants PA
Newark, Delaware, 19713
Christiana Care Health System-Christiana Hospital
Newark, Delaware, 19718
Beebe Health Campus
Rehoboth Beach, Delaware, 19971
Christiana Care Health System-Wilmington Hospital
Wilmington, Delaware, 19801
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
UM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, 33166
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Miami Cancer Institute
Miami, Florida, 33176
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, 33181
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Grady Health System
Atlanta, Georgia, 30303
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854
OSF Saint Anthony's Health Center
Alton, Illinois, 62002
OSF Saint Joseph Medical Center
Bloomington, Illinois, 61701
Illinois CancerCare-Bloomington
Bloomington, Illinois, 61704
Illinois CancerCare-Canton
Canton, Illinois, 61520
Memorial Hospital of Carbondale
Carbondale, Illinois, 62902
SIH Cancer Institute
Carterville, Illinois, 62918
Illinois CancerCare-Carthage
Carthage, Illinois, 62321
Centralia Oncology Clinic
Centralia, Illinois, 62801
Northwestern University
Chicago, Illinois, 60611
Rush MD Anderson Cancer Center
Chicago, Illinois, 60612
University of Illinois
Chicago, Illinois, 60612
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Decatur Memorial Hospital
Decatur, Illinois, 62526
Illinois CancerCare-Dixon
Dixon, Illinois, 61021
Crossroads Cancer Center
Effingham, Illinois, 62401
Illinois CancerCare-Eureka
Eureka, Illinois, 61530
Illinois CancerCare-Galesburg
Galesburg, Illinois, 61401
Illinois CancerCare-Kewanee Clinic
Kewanee, Illinois, 61443
Illinois CancerCare-Macomb
Macomb, Illinois, 61455
SSM Health Good Samaritan
Mount Vernon, Illinois, 62864
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269
HSHS Saint Elizabeth's Hospital
O'Fallon, Illinois, 62269
Rush MD Anderson Cancer Center at Rush Oak Park
Oak Park, Illinois, 60304
Northwestern Medicine Orland Park
Orland Park, Illinois, 60462
Illinois CancerCare-Ottawa Clinic
Ottawa, Illinois, 61350
Illinois CancerCare-Pekin
Pekin, Illinois, 61554
Illinois CancerCare-Peoria
Peoria, Illinois, 61615
OSF Saint Francis Radiation Oncology at Peoria Cancer Center
Peoria, Illinois, 61615
Methodist Medical Center of Illinois
Peoria, Illinois, 61636
OSF Saint Francis Medical Center
Peoria, Illinois, 61637
Illinois CancerCare-Peru
Peru, Illinois, 61354
Valley Radiation Oncology
Peru, Illinois, 61354
Illinois CancerCare-Princeton
Princeton, Illinois, 61356
Southern Illinois University School of Medicine
Springfield, Illinois, 62702
Springfield Clinic
Springfield, Illinois, 62702
Springfield Memorial Hospital
Springfield, Illinois, 62781
Illinois CancerCare - Washington
Washington, Illinois, 61571
UI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa, 50023
Mercy Cancer Center-West Lakes
Clive, Iowa, 50325
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa, 50325
Greater Regional Medical Center
Creston, Iowa, 50801
Iowa Methodist Medical Center
Des Moines, Iowa, 50309
UI Health Care Mission Cancer and Blood - Des Moines Clinic
Des Moines, Iowa, 50309
Mercy Medical Center - Des Moines
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Waukee Clinic
Waukee, Iowa, 50263
Mercy Medical Center-West Lakes
West Des Moines, Iowa, 50266
The Iowa Clinic PC
West Des Moines, Iowa, 50266
Central Care Cancer Center - Garden City
Garden City, Kansas, 67846
Central Care Cancer Center - Great Bend
Great Bend, Kansas, 67530
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
Mercy Hospital Pittsburg
Pittsburg, Kansas, 66762
University of Kansas Health System Saint Francis Campus
Topeka, Kansas, 66606
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Ascension Via Christi Hospitals Wichita
Wichita, Kansas, 67214
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Louisiana Hematology Oncology Associates LLC
Baton Rouge, Louisiana, 70809
Mary Bird Perkins Cancer Center
Baton Rouge, Louisiana, 70809
Mary Bird Perkins Cancer Center - Metairie
Metairie, Louisiana, 70002
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Bronson Battle Creek
Battle Creek, Michigan, 49017
University of Michigan - Brighton Center for Specialty Care
Brighton, Michigan, 48116
Henry Ford Cancer Institute-Downriver
Brownstown, Michigan, 48183
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, 48038
Henry Ford Medical Center-Fairlane
Dearborn, Michigan, 48126
Henry Ford Hospital
Detroit, Michigan, 48202
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
Grand Rapids, Michigan, 49503
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids, Michigan, 49503
Trinity Health Grand Rapids Hospital
Grand Rapids, Michigan, 49503
Allegiance Health
Jackson, Michigan, 49201
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007
West Michigan Cancer Center
Kalamazoo, Michigan, 49007
Beacon Kalamazoo
Kalamazoo, Michigan, 49048
Trinity Health Muskegon Hospital
Muskegon, Michigan, 49444
Corewell Health Lakeland Hospitals - Niles Hospital
Niles, Michigan, 49120
Cancer and Hematology Centers of Western Michigan - Norton Shores
Norton Shores, Michigan, 49444
Henry Ford Medical Center-Columbus
Novi, Michigan, 48377
Corewell Health Reed City Hospital
Reed City, Michigan, 49677
Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
Saint Joseph, Michigan, 49085
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
Saint Joseph, Michigan, 49085
Munson Medical Center
Traverse City, Michigan, 49684
Henry Ford West Bloomfield Hospital
West Bloomfield, Michigan, 48322
Henry Ford Wyandotte Hospital
Wyandotte, Michigan, 48192
University of Michigan Health - West
Wyoming, Michigan, 49519
Minnesota Oncology - Burnsville
Burnsville, Minnesota, 55337
Mercy Hospital
Coon Rapids, Minnesota, 55433
Fairview Southdale Hospital
Edina, Minnesota, 55435
Fairview Clinics and Surgery Center Maple Grove
Maple Grove, Minnesota, 55369
Minnesota Oncology Hematology PA-Maplewood
Maplewood, Minnesota, 55109
Saint John's Hospital - Healtheast
Maplewood, Minnesota, 55109
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Hennepin County Medical Center
Minneapolis, Minnesota, 55415
Monticello Cancer Center
Monticello, Minnesota, 55362
North Memorial Medical Health Center
Robbinsdale, Minnesota, 55422
Coborn Cancer Center at Saint Cloud Hospital
Saint Cloud, Minnesota, 56303
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Saint Francis Regional Medical Center
Shakopee, Minnesota, 55379
Lakeview Hospital
Stillwater, Minnesota, 55082
Ridgeview Medical Center
Waconia, Minnesota, 55387
Rice Memorial Hospital
Willmar, Minnesota, 56201
Minnesota Oncology Hematology PA-Woodbury
Woodbury, Minnesota, 55125
Central Care Cancer Center - Bolivar
Bolivar, Missouri, 65613
Mercy Cancer Center - Cape Girardeau
Cape Girardeau, Missouri, 63703
Saint Francis Medical Center
Cape Girardeau, Missouri, 63703
MU Health - University Hospital/Ellis Fischel Cancer Center
Columbia, Missouri, 65212
Parkland Health Center - Farmington
Farmington, Missouri, 63640
Freeman Health System
Joplin, Missouri, 64804
Mercy Hospital Joplin
Joplin, Missouri, 64804
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri, 64116
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
Lake Regional Hospital
Osage Beach, Missouri, 65065
Mercy Clinic-Rolla-Cancer and Hematology
Rolla, Missouri, 65401
Phelps Health Delbert Day Cancer Institute
Rolla, Missouri, 65401
Heartland Regional Medical Center
Saint Joseph, Missouri, 64506
Sainte Genevieve County Memorial Hospital
Sainte Genevieve, Missouri, 63670
Mercy Hospital Springfield
Springfield, Missouri, 65804
CoxHealth South Hospital
Springfield, Missouri, 65807
Mercy Hospital South
St Louis, Missouri, 63128
Missouri Baptist Medical Center
St Louis, Missouri, 63131
Mercy Hospital Saint Louis
St Louis, Missouri, 63141
Missouri Baptist Sullivan Hospital
Sullivan, Missouri, 63080
BJC Outpatient Center at Sunset Hills
Sunset Hills, Missouri, 63127
Billings Clinic Cancer Center
Billings, Montana, 59101
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405
Great Falls Clinic
Great Falls, Montana, 59405
Hi-Line Sletten Cancer Center
Havre, Montana, 59501
Logan Health Medical Center
Kalispell, Montana, 59901
Community Medical Center
Missoula, Montana, 59804
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, 07920
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645
Memorial Sloan Kettering Commack
Commack, New York, 11725
Memorial Sloan Kettering Westchester
East White Plains, New York, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Highland Hospital
Rochester, New York, 14620
University of Rochester
Rochester, New York, 14642
Memorial Sloan Kettering Nassau
Uniondale, New York, 11553
Wilmot Cancer Institute at Webster
Webster, New York, 14580
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Duke University Medical Center
Durham, North Carolina, 27710
UH Seidman Cancer Center at UH Avon Health Center
Avon, Ohio, 44011
UHHS-Chagrin Highlands Medical Center
Beachwood, Ohio, 44122
Case Western Reserve University
Cleveland, Ohio, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
UH Seidman Cancer Center at Lake Health Mentor Campus
Mentor, Ohio, 44060
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Mercy Hospital Oklahoma City
Oklahoma City, Oklahoma, 73120
Christiana Care Health System-Concord Health Center
Chadds Ford, Pennsylvania, 19317
Medical University of South Carolina
Charleston, South Carolina, 29425
Gibbs Cancer Center-Gaffney
Gaffney, South Carolina, 29341
Self Regional Healthcare
Greenwood, South Carolina, 29646
Gibbs Cancer Center-Pelham
Greer, South Carolina, 29651
Spartanburg Medical Center
Spartanburg, South Carolina, 29303
SMC Center for Hematology Oncology Union
Union, South Carolina, 29379
Vanderbilt Breast Center at One Hundred Oaks
Nashville, Tennessee, 37204
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
MD Anderson in The Woodlands
Conroe, Texas, 77384
Parkland Memorial Hospital
Dallas, Texas, 75235
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
M D Anderson Cancer Center
Houston, Texas, 77030
MD Anderson West Houston
Houston, Texas, 77079
MD Anderson League City
League City, Texas, 77573
MD Anderson in Sugar Land
Sugar Land, Texas, 77478
Bon Secours Memorial Regional Medical Center
Mechanicsville, Virginia, 23116
Bon Secours Saint Francis Medical Center
Midlothian, Virginia, 23114
Bon Secours Saint Mary's Hospital
Richmond, Virginia, 23226
Bon Secours Cancer Institute at Reynolds Crossing
Richmond, Virginia, 23230
Langlade Hospital and Cancer Center
Antigo, Wisconsin, 54409
Cancer Center of Western Wisconsin
New Richmond, Wisconsin, 54017
Aspirus Cancer Care - James Beck Cancer Center
Rhinelander, Wisconsin, 54501
Aspirus Cancer Care - Stevens Point
Stevens Point, Wisconsin, 54481
Aspirus Regional Cancer Center
Wausau, Wisconsin, 54401
Aspirus Cancer Care - Wisconsin Rapids
Wisconsin Rapids, Wisconsin, 54494
Memorial Hospital of Laramie County
Cheyenne, Wyoming, 82001