Testing the Addition of the Anti-cancer Drug, Cabozantinib, to the Usual Immunotherapy Treatment, Avelumab, in Patients With Metastatic Urothelial Cancer, MAIN-CAV Study

Stage IV Bladder Cancer AJCC v8 Clinical Trial

Official title:

MAIN-CAV: Phase III Randomized Trial of Maintenance Cabozantinib and Avelumab vs Maintenance Avelumab After First-Line Platinum-Based Chemotherapy in Patients With Metastatic Urothelial Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05092958
• Other study ID #: NCI-2021-11166
• Secondary ID: NCI-2021-11166A0
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 3, 2022
• Est. completion date: December 10, 2024

Study information

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

Clinical Trial Summary

This phase III trial compares the effect of adding cabozantinib to avelumab versus avelumab alone in treating patients with urothelial cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and avelumab together may further shrink the cancer or prevent it from returning/progressing.

Description:

PRIMARY OBJECTIVE: I. To evaluate the effect of cabozantinib S-malate (cabozantinib) in combination with avelumab on overall survival (OS) compared to avelumab alone in patients with metastatic urothelial cancer (mUC) who did not progress during first-line platinum-based chemotherapy therapy, i.e. patients who had complete response (CR), partial response (PR) or stable disease (SD) after completion of first line platinum-based chemotherapy. SECONDARY OBJECTIVES: I. To evaluate the effect of cabozantinib in combination with avelumab on progression-free survival (PFS) compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy. II. To evaluate the safety and tolerability of cabozantinib in combination with avelumab in mUC compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy. III. To evaluate activity of cabozantinib in combination with avelumab based on Response Evaluation Criteria in Solid Tumors (RECIST) compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy. IV. Results of the primary analysis will be examined for consistency, while accounting for the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue. V. To evaluate the activity of cabozantinib in combination with avelumab compared to avelumab alone based on PD-L1 status of patients' tumors. QUALITY OF LIFE (QOL) OBJECTIVES: I. To compare quality-adjusted survival between patients randomized to receive cabozantinib and avelumab versus (vs.) avelumab alone using the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L). II. To compare patient-reported fatigue as assessed by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue 4a from baseline through 12 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone. III. To compare patient-reported global health status/quality of life as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 from baseline through 12 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone. IV. To compare scale scores of the EORTC QLQ-Bladder Cancer Muscle-Invasive (BLM)30 (urinary symptoms, urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, body image, sexual function) at 3, 6, 12, 18, and 24 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone. V. To compare scale scores of the EORTC QLQ-C30 (global health status/quality of life; physical, role, emotional, cognitive, and social function; symptoms) at 3, 6, 12, 18, and 24 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive avelumab intravenously (IV) over 60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone scan at screening and undergo computed tomography (CT) or magnetic resonance imaging (MRI) and biospecimen collection throughout the trial. ARM B: Patients receive avelumab IV over 60 minutes on days 1 and 15 of each cycle and cabozantinib orally (PO) daily on days 1-28 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo bone scan at screening and undergo CT or MRI and biospecimen collection throughout the trial. After completion of study treatment, patients are followed every 30 days through 90 days, then every 3 months for 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 654
• Est. completion date: December 10, 2024
• Est. primary completion date: December 10, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically-confirmed diagnosis of advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies except for small-cell histology), including N3 only disease prior to start of first-line platinum-based chemotherapy
• Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy (platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin, methotrexate, vinblastine, doxorubicin and cisplatin [MVAC] or dose-dense [dd]MVAC)
• No more than 1 line of prior chemotherapy for metastatic or locally advanced disease (neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more months prior to registration)
• Tumor objective response of CR, PR, or SD upon completion of first line platinum-based chemotherapy by treating physician's assessment
• The last dose of first-line chemotherapy must have been received no less than 3 weeks, and no more than 10 weeks, prior to randomization in the present study
• No prior immunotherapy with IL-2, IFN-alpha, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
• Women of childbearing potential must have a negative pregnancy test =< 14 days prior to registration.
• Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
• No use of immunosuppressive medication within 7 days prior to randomization except:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
• Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent;
• Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• None of the following:
• Active autoimmune disease that might deteriorate when receiving the anti PD-L1 agent, avelumab.
• No known symptomatic central nervous system (CNS) metastases. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for at least 2 weeks, and are neurologically stable. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.
• No major surgery within 4 weeks prior to randomization. Subjects must have complete wound healing from surgery before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• No palliative radiotherapy within 48 hours prior to patient randomization.
• No hemoptysis of = 0.5 teaspoon (2.5 mL) of red blood, clinically significant hematuria, hematemesis, coagulopathy, or other history of significant bleeding (eg. Pulmonary hemorrhage) within 3 months before randomization.
• No known cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
• No administration of a live, attenuated vaccine within 30 days prior to randomization. The use of inactivated (killed) vaccines for the prevention of infectious disease is permitted. The use of COVID-19 vaccines is permitted.
• No uncontrolled, significant intercurrent or recent illness including, but not

limited to, the following conditions:

• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
• The patient has a known history of corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms and confirmed by electrocardiogram (ECG) within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is = 500 ms, the subject meets eligibility in this regard.
• Any history of congenital long QT syndrome.
• Stroke, transient ischemic attack (TIA), myocardial infarction, or other symptomatic ischemic event or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism [DVT/PE]) within 6 months before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if asymptomatic and stable at screening and treated with low molecular weight heparin (LMWH) or the direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before randomization. Non-symptomatic white matter disease in the brain is acceptable.
• No significant gastrointestinal disorders, particularly those associated with a high risk of perforation or fistula formation including unresolved active peptic ulcer disease, cholecystitis, diverticultis, symptomatic cholangitis or appendicitis, or malabsorption syndrome within 28 days of randomization.
• No other clinically significant disorders such as:
• Any active infection requiring systemic treatment within 14 days before randomization. Subjects receiving oral (including prophylactic) antibiotics with no symptoms of infection at randomization are eligible.
• Serious non-healing wound/ulcer/bone fracture within 28 days before randomization
• History of organ or allogeneic stem cell transplant
• No persisting toxicity related to prior therapy grade > 2 constituting a safety risk based on the investigator's judgment.
• No diagnosis of any other malignancy within 3 years prior to randomization, except for locally curable cancers that have been adequately treated such as basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, Gleason < 7 prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms and no indication for treatment.
• No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel).
• Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 g/dL
• Calculated (Calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
• Total serum bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
• Urine protein creatinine (UPC) ratio =< 1 or 24-hour protein < 1 g
• Physicians should consider whether any of the following may render the patient

inappropriate for this protocol:

• Psychiatric illness which would prevent the patient from giving informed consent.
• Uncontrolled medical conditions which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Patients who cannot swallow oral formulations of the agent(s).

In addition:

• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and or steroids equivalent to < 10 mg prednisone daily, not on immunosuppressive medications and patients with positive serology are eligible. Patients with vitiligo, endocrine deficiencies including hypo or hyper thyroid disease managed with replacement, diabetes type 1 are eligible.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the study and continue for 4 months after the last dose of study drugs, even if oral contraceptives are also used.

Related Conditions & MeSH terms

• Advanced Bladder Urothelial Carcinoma
• Advanced Ureter Urothelial Carcinoma
• Carcinoma
• Carcinoma, Transitional Cell
• Kidney Neoplasms
• Metastatic Bladder Urothelial Carcinoma
• Metastatic Renal Pelvis Urothelial Carcinoma
• Metastatic Ureter Urothelial Carcinoma
• Metastatic Urethral Urothelial Carcinoma
• Pelvic Neoplasms
• Stage III Bladder Cancer AJCC v8
• Stage III Renal Pelvis and Ureter 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 and Ureter Cancer AJCC v8
• Stage IV Renal Pelvis Cancer AJCC v8
• Stage IV Ureter Cancer AJCC v8
• Stage IV Urethral Cancer AJCC v8
• Ureteral Neoplasms
• Urethral Neoplasms
• Urinary Bladder Neoplasms

Intervention

Drug:
• Avelumab
Given IV

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Bone Scan
Undergo bone scan

Drug:
• Cabozantinib S-malate
Given PO

Procedure:
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	Avera Cancer Institute-Aberdeen	Aberdeen	South Dakota
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	University Cancer Specialists - Alcoa	Alcoa	Tennessee
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	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Harold Alfond Center for Cancer Care	Augusta	Maine
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Advocate Good Shepherd Hospital	Barrington	Illinois
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
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	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Atrium Health University City/LCI-University	Charlotte	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Levine Cancer Institute-Ballantyne	Charlotte	North Carolina
United States	Levine Cancer Institute-SouthPark	Charlotte	North Carolina
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Advocate Illinois Masonic Medical Center	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Atrium Health Cabarrus/LCI-Concord	Concord	North Carolina
United States	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Northwest Cancer Center - Main Campus	Crown Point	Indiana
United States	AMG Crystal Lake - Oncology	Crystal Lake	Illinois
United States	UT Southwestern Simmons Cancer Center - RedBird	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Blood and Cancer Center	Dayton	Ohio
United States	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Advocate Good Samaritan Hospital	Downers Grove	Illinois
United States	Northwest Oncology LLC	Dyer	Indiana
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Advocate Sherman Hospital	Elgin	Illinois
United States	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Palo Alto Medical Foundation-Fremont	Fremont	California
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	Glens Falls Hospital	Glens Falls	New York
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Health Medical Group - Andrews Patel Hematology/Oncology East	Harrisburg	Pennsylvania
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Advocate South Suburban Hospital	Hazel Crest	Illinois
United States	OptumCare Cancer Care at Seven Hills	Henderson	Nevada
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Northwest Cancer Center - Hobart	Hobart	Indiana
United States	Saint Mary Medical Center	Hobart	Indiana
United States	Saint Catherine Hospital	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Ascension Borgess Cancer Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico
United States	OptumCare Cancer Care at Charleston	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	AMG Libertyville - Oncology	Libertyville	Illinois
United States	Condell Memorial Hospital	Libertyville	Illinois
United States	Atrium Health Lincoln/LCI-Lincolnton	Lincolnton	North Carolina
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Baptist Health Louisville	Louisville	Kentucky
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Solinsky Center for Cancer Care	Manchester	New Hampshire
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Bon Secours Memorial Regional Medical Center	Mechanicsville	Virginia
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Bon Secours Saint Francis Medical Center	Midlothian	Virginia
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Medical Center	Modesto	California
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Morristown Medical Center	Morristown	New Jersey
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	The Community Hospital	Munster	Indiana
United States	Women's Diagnostic Center - Munster	Munster	Indiana
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Cancer and Hematology Centers of Western Michigan - Norton Shores	Norton Shores	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Upstate Cancer Center at Oswego	Oswego	New York
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Jefferson Methodist Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	21st Century Oncology-Pontiac	Pontiac	Michigan
United States	Hope Cancer Center	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Valley Medical Center	Renton	Washington
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	Bon Secours Saint Mary's Hospital	Richmond	Virginia
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Levine Cancer Institute-Rock Hill	Rock Hill	South Carolina
United States	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois
United States	Sutter Roseville Medical Center	Roseville	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	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	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Atrium Health Cleveland/LCI-Cleveland	Shelby	North Carolina
United States	Memorial Hospital East	Shiloh	Illinois
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	VCU Community Memorial Health Center	South Hill	Virginia
United States	Memorial Medical Center	Springfield	Illinois
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	Stony Brook University Medical Center	Stony Brook	New York
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	Overlook Hospital	Summit	New Jersey
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	SUNY Upstate Medical Center-Community Campus	Syracuse	New York
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Northwest Cancer Center - Valparaiso	Valparaiso	Indiana
United States	Legacy Cancer Institute Medical Oncology and Day Treatment	Vancouver	Washington
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Upstate Cancer Center at Verona	Verona	New York
United States	South Pointe Hospital	Warrensville Heights	Ohio
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Cleveland Clinic-Weston	Weston	Florida
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Shenandoah Oncology PC	Winchester	Virginia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts
United States	University of Michigan Health - West	Wyoming	Michigan
United States	Avera Cancer Institute at Yankton	Yankton	South Dakota
United States	Rush-Copley Healthcare Center	Yorkville	Illinois
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)	Subgroup analyses will be done using a stratified Cox model that includes the treatment arm assignment as an explanatory variable and a separate model will be generated for each level for the subgroup of interest.	Time from randomization until death due to any cause, assessed up to 5 years
Secondary	Progression free survival (PFS)	A stratified Cox model will be used to compare the outcomes between the two treatment groups. The subgroup analyses will be done using a stratified Cox model that includes the treatment arm assignment as an explanatory variable and a separate model will be generated for each level for the subgroup of interest.	Time from randomization until disease progression as assessed by the treating physician using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, assessed up to 5 years
Secondary	Tumor response	Will be defined as a complete response or partial response (PR) as measured with Immune-Modified RECIST. Will be compared between the arms using a Mantel-Haenszel test (that accounts for the randomization stratification factors) comparing the response rates between the two treatment arms. This analysis will only include patients who had a PR or stable disease (SD) response to first-line therapy. An additional analysis will be conducted using logistic regression analysis that includes treatment arm and any baseline variables that are imbalanced between the arms as explanatory variable.	Up to 5 years
Secondary	Incidence of adverse events (AE)	Will be assessed by Common Terminology Criteria for Adverse Events 5.0. Will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that experience each observed adverse event will be summarized by treatment arm. In addition, the proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as the number and percent of patients by treatment arm. The primary summary will be regardless of attribution. Will also do an analogous summary for the adverse events that were deemed at least possibly related to treatment.	Up to 5 years