Testing the Addition of an Anti-Cancer Immunotherapy Drug, Avelumab, to Gemcitabine and Carboplatin Chemotherapy Prior to Surgery in Muscle Invasive Urinary Tract Cancer vs. Surgery Alone in Patients Who Are Not Able to Receive Cisplatin Therapy (SWOG GAP TRIAL)
- Conditions
- Bladder Carcinoma Infiltrating the Muscle of the Bladder WallInfiltrating Renal Pelvis and Ureter Urothelial CarcinomaStage II Bladder Cancer AJCC v8
- Interventions
- Procedure: Therapeutic Conventional SurgeryDrug: AvelumabDrug: Gemcitabine HydrochlorideDrug: Carboplatin
- Registration Number
- NCT04871529
- Lead Sponsor
- SWOG Cancer Research Network
- Brief Summary
This phase II trial studies the effect of avelumab, gemcitabine and carboplatin before surgery compared with surgery alone in treating patients with muscle invasive bladder or upper urinary tract cancer who are not able to receive cisplatin therapy. 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. Chemotherapy drugs, such as gemcitabine and carboplatin, 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 avelumab together with gemcitabine and carboplatin before surgery may work better in lowering the chance of muscle invasive urinary tract cancer growing or spreading, in patients who cannot receive cisplatin therapy compared to surgery alone.
- Detailed Description
PRIMARY OBJECTIVE:
I. To compare pathologic complete response (pCR, pT0N0) with avelumab plus gemcitabine and carboplatin (AGCa) versus (vs.) no neoadjuvant therapy preceding protocol surgery for muscle-invasive bladder cancer or upper tract urothelial carcinoma (MIBC/UTUC) for participants who are ineligible for cisplatin-based chemotherapy.
SECONDARY OBJECTIVES:
I. To evaluate toxicities with AGCa, and to compare resectability rates and surgical complications by arm in this population.
II. To compare event-free survival (EFS) with AGCa versus no neoadjuvant therapy in this population.
III. To compare overall survival (OS) with AGCa versus no neoadjuvant therapy preceding surgery in this population.
IV. To compare pathologic complete response (pCR, pT0N0) with avelumab plus gemcitabine and carboplatin (AGCa) vs. no neoadjuvant therapy preceding protocol surgery in the subset of participants who received at least 2 cycles of neoadjuvant therapy in Arm A.
BANKING OBJECTIVE:
I. To bank tumor tissue, blood, and urine for future correlative genomic, transcriptomic, and proteomic studies to discover molecular signatures associated with pCR and resistance.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive avelumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery.
ARM B: Patients undergo standard of care surgery.
After completion of study treatment, patients are followed up every 12 weeks for years 1-2, every 6 months for year 3, then annually in years 4-5.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 6
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Participants must have one of the following:
- Histologically documented muscle-invasive bladder carcinoma (MIBC) from transurethral resection of bladder tumor (TURBT) within 56 days prior to registration
- Histologically confirmed high grade upper tract urothelial carcinoma (UTUC) within 56 days prior to registration, with invasion confirmed by either a mass on cross-sectional imaging or a tumor directly visualized during upper urinary tract endoscopy within 56 days prior to registration
- Participants diagnosed with mixed urothelial carcinoma and variant histology within 56 days prior to registration may be eligible if the majority (> 50%) of the tumor consists of urothelial carcinoma. Participants with pure non-urothelial variant histologies or any small cell histology are not eligible
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Participants must have clinical stage T2-T4aN0M0 bladder or upper tract cancer confirmed by radiologic staging (computed tomography [CT] scan/magnetic resonance imaging [MRI] abdomen and pelvis, and CT scan/x-ray of the chest) within 56 days prior to registration
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Participants must have a bone scan within 56 days prior to registration if they have bone pain or elevated serum alkaline phosphatase
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Participants must have a bimanual examination under anesthesia within 56 days prior to registration
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Participants must not have received prior systemic chemotherapy, immunotherapy or radiotherapy for the treatment of muscle invasive bladder cancer (MIBC) or upper tract urothelial carcinoma (UTUC). Other prior pelvic radiotherapy is allowed if it does not preclude surgery (radical cystectomy, nephroureterectomy or ureterectomy, based on location of primary tumor). Prior intravesical therapy is allowed
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Participants must not have received immunosuppressive medication within 14 days prior to registration, with the exception of 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
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Participants must be >= 18 years of age
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Participants must have Zubrod performance status 0-2
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Participants must have history and physical examination within 28 days prior to registration
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Participants must be surgical candidates as deemed by the local site oncologic surgeon within 28 days prior to registration. This must be clearly documented
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Participants must have a serum creatinine =< the institutional upper limit of normal (IULN) OR measured OR calculated creatinine clearance >= 30 mL/min using the Crockroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration
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Participants must be deemed cisplatin-ineligible based on greater than or equal to 1 of the following:
- Zubrod performance status = 2
- Creatinine clearance (calculated by Crockroft-Gault formula or measured) 30 to < 60 ml/min,
- Neuropathy > grade 1
- Hearing loss > grade 1
- Congestive heart failure > grade 2
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Hemoglobin >= 9.0 g/dL (within 28 days prior to registration)
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Absolute neutrophil count >= 1,500/mcL (within 28 days prior to registration)
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Platelets >= 100,000/mcL (within 28 days prior to registration)
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Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to registration)
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Aspartate aminotransferase (AST) =< 2.5 x institutional ULN (within 28 days prior to registration)
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Alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 28 days prior to registration)
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Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification and be class 2B or better
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Participants with known human immunodeficiency virus (HIV) must be on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration
- Participant must not have any other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer Gleason score =< 3+4 in active surveillance, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years
- Participants must not be pregnant or nursing due to the risk of harm to a fetus or nursing infant. Women/men of reproductive potential must have a negative serum or urine pregnancy test within 28 days prior to registration and must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
- Participants must not have a history of active primary immunodeficiency
- Participants must not have a history of or active autoimmune or inflammatory disorder, with the exception of vitiligo, alopecia, hypothyroidism (stable on hormone replacement), or chronic skin condition that does not require systemic therapy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A (avelumab, gemcitabine, carboplatin, surgery) Gemcitabine Hydrochloride Patients receive avelumab IV over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery. Arm B (surgery) Therapeutic Conventional Surgery Patients undergo standard of care surgery. Arm A (avelumab, gemcitabine, carboplatin, surgery) Therapeutic Conventional Surgery Patients receive avelumab IV over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery. Arm A (avelumab, gemcitabine, carboplatin, surgery) Avelumab Patients receive avelumab IV over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery. Arm A (avelumab, gemcitabine, carboplatin, surgery) Carboplatin Patients receive avelumab IV over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery.
- Primary Outcome Measures
Name Time Method Pathologic Complete Response Measured once - at the time of surgery Compare pathologic complete response (pCR) between arms. pCR is defined as s absence of all disease in the surgical specimen from radical cystectomy, nephroureterectomy or ureterectomy as determined by the pathologist at the institution. This is determined by a biopsy taken at the time of surgery.
- Secondary Outcome Measures
Name Time Method Event-free Survival From randomization to the first event, assessed up to study closure Compare event-free survival between arms. Event-free survival is defined as the time from randomization to the first EFS event. For those who do not undergo surgery, event time will be assigned to the date of disease assessment that indicated surgery was no longer indicated or physician decision not to conduct the surgery.
Incidence of Adverse Events treatment start to 90 days post surgery Evaluate toxicities on both arms. Number of participants with Grade 3-5 adverse events that are possibly, probably or definitely related to study drug are reported. Measured using CTCAE v5.0.
Overall Survival Up to 5 years post-surgery To compare overall survival between arms. Overall survival is defined as time from date of registration to date of death due to any cause or patients last known to be alive are censored at their last contact date.
Pathologic Complete Response - After 2 Cycles Measured once - at the time of surgery Compare pathologic complete response (pCR) between surgery only arm and participants in the avelumab, gemcitabine, carboplatin, surgery arm who received at least two cycles of treatment. pCR is defined as s absence of all disease in the surgical specimen from radical cystectomy, nephroureterectomy or ureterectomy as determined by the pathologist at the institution. This is determined using a biopsy taken at the time of surgery.
This outcome uses a subset of participants in arm A who completed exactly 2 cycles of neoadjuvant treatment.
Trial Locations
- Locations (92)
NorthShore University HealthSystem-Glenbrook Hospital
🇺🇸Glenview, Illinois, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Illinois CancerCare-Eureka
🇺🇸Eureka, Illinois, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
Illinois CancerCare-Macomb
🇺🇸Macomb, Illinois, United States
Illinois CancerCare-Princeton
🇺🇸Princeton, Illinois, United States
Cleveland Clinic Cancer Center/Fairview Hospital
🇺🇸Cleveland, Ohio, United States
UT Southwestern Simmons Cancer Center - RedBird
🇺🇸Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Marshfield Medical Center-River Region at Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
Marshfield Medical Center - Weston
🇺🇸Weston, Wisconsin, United States
Straub Clinic and Hospital
🇺🇸Honolulu, Hawaii, United States
McFarland Clinic - Trinity Cancer Center
🇺🇸Fort Dodge, Iowa, United States
McFarland Clinic - Marshalltown
🇺🇸Marshalltown, Iowa, United States
LSU Healthcare Network / Metairie Multi-Specialty Clinic
🇺🇸Metairie, Louisiana, United States
Mercy Hospital
🇺🇸Coon Rapids, Minnesota, United States
Saint Joseph Mercy Brighton
🇺🇸Brighton, Michigan, United States
McFarland Clinic - Boone
🇺🇸Boone, Iowa, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
🇺🇸Brighton, Michigan, United States
McFarland Clinic - Jefferson
🇺🇸Jefferson, Iowa, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Genesys Hurley Cancer Institute
🇺🇸Flint, Michigan, United States
Ascension Saint Mary's Hospital
🇺🇸Saginaw, Michigan, United States
Oncology Hematology Associates of Saginaw Valley PC
🇺🇸Saginaw, Michigan, United States
Saint Joseph Mercy Canton
🇺🇸Canton, Michigan, United States
Trinity Health Saint Mary Mercy Livonia Hospital
🇺🇸Livonia, Michigan, United States
Saint Francis Medical Center
🇺🇸Cape Girardeau, Missouri, United States
Genesee Hematology Oncology PC
🇺🇸Flint, Michigan, United States
Cleveland Clinic Wooster Family Health and Surgery Center
🇺🇸Wooster, Ohio, United States
Marshfield Clinic-Minocqua Center
🇺🇸Minocqua, Wisconsin, United States
Saint Joseph Mercy Oakland
🇺🇸Pontiac, Michigan, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Missouri Baptist Sullivan Hospital
🇺🇸Sullivan, Missouri, United States
Hillcrest Hospital Cancer Center
🇺🇸Mayfield Heights, Ohio, United States
Saint Joseph Mercy Chelsea
🇺🇸Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
Ascension Saint Joseph Hospital
🇺🇸Tawas City, Michigan, United States
Huron Gastroenterology PC
🇺🇸Ypsilanti, Michigan, United States
Illinois CancerCare-Carthage
🇺🇸Carthage, Illinois, United States
Pali Momi Medical Center
🇺🇸'Aiea, Hawaii, United States
UCHealth Highlands Ranch Hospital
🇺🇸Highlands Ranch, Colorado, United States
Queen's Medical Center
🇺🇸Honolulu, Hawaii, United States
Illinois CancerCare-Canton
🇺🇸Canton, Illinois, United States
Saint Anthony's Health
🇺🇸Alton, Illinois, United States
Carle at The Riverfront
🇺🇸Danville, Illinois, United States
Northwestern Medicine Cancer Center Kishwaukee
🇺🇸DeKalb, Illinois, United States
Carle Physician Group-Effingham
🇺🇸Effingham, Illinois, United States
Illinois CancerCare-Dixon
🇺🇸Dixon, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸Evanston, Illinois, United States
Crossroads Cancer Center
🇺🇸Effingham, Illinois, United States
Northwestern Medicine Cancer Center Delnor
🇺🇸Geneva, Illinois, United States
NorthShore University HealthSystem-Highland Park Hospital
🇺🇸Highland Park, Illinois, United States
Illinois CancerCare-Kewanee Clinic
🇺🇸Kewanee, Illinois, United States
Northwestern Medicine Lake Forest Hospital
🇺🇸Lake Forest, Illinois, United States
Illinois CancerCare-Ottawa Clinic
🇺🇸Ottawa, Illinois, United States
Carle Physician Group-Mattoon/Charleston
🇺🇸Mattoon, Illinois, United States
Illinois CancerCare-Pekin
🇺🇸Pekin, Illinois, United States
Cancer Care Center of O'Fallon
🇺🇸O'Fallon, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸Peoria, Illinois, United States
Illinois CancerCare-Peru
🇺🇸Peru, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Springfield Clinic
🇺🇸Springfield, Illinois, United States
Illinois CancerCare - Washington
🇺🇸Washington, Illinois, United States
Memorial Medical Center
🇺🇸Springfield, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
🇺🇸Warrenville, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Mary Greeley Medical Center
🇺🇸Ames, Iowa, United States
McFarland Clinic - Ames
🇺🇸Ames, Iowa, United States
Hematology Oncology Consultants-Clarkston
🇺🇸Clarkston, Michigan, United States
Newland Medical Associates-Clarkston
🇺🇸Clarkston, Michigan, United States
Parkland Health Center - Farmington
🇺🇸Farmington, Missouri, United States
Sainte Genevieve County Memorial Hospital
🇺🇸Sainte Genevieve, Missouri, United States
North Coast Cancer Care
🇺🇸Sandusky, Ohio, United States
Newland Medical Associates-Pontiac
🇺🇸Pontiac, Michigan, United States
Illinois CancerCare-Bloomington
🇺🇸Bloomington, Illinois, United States
Missouri Baptist Medical Center
🇺🇸Saint Louis, Missouri, United States
Cleveland Clinic Cancer Center Mansfield
🇺🇸Mansfield, Ohio, United States
Cancer Care Specialists of Illinois - Decatur
🇺🇸Decatur, Illinois, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
🇺🇸Ypsilanti, Michigan, United States
East Jefferson General Hospital
🇺🇸Metairie, Louisiana, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Genesee Cancer and Blood Disease Treatment Center
🇺🇸Flint, Michigan, United States
Missouri Baptist Outpatient Center-Sunset Hills
🇺🇸Sunset Hills, Missouri, United States
ProMedica Flower Hospital
🇺🇸Sylvania, Ohio, United States
UT Southwestern/Simmons Cancer Center-Fort Worth
🇺🇸Fort Worth, Texas, United States
UT Southwestern Clinical Center at Richardson/Plano
🇺🇸Richardson, Texas, United States
Illinois CancerCare-Galesburg
🇺🇸Galesburg, Illinois, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Saint Joseph Mercy Hospital
🇺🇸Ann Arbor, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Trinity Health IHA Medical Group Hematology Oncology - Canton
🇺🇸Canton, Michigan, United States