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)

Stage II Bladder Cancer AJCC v8 Clinical Trial

Official title:

Randomized Phase II Trial of Gemcitabine, Avelumab and Carboplatin vs. No Neoadjuvant Therapy Preceding Surgery for Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma: SWOG GAP TRIAL

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04871529
• Other study ID #: S2011
• Secondary ID: NCI-2021-02265S1
• Status: Suspended
• Phase: Phase 2
• Start date: August 10, 2022
• Est. completion date: April 30, 2029

Study information

• Verified date: August 2023
• Source: SWOG Cancer Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Suspended
• Enrollment: 196
• Est. completion date: April 30, 2029
• Est. primary completion date: April 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

• 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

• Participants must have a bone scan within 56 days prior to registration if they have bone pain or elevated serum alkaline phosphatase

• Participants must have a bimanual examination under anesthesia within 56 days prior to registration

• 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

• 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

• Participants must be >= 18 years of age

• Participants must have Zubrod performance status 0-2

• Participants must have history and physical examination within 28 days prior to registration

• Participants must be surgical candidates as deemed by the local site oncologic surgeon within 28 days prior to registration. This must be clearly documented

• 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

• 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

• Hemoglobin >= 9.0 g/dL (within 28 days prior to registration)

• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to registration)

• Platelets >= 100,000/mcL (within 28 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to registration)

• Aspartate aminotransferase (AST) =< 2.5 x institutional ULN (within 28 days prior to registration)

• Alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 28 days prior to registration)

• 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

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall
• Carcinoma
• Carcinoma, Transitional Cell
• Stage II Bladder Cancer AJCC v8
• Urinary Bladder Neoplasms

Intervention

Procedure:
• Therapeutic Conventional Surgery
Undergo surgery

Drug:
• Avelumab
Given IV
• Gemcitabine Hydrochloride
Given IV
• Carboplatin
Given IV

Locations

Country	Name	City	State
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Saint Anthony's Health	Alton	Illinois
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	University of Colorado Hospital	Aurora	Colorado
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
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	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	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Northwestern University	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	Mercy Hospital	Coon Rapids	Minnesota
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	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Parkland Health Center - Farmington	Farmington	Missouri
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	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	UCHealth Highlands Ranch Hospital	Highlands Ranch	Colorado
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
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	East Jefferson General Hospital	Metairie	Louisiana
United States	LSU Healthcare Network / Metairie Multi-Specialty Clinic	Metairie	Louisiana
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	AdventHealth Orlando	Orlando	Florida
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	North Coast Cancer Care	Sandusky	Ohio
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	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
SWOG Cancer Research Network	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	pathologic complete response		up to 5 years post-surgery
Secondary	Event-free survival		From randomization to the first event, assessed up to 5 years post surgery
Secondary	Incidence of adverse events	Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting	Up to 90 days post-surgery
Secondary	Overall survival		Up to 5 years post-surgery