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)

• Sponsor: Southwest Oncology Group (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04871529
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 196
• Locations: 70
• Arms: 2
• Anticipated Duration (Months): 90.8
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall; Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma; Stage II Bladder Cancer AJCC v8	Procedure: Therapeutic Conventional Surgery; Drug: Avelumab; Drug: Gemcitabine Hydrochloride; Drug: Carboplatin	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

1. To evaluate toxicities with AGCa, and to compare resectability rates and surgical complications by arm in this population.

2. To compare event-free survival (EFS) with AGCa versus no neoadjuvant therapy in this population.

3. To compare overall survival (OS) with AGCa versus no neoadjuvant therapy preceding surgery in this population.

4. 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:

1. 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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 196 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Oct 6, 2021
• Anticipated Primary Completion Date: Apr 30, 2027
• Anticipated Study Completion Date: Apr 30, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (avelumab, gemcitabine, carboplatin, 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.	Procedure: Therapeutic Conventional Surgery; Undergo surgery; Drug: Avelumab; Given IV; Other Names: 1537032-82-8 Bavencio Immunoglobulin G1-lambda1 Anti-(Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, pd-l1, B7 Homolog 1, B7H1)) Homo sapiens Monoclonal Antibody MSB-0010718C MSB0010718C ; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: 1-(2-Oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose, hydrochloride 122111-03-9 2''Deoxy-2'',2''-Difluorocytidine Hydrochloride dFdCyd Difluorodeoxycytidine Hydrochloride FF 10832 FF-10832 FF10832 Gemcitabine HCI Gemzar LY-188011 LY188011 ; Drug: Carboplatin; Given IV; Other Names: (SP-4-2)-diammine[1,1-cyclobutanedicarboxylato(2--)-O,O'']platinum 1,1-cyclobutanedicarboxylic acid platinum complex 41575-94-4 Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA cis-diammine(1,1-cyclobutanedicarboxylato) platinum(II) Cis-Diammine(cyclobutane-1,1-dicarboxylato)platinum cis-diammine(cyclobutanedicarboxylato)platinum II Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine platinum diammine(1,1-cyclobutanedicarboxylato(2-))-, (SP-4-2)
Experimental: Arm B (surgery) Patients undergo standard of care surgery.	Procedure: Therapeutic Conventional Surgery; Undergo surgery

Outcome Measures

Primary Outcome Measures

1. pathologic complete response [up to 5 years post-surgery]

Secondary Outcome Measures

1. Event-free survival [From randomization to the first event, assessed up to 5 years post surgery]

2. Incidence of adverse events [Up to 90 days post-surgery]

   Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting

3. Overall survival [Up to 5 years post-surgery]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital	Aurora	Colorado	United States	80045
2	UCHealth Highlands Ranch Hospital	Highlands Ranch	Colorado	United States	80129
3	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
4	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
5	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
6	Carle on Vermilion	Danville	Illinois	United States	61832
7	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois	United States	62526
8	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
9	Illinois CancerCare-Dixon	Dixon	Illinois	United States	61021
10	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
11	Crossroads Cancer Center	Effingham	Illinois	United States	62401
12	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
13	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
14	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
15	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois	United States	60026
16	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois	United States	60035
17	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
18	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
19	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
20	Cancer Care Center of O'Fallon	O'Fallon	Illinois	United States	62269
21	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
22	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
23	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
24	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
25	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
26	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
27	Springfield Clinic	Springfield	Illinois	United States	62702
28	Memorial Medical Center	Springfield	Illinois	United States	62781
29	Carle Cancer Center	Urbana	Illinois	United States	61801
30	Illinois CancerCare - Washington	Washington	Illinois	United States	61571
31	Mary Greeley Medical Center	Ames	Iowa	United States	50010
32	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
33	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
34	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa	United States	50501
35	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
36	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
37	East Jefferson General Hospital	Metairie	Louisiana	United States	70006
38	LSU Healthcare Network / Metairie Multi-Specialty Clinic	Metairie	Louisiana	United States	70006
39	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
40	Saint Joseph Mercy Brighton	Brighton	Michigan	United States	48114
41	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan	United States	48114
42	Saint Joseph Mercy Canton	Canton	Michigan	United States	48188
43	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan	United States	48188
44	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
45	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan	United States	48118
46	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan	United States	48346
47	Newland Medical Associates-Clarkston	Clarkston	Michigan	United States	48346
48	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan	United States	48503
49	Genesee Hematology Oncology PC	Flint	Michigan	United States	48503
50	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
51	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan	United States	48154
52	Newland Medical Associates-Pontiac	Pontiac	Michigan	United States	48341
53	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
54	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan	United States	48604
55	Ascension Saint Joseph Hospital	Tawas City	Michigan	United States	48764
56	Huron Gastroenterology PC	Ypsilanti	Michigan	United States	48106
57	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan	United States	48197
58	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
59	Parkland Health Center - Farmington	Farmington	Missouri	United States	63640
60	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
61	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
62	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
63	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
64	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
65	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio	United States	44124
66	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
67	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
68	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
69	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas	United States	76104
70	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas	United States	75080

Sponsors and Collaborators

• Southwest Oncology Group
• National Cancer Institute (NCI)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Southwest Oncology Group
• ClinicalTrials.gov Identifier: NCT04871529
• Other Study ID Numbers: S2011; NCI-2021-02265; S1905; S1905; U10CA180888
• First Posted: May 4, 2021
• Last Update Posted: Jul 7, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Gemcitabine; Carboplatin; Avelumab; Immunoglobulins; Immunoglobulin G; Antibodies, Monoclonal

Study Results

No Results Posted as of Jul 7, 2022