Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations
Purpose
This phase II trial studies how well gemcitabine hydrochloride and cisplatin work in treating participants with invasive bladder urothelial cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, 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.
Conditions
- Infiltrating Bladder Urothelial Carcinoma
- Stage II Bladder Urothelial Carcinoma
- Stage III Bladder Urothelial Carcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- Step 1 Patient Registration Eligibility Criteria
- Histologically confirmed muscle-invasive urothelial carcinoma of the bladder.
Urothelial carcinoma invading into the prostatic stroma with no histologic muscle
invasion is allowed, provided the extent of disease is confirmed via imaging and/or
examination under anesthesia (EUA). The diagnostic TURBT sample must have been
obtained within 60 days prior to registration
- 20 unstained slides (10 micron thickness) of formalin-fixed paraffin-embedded (FFPE)
pre-treatment diagnostic transurethral resection (TUR) specimen available (for
sequencing), with 2 (5 micron) slides at the start and end of the 20 slides, for a
total of 22 unstained slides. An FFPE block is also acceptable
- Clinical stage T2-T4aN0/xM0 disease
- Medically appropriate candidate for radical cystectomy as assessed by surgeon
- No concomitant multifocal carcinoma in situ; a single focus is allowed
- A single muscle-invasive bladder tumor measuring ≤5 cm in size as defined by the
surgeons at cystoscopic evaluation. When documented, pathologic size at cystoscopy
and TURBT will take precedence over radiographic measurements of tumor size.
- No clinical or radiographic evidence for locally advanced or metastatic disease
- No prior anti-PD-1 or anti PD-L1 therapies, or systemic chemotherapy within the past
5 years (prior intravesical induction immunotherapy for non-muscle invasive disease
is allowed, defined as BCG x6 doses and maintenance therapy); BCG refractory
disease, defined as disease recurrence within 3 months of BCG therapy, is not
allowed. Intravesical chemotherapy is allowed.
- No prior radiation therapy to the bladder or prostate
- No major surgery or radiation therapy =< 4 weeks of registration (TURBT is allowed).
- Not pregnant and not nursing. This study involves an agent that has known genotoxic,
mutagenic and teratogenic effects. For women of childbearing potential only, a
negative pregnancy test done =< 14 days prior to registration is required
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Platelet count >= 100,000/mm^3
- Calculated creatinine clearance ≥ 55 mL/min using formula per institutional standard
or investigator's discretion. The same formula should be used to calculate all
subsequent creatinine clearances.
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
* (For patients with documented Gilbert's syndrome Total Bilirubin =< 3 x ULN)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
- Alkaline phosphatase =< 2.5 x ULN
- No evidence of New York Heart Association (NYHA) functional class III or IV heart
disease
- No ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade >= 2
- No pre-existing sensory grade >= 2 neuropathy
- No pre-existing grade >= 2 hearing loss
- No serious intercurrent medical or psychiatric illness, including serious active
infection
- None of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident, or transient
ischemic attack
- No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness or other active infection. HIV-positive patients on
combination antiretroviral therapy are ineligible because of the potential for
pharmacokinetic interactions with the drugs used in this trial. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy, when indicated
- No history of allergic reaction attributed to compounds of similar chemical or
biologic composition to the agents used in this study
- No concurrent treatment on another clinical trial; supportive care trials or
non-therapeutic trials (e.g., quality of life) are allowed
- No prior malignancy except for: adequately treated basal or squamous cell skin
cancer, in situ cervical cancer, adequately treated stage I or II cancer from which
the patient is currently in complete remission, or any other cancer from which the
patient has been disease free for five years. Patients with localized prostate
cancer who are being followed by an active surveillance program are also eligible
- Step 2 Patient Registration Eligibility Criteria
- Patients must have completed 4 or more cycles of protocol-directed chemotherapy and
DDR gene results must be available
- Step 3 Patient Registration Eligibility Criteria (only patients with a DDR gene
alteration)
- Deleterious alteration within 1 or more of 9 pre-defined DDR genes within the
pre-treatment TURBT deoxyribonucleic acid (DNA)
- Cystoscopy and imaging performed to determine stage/treatment assignment
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm I (gemcitabine, cisplatin, bladder sparing) |
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage < cT1 undergo bladder sparing. |
|
|
Experimental Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy) |
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage >= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy. |
|
Recruiting Locations
Fairbanks, Alaska 99701
Phoenix, Arizona 85004
Fort Smith, Arkansas 72903
Site Public Contact
800-378-9373
Little Rock, Arkansas 72205
Site Public Contact
501-686-8274
Arroyo Grande, California 93420
Carmichael, California 95608
Carmichael, California 95608
Elk Grove, California 95758
Martinez, California 94553-3156
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925-957-5400
Marysville, California 95901
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530-749-4400
Rocklin, California 95765
Sacramento, California 95816
Sacramento, California 95817
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916-734-3089
San Luis Obispo, California 93401
Santa Maria, California 93444
Woodland, California 95695
Aurora, Colorado 80012
Boulder, Colorado 80304
Colorado Springs, Colorado 80907
Colorado Springs, Colorado 80907
Colorado Springs, Colorado 80923
Denver, Colorado 80218
Englewood, Colorado 80113
Lakewood, Colorado 80228
Littleton, Colorado 80120
Longmont, Colorado 80501
Pueblo, Colorado 81004
Thornton, Colorado 80260
Hartford, Connecticut 06102
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860-545-5363
Meriden, Connecticut 06451
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866-662-5678
New Britain, Connecticut 06050
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860-224-5660
Fort Lauderdale, Florida 33308
Gainesville, Florida 32610
Boise, Idaho 83706
Caldwell, Idaho 83605
Coeur d'Alene, Idaho 83814
Meridian, Idaho 83642
Nampa, Idaho 83687
Post Falls, Idaho 83854
Aurora, Illinois 60504
Bloomington, Illinois 61704
Canton, Illinois 61520
Carbondale, Illinois 62902
Carterville, Illinois 62918
Carthage, Illinois 62321
Centralia, Illinois 62801
Centralia, Illinois 62801
Danville, Illinois 61832
Decatur, Illinois 62526
Decatur, Illinois 62526
Dixon, Illinois 61021
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815-285-7800
Effingham, Illinois 62401
Effingham, Illinois 62401
Eureka, Illinois 61530
Galesburg, Illinois 61401
Harvey, Illinois 60426
Kewanee, Illinois 61443
Macomb, Illinois 61455
Mattoon, Illinois 61938
Mount Vernon, Illinois 62864
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618-242-4600
O'Fallon, Illinois 62269
O'Fallon, Illinois 62269
Ottawa, Illinois 61350
Pekin, Illinois 61554
Pekin, Illinois 61554
Peoria, Illinois 61615
Peoria, Illinois 61615
Peoria, Illinois 61636
Peoria, Illinois 61637
Peru, Illinois 61354
Peru, Illinois 61354
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815-664-4141
Princeton, Illinois 61356
Springfield, Illinois 62702
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217-545-7929
Springfield, Illinois 62702
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800-444-7541
Springfield, Illinois 62781
Urbana, Illinois 61801
Urbana, Illinois 61801
Washington, Illinois 61571
Richmond, Indiana 47374
Garden City, Kansas 67846
Great Bend, Kansas 67530
Lexington, Kentucky 40504
Lexington, Kentucky 40504
Lexington, Kentucky 40509
Baton Rouge, Louisiana 70805
Baton Rouge, Louisiana 70808
Baton Rouge, Louisiana 70808
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225-765-7659
Baton Rouge, Louisiana 70809
Baton Rouge, Louisiana 70809
Covington, Louisiana 70433
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504-584-6990
Metairie, Louisiana 70006
Metairie, Louisiana 70006
New Orleans, Louisiana 70112
Ann Arbor, Michigan 48106
Brighton, Michigan 48114
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Canton, Michigan 48188
Canton, Michigan 48188
Caro, Michigan 48723
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Detroit, Michigan 48236
Flint, Michigan 48503
Flint, Michigan 48503
Grosse Pointe Woods, Michigan 48236
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Saginaw, Michigan 48601
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Tawas City, Michigan 48764
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Bemidji, Minnesota 56601
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Burnsville, Minnesota 55337
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Deer River, Minnesota 56636
Detroit Lakes, Minnesota 56501
Duluth, Minnesota 55805
Duluth, Minnesota 55805
Duluth, Minnesota 55805
Edina, Minnesota 55435
Fosston, Minnesota 56542
Hibbing, Minnesota 55746
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218-786-3308
Maple Grove, Minnesota 55369
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Minneapolis, Minnesota 55407
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Park Rapids, Minnesota 56470
Robbinsdale, Minnesota 55422
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Sandstone, Minnesota 55072
Shakopee, Minnesota 55379
Stillwater, Minnesota 55082
Virginia, Minnesota 55792
Waconia, Minnesota 55387
Willmar, Minnesota 56201
Woodbury, Minnesota 55125
Bolivar, Missouri 65613
Cape Girardeau, Missouri 63703
Cape Girardeau, Missouri 63703
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573-651-5550
Columbia, Missouri 65212
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Creve Coeur, Missouri 63141
Farmington, Missouri 63640
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314-996-5569
Jefferson City, Missouri 65109
Joplin, Missouri 64804
Joplin, Missouri 64804
Rolla, Missouri 65401
Rolla, Missouri 65401
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Saint Joseph, Missouri 64506
Saint Louis, Missouri 63110
Saint Louis, Missouri 63128
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Saint Louis, Missouri 63131
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Saint Louis, Missouri 63136
Saint Louis, Missouri 63141
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Sainte Genevieve, Missouri 63670
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Springfield, Missouri 65804
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Springfield, Missouri 65807
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Sullivan, Missouri 63080
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Sunset Hills, Missouri 63127
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Billings, Montana 59101
Bozeman, Montana 59715
Great Falls, Montana 59405
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Kalispell, Montana 59901
Missoula, Montana 59804
Kearney, Nebraska 68847
Omaha, Nebraska 68122
Omaha, Nebraska 68124
Omaha, Nebraska 68130
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Basking Ridge, New Jersey 07920
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Commack, New York 11725
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Oswego, New York 13126
Rochester, New York 14642
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Verona, New York 13478
Bismarck, North Dakota 58501
Fargo, North Dakota 58103
Fargo, North Dakota 58122
Fargo, North Dakota 58122
Jamestown, North Dakota 58401
Beavercreek, Ohio 45431
Boardman, Ohio 44512
Centerville, Ohio 45459
Cincinnati, Ohio 45220
Cincinnati, Ohio 45236
Cincinnati, Ohio 45242
Cleveland, Ohio 44195
Columbus, Ohio 43210
Dayton, Ohio 45415
Findlay, Ohio 45840
Findlay, Ohio 45840
Findlay, Ohio 45840
Franklin, Ohio 45005
Greenville, Ohio 45331
Greenville, Ohio 45331
Kettering, Ohio 45409
Kettering, Ohio 45429
Troy, Ohio 45373
Warren, Ohio 44484
Youngstown, Ohio 44501
Oklahoma City, Oklahoma 73104
Oklahoma City, Oklahoma 73120
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405-752-3402
Allentown, Pennsylvania 18103
Bethlehem, Pennsylvania 18017
Danville, Pennsylvania 17822
East Stroudsburg, Pennsylvania 18301
Hazleton, Pennsylvania 18201
Lewisburg, Pennsylvania 17837
Lewistown, Pennsylvania 17044
Pottsville, Pennsylvania 17901
Scranton, Pennsylvania 18510
Selinsgrove, Pennsylvania 17870
Wilkes-Barre, Pennsylvania 18711
Providence, Rhode Island 02903
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401-444-1488
Gaffney, South Carolina 29341
Greer, South Carolina 29651
Spartanburg, South Carolina 29303
Union, South Carolina 29379
Sioux Falls, South Dakota 57104
Sioux Falls, South Dakota 57117-5134
Bremerton, Washington 98310
Silverdale, Washington 98383
Antigo, Wisconsin 54409
Ashland, Wisconsin 54806
Ashland, Wisconsin 54806
Eau Claire, Wisconsin 54701
Hayward, Wisconsin 54843
La Crosse, Wisconsin 54601
Ladysmith, Wisconsin 54848
Marshfield, Wisconsin 54449
Medford, Wisconsin 54451
Minocqua, Wisconsin 54548
New Richmond, Wisconsin 54017
Rhinelander, Wisconsin 54501
Rice Lake, Wisconsin 54868
Spooner, Wisconsin 54801
Stevens Point, Wisconsin 54481
Stevens Point, Wisconsin 54482
Superior, Wisconsin 54880
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701-364-6272
Wausau, Wisconsin 54401
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877-405-6866
Weston, Wisconsin 54476
Weston, Wisconsin 54476
Wisconsin Rapids, Wisconsin 54494
Site Public Contact
715-422-7718
Sheridan, Wyoming 82801
More Details
- NCT ID
- NCT03609216
- Status
- Recruiting
- Sponsor
- Alliance for Clinical Trials in Oncology
Detailed Description
PRIMARY OBJECTIVES: I. To determine the 3-year event free survival, defined as the proportion of patients without invasive or metastatic recurrence following definitive gemcitabine hydrochloride (gemcitabine) and cisplatin (standard or dose-dense) chemotherapy in those patients whose pre-treatment transurethral resection of bladder tumor (TURBT) tumors harbor deleterious DDR gene alterations and who achieve < cT1 response to chemotherapy. SECONDARY OBJECTIVES: I. To determine the clinical response rate (< cT1) for patients harboring deleterious DDR gene alterations following dose dense gemcitabine and cisplatin. II. To determine the bladder-intact and overall survival for DDR-altered patients with < cT1. III. For DDR gene altered patients who elect radical cystectomy despite < cT1, to determine the pT0 rate in this patient population. IV. To determine the pathologic response rate at cystectomy and 3-year recurrence-free and overall survival for patients without DDR mutations who are registered onto this trial. V. To assess the local treatment burden (Bacillus Calmette-Guerin [BCG] therapy, resection of non-invasive disease, checkpoint blockade) over time in the bladder-sparing group. VI. To determine the bladder-intact disease-free survival in patients who elect to undergo chemoradiation therapy in the DDR mutant group and the DDR wild-type group. OUTLINE: Participants receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim subcutaneously (SC) on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants are then assigned to 1 of 2 arms. ARM I: Participants with DDR gene alteration and disease stage < cT1 undergo bladder sparing. ARM II: Participants with DDR gene alteration and disease stage >= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy. After completion of study treatment, participants are followed up for 5 years.