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
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800-378-9373
Little Rock, Arkansas 72205
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501-686-8274
Arroyo Grande, California 93420
Carmichael, California 95608
Carmichael, California 95608
Elk Grove, California 95758
Marysville, California 95901
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530-749-4400
Merced, California 95340
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
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
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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
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Galesburg, Illinois 61401
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Harvey, Illinois 60426
Kewanee, Illinois 61443
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O'Fallon, Illinois 62269
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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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Springfield, Illinois 62781
Urbana, Illinois 61801
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Washington, Illinois 61571
Richmond, Indiana 47374
Garden City, Kansas 67846
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Lexington, Kentucky 40504
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Ann Arbor, Michigan 48106
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Bolivar, Missouri 65613
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Cape Girardeau, Missouri 63703
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Joplin, Missouri 64804
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Billings, Montana 59101
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Kearney, Nebraska 68847
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Basking Ridge, New Jersey 07920
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Dayton, Ohio 45415
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Franklin, Ohio 45005
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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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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
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Dallas, Texas 75235
Dallas, Texas 75237
Dallas, Texas 75390
Fort Worth, Texas 76104
Richardson, Texas 75080
Bremerton, Washington 98310
Bremerton, Washington 98310
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
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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.