Gemcitabine Hydrochloride and Cisplatin in Treating Patients with Invasive Bladder Urothelial Cancer
- 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
- 10-20 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 x 6 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 DNA
- Cystoscopy and imaging performed to determine stage/treatment assignment
San Luis Obispo
West Des Moines
Grosse Pointe Woods
Saint Louis Park
Thief River Falls
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 deoxyribonucleic acid (DNA) damage response (DDR) gene alterations and who achieve < cT1 response to chemotherapy.
I. To determine the clinical response rate (< cT1) for patients harboring deleterious DDR gene alterations following dose dense gemcitabine and cisplatin (standard or dose dense).
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: Patients are assigned to 1 of 2 dose regimens.
DOSE-DENSE REGIMEN: Patients 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 6 cycles in the absence of disease progression or unaccepted toxicity. Patients are then assigned to 1 of 2 arms.
STANDARD DOSE REGIMEN: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, cisplatin IV on day 1, and pegfilgrastim SC on day 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unaccepted toxicity. Patients are then assigned to 1 of 2 arms.
ARM I: Patients with DDR gene alteration and disease stage < cT1 undergo bladder sparing. Patients who achieve a clinical complete response or non-invasive residual disease 14-28 days after the last dose of chemotherapy may forgo bladder sparing.
ARM II: Patients with DDR gene alteration and disease stage >= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
After completion of study treatment, patients who do not undergo surgery are followed up every 3 months for years 1-2, every 6 months for years 3-4, and then once during year 5. Patients who undergo surgery are followed up every 3 months for 2 years, and then annually for 3 years.
Trial Phase Phase II
Trial Type Treatment
Alliance for Clinical Trials in Oncology
Gopakumar V. Iyer
- Primary ID A031701
- Secondary IDs NCI-2018-01531
- Clinicaltrials.gov ID NCT03609216