Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Gemcitabine Plus Cisplatin Chemotherapy in Patients With Muscle-invasive Bladder Cancer With Bladder Preservation for Those Patients Whose Tumors Harbor Deleterious DNA Damage Response (DDR) Gene Alterations

Conditions
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Infiltrating Bladder Urothelial Carcinoma, Stage II Bladder Urothelial Carcinoma, Stage III Bladder Urothelial Carcinoma

Intervention / Treatment
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* Drug: Gemcitabine Hydrochloride
* Drug: Cisplatin
* Biological: Pegfilgrastim
* Procedure: Conventional Surgery
* Procedure: Radical Cystectomy
* Other: Chemoradiotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (gemcitabine, cisplatin, bladder sparing)<br>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. | Drug: Gemcitabine Hydrochloride<br>* Given IV<br>Drug: Cisplatin<br>* Given IV<br>Biological: Pegfilgrastim<br>* Given SC<br>Procedure: Conventional Surgery<br>* Undergo bladder sparing<br>|
| Experimental: Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)<br>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. | Drug: Gemcitabine Hydrochloride<br>* Given IV<br>Drug: Cisplatin<br>* Given IV<br>Biological: Pegfilgrastim<br>* Given SC<br>Procedure: Radical Cystectomy<br>* Undergo radical cystectomy<br>Other: Chemoradiotherapy<br>* Undergo chemoradiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach | Will use Kaplan Meier survival analysis to estimate the proportion of patients who are recurrence-free at three years. Will use a one-sided 90% confidence interval. | At 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate for patients harboring deleterious DDR gene alterations | Will be defined as the number of patients with less than a cT1 response divided by the total number of patients harboring deleterious DDR gene alterations who completed 6 cycles of dose dense gemcitabine and cisplatin. | After 6 courses (84 days) | 
| Bladder-intact survival in DDR-altered patients with < cT1 responses who selected the bladder sparing approach | Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals. | Time from registration up to 5 years | 
| Overall survival | Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals. | Time from study registration up to 5 years | 
| Pathologic response (pT0) rate at cystectomy in participants without DDR gene alterations | This will be the number of patients without DDR gene alterations with pT0 at cystectomy divided by the number of patients without DDR gene alterations who underwent cystectomy following the completion of dose dense gemcitabine and cisplatin treatment. Will be estimated with a binomial point estimate and corresponding 95% binomial confidence intervals. | Up to 5 years | 
| Recurrence-free survival | The Kaplan-Meier estimator will be used to estimate the proportion of patients who are recurrence-free success at three years under the two alternative definitions of recurrence-free success above. The point estimate for the three-year recurrence free survival rate will be reported with a 95% confidence interval. These analyses will also be repeated for 5-year recurrence free survival. | Time from study registration up to 5 years | 
| The rate of cystectomies in patients with a DDR alteration and with a cT0/CIS/Ta response | Will be computed as the number of patients with a DDR alteration and with a cT0/CIS/Ta response who undergo a cystectomy within 3 years divided by the total number of patients with a DDR alteration and with a cT0/CIS/Ta response. Will be estimated with a binomial point estimate and corresponding 95% binomial confidence intervals. | Within 3 years | 
| Proportion of patients in the bladder-sparing group who undergo local therapy | Will be estimated with a binomial point estimate and 95% binomial confidence interval. The estimate will be determined as the number of patients who undergo local treatment (BCG or resection of non-invasive disease) in the bladder-sparing group divided by the total number of patients in the bladder-sparing group. | Up to 5 years |