Gemcitabine for the Prevention of Intravesical Recurrence of Urothelial Cancer in Patients With Upper Urinary Tract Urothelial Cancer Undergoing Radical Nephroureterectomy, GEMINI Study

Study Overview
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Brief Summary
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This phase II trial studies how well gemcitabine works in preventing urothelial cancer from coming back within the bladder (intravesical recurrence) in patients with upper urinary tract urothelial cancer undergoing radical nephroureterectomy. Drugs used in chemotherapy, such as gemcitabine, 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. Instilling gemcitabine into the bladder during surgery, may reduce the chance of recurrence of upper urinary tract urothelial cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the efficacy of a single intraoperative intravesical instillation of gemcitabine hydrochloride (gemcitabine) at time of radical nephroureterectomy (RNU) for clinically localized upper tract urothelial carcinoma (UTUC) in preventing intravesical recurrence of urothelial cancer (UC) at one year. SECONDARY OBJECTIVES: I. To assess time to recurrence for entire duration of follow-up. II. To assess the qualitative and quantitative toxicities. EXPLORATORY OBJECTIVES: I. To stratify intravesical UC recurrence free survival by tumor grade, neoadjuvant chemotherapy, tumor stage, ureteral tumor location, and history of bladder cancer. II. To assess incidence and time to development of muscle-invasive bladder cancer (MIBC). OUTLINE: Patients receive gemcitabine hydrochloride intravesically for at least 1 hour at the time of RNU. After completion of study, patients are followed up at 2 weeks, and 3, 6, 12, 18, and 24 months.

Official Title
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GEMINI: An Open-Label, Single-Arm, Phase II Study of Intraoperative Gemcitabine Intravesical Instillation in Patients Undergoing Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Conditions
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Stage 0a Renal Pelvis and Ureter Cancer AJCC v8, Stage 0a Renal Pelvis Cancer AJCC v8, Stage 0a Ureter Cancer AJCC v8, Stage 0is Renal Pelvis and Ureter Cancer AJCC v8, Stage 0is Renal Pelvis Cancer AJCC v8, Stage 0is Ureter Cancer AJCC v8, Stage I Renal Pelvis and Ureter Cancer AJCC v8, Stage I Renal Pelvis Cancer AJCC v8, Stage I Ureter Cancer AJCC v8, Stage II Renal Pelvis and Ureter Cancer AJCC v8, Stage II Renal Pelvis Cancer AJCC v8, Stage II Ureter Cancer AJCC v8, Stage III Renal Pelvis and Ureter Cancer AJCC v8, Stage III Renal Pelvis Cancer AJCC v8, Stage III Ureter Cancer AJCC v8, Stage IV Renal Pelvis and Ureter Cancer AJCC v8, Stage IV Renal Pelvis Cancer AJCC v8, Stage IV Ureter Cancer AJCC v8

Intervention / Treatment
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* Drug: Gemcitabine Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of localized (clinical American Joint Committee on Cancer [AJCC] stage Ta-T4N0M0) low- and high-grade UC of the renal pelvis and/or ureter Plan to undergo RNU Creatinine < 2.2 mg/dL (194 mmol/L) Hemoglobin > 9 g/dL White blood cell count >= 3000/uL Platelet count > 75,000/uL and < 500,000/uL Serum bilirubin levels below 2 times the institution's upper limits of normal Alkaline phosphatase levels below 2 times the institution's upper limits of normal Aspartate aminotransferase levels below 2 times the institution's upper limits of normal Alanine aminotransferase levels below 2 times the institution's upper limits of normal Eastern Cooperative Oncology Group (ECOG) performance status score 0 - 2 Suitable candidate for surgery at the discretion of the investigator Patient must be capable of giving appropriate approved informed consent or have an appropriate representative available to do Patient with a prior malignancy allowed if adequately treated > 3 years ago with no current evidence of disease Women of childbearing potential (WOCBP) must have a negative pregnancy urine test within 28 days of registration, and be using an adequate method of contraception to avoid pregnancy prior to and for at least 6 months after gemcitabine instillation to minimize the risk of pregnancy Male patient who has a partner that is a WOCBP must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) and should avoid conceiving children prior to and for 6 months following gemcitabine instillation Exclusion Criteria: Pure non-urothelial histology; urothelial carcinoma with differentiation allowed Evidence of nodal or distant metastases; enlarged retroperitoneal lymph nodes > 2 cm or histologically positive lymph nodes History of UC of the bladder within 12 months preceding RNU, or receipt of intravesical therapy within 6 months History of or current prostatic urethral, urethral, or contralateral upper tract UC Planned radical cystectomy at time of RNU Symptomatic urinary tract infection of bacterial cystitis (once satisfactorily treated, patients can enter the study) Patient with any current malignancy except for basal or squamous cell skin cancers, noninvasive cancer of the cervix, or any other cancer deemed to be of low-risk for progression or patient morbidity during the trial period (i.e. Gleason 6 prostate cancer, renal mass < 3 cm) Women who are pregnant or breastfeeding Prisoners or subjects who are involuntarily incarcerated Inability for adequate follow-up, including concerns for patient compliance or geographic proximity

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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (gemcitabine hydrochloride)<br>Patients receive gemcitabine hydrochloride intravesically for at least 1 hour at the time of RNU. | Drug: Gemcitabine Hydrochloride<br>* Given intravesically<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urothelial Carcinoma Relapse-free Survival | Number of participants without recurrence of Urothelial Carcinoma. Relapse-free survival will be assessed by cystoscopy and urine cytology. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recurrence | Number of days from Radical Nephroureterectomy to date of histologic proof of recurrence/relapse of Urothelial Carcinoma | Up to 1 year | 
| Incidence of Adverse Events | Adverse events will be categorized by grade and further distinguished as serious adverse events. Furthermore, they will be designated by each site as not related, unlikely, possible, probably, and definitely related to treatment adverse events. they will also be summarized and organized by organ system, with the number and percent of patients experiencing the adverse event at least once and the number of patients exposed. Adverse events will be described and analyzed qualitatively. Adverse events will be grouped into categories and numerically described. | Up to 2 years |