Neoadjuvant Chemotherapy Versus Surgery Alone in Patients With High-Grade UTUC

Study Overview
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Brief Summary
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The purpose of this study is to see if getting chemotherapy with Gemcitabine and Cisplatin (GC) for 2-4 cycles can help shrink the tumor before undergoing surgery and improves the overall survival for high-grade upper tract urothelial carcinoma.

Detailed Description
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The purpose of this study is to see if getting chemotherapy with Gemcitabine and Cisplatin (Gemcitabine, 1250mg/m2, d1 d8, Cisplatin, 75mg/m2, d1-d3, 21d, 2-4 cycles) for 2-4 cycles can help shrink the tumor before undergoing surgery and improves the overall survival for high-grade upper tract urothelial carcinoma.

Official Title
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Neoadjuvant Chemotherapy Versus Surgery Alone in Patients With High-Grade Upper Tract Urothelial Carcinoma

Conditions
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High-Grade Upper Tract Urothelial Carcinoma

Intervention / Treatment
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* Procedure: Radical nephroureterectomy
* Procedure: Distal ureterectomy
* Drug: Neoadjuvant Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed high-grade upper tract transitional cell carcinoma at MSKCC or a participating site and/or radiographically visible tumor stage T2-T4a N0/X M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. Medically appropriate candidate for radical nephroureterectomy or ureterectomy as per MSKCC or a participating site attending urologic oncologist Karnofsky Performance Status ≥ 70% Age ≥ 18 years of age Required Initial Laboratory Values: Absolute neutrophil count ≥ 1500 cells/mm3 Platelets ≥ 100,000 cells/mm3 Hemoglobin ≥ 9.0g/dL Bilirubin ≤ 1.5 Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for the institution Alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) for the institution Serum creatinine ≤ 1.5 mg/dL and calculated creatinine clearance ≥ 55 If female of childbearing potential, serum pregnancy test is negative. Patients with reproductive potential must use an effective method to avoid pregnancy for the duration of the trial. ml/min/1.73m2 using the formula: Chronic kidney disease (CKD) epi : glomerular filtration rate (GFR) = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993 Age X 1.018 [if female] X 1.159 [if black] Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1. If female of childbearing potential, serum pregnancy test is negative. Patients with reproductive potential must use an effective method to avoid pregnancy for the duration of the trial Exclusion Criteria: Concomitant bladder urothelial carcinoma is acceptable if it is organ confined and surgically resectable. Presence of carcinoma in situ (CIS) Prior systemic chemotherapy (prior intravesical therapy is allowed) Prior radiation therapy to the bladder Evidence of New York Heart Association (NYHA) functional class III or IV heart disease. Serious intercurrent medical or psychiatric illness, including serious active infection. Preexisting sensory grade 3 neuropathy Major surgery or radiation therapy < 4 weeks of starting study treatment. Concomitant use of any other investigational drugs Any 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, or pulmonary embolism. Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2. Uncontrolled hypertension (>150/100 mmHg despite optimal medical therapy). Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection. Patients with HIV but no evidence of AIDS will be considered candidates. Concurrent treatment on another clinical trial involving an intervention which may affect the primary endpoint. Supportive care trials or non-treatment trials, e.g. QOL, are allowed. Ongoing treatment with therapeutic doses of warfarin or low molecular weight heparin (low dose warfarin up to 2 mg po daily or use of subcutaneous low molecular weight heparin for thromboembolic prophylaxis is allowed). Pregnancy or breast-feeding. Patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the MSKCC and participating site PI. Male patients must be surgically sterile or agree to use effective contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgery alone<br>Surgeons: the operation shall be performed by senior urologic surgeons. Try to achieve the consistency of operation quality. Operation: Radical nephroureterectomy (RNU) with an ipsilateral bladder cuff or distal ureterectomy. | Procedure: Radical nephroureterectomy<br>* Radical nephroureterectomy (RNU) with an ipsilateral bladder cuff<br>Procedure: Distal ureterectomy<br>* Distal ureterectomy.<br>|
| Experimental: Neoadjuvant chemotherapy and Surgery<br>Experimental: Neoadjuvant chemotherapy group Neoadjuvant chemotherapy(Gemcitabine and Cisplatin): Gemcitabine, 1250mg/m2, d1 d8, Cisplatin, 75mg/m2, d1-d3, 21d, 2-4 cycles. Surgery: 2-3weeks after Neoadjuvant chemotherapy Surgeons: the operation shall be performed by senior urologic surgeons. Try to achieve the consistency of operation quality. Operation: Radical nephroureterectomy (RNU) with an ipsilateral bladder cuff or distal ureterectomy. | Procedure: Radical nephroureterectomy<br>* Radical nephroureterectomy (RNU) with an ipsilateral bladder cuff<br>Procedure: Distal ureterectomy<br>* Distal ureterectomy.<br>Drug: Neoadjuvant Chemotherapy<br>* Gemcitabine, 1250mg/m2, d1 d8, Cisplatin, 75mg/m2, d1-d3, 21d, 2-4 cycles.<br>* Other names: GC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | Disease-free survival | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | after neoadjuvant chemotherapy completion, assessed up to 4 weeks | 
| Overall survival (OS) | Overall survival | From date of surgery until the date of first documented recurrence or date of death from any cause, whichever came first, assessed up to 100 months death from any cause, whichever came first, assessed up to 100 months | 
| Number of participants with chemotherapy-related adverse events as assessed by National Cancer Institute Common Toxicity Criteria version 4.0. | Number of participants with chemotherapy-related adverse events as assessed by National Cancer Institute Common Toxicity Criteria version 4.0. | Through neoadjuvant chemotherapy completion, assessed up to 4 weeks | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant chemotherapy, upper tract urothelial carcinoma