Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy in Patients With High-Grade Upper Tract Urothelial Carcinoma

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 for four 21 day cycles for a total of 12 weeks can help shrink the tumor before undergoing surgery for kidney cancer.

Official Title
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Phase II Study of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy in Patients With High-Grade Upper Tract Urothelial Carcinoma

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Gemcitabine and Cisplatin


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 or high-grade concomitant bladder tumor. Hydronephrosis associated with tumor on 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 ≤ 1.2 Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for the institution Alkaline phosphatase ≤ 2.5 x ULN for the institution Serum creatinine ≤ 1.3 mg/dL if male or ≤ 1.1 mg/dL if female OR calculated creatinine clearance ≥ 55 ml/min/1.73m^2 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: CKD epi : GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age 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 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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine and Cisplatin<br>This is a Phase II Study of Gemcitabine and Cisplatin (GC) as neoadjuvant chemotherapy in patients with upper tract high-grade urothelial carcinoma who are candidates for radical nephroureterectomy or distal ureterectomy. | Drug: Gemcitabine and Cisplatin<br>* Patients will receive four cycles of GC administered every 21 days. Gemcitabine 1,000 mg/m2 and Cisplatin 35 mg/m2 will be administered intravenously on days 1 and 8. A total of four cycles of therapy will be administered at 21 day intervals followed by radical nephroureterectomy or distal ureterectomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the pathologic response rate (<pT2) | of neoadjuvant Gemcitabine and Cisplatin regimen in patients with upper tract high-grade urothelial carcinoma. And is defined as the absence of high-grade carcinoma (<pT2 disease) and the absence of microscopic lymph node metastases (N0) on the final nephroureterectomy specimen. | The time to disease progression is measured from the time of initiation of chemotherapyuntil the first date that systemic recurrence is objectively documented. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the time to disease progression | will be estimated using the methods of Kaplan and Meier in patients with upper tract high-grade urothelial carcinoma with neoadjuvant GC followed by radical nephroureterectomy. | Time to progression is measured from the time of initiation of chemotherapy until the 1st date that systemic recurrence is objectively documented. Systemic recurrence for this trial is defined as either metastatic or local pelvic recurrence. | 
| To determine overall survival of patients | will be estimated using the methods of Kaplan and Meier in patients with upper tract high-grade urothelial carcinoma treated with neoadjuvant GC followed by radical nephroureterectomy. | 3 years | 
| To evaluate the safety and tolerability | of neoadjuvant Gemcitabine and Cisplatin in this setting. Toxicity will be graded according to the National Cancer Institute Common Toxicity Criteria version 4.0. | every 2 weeks per cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gemcitabine, Cisplatin, Bladder, radical nephroureterectomy, ureterectomy, 10-208