Neoadjuvant Nivolumab for Upper Tract Urothelial Carcinoma

Inclusion Criteria:

1. Have a histologically or clinically confirmed diagnosis of locally advanced (cT2-T4and N0M0) urothelial carcinoma of the renal pelvis and/or ureter (UTUC). Pureurothelial carcinoma or urothelial carcinoma mixed with other histological variant areallowed, but urothelial carcinoma must be the predominant histology.
2. Have at least a measurable lesion based on RECIST 1.1 as determined by the local siteinvestigator/radiology assessment.
3. Voluntarily agree to participate by providing written informed consent/assent for thetrial.
4. Age (at the time of informed consent): 20 years and older
5. Have received no prior systemic chemotherapy for advanced urothelial carcinoma, withthe following exceptions:
6. Platinum-based chemotherapy for previous a history of ipsilateral UTUC or bladdercancer in purpose of neoadjuvant or adjuvant treatment with recurrence > 6 monthsfrom completion of therapy is permitted.
7. Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5-FU, mitomycinplus 5-FU, or cisplatin plus paclitaxel) given concurrently with radiation tourothelial carcinoma of bladder is not considered systemic therapy.
8. Have willing to provide tissue for exploratory biomarker analysis from a newlyobtained core or excisional biopsy of a tumor lesion from the renal pelvis or uretertumor.
9. Have an ECOG PS of 0, 1, or 2.
10. Have adequate organ function as defined in Table 6. (All screening labs should beperformed within 3 weeks prior to treatment initiation.)
11. Female subjects of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of trial medication.If the urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.
12. Female subjects of childbearing potential must be willing to use an adequate method ofcontraception as outlined in Section 7.5.2 - Contraception, for the course of thetrial through 5 months or more after the last dose of nivolumab

Exclusion Criteria:

• 1. Is currently participating and receiving study therapy or investigational agents.Patients who withdraw of previous clinical trials should have a 4-weeks washout periodof investigational drug before participating this study.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to randomization.
3. Has an active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,etc.) is not considered a form of systemic treatment.
4. Short-term (<7 days) use of systemic corticosteroids is allowed when use isconsidered SOC.
5. Subjects with vitiligo, type I diabetes mellitus, hypothyroidism, or resolvedchildhood asthma/atopy would be an exception to this rule.
6. Subjects who require intermittent use of bronchodilators, inhaled steroids, orlocal steroid injections would not be excluded from the trial.
7. Has a known additional malignancy that is progressing or requires activetreatment within the past 5 years.
8. Exceptions include basal cell carcinoma of the skin; squamous cell carcinoma ofthe skin that has undergone potentially curative surgery; in situ cervicalcancer; early stage of prostate cancer (stage 1) with low Gleason score ≤6; andprostate-specific antigen (PSA) undetectable.
9. A history of urothelial carcinoma, including upper tract urothelial carcinoma orbladder cancer who received curative-intent surgery (nephroureterectomy,segmentectomy, TURBT, partial cystectomy, radical cystoprostectomy) > 12 monthsbefore first-dose trial treatment will be the exception.
10. Has a history of (non-infectious) pneumonitis or interstitial lung disease orpulmonary fibrosis diagnosed based on imaging (CT of chest preferably).
11. Has active tuberculosis (TB) (Bacillus tuberculosis). 7. Has an activeinfection requiring systemic therapy within 7 days prior to the first dose oftrial treatment.
12. Is pregnant or breastfeeding, or expecting to conceive or father childrenwithin the projected duration of the trial, starting with the screening visitthrough 5 months or more after the last dose of nivolumab.
13. Has a history of uncontrolled or significant cardiovascular disease meetingany of the following:
14. Myocardial infarction within 180 days before first-dose of trial treatment
15. New York Heart Association (NYHA) class III or IV congestive heart failure
16. Myocarditis, no matter what etiology should be excluded
17. Arrhythmia requiring treatment (e.g. atrial fibrillation/flutter, ventriculartachycardia or fibrillation, paroxysmal supraventricular tachycardia, symptomaticbradycardia, sick sinus syndrome or high-grade atrioventricular block).
18. Has permanent pacemaker implantation or implantable cardioverter defibrillator (ICD).
19. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2agent or with an agent directed to another co-inhibitory T-cell receptor (e.g.,CTLA-4, OX-40, CD137).
20. Has undergone major surgery (any surgery involving general anesthesia) within 28 days before first-dose of study therapy.
21. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2antibodies).
22. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCVRNA [qualitative] is detected). Controlled (treated) hepatitis B subject will beallowed if they meet the following criteria:
23. Antiviral therapy for HBV must be given for at least 8 weeks and HBV viral loadmust be less than 100 IU/mL prior to first dose of study drug.
24. Subject who are anti-HBc (+), negative for HBsAg, negative for anti-HBs and havean HBV viral load under 100 IU/mL don't need HBV anti-viral prophylaxis.
25. Has received a live virus vaccine within 30 days of planned start of trialtherapy.
26. Has known CNS metastases and/or leptomeningeal carcinomatosis. 16. Hassymptomatic ascites or pleural effusion. 17. Has had a prior allogeneic stem cellor bone marrow transplant. 18. Has received any unapproved or unlicensed drug (e.g. marketed drugs unapproved for urothelial carcinoma, investigational use ofdrugs, herb combination) within 28 days before first-dose of study drug.
27. Are otherwise unfit for the study in the investigator's or sub-investigator'sopinion.