An Open Label, Single-arm, Phase 2 Study of Neoadjuvant Nivolumab and Nab-paclitaxel Before Radical Cystectomy for Patients With Muscle-invasive Bladder Cancer (NURE-Combo)

Inclusion Criteria:

• Female or male subjects, >18 years of age, able to understand and give writteninformed consent.
• Histopathologically confirmed urothelial carcinoma. Patients with mixed histologiesare required to have a dominant (i.e. 50% at least) transitional cell pattern.
• Fit and planned for RC (according to local guidelines).
• ECOG performance status score of 0 or 1.
• Adequate hematologic counts without transfusional or growth factor support within 2weeks of study drug initiation (Hemoglobin ≥ 9 g/dL, ANC ≥ 1,500/ mm3, and Platelets ≥ 100,000/ μL).
• Adequate hepatic function (Bilirubin ≤ 1.5 IULN, AST and ALT ≤ 2.5 x IULN or ≤ 5 xIULN if known liver metastases and serum albumin >3 g/dl).
• Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation.
• Female subjects of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of study medication,and must not be lactating. If the urine test is positive or cannot be confirmed asnegative, a serum pregnancy test will be required.
• Female subjects of childbearing potential must be willing to use 2 methods of birthcontrol or be surgically sterile or abstain from heterosexual activity for the courseof the study through 4 months after the last dose of study medication. Subjects ofchildbearing potential are those who have not been surgically sterilized or have notbeen free from menses for >2 years.
• Male subjects must agree to use an adequate method of contraception starting with thefirst dose of study therapy through 6 months after the last dose of study therapy.
• Clinical stage T2-T4aN0M0 MIBC, assessed by CT + PET/CT + mpMRI.
• The patient accepts to undergo RC.
• Ineligibility to receive cisplatin-based neoadjuvant chemotherapy based on Galsky'scriteria (Galsky MD, et al. J Clin Oncol. 2011 Jun 10;29(17):2432-8) OR refusal toreceive neoadjuvant cisplatin-based chemotherapy.

Exclusion Criteria:

• Has received prior systemic anti-cancer therapy including investigational agents andimmunotherapy.
• Prior immunotherapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with anagent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,OX-40, CD137.
• Has received prior radiotherapy on the bladder tumor.
• Have received a partial cystectomy.
• Refusal to undergo RC.
• Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injectionare generally killed virus vaccines and are allowed; however, intranasal influenzavaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• Has received any antibiotics within 30 days prior to the first dose of study drug.
• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first dose ofstudy treatment. Note: Participants who have entered the follow-up phase of an investigational study mayparticipate as long as it has been 4 weeks after the last dose of the previousinvestigational agent.
• Has a known additional malignancy that is progressing or has required active treatmentwithin the past 3 years.
• Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma ofthe skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) thathave undergone potentially curative therapy are not excluded. Participants withlow-risk early stage prostate cancer defined as follows are not excluded; Stage T1c orT2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL eithertreated with definitive intent or untreated in active surveillance that has beenstable for the past year prior to study allocation.
• Has severe hypersensitivity (≥Grade 3) to nivolumab or nab-paclitaxel and/or any ofits excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.
• Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease)or GI perforation within 6 months of enrollment
• Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the subject'sparticipation for the full duration of the study, or is not in the best interest ofthe subject to participate, in the opinion of the treating investigator.
• Have active cardiac disease, defined as:
• Myocardial infarction or unstable angina pectoris within 6 months of C1D1
• History of serious ventricular arrhythmia (i.e., ventricular tachycardia orventricular fibrillation), high-grade atrioventricular block, or other cardiacarrhythmias requiring anti-arrhythmic medications (except for atrial fibrillationthat is well controlled with antiarrhythmic medication); history of QT intervalprolongation
• NYHA Class III or greater congestive heart failure or left ventricular ejectionfraction of < 40%
• Have known history of HIV-1/2 infection.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] isdetected) infection.
• Have other concurrent medical or psychiatric conditions that, in the Investigator'sopinion, may be likely to confound study interpretation or prevent completion of studyprocedures and follow-up examinations.
• High dose systemic corticosteroids (≥20 mg of prednisolone or its equivalent) are notallowed within 2 weeks of C1D1.
• Have received or are currently receiving (within the previous 2 weeks) antibiotics.
• Have a pre-existing motor or sensory neuropathy of a severity >= grade 2 by NCI-CTCcriteria due to the potential for neuropathy of nab-paclitaxel.