Overview

To assess whether nivolumab+nab-paclitaxel combination results in patients with muscle-invasive bladder cancer

Eligibility

Inclusion Criteria:

• Female or male subjects, >18 years of age, able to understand and give written informed consent.
• Histopathologically confirmed urothelial carcinoma. Patients with mixed histologies are 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 2 weeks 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 x IULN 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 serum pregnancy 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 as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 4 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 years.
• Male subjects must agree to use an adequate method of contraception starting with the first 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's criteria (Galsky MD, et al. J Clin Oncol. 2011 Jun 10;29(17):2432-8) OR refusal to receive neoadjuvant cisplatin-based chemotherapy.

Exclusion Criteria:

• Has received prior systemic anti-cancer therapy including investigational agents and immunotherapy.
• Prior immunotherapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 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, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (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 investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

        Note: Participants who have entered the follow-up phase of an investigational study may
        participate as long as it has been 4 weeks after the last dose of the previous
        investigational agent.
          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years.
          -  Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of
             the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that
             have undergone potentially curative therapy are not excluded. Participants with
             low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or
             T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either
             treated with definitive intent or untreated in active surveillance that has been
             stable for the past year prior to study allocation.
          -  Has severe hypersensitivity (≥Grade 3) to nivolumab or nab-paclitaxel and/or any of
             its 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 immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.
          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.
          -  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 abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the 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 or
                  ventricular fibrillation), high-grade atrioventricular block, or other cardiac
                  arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation
                  that is well controlled with antiarrhythmic medication); history of QT interval
                  prolongation
               -  NYHA Class III or greater congestive heart failure or left ventricular ejection
                  fraction 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] is
             detected) infection.
          -  Have other concurrent medical or psychiatric conditions that, in the Investigator's
             opinion, may be likely to confound study interpretation or prevent completion of study
             procedures and follow-up examinations.
          -  High dose systemic corticosteroids (≥20 mg of prednisolone or its equivalent) are not
             allowed 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-CTC
             criteria due to the potential for neuropathy of nab-paclitaxel.