BLASST-1 (Bladder Cancer Signal Seeking Trial): Nivolumab, Gemcitabine, and Cisplatin in Treatment of Muscle Invasive Bladder Cancer (MIBC) Undergoing Cystectomy
Condition: Muscle Invasive Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Intervention: Nivolumab; Cisplatin; Gemcitabine
Intervention description: Nivolumab will be given at a fixed dose of 360 mg IV over 30 minutes on Day 8 every 21 days for 4 cycles.; Cisplatin will be given at 70 mg/m2 IV over 30 minutes on Day 1 every 21 days, and based on treating physician's discretion, split-dose cisplatin can be given at 35 mg/m2 IV Day 1 and Day 8 every 21 days for 4 cycles.; Gemcitabine will be given at 1000 mg/m2 IV over 30 minutes on days 1, 8, and every 21 days for 4 cycles.
Intervention MeSH terms: Gemcitabine; Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MIBC; UC; Immunotherapy; Bladder Cancer; Neoadjuvant; Nivolumab; Cisplatin; Gemcitabine

Summary:

      This is a multi-center Phase II study to determine the safety and efficacy of nivolumab when
      given in combination with cisplatin and gemcitabine as neoadjuvant treatment in patients with
      muscle-invasive bladder cancer (MIBC) prior to standard of care radical cystectomy. Patients
      will receive neoadjuvant treatment with nivolumab in combination with gemcitabine-cisplatin
      (GC) every 3 weeks for 4 treatment cycles over 12 weeks followed by standard of care radical
      cystectomy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and
             N<1 disease (solitary lymph node measuring < 2 cm) and M0 and deemed eligible for
             radical cystectomy.

          -  Age ≥ 18 years

          -  ECOG Performance Status of 0 or 1.

          -  Required initial laboratory values within 14 days of study enrollment:

               -  Absolute Neutrophil Count ≥ 1500 cells/mm^3

               -  Platelets ≥ 100,000 cells/mm^3

               -  Hemoglobin ≥ 9.0 g/dL

               -  Bilirubin ≤ 1.5 times the upper limit of normal (ULN) for the institution (For
                  patients with known Gilbert's disease: bilirubin ≤ 3 x ULN)

               -  Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN for the
                  institution

               -  Creatinine clearance ≥ 50 ml/min by Cockcroft-Gault formula or 24 hour urinary
                  clearance (CrCl = [140-age (years)] x actual weight (kg) / [72 x serum Cr
                  (mg/dL)] (if patient is female multiply the above by 0.85) or 24 hour urinary
                  creatinine clearance.

               -  Alkaline phosphatase ≤ 2.5 x ULN for the institution

               -  INR and aPTT ≤ 1.5 x ULN if not on therapeutic anticoagulation. Patients
                  receiving therapeutic anticoagulation will be allowed if maintained on a stable
                  dose.

          -  Females of childbearing potential and males who are not surgically sterile and with
             partners of childbearing potential must agree to use effective contraception during
             study treatment for 5 months for females and 7 months for males after the last dose of
             nivolumab.

          -  Ability to provide a signed and dated consent or have a legally authorized
             representative to provide written and signed consent prior to the initiation of any
             research related procedures.

          -  Patient must agree to submission of archived tumor (20-25 formalin-fixed paraffin
             embedded (FFPE) slides of 5-10 microns in thickness) from TURBT and radical cystectomy
             tissues. If archived samples are not available fresh tissue will be used.

          -  Ability to provide written consent prior to the initiation of any research related
             procedures.

        Exclusion Criteria:

          -  Presence of N2-3 or M1 disease.

          -  Ineligible to receive cisplatin by meeting one or more of the following criteria;

               -  Creatinine clearance of < 50 mL/min

               -  Hearing loss of 25 dB at two contiguous frequencies with testing required if a
                  patient has hearing loss - At the investigator's discretion, and after discussion
                  with the patient, this exclusion may be waived if the potential benefit of
                  cisplatin therapy is felt to outweigh the risk of further hearing loss.

               -  CTCAE v4 Grade 2 or higher peripheral neuropathy,

               -  New York Heart Association Class III or IV heart failure

               -  ECOG performance status 2 or higher.

          -  Prior systemic therapy (intravenous) is not permitted. Prior intravesical therapies
             including intravesical gemcitabine is permitted for non-muscle invasive disease (i.e.
             T1 or lower).

          -  Prior treatment with cisplatin for bladder cancer.

          -  Prior treatment with anti-PD-1, CTLA-4, or anti-PD-L1 therapeutic antibody or
             pathway-targeting agents.

          -  Prior therapeutic radiation to the bladder.

          -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
             need for a major surgical procedure during the course of the study.

          -  Any of the following within the 6 months prior to study drug administration:
             myocardial infarction, severe/unstable angina, symptomatic congestive heart failure
             (>New York Heart Association Class 2), stroke, serious cardiac arrhythmia.

          -  Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome
             (AIDS)-related illness.

          -  Pregnancy, lactation, or breast-feeding. Women of childbearing potential must have a
             negative urine pregnancy test at screening.

          -  History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, Wegener's granulomatosis, vascular thrombosis associated
             with antiphospholipid syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple
             sclerosis, systemic vasculitis, or glomerulonephritis.

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan, history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted.

          -  Active hepatitis B virus (HBV, chronic or acute, defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C antibody.
             Patients with past HBV infection or resolved HBV infection (defined as the presence of
             hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be
             obtained in these patients prior to Cycle 1, Day 1 and confirmed to be negative.
             Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
             chain reaction is negative for HCV RNA.

          -  Active tuberculosis or BCG infection

          -  Active infection requiring systemic antibiotics for more than 7 days within 3 days
             prior to Cycle 1, Day 1. Prophylactic short-term antibiotics will be allowed.

          -  Administration of intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before
             Cycle 1, Day 1

          -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
             anticipation that such a live attenuated vaccine will be required during the study.

          -  Persisting toxicity from prior therapy (NCI CTCAE v4.03 Grade >1); however alopecia or
             other Grade <2 AEs not constituting a safety risk, based on Investigator's judgement,
             are acceptable.

          -  History of or active bone marrow disorders expected to interfere with study therapy
             (e.g. acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic
             lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
             myeloma).

          -  Prior allogeneic stem cell or solid organ transplant.

          -  Known primary central nervous system (CNS) malignancy.

          -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
             dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
             excluded) are permitted but patients with psoriasis require a baseline ophthalmologic
             exam to rule out ocular manifestations. Rash must cover less than 10% of body surface
             area (BSA) and must be well controlled at baseline and only requiring topical
             steroids.

          -  Any other chronic medical condition or psychiatric condition, physical examination
             finding, or clinical laboratory finding giving reasonable suspicion of a disease or
             condition that contraindicates the use of an investigational drug or that may affect
             the interpretation of the results or render the patient at high risk from treatment
             complications

          -  Known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin or in situ cervical cancer that has undergone potentially curative therapy.
             Patients on androgen deprivation therapy as part of adjuvant therapy after radiation
             for prostate cancer or patients on adjuvant hormonal therapies for breast cancer will
             be allowed if they are being considered for curative intent for bladder cancer.

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon [IFN]-a or interleukin [IL]-2) within 4 weeks or five half-lives of the
             drug (whichever is shorter) prior to Cycle 1, Day 1

          -  Concomitant use of systemic corticosteroids at physiologic doses or <10 mg/day of
             prednisone or equivalent.

          -  Concomitant use of another investigational agent and/or treatment with an
             investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five halflives
             of the investigational product, whichever is longer).

          -  Use of bisphosphonate therapy for osteoporosis will be allowed if started prior to
             study enrollment.