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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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,
- 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
- 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
- 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
- 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