Neoadjuvant Nivolumab With and Without Urelumab in Patients With Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma of the Bladder

This is phase II clinical trial design randomizing patients with cisplatin-ineligible MIBC
(stages T2-T4, N0-1, M0) to one of two treatment arms: Arm A - Nivolumab in combination with
Urelumab or Arm B - Nivolumab monotherapy.

The study population will include male and female patients over the age of 18 with muscle
invasive urothelial carcinoma of the bladder (MIBC) who are not suitable for cisplatin-based
chemotherapy, but are fit to undergo surgical resection of their cancer by cystectomy.
Patients with resectable clinical node positive disease within the true pelvis (N1) are
eligible.

Inclusion Criteria:

- Ineligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one
of the following criteria:

- Creatinine clearance < 60 ml/min

- ECOG status =2

- Grade > 2 hearing loss

- Grade > 2 neuropathy

- New York Heart Association Class III heart failure

- Age ≥ 18 years old at time of consent

- Patients must have the following laboratory values:

a) Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 (must be stable off any growth factor
within 4 weeks of first study drug administration) b) Platelets ≥ 100 K/mm3
(transfusion to achieve this level is not permitted within 2 weeks of first study drug
administration) c) Hemoglobin (Hgb) ≥ 9 g/dL d) Serum total bilirubin: ≤ 1.5 x ULN e)
ALT and AST ≤ 3.0 x ULN f) Serum creatinine clearance (CrCl) ≥ 30 mL/min using the
Cockcroft-Gault equation, see formula below:

- CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female
multiply the above by 0.85)

- Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

- Patients with locally advanced unresectable or metastatic urothelial carcinoma as
assessed on baseline radiographic imaging obtained within 28 days prior to study
registration. The required radiographic imaging includes:

a) Abdomen/Pelvis - CT scan b) Chest - chest x-ray or CT scan

- Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive
urothelial carcinoma.

- Patients with another active second malignancy other than non-melanoma skin cancers
and biochemical relapsed prostate cancer

- Patients who have received the last administration of an anti-cancer therapy including
chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting
study drug, or who have not recovered from the side effects of such therapy

- Patients who have received prior therapy with immune checkpoint inhibitors (e.g.
anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4) or immune costimulatory molecules (e.g.
anti-CD137, anti-OX40, anti-GITR) directed agents.

- Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have
not recovered from radiotherapy toxicities

- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting
study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous
biopsies or placement of vascular access device ≤ 1 week prior to starting study drug,
or who have not recovered from side effects of such procedure or injury

- Patients with history of alcoholic or non-alcoholic steatohepatitis (NASH),
auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis.

- Patient with history of prior solid organ or allogeneic bone marrow transplant.

- Patients with any of the following concurrent severe and/or uncontrolled medical
conditions which could compromise participation in the study:

1. Clinically significant cardiac diseases, including any of the following:

i. History or presence of serious uncontrolled ventricular arrhythmias

ii.Clinically significant resting bradycardia

iii.Any of the following within 3 months prior to starting study drug: myocardial
infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive
Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA),
Pulmonary Embolism (PE)

iv.Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or
without anti-hypertensive medication(s)

b) Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

c) Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory)

d) Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant,
rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that
requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory
medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors
for the treatment of gout are permitted. For questions, please consult the study chair.

e) Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active
or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety
risks or compromise compliance with the protocol

- Pregnant or breast-feeding women

- Women of child-bearing potential, who are biologically able to conceive, and not
employing two forms of highly effective contraception. Highly effective contraception
must be used throughout the trial and up to 8 weeks after the last dose of study drug
(e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device).
Women of child-bearing potential, defined as sexually mature women who have not
undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive
months), must have a negative serum pregnancy test ≤ 14 days prior to starting study
drug

- Fertile males not willing to use contraception, as stated above

- Patients unwilling or unable to comply with the protocol