Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

Bladder cancer (BC) is the 6th most common malignancy in the United States with an estimated
79,030 new cases and 16,870 deaths in 2017. It is the 4th most common cancer in men and there
are presently >500,000 BC patients alive in the US. It accounts for about 5% of all new
cancers in the US. It is also the most expensive cancer to treat from diagnosis to death.
Almost a third of BC patients present with MIBC.

This is a Phase Ib open-label clinical trial for patients with cisplatin-ineligible MIBC
(Stage T2-T4a, N0-N1, M0). Neoadjuvant treatment must start within 8 weeks of transurethral
resection of the first transurethral resection of bladder tumor (TURBT) that showed
muscularis propria invasion.

Patients must have sufficient baseline tumor tissue. Tumor tissue content for CD8+ T-cell
density assessment must be qualified as sufficient (≥ 20% tumor content in the specimen) for
analysis and must be documented by the local pathologist prior to registration.

The first 12 patients will be enrolled into Cohort 1 and treated with nivolumab before a
planned RC.

In the absence of the occurrence of high rate of treatment related Adverse Events (AEs) with
nivolumab, the study will proceed with enrollment into Cohort 2 with the combination of
nivolumab/lirilumab before a planned RC.

Each group will receive a total of 2 doses (week 0 and 4) of nivolumab (Cohort 1) or
nivolumab/lirilumab (Cohort 2) therapy followed by RC with bilateral (standard or extended)
pelvic lymph node dissection (PLND).

Mandatory tumor tissue at Screening (archived tumor tissue from Transurethral Resection of
Bladder Tumor [TURBT] may be used) and at time of RC. Peripheral blood and urine samples are
also required.

- Patients must have histologically confirmed MIBC (T2-T4a, N0-N1, M0 per American Joint
Commission on Cancer [AJCC]) pure or mixed histology urothelial carcinoma. Clinical
node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined
to the true pelvis and are within the planned surgical LN dissection template.

- The initial TURBT that showed muscularis propria invasion should be within 8 weeks
prior to beginning study therapy. Patients must have sufficient baseline tumor tissue
from either initial or repeat TURBTs. The local site pathologist will be asked to
estimate and record the rough approximate percentage of viable tumor in the TURBT
sample (initial or repeat TURBT with highest tumor content) to document at least 20%
viable tumor content prior to registration.

- Patients must be ineligible for cisplatin-based chemotherapy due to any of the
following:

- Creatinine clearance(CrCl) <60 mL/min with Easter Cooperative Oncology Group
(ECOG) Performance Status (PS) 0-1

- Hearing impaired ≥ Grade 2 by CTCAE criteria

- Neuropathy ≥ Grade 2 by CTCAE criteria

- Heart failure New York Heart Association (NYHA) ≥ III

- Patients must be medically fit for TURBT and RC.

- Age ≥ 18 years.

- Ability to understand and willingness to sign Institutional Review Board
(IRB)-approved informed consent.

- Willing to provide tumor tissue, blood, and urine samples for research.

- Adequate organ function as measured by the following criteria, obtained ≤ 4 weeks
prior to registration:

- Absolute Neutrophil Count (ANC) ≥ 1000/mm³ (stable off growth factor within 4
weeks of first study drug administration)

- Platelets ≥ 100,000/mm³

- Hemoglobin ≥ 8 g/dL

- Serum Creatinine Clearance ≥ 30 mL/min using the Cockcroft-Gault formula

- Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x Upper
Limit of Normal (ULN)

- Total Bilirubin ≤ 1.5x ULN (in the absence of previously diagnosed Gilbert's
disease)

- Women must not be pregnant or breastfeeding since we do not know the effects of
nivolumab and lirilumab on the fetus or breastfeeding child.

- Sexually active women of child-bearing potential with a non-sterilized male partner
and sexually active men must agree to use 2 methods of adequate contraception
(hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the
duration of study participation, and for 5 months for women and 7 months for men
following last dose of study drugs.

- Active or prior documented autoimmune disease within the past 2 years prior to
Screening or other immunosuppressive agent within 14 days of study treatment.

- Patients may not have locally advanced unresectable or metastatic urothelial carcinoma
as assessed on baseline radiographic imaging obtained within 28 days prior to study
registration.

- Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis)
invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) upper
tract urothelial carcinoma that has been definitively treated with at least one
post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates
no evidence of residual disease are eligible.

- Patients may not have another malignancy that could interfere with the evaluation of
safety or efficacy of the study drugs. Patients with a prior malignancy will be
allowed without study chair approval in the following circumstances:

- Not currently active and diagnosed at least 3 years prior to the date of
registration.

- Non-invasive diseases such as low risk cervical cancer or any cancer in situ.

- Localized (early stage) cancer treated with curative intent (without evidence of
recurrence and intent for further therapy), and in which no chemotherapy was
indicated.(e.g. low/intermediate risk prostate cancer, etc.).

- Patients may not have received any prior immune checkpoint inhibitor (i.e. anti-KIR,
anti-PD-1, anti-PD-L1, or other).

- Patients may not have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer
treatment ≤ 4 weeks prior to starting study drug, or patients who have had
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 must not have clinically significant cardiac disease.

- Patients may not have chronic active liver disease or evidence of acute or chronic
Hepatitis B Virus (HBV) or Hepatitis C (HCV).

- Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection.
Testing is not required in absence of clinical suspicion.

- Patients may not have known diagnosis of any condition (e.g. post-hematopoietic or
solid organ transplant, pneumonitis, 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.

- Patients with any serious and/or uncontrolled concurrent medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that
could, in the investigator's opinion, cause unacceptable safety risks or potentially
interfere with the completion of the treatment according to the protocol are not
eligible.

- Patients may not have any live viral vaccine used for prevention of infectious
diseases within 4 weeks prior to study drug(s).

- Patients unwilling or unable to comply with the protocol.