Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy

PRIMARY OBJECTIVES:

I. To determine if maintenance therapy with nivolumab can decrease the incidence of colon
adenomas in a population of patients with genetic predisposition to colorectal cancer and a
history of hemicolectomy due to colon cancer or advanced colon adenoma.

SECONDARY OBJECTIVES:

I. To assess the safety of nivolumab maintenance therapy in this population. II. To obtain
preliminary data on the short-term incidence of advanced colon adenomas (measuring greater
than 10 mm or with high-grade dysplasia) and colon and non-colonic cancers in Lynch patients
treated with maintenance nivolumab.

EXPLORATORY OBJECTIVES:

I. To determine biomarkers of immunologic activity associated with biologic activity of
nivolumab in this population.

OUTLINE:

Participants receive nivolumab intravenously (IV) over 60 minutes on day 1. Treatment repeats
every 3 months for a total of 8 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, participants are followed up at 3 months, every 6 months
for 1 year, then every 12 weeks thereafter.

Inclusion Criteria:

- Patient must have a diagnosis of Lynch syndrome confirmed by the identification of a
germline mutation in MLH1 or MSH2.

- Patient must have a history of colon cancer or advanced colon adenoma requiring
hemicolectomy with at least 60 cm of colon remaining without evidence of disease.

- Be willing and able to provide written informed consent/assent for the trial.

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale.

- Absolute neutrophil count (ANC) >= 1,500 /mcL within 10 days of treatment initiation.

- Platelets >= 100,000 / mcL within 10 days of treatment initiation.

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency within 10 days of treatment initiation.

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN within 10 days of treatment initiation.

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN within 10 days of treatment initiation.

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases within 10 days of treatment
initiation.

- Albumin >= 2.5 mg/dL within 10 days of treatment initiation.

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants within 10
days of treatment initiation.

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants within 10 days of treatment initiation.

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study drug.

- Women must not be breastfeeding.

- WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with nivolumab plus 5 half-lives of nivolumab (19 weeks) plus 30
days (duration of ovulatory cycle) for a total of 23 weeks post-treatment completion.

- Men who are sexually active with WOCBP must agree to follow instructions for method(s)
of contraception for the duration of treatment with nivolumab plus 5 half-lives of the
study drug (19 weeks) plus 90 days (duration of sperm turnover) for a total of 31
weeks post-treatment completion.

- Hemicolectomy and adjuvant chemotherapy (if given) must be completed at least one year
prior to study entry.

- All subjects must take at least 81 mg of aspirin per day. Daily doses up to 650 mg of
aspirin per day will be accepted.

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7
days prior to the first dose of trial treatment. Individuals who are receiving
systemic steroid therapy at a stable dose less than or equal to 10 mg of prednisone
per day or its equivalent will be permitted to participate.

- Has a known history of active TB (Bacillus tuberculosis).

- Hypersensitivity to nivolumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.

- Has had hemicolectomy, prior chemotherapy, targeted small molecule therapy, or
radiation therapy within one year prior to study day 1 or who has not recovered (i.e.,
=< grade 1 or at baseline) from adverse events due to a previously administered agent.

- Note: Subjects with =< grade 2 neuropathy and/or alopecia are an exception to
this criterion and may qualify for the study.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids exceeding 10 mg prednisone
per day or its equivalent, or immunosuppressive drugs). Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.

- Has known history of, or any evidence of, active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject?s
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Have a known history of a bleeding disorder or gastrointestinal ulceration that would
preclude the use of a daily 81 mg aspirin.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding or is expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected).

- Has received a live vaccine within 30 days of planned start of study therapy.

- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed.

- Subjects with germline MSH6, PMS2, or EPCAM mutations will be excluded from
participation.

- Prisoners or individuals who are compulsorily detained will be excluded from
participation.