Nivolumab and Radiation Therapy or Ipilimumab as Adjuvant Therapy in Treating Patients With Merkel Cell Cancer

PRIMARY OBJECTIVES:

I. To assess the tolerability of two different experimental immunotherapy regimens in the
adjuvant setting in patients with Merkel cell carcinoma (MCC).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability profile of each of the treatment using Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0.

II. To assess the efficacy of each of the treatment arms according to recurrence-free
survival (RFS) at one and half years, defined as the time between the date of randomization
and the date of first progression (local, regional or distant metastasis) or death (whatever
the cause), whichever occurs first.

III. To assess the efficacy of each of the treatment arms according to overall survival (OS)
at three years, defined from the time of randomization and the date of death, compared to
historical registry control.

EXPLORATORY OBJECTIVES:

I. To explore potential biomarkers, next generation T cell receptor (TCR) sequencing will be
performed to identify and longitudinally track individual T cell clones thus granting a
comprehensive insight into immunological changes that occur within the tumor and peripheral
blood throughout the course of the disease.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes at week 0. Treatments
repeat every 4 weeks for 1 year in the absence of disease progression or unacceptable
toxicity. Beginning week 2, patients also receive radiation therapy on Monday-Friday or 5
days per week for 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes at
week 0. Treatments repeat every 2 weeks for nivolumab and 6 weeks for ipilimumab for up to 1
year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 1 year.

Inclusion Criteria:

- Be willing and able to understand and give written informed consent and comply with
all study related procedures

- All patients should undergo definitive surgical resection, including when possible
sentinel lymph node dissection

- Patients must have recovered after any recent surgery and be ambulatory

- Have node positive disease (stage pIIIA or pIIIB) +/- extracapsular extension

- Have node negative disease and any of the following high risk features

- Tumor size >= 2 cm

- Margins =< 1-2 cm and re-resection is not possible

- Evidence of perineural or lymphovascular invasion

- Human immunodeficiency virus (HIV) patients with undetectable viral load and CD4+
T-cell counts >= 350 cells/uL

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 16 days of treatment
initiation)

- Platelets >= 100,000/mcL in the absence of transfusion support within 7 days of
determining eligibility (performed within 16 days of treatment initiation)

- Hemoglobin >= 8 g/dL (performed within 16 days of treatment initiation)

- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR Measured or calculated
creatinine clearance >= 40 mL/min creatinine clearance (performed within 16 days of
treatment initiation) (Glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl])

- Creatinine clearance should be calculated per institutional standard

- Serum total bilirubin =< 1.5 x ULN OR Except subjects with Gilbert Syndrome, who can
have total bilirubin < 3.0 x ULN (performed within 16 days of treatment initiation)

- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x
ULN (performed within 16 days of treatment initiation)

- Female subject of childbearing potential should have a negative urine or serum
pregnancy at screening and within 24 hours prior to receiving the first dose of study
medication and then every 4 weeks while on treatment. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 5 months after the last dose of study medication. Subjects should
agree to ongoing pregnancy testing during the course of the study and after the end of
study therapy. Female subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 7 months after the last dose of study therapy.
Males must refrain from donating sperm during study participation and for 7 months
after the last dose of study medication. Female subject should agree to use an
adequate method of contraception starting with the first dose of study therapy through
5 months after the last dose of study therapy

Exclusion Criteria:

- Has known distant metastatic MCC

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

- Hypersensitivity to any study agents

- Have received prior immunotherapy with any PD-1/PDL-1 inhibitors or CTLA-4 antibodies
at any time in the past

- Has had prior chemotherapy or radiation therapy for treatment of MCC

- Has a clinically significant medical condition, which in the judgment of the attending
physician would contraindicate immunotherapy or radiotherapy, such as serious
autoimmune disease, hypersensitivity to investigational product or any component in
its formulations, per Food and Drug Administration (FDA) prescription notice

- Subjects with prior history of non-Merkel cell carcinoma malignancies are excluded
except

- Adequately treated basal cell, squamous cell skin cancer, chronic lymphocytic
leukemia (CLL) or other indolent malignancies not requiring therapy (ie. active
surveillance)

- Adequately treated malignancies and patient has been in complete remission for at
least two years

- Patients with history of breast cancer and no evidence of disease on hormonal
therapy to prevent recurrence

- Patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA
are eligible

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

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization will be excluded. Inhaled or topical steroids are permitted in
the absence of active autoimmune disease

- Has an active infection requiring intravenous systemic therapy

- Solid organ transplant recipients and patients with concurrent hematological
malignancies including thymomas, leukemias (other than CLL) and lymphomas actively
undergoing treatment or completed < 5 years prior

- Clinically significant cardiovascular disease with uncontrolled arrhythmia, New York
Association class 3 or 4 congestive heart failure, history of myocardial infarction
within 6 months, or prolonged corrected QT (QTc) > 500 msec

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