Treatment of Advanced Melanoma With MK-3475 and Peginterferon

This is a safety and dose-seeking study of combination MK-3475 and peginterferon alfa-2b for
adult patients (≥18) with advanced melanoma. A total of 32 patients will be included.
Subjects will undergo screening evaluations to determine eligibility within 28 days (4 weeks)
of the first dose. Each 21 day dosing period will constitute a cycle.

Peginterferon alfa-2b is given subcutaneously, weekly according to the regimen below.
peginterferon alfa-2b (Sylatron) is FDA-approved for the adjuvant treatment of patients with
melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical
resection including complete lymphadenectomy.

MK-3475 is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 receptor,
thus inhibiting its interaction with PD-L1 and PD-L2. MK-3475 has an acceptable preclinical
safety profile and is being advanced for clinical development as an immunotherapy for
advanced malignancies. In this protocol, MK-3475 is being evaluated at 2 mg/kg intravenously
every 3 weeks for 2 years in combination with peginterferon alfa-2b at 1 µg/kg/week, 2
µg/kg/week, or 3 µg/kg/week by subcutaneous injection.

Inclusion Criteria:

- Patient must have a histologically or cytologically confirmed diagnosis of
unresectable stage III or IV melanoma. Patient may not have a diagnosis of uveal
melanoma.

- Patients may be previously untreated or have received up to 3 prior systemic therapies
for metastatic disease. Prior radiation therapy (any number) and interferon use in the
adjuvant or metastatic disease settings is permitted (in this trial interferon is
mainly used to enhance or initiate immune responses to MK-3475). Vaccine therapy will
not be counted as systemic therapy. All prior therapies must have been discontinued
for at least 4 weeks. A 2 week washout for kinase inhibitors is acceptable.

- Patients can be either ipilimumab naïve or refractory to ipilimumab, defined as
received at least two doses of ipilimumab and documented disease progression. Patients
who were re-treated with ipilimumab and patients who were on maintenance ipilimumab
will be allowed to enter the trial as long as there is documented PD. Progressive
disease will be defined as increase in tumor burden > 25% relative to nadir (minimum
recorded tumor burden) which is confirmed by repeat assessment no less than four weeks
from the date of the first documented PD. Once PD is confirmed, initial date of PD
documentation will be considered as the date of disease progression.

- Full resolution of ipilimumab related AEs to baseline (including irAEs) off of steroid
treatment (> 10 mg/day prednisone or equivalent dose) for irAEs for at least two weeks
prior to first dose of study drug.

1. No history of severe irAEs from ipilimumab of CTCAE Grade 4 requiring steroid
treatment; no history of CTCAE Grade 3 requiring steroid treatment (> 10mg/day
prednisone or equivalent dose) for > 12 weeks.

2. Minimum of four weeks (wash out period) from the last dose of ipilimumab.

- Patients must consent to participate in the correlative studies and should have
available tumor tissue for tumor biopsies.

- Patient must have measurable disease as per RECIST version 1.1. At least 1 of the
tumor sites must be amenable to biopsy and this may not be the site of disease used to
measure antitumor response.

- Patient is ≥ 18 years of age on day of signing informed consent.

- Patient must have a performance status of 0 or 1 on the ECOG Performance Scale

- Patient must have adequate organ function as indicated by the following laboratory
values (within 4 weeks prior to starting the study drugs):

1. Absolute neutrophil count (ANC) ≥ 1,500/uL

2. Platelets ≥ 100,000/uL

3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

4. Serum creatinine ≤ 1.5 X upper limit of normal (ULN)

5. Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for patients with
total bilirubin level 1.5 ULN

6. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver
metastases

7. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN unless
the patient is receiving anticoagulant therapy

8. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless the patient is
receiving anticoagulant therapy

- Patient has voluntarily agreed to participate by giving written informed
consent/assent for the trial.

- Female patient of childbearing potential has a negative urine or serum pregnancy test
within 7 days prior to receiving the first dose of study medication. If the urine test
is positive or cannot be confirmed as negative, a serum pregnancy test will be
required. The serum pregnancy test must be negative for the patient to be eligible.

- Female patients enrolled in the study, who are not free from menses for > 2 years,
post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use
either 2 adequate barrier methods or a barrier method plus a hormonal method of
contraception to prevent pregnancy, or to abstain from heterosexual activity
throughout the study, starting with the first dose of study drug at visit 1 through
120 days after the last dose of study drug. Approved contraceptive methods include for
example: intra-uterine device, diaphragm with spermicide, cervical cap with
spermicide, male condoms, or female condom with spermicide. Spermicides alone are not
an acceptable method of contraception. Male patients must agree to use an adequate
method of contraception starting with the first dose of study drug through 120 days
after the last dose of study drug.

Exclusion Criteria:

- Patient who has had chemotherapy, radioactive, or biological cancer therapy within
four weeks prior to the first dose of study drug, or who has not recovered to CTCAE
Grade 1 or better from the AEs due to cancer therapeutics administered more than four
weeks earlier. Subjects with ≤ grade 2 neuropathy are an exception to this criterion
and may qualify for the study.

Note: If patient received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.

Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion
requirements for laboratory parameters defined in Inclusion Criterion #9.

- Patient is currently participating or has participated in a study of an
investigational agent or using an investigational device within 4 weeks of the first
dose of study drug.

- Patient is expected to require any other form of systemic or localized antineoplastic
therapy while on study.

- Patient is on chronic systemic steroid therapy (> 10 mg/kg prednisone or equivalent)
within two weeks before the planned date for first dose randomized treatment or on any
other form of immunosuppressive medication (Premedication with corticosteroid for
nausea is permitted.)

- Patient has a known history of a hematologic malignancy, primary brain tumor or
sarcoma, or of another primary solid tumor, unless the patient has undergone
potentially curative therapy with no evidence of that disease for five years.

Note: The time requirement also does not apply to patients who underwent successful
definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder
cancer, in situ cancers including cervical cancer, breast cancer, melanoma, or other in
situ cancers.

- Patient has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by MRI for at least four weeks prior
to the first dose of study drug), have no evidence of new or enlarging brain
metastases and are off systemic steroids (≤ 10 mg/day prednisone or equivalent) for at
least two weeks prior to enrollment.

- Patient previously had a severe hypersensitivity reaction to treatment with another
mAb or IFN-α2b.

- Patient has an active autoimmune disease or a documented history of autoimmune disease
or syndrome that requires systemic steroids or immunosuppressive agents. Patients with
vitiligo, type I diabetes, resolved childhood asthma/atopy would be exceptions to this
rule. Patients who require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Patients with hypothyroidism stable
on hormone replacement will also not be excluded from the study.

- Patient has evidence of interstitial lung disease.

- Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart
failure, hypertension, cardiac ischemia, myocardial infarction, and severe cardiac
arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or
restrictive pulmonary diseases, active systemic infections, and inflammatory bowel
disorders. This includes HIV or AIDS-related illness, or active HBV and HCV.

- Patient had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent.

- Patient has an active infection requiring systemic therapy.

- Patient has known history of human Immunodeficiency virus (HIV) (HIV 1/2 antibodies).

- Patient positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA
[qualitative] is detected).

- Patient has received a live vaccine within 4 weeks prior to the first dose of
treatment.

- Patient has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.

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

- Patient is, at the time of signing informed consent, a regular user (including illicit
drugs or had a recent history (within the last year) of substance abuse (including
alcohol).

- Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.

- Patient has prior history of intolerance to adjuvant interferon-α therapy