Evaluating the Combination of MK-3475 and Sterotactic Body Radiotherapy in Patients With Metastatic Melanoma or NSCLC

The phase 1b portion of the trial is a radiation dose escalation study to determine the
maximum tolerated dose (MTD) of SBRT when given to patients previously and subsequently
exposed to MK-3475. Because the class of PD-1 inhibitory antibodies conveys a risk of
pneumonitis, there will be two parallel dose escalation arms- Arm A will include SBRT targets
in the lung parenchyma, and Arm B will be limited to targets outside the lung parenchyma.
Each arm will be separately escalated, and two MTDs will be determined. The starting dose
will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3
fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction).
If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to
that site will be discontinued.

The phase 2a portion of the study includes 2 expansion cohorts, for melanoma and NSCLC, with
SBRT delivered at the MTD. The primary endpoint of this phase of the study is the overall
response rate to post-SBRT MK-3475. Secondary endpoints include determining the time to
progression, overall survival, and exploratory biomarkers.

IND exempt per FDA.

Inclusion/Exclusion Criteria Updated 4/7/2016

Inclusion Criteria:

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

- Have metastatic melanoma or NSCLC, or locally advanced NSCLC not suitable for
curative-intent local therapy.

- For melanoma patients and NSCLC patients treated with prior anti-PD-1 therapy,
patients must have received prior PD-1 therapy and have progressed (irPD) by irRC.

- Have 2 or more measurable sites of disease as defined by either RECIST 1.1, or
cutaneous lesions at least 1 cm in greatest dimension

- Have at least one site of disease that is considered potentially suitable for
treatment with SBRT

- Have provided tissue from an archival or newly obtained tissue sample of a tumor
lesion, sufficient for analysis of PD-L1 and other biomarkers. Patients who have had
PD-L1 analysis previously performed at Merck can substitute earlier analysis results
and are not required to submit additional tissue for PD-L1 testing. Expression of
PD-L1 is NOT required for study entry.

- Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.

- Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 28 days of protocol treatment.

Table 1. Adequate Organ Function Laboratory Values (System/Laboratory Value)

Hematological

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL

Renal

- Measured or calculated creatinine** clearance ≤1.5 X upper limit of normal (ULN)

- (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for subject with
creatinine levels > 1.5 X institutional ULN Hepatic

- Serum total bilirubin ≤ 1.5 X ULN OR

- Direct bilirubin Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5
ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

**(Creatinine clearance should be calculated per institutional standard. )

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours 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.

- 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 120 days after the last dose of study medication (Reference
Section 5.7.2). 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 120 days after the last dose of study therapy

Exclusion Criteria:

- Has had radiation therapy within 2 weeks of the first protocol treatment.

- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 2 weeks of the first protocol
treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 2 weeks of the first protocol
treatment. The use of low-dose steroids for management of chronic conditions is
allowed.

- Non-small cell lung cancer patients enrolling to MK-3475 as first protocol therapy (no
prior anti-PD-1 therapy): Has had a prior monoclonal antibody within 4 weeks prior to
first protocol treatment 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 prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks of the first protocol treatment 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 are an exception to this criterion and may
qualify for the study.

- Note: Patients who have had prior treatments with Tyrosine Kinase Inhibitors (e.g.
Tarceva) require only a 72-hour washout period prior to starting protocol treatment.

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

- Has known active and untreated brain (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate.

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
resolved childhood asthma/atopy would be an example of an exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study. Those with a history of hypothyroidism who are
now stable on hormone replacement will not be excluded. Those with Sjorgen's syndrome
will not be excluded from the study.

- Has a history of (non-infectious) pneumonitis that required steroids, current
pneumonitis or evidence of interstitial lung disease.

- Has an active infection requiring systemic therapy.

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

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

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Has received a live vaccine within 30 days prior to the first protocol treatment.