Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

PRIMARY OBJECTIVES:

I. To investigate the immunomodulatory activity of radiation therapy (RT) or RT in
combination with anti-programmed cell death 1 (PD)-1 antibody (MK-3475) in patients with
recurrent/metastatic head and neck cancer, renal cell cancer, melanoma and lung cancer.

SECONDARY OBJECTIVES:

I. To explore whether programmed cell death ligand 1 (PD-L1) expression is associated with
treatment response to the combination of RT and PD-1 blockade in renal cell cancer (RCC),
head and neck cancer (HNC), lung cancer and melanoma.

II. To explore whether circulating tumor cells can be used to determine PD-L1 expression.

III. To explore other immune-related biomarker changes after RT: soluble PD-L1, cytokines
etc.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A1: Patients undergo radiation therapy on day 1 per standard of care and then undergo
biopsy 3-10 days later. Beginning 0-7 days after biopsy, patients receive MK-3475
intravenously (IV) over 30 minutes on day 1. Courses of MK-3475 repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

ARM A2: Patients undergo radiation therapy on days 1-5 and then undergo biopsy 3-10 days
later. Beginning 0-7 days after biopsy, patients receive MK-3475 as in Arm A1.

ARM B1: Patients receive one dose of MK-3475 IV over 30 minutes on day 1 and then undergo 1
fraction of RT. Patients then receive MK-3475 IV over 30 minutes in the absence of disease
progression or unacceptable toxicity.

ARM B2: Patients receive MK-3475 as in Arm B1 and undergo 5 fractions of RT.

After completion of study treatment, patients are followed up at approximately 30 days and
then every 8 weeks.

Inclusion Criteria:

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

2. Be ≥ 18 years of age on day of signing informed consent.

3. Have provided tissue from an archival tissue sample ( < 6 months old) or newly
obtained core biopsy of a tumor lesion before radiation therapy. A core biopsy will be
required. It is mandatory to have post-radiation re-biopsy.

4. In addition to index lesion, there are ≥ 1 measurable lesion(s).

5. Have a performance status of ≤ 1 on the ECOG Performance Scale.

6. Demonstrate adequate organ function defined as the following:

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

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

- Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.8 X upper limit of normal (ULN) OR

≥50 mL/min for subject with creatinine levels > 1.8 X institutional ULN

- Serum total bilirubin ≤ 1.5 X ULN OR 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

7. Female subjects of childbearing potential should have a negative urine or serum
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.

8. 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.

9. 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:

1. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 2 weeks of the radiation therapy.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the radiation therapy.

3. Has had a prior monoclonal antibody within 4 weeks prior to radiation therapy or who
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.

4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to radiation therapy or who has not recovered (i.e., ≤ Grade 1 or
at baseline) from adverse events due to a previously administered agent.

- Note: Prior radiation therapy does not necessary excludes patients. The index
lesion may be acceptable for stereotactic radiosurgery (SRS) and this will be
determined by radiation oncologist.

- Note: If there are more than one symptomatic lesions, patients will be excluded
if the lesions can't be encompassed within one radiation portal.

- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.

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

5. 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, superficial bladder cancer or in situ cervical cancer that has undergone
potentially curative therapy.

6. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the radiation therapy and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not using steroids for
at least 7 days prior to radiation treatment.

7. 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 exception to this rule. Subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study.

8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

9. Has an active infection requiring systemic therapy.

10. 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.

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

12. 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.

13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

14. Has a known Human Immunodeficiency Virus infection (HIV 1/2 antibodies) or Acquired
Immunodeficiency Syndrome((HIV/AIDS).

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

16. Has received a live vaccine within 30 days prior to the radiation therapy.