Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)

Research Hypothesis:

1. Through a combination of local RT and ipilimumab an anti-tumor immune response is
elicited at the irradiated site, as an in vivo, individualized immunization that is
systemically effective, as reflected by objective responses outside the RT field
(abscopal effect).

2. The immune response can be prospectively monitored among the treated patients.

Objective 1: Evaluate the safety and therapeutic efficacy of anti-cytotoxic
T-lymphocyte-associated protein -4 mono clonal Antibody (anti-CTLA-4 mAb) and concurrent
local RT in NSCLC patients with metastatic disease.

An open label phase II trial will evaluate the preliminary efficacy of the combination of
Ipi and RT, applied to a single metastatic site. Efficacy is measured with respect to
systemic tumor responses (abscopal response, outside the field of therapy) defined by
immune-related Response Criteria (irRC) in all non-irradiated measurable lesions, as a
demonstration of an effective anti-tumor immune response. Secondary endpoints include local
response in the RT treated tumor, progression free survival, and overall survival.

Objective 2: Determine the effects of RT and anti-CTLA-4 mAb on development of anti-tumor
immunity.

The investigators hypothesize that RT will convert the irradiated tumor into an in situ
vaccine and elicit an endogenous tumor-specific cellular and humoral immune response, which
in the presence of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade will
promote immune-mediated destruction of the irradiated and abscopal metastases. Pre- and
post-treatment tumor biopsies will be examined for changes in immune contexture, and blood
for evidence of emerging anti-tumor immune responses. Associations with clinical response
will be explored.

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent
document;

2. Histologic diagnosis of metastatic NSCLC;

3. Any Kras or EGFR status is permitted;

4. Patients must have at least two distinct measurable metastatic sites, with one of at
least 1 cm or larger in its largest diameter. Patients may have additional
non-measurable metastatic lesions (e.g., bone metastases);

5. Patients must have prior treatment with at least one line of therapy for metastatic
NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab;

6. An interval of 2 weeks from last previous therapy is required;

7. Patients must have adequate organ and marrow function as defined by initial
laboratory tests:

- WBC ≥ 2000/uL

- ANC ≥ 1000/uL

- Platelets ≥ 50 x 103/uL

- Hemoglobin ≥ 8 g/dL

- Creatinine ≤ 3.0 x ULN

- AST/ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.

- Bilirubin ≤ 3.0 x ULN (except patients with Gilbert's Syndrome, who must have a
total bilirubin ≤ 3.0 mg/dL);

8. Performance status ECOG 0-1;

9. Men and women, ages > 18 years of age;

10. Life expectancy > 3 months;

11. Patients may have brain metastases if these are stable for at least 4 weeks, or
greater than 2 weeks post gamma knife therapy and patients are not steroid dependent;

12. Brain Scan (CT/MRI) prior to enrollment

13. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
last dose of Ipi.

Exclusion Criteria:

1. Patients having no lesions outside the field of radiation thus nullifying the ability
to measure an abscopal effect;

2. Autoimmune disease: Patients with a history of inflammatory bowel disease are
excluded from this study as are patients with a history of symptomatic disease (e.g.,
rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic lupus
erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];

3. Any underlying medical or psychiatric condition, which in the opinion of the
Investigator, will make the administration of study drug hazardous or obscure the
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea;

4. Concomitant therapy with any of the following: Interleukin-2 (IL-2), interferon or
other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
agents; other investigation therapies; or chronic use of systemic corticosteroids;

5. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;

6. Women who are unwilling or unable to use an acceptable method to avoid pregnancy for
the entire study period and for at least 8 weeks after cessation of study drug, or
have a positive pregnancy test at baseline, or are pregnant or breastfeeding;

7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness.