Pembrolizumab After Lung SBRT for Medically Inoperable Early Stage Non-small Cell Lung Cancer

The primary objective of this pilot safety study is to determine the tolerability and
feasibility of administering pembrolizumab in the adjuvant setting following completion of
definitive SBRT to the lung for patients with medically inoperable early stage NSCLC with
tumors greater than 3 cm in diameter

Secondary Objectives

1. Distant metastases free survival (DMFS)

2. Disease Free Survival (DFS)

3. Overall survival (OS)

Study design including dose escalation / cohorts

This is an open-label, single arm feasibility study of lung SBRT followed 2 to 4 weeks after
completion by the addition of pembrolizumab.

Eligible patients will have biopsy-confirmed T1b-T3N0M0 (stage IA-IIB) non-small cell lung
cancer (adenocarcinoma, squamous cell carcinoma, or large cell/NSCLC NOS), performance status
0-2, deemed medically inoperable by a thoracic surgeon or pulmonologist, and no
contraindications to pembrolizumab.

The primary endpoint for this study is safety and feasibility. For the first stage of this
study, 8 patients will be enrolled. If >7 of the initial 8 patients complete the therapy
without experiencing a Grade >3 pulmonary toxicity or any Grade >4 toxicity, an additional 7
patients will be enrolled for a total of 15 patients. If >2 of the original 8 patients (>25%)
experience a Grade >3 pulmonary toxicity or any Grade >4 toxicity the trial will be closed
and the study therapy will be considered too toxic. If >4 of 15 patients (>26.7%) experience
a Grade >3 pulmonary toxicity or any Grade >4 toxicity, the study drug regimen will be deemed
too toxic and unsafe. If >12 out of 15 patients complete the study without experiencing a
Grade >3 pulmonary toxicity or any Grade >4 toxicity, the study drug regimen will be
considered safe and feasible for further study.

Inclusion Criteria:

- Histologically confirmed T1b-T3N0M0 (stage IA-IIB) NSCLC, which have been judged to be
medically inoperable and will have undergone a course of lung SBRT will be enrolled in
this trial. Eligible patients who will have completed lung SBRT will have had
appropriate staging studies identifying them as specific subsets of American Joint
Committee on Cancer (AJCC) 7th edition stage I or stage II based on only one of the
following combinations of primary tumor, regional nodes, metastasis (TNM) staging
using size criteria:

- A. T2a (>3cm, < 5cm) N0 M0, Stage IB

- B. T2b (>5 cm, < 7cm) N0 M0, Stage IIA

- C. T3 (>7cm) N0 M0, Stage IIB

In order to be eligible for participation in this trial, the subject must:

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

- Have measurable or unmeasurable disease based on RECIST 1.1.

- Be willing to provide archival tissue from a tumor lesion.

- Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.

- All screening labs should be performed within 10 days of treatment initiation.

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9g/dL or ≥5.6mmol/L without transfusion or erythropoietin dependency
(within 7 days of assessment

- Serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or measured or
calculated creatinine clearance ≥ 60 mL/min for subjects with creatinine levels >
1.5 times ULN

- Serum total bilirubin ≤ 1.5 times ULN or direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN

- aspartate aminotransferase (AST) (SGOT) and Alanine transaminase (ALT) (SGPT) ≤
2.5 times ULN or ≤ 5 times ULN for subjects with liver metastases

- Albumin ≥ 2.5mg/dL

- 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 must be willing to use an adequate method of
contraception - Contraception, for the course of the study through 120 days after the
last dose of study medication.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

- Male subjects of childbearing potential must agree to use an adequate method of
contraception - Contraception, starting with the first dose of study therapy through 120
days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Exclusion Criteria:

- Has received lung SBRT for stage IA disease, or for any T2 primary tumors involving
the main bronchus, 2 cm of more distal to the carina; or with associated with
atelectasis that extends to the hilar region; or for any T3 tumors that invade the
chest wall, mediastinal pleura, diaphragm, phrenic nerve, parietal pericardium, tumor
or the main bronchus less than 2 cm distal to the carina; atelectasis of the entire
lung; or with separate tumor nodule(s) in the same lobe.

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

- Has a known history of active Bacillus Tuberculosis (TB).

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had any prior chemotherapy or targeted small molecule therapy for the currently
diagnosed cancer.

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

- 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has known history of, or any evidence of active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- 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.

- 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 pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- 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 (HCV).

- Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.