Pembrolizumab, Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients With Stage II-IIIB Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To assess safety and toxicity of anti-programmed cell death 1 (PD-1) inhibition with
pembrolizumab with concurrent chemoradiation therapy for non-operable, locally advanced
non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To evaluate local control and distant metastasis-free survival, progression-free and
overall survival with the addition of pembrolizumab to chemoradiotherapy.

II. To evaluate the rates of pneumonitis that may result from combination pembrolizumab and
chemoradiotherapy.

TERTIARY OBJECTIVES:

I. To assess whether programmed cell death ligand 1 (PDL1) status on immunohistochemistry is
predictive of response to pembrolizumab when combined with chemoradiation therapy.

II. To assess T cell (cluster of differentiation 8 positive [CD8+] T cells and CD4+ forkhead
box P3 positive [FoxP3+] regulatory cells) responses at weeks 1, 3, 6 during chemoradiation
therapy and before each administration of pembrolizumab for cycles 1, 2, 3.

OUTLINE: This is a dose-escalation study of pembrolizumab.

Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30 minutes
on days 1, 8, 15, 22, 29, and 36. Patients undergo 3-dimensional (3D) conformal radiation
therapy (CRT) or intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a week
for 6 weeks . Beginning 2-6 weeks after, 2 weeks before the end, or at the start of
chemotherapy and radiation therapy , patients also receive pembrolizumab IV over 30 minutes
on day 1. Treatment with pembrolizumab repeats every 21 days for up to 18 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days every 12 weeks for 1
year, every 16 weeks for 1 year, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

- Written informed consent and Health Insurance Portability and Accountability Act
(HIPPA) authorization for release of personal health information

- Subjects with any kind of non-small cell lung carcinoma (NSCLC) histology documented
by histology or cytology from bronchial brushing or washing, or needle aspiration of a
defined lesion but not from sputum cytology alone

- Must have American Joint Committee on Cancer (AJCC) 7th edition (ed) inoperable stage
II disease requiring chemoradiation therapy or stage IIIA or IIIB NSCLC based on
appropriate staging studies including brain magnetic resonance imaging (MRI) or head
computed tomography (CT), CT chest, and fluorodeoxyglucose (FDG) positron emission
tomography (PET)/CT scan

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion; newly-obtained is defined as a specimen obtained up to 8 weeks (56 days)
before initiation of treatment on day 1; subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the sponsor or may undergo fine needle
aspiration

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days
before registration for protocol therapy

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

- Platelets >= 100,000/mcL

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

- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance rate
[CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with
creatinine levels > 1.5 X institutional ULN

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases

- Albumin >= 2.5 mg/dL

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Forced expiratory volume >= 1.0 L or >= 40% of predicted with or without
bronchodilators by pulmonary function testing

- Women 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

- Women 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; 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

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

Exclusion Criteria:

- 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 before 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 a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 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 prior to study day 1 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: if subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy

- 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 known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may not participate

- 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 (eg., 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- programmed cell
death 1 ligand 2 (PD-L2) agent

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg]
reactive) or hepatitis C (HCV) (e.g., HCV ribonucleic acid [RNA] [qualitative] is
detected)

- Has received a live vaccine within 30 days of planned start of study therapy

- Pleural effusion that cannot be controlled despite appropriate interventions

- History of allergy or hypersensitivity to any component of the treatment

- No active second cancers