Atezolizumab and Stereotactic Body Radiation Therapy in Treating Patients With Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of MPDL3280A (atezolizumab) that can be
given with stereotactic ablative radiotherapy (SAR) (stereotactic body radiation therapy) in
patients with inoperable stage I non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To characterize the safety profile of this regimen using CTCAE v4 (Common Toxicity
Criteria for Adverse Events version 4).

II. To provide preliminary efficacy data of the combination as determine by objective
response rate and disease free survival using RECIST 1.1 (Response Evaluation Criteria for
Solid Tumors) and Immune Related RECIST (irRECIST).

TERTIARY OBJECTIVES:

I. To analyze serial blood for change in cytokine signatures, fluorescence activated cell
sorting (FACS) and immunophenotyping of peripheral blood mononuclear cells (PBMCs) and tumor
infiltrating immune cells.

II. To evaluate pre and post treatment tumor tissue (if available) for programmed cell
death-ligand 1 (PD-L1) and other immune proteins in the tumor and tumor microenvironment and
for molecular profiling in a subset of patient samples.

III. To discover biomarkers of response from the data obtained.

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

DOSE ESCALATION PHASE: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on
day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or
unacceptable toxicity. Within 24-48 hours after receiving atezolizumab, patients also undergo
4-5 fractions of stereotactic body radiation therapy over days 1-5 of course 3.

EXPANSION PHASE: Patients receive atezolizumab IV over 30-60 minutes on day 1. Courses repeat
every 3 weeks in the absence of disease progression or unacceptable toxicity. Within 24-48
hours after receiving atezolizumab, patients also undergo 4-5 fractions of stereotactic body
radiation therapy over days 1-5 of course 3.

After completion of study treatment, patients are followed up at 30 days, every 3 months for
2 years, and then every 6 months for 3 years.

Inclusion Criteria:

- Histologically proven stage I NSCLC =< 5 cm diameter

- One or more high-risk features identified:

- Tumor diameter >= 2 cm

- Tumor standardized uptake value maximum (SUVmax) >= 6.2

- Moderately, poorly differentiated or undifferentiated histology

- Evaluable disease per RECIST 1.1

- Patients must be medically or surgically inoperable as determined by a physician OR
unwilling to undergo surgical resection

- All patients must have an forced expiratory volume in 1 second (FEV1) >= 700cc

- All patients must have a carbon monoxide diffusing capability test (DLCO) >= 5.5
m/min/mmHg

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2

- Life expectancy >= 12 months

- Absolute neutrophil count (ANC) > 1500 cells/uL

- White blood cell count (WBC) > 2500/uL

- Lymphocyte count > 500/uL

- Platelet count > 100,000/uL

- Hemoglobin > 9 g/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper
limit of normal (ULN) with alkaline phosphatase =< 2.5 x ULN OR AST and ALT =< 1.5 x
ULN, with alkaline phosphatase > 2.5 x ULN

- Serum bilirubin =< 1.0 x ULN

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
< 1.5 x ULN (for patients on anticoagulation they must be receiving a stable dose for
at least 1 week prior to enrollment)

- Creatinine clearance > 30 mL/min by Cockcroft-Gault formula

- No history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)

- No other active malignancy

- Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone are eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are
eligible

- Archival tumor sample available; tissue from an fine-needle aspiration (FNA) is
allowed but tumor tissue from a core needle biopsy is preferred

- For female patients of childbearing potential and male patients with partners of
childbearing potential agreement (by patient and/or partner) to use highly effective
form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year]
when used consistently and correctly) and to continue its use for 6 months after the
last dose of MPDL3280A

- Signed informed consent

- Ability to comply with the protocol

Exclusion Criteria:

- Uncontrolled concomitant disease

- Significant cardiovascular disease (New York Heart Association Class [NYHA] class II
or greater); myocardial infarction within 3 month prior to randomization, unstable
arrhythmias, unstable angina or a patient with a known left ventricular ejection
fraction (LVEF) < 40%

- Severe infection within 4 weeks prior to enrollment

- Active tuberculosis

- Oral or IV antibiotics within 2 weeks or 5 half-lives prior to enrollment

- History of autoimmune disease

- Positive for human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface
antigen [HBsAg] reactive), or hepatitis C virus (hepatitis C virus ribonucleic acid
[HCV RNA] [qualitative] is detected)

- History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing
pneumonia

- Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of
the drug, whichever is shorter, prior to enrollment

- Treatment with systemic corticosteroids or other systemic immunosuppressive
medications within past 4 weeks or 5 half-lives whichever is shorter

- Pregnant and/or lactating women