SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. Evaluate the safe dose of fresolimumab in combination with stereotactic ablative
radiotherapy (SABR) in patients. (Phase I) II. Evaluate the rate of radiation induced
pulmonary fibrosis after SABR plus fresolimumab. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate potential adverse events in patients receiving fresolimumab plus SABR. (Phase I)
II. Evaluate post treatment changes in pulmonary function. (Phase I) III. Evaluate recurrence
rates and progression free survival. (Phase I) IV. Assess pharmacokinetics (PK) of
fresolimumab in combination with SABR (optional for patient). (Phase I) V. Evaluate the rate
and severity of radiation induced pulmonary fibrosis after SABR plus fresolimumab. (Phase I)
VI. Evaluate the severity of radiation induced pulmonary fibrosis after SABR plus
fresolimumab. (Phase II) VII. Evaluate potential adverse events in patients receiving
fresolimumab plus SABR. (Phase II) VIII. Evaluate post treatment changes in pulmonary
function. (Phase II) IX. Evaluate recurrence rates and progression free survival. (Phase II)

OUTLINE: This is a phase I, dose escalation study of fresolimumab followed by a phase II
study.

Patients receive fresolimumab intravenously (IV) on days 1, 15, and 36 and undergo SABR in 4
fractions between days 8 and 12.

After completion of study treatment, patients are followed up at 3, 6, and 12 months.

Inclusion Criteria:

- Newly diagnosed, histologically proven (or strongly suspected, see below) T1-T2aN0M0
(Stage IA-IB) non-small cell lung cancer (NSCLC), with maximum tumor diameter =< 5 cm
under consideration for stereotactic ablative body radiotherapy (SABR) as definitive
primary treatment

- Pathologic confirmation of NSCLC diagnosis is recommended whenever possible; this will
generally be accomplished using computed tomography (CT) guided or bronchoscopic
biopsies; if pathologic confirmation is not possible, a target lesion must be a non
calcified pulmonary nodule that is present on at least 2 imaging studies (can include
simulation scan); the nodule must have increased in size or proportion of solid
component on CT and/or show increased fluorodeoxyglucose (FDG) uptake on positron
emission tomography (PET) over at least 2 imaging studies

- No history of prior radiotherapy overlapping with high dose region of planned SABR
course

- No prior receipt of systemic treatment (chemotherapy, targeted therapy, or
immunotherapy) for the lesion under consideration of treatment

- No uncontrolled, inter-current or recent illness that in the investigator's opinion
precludes participation in the study, including those undergoing therapy for a
separate invasive malignancy

- Able to give informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2

Exclusion Criteria:

- No significant anemia (hemoglobin below 9.0 g/dL) or neutropenia (absolute neutrophil
count [ANC] < 1000/mm^3)

- No prior history of lung resection on ipsilateral side

- No prior history of multifocal adenocarcinoma in situ (ie, classic or pure
bronchioloalveolar carcinoma)

- No prior history of idiopathic pulmonary fibrosis

- No prior history of keratoacanthoma (well differentiated squamous cell skin cancer
variant, often centrally ulcerated); history of basal cell cancer is allowed

- No contraindication to receiving radiotherapy and no known allergy to components of
fresolimumab

- No pregnant or breastfeeding women; men or women of child bearing potential must agree
to use an acceptable method of birth control (hormonal or barrier method of birth
control; abstinence) to avoid pregnancy for at least 90 days after last study
treatment (radiation or fresolimumab); all women of child bearing potential (last
menstrual period within the previous 12 months and not surgically sterile) will be
tested for pregnancy at pre-entry