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

PRIMARY OBJECTIVES:

Phase 1: Evaluate the safe dose of fresolimumab in combination with stereotactic ablative radiotherapy (SABR) in patients.

Phase 2. Evaluate the rate of radiation induced pulmonary fibrosis after SABR plus fresolimumab.

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.

• Phase 1: A cohort of 5 patients receive the pre-selected dose of 3mg/kg of fresolimumab. If one patient experiences a DLT, an additional 5 patients will be enrolled at 3 mg/kg. If no more patients experience a DLT, then 3 mg/kg will be the dose for the Phase 2 component. If 2 or more patients experience a DLT in the total expanded cohort (or 2 or more patients in the initial cohort experience DLT), then the investigational dose of fresolimumab will be changed to 1 mg/kg. If 2 or more patients in the initial cohort experience DLT before all 5 patients have been enrolled, the remaining patients will receive the lower dose of 1 mg/kg.
• Phase 2: 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
• Patient judged to be inoperable or at high surgical risk by a board qualified thoracic cancer surgeon who has evaluated the subject within the prior 12 weeks, or the patient's case has been discussed at a multidisciplinary tumor board with a thoracic cancer surgeon in attendance, or a patient who refuses surgery or declines to be evaluated for surgery.
• Able to give informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2
• 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)

Exclusion criteria

• Significant anemia (hemoglobin below 9.0 g/dL) or neutropenia (absolute neutrophil count [ANC] < 1000/mm^3)
• Prior history of multifocal adenocarcinoma in situ (ie, classic or pure bronchioloalveolar carcinoma)
• Prior history of keratoacanthoma (well differentiated squamous cell skin cancer variant, often centrally ulcerated); history of basal cell cancer is allowed
• Pre malignant skin lesion(s) noted on prescreening skin exam, except for actinic (solar) keratosis
• Prior radiotherapy overlapping with high dose region of planned SABR course
• Prior history of head and neck; oral; or bladder cancer
• Prior receipt of systemic treatment (chemotherapy, targeted therapy, or immunotherapy) for the lesion under consideration of treatment
• 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
• Contraindication to receiving radiotherapy
• Known allergy to components of fresolimumab
• Pregnant or breastfeeding. 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.