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

Study Overview
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Brief Summary
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The SABR-ATAC trial (Stereotactic Ablative Radiotherapy and anti-TGFB Antibody Combination) is a phase I/II trial that studies the side effects and efficacy of fresolimumab, an anti-transforming growth factor beta (TGFB) antibody, when given with stereotactic ablative radiotherapy in patients with stage IA-IB non-small cell lung cancer. Fresolimumab may inhibit radiation side effects and block tumor growth through multiple mechanisms. Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), is a specialized form of radiation therapy that precisely delivers high dose radiation directly to tumors, thus killing tumor cells and minimizing damage to normal tissue. Giving fresolimumab with SABR may work better in treating patients with early stage non-small cell lung cancer than treating with SABR alone.

Detailed Description
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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.

Official Title
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Fresolimumab and Stereotactic Ablative Radiotherapy in Early Stage Non-small Cell Lung Cancer

Conditions
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Stage IA Non-Small Cell Lung Carcinoma, Stage IB Non-Small Cell Lung Carcinoma

Intervention / Treatment
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* Biological: Fresolimumab
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Phase 1) Fresolimumab 3 mg/kg<br>Patients receive fresolimumab 3 mg/kg IV on days 1, 15, and 36 and undergo SABR in 4 fractions between days 8 and 12. | Biological: Fresolimumab<br>* Given IV<br>* Other names: Immunoglobulin G4, anti-(transforming growth factor beta) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, Dimer;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SABR<br>* Other names: SBRT;|
| Experimental: (Phase 1) Fresolimumab 1 mg/kg<br>Patients receive fresolimumab 1 mg/kg IV on days 1, 15, and 36 and undergo SABR in 4 fractions between days 8 and 12. | Biological: Fresolimumab<br>* Given IV<br>* Other names: Immunoglobulin G4, anti-(transforming growth factor beta) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, Dimer;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SABR<br>* Other names: SBRT;|
| Experimental: (Phase 2) Fresolimumab<br>Fresolimumab will be administered IV at the dose selected in the preceding Phase 1 on Days 1, 15 and 36 and SABR will be administered in 4 fractions between Days 8 and 12. | Biological: Fresolimumab<br>* Given IV<br>* Other names: Immunoglobulin G4, anti-(transforming growth factor beta) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, Dimer;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SABR<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLTs) of fresolimumab when combined with SABR defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher radiation pneumonitis or bronchopulmonary hemorrhage (Phase I) | Dose limiting toxicity (DLT) is defined as the following grade 3; 4; or 5 CTCAE v4 events determined to be of possibly; probably; of definite relationship to treatment; occurring after 1st dose of fresolimumab and up to 30 days after the last dose of fresolimumab: Radiation pneumonitis, or Bronchopulmonary hemorrhage A safe dose of fresolimumab is reached when =< 10% of the patients receiving fresolimumab plus SABR develop DLTs. | Up to 30 days | 
| Presence of late radiation induced fibrosis (Phase II) |  | Up to 12 months |