Fresolimumab and Stereotactic Ablative Radiotherapy in Early Stage Non-small Cell Lung Cancer
Phase: PHASE1
Conditions: Stage IA Non-Small Cell Lung Carcinoma, Stage IB Non-Small Cell Lung Carcinoma
Sponsor: Maximilian Diehn

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Fresolimumab and Stereotactic Ablative Radiotherapy in  
Early Stage Non-Small Cell Lung Cancer 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
Protocol Director  
Max Diehn, MD, PhD 
875 Blake Wilbur Drive 
Stanford, CA 94305 
650-721-1550 
Fax:  650-725-8231 
diehn@stanford.edu 
Radiation Co-Protocol Director 
Billy Loo, MD, PhD  
875 Blake Wilbur Drive 
Stanford, CA 94305 
650-736-7143 
Fax:  650-725-8231 
 
Medical Oncology Co-Protocol Director 
Joel Neal, MD, PhD  
875 Blake Wilbur Dr 
Stanford, CA 94305 
 
 
 
Medical Oncology Co-Investigator 
Thomas Chen, MD 
  
San Jose, CA 95124 
Phone: 
 
Fax: 
 
tchen@stanfordhealthcare.org 
 
Medical Oncology Co-Investigator 
Millie Das, MD  
875 Blake Wilbur Drive 
Stanford, CA 94305 
650-498-6000 
Fax:  650-725-9113 
mdas@stanford.edu 
 
Medical Oncology Co-Investigator 
Omid Tehrani, MD, PhD  
 
San Jose, CA 95124 
Phone: 
 
Fax: 
 
tehrani@stanford.edu 
 
Biostatistician 
 
Study Coordinator 
 
800 Welch Road 
Palo Alto, CA 94304 
 
 
 
 
 
 
 

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Original Date:   
10 July 2015 
Version Date: 
7 August 2015 
Version Date: 
30 September 2015 
Version Date: 
6 October 2015 
Version Date: 
26 June 2017 
Version Date: 
22 November 2017 
Version Date:  
1 February 2019 
Version Date:  
19 June 2019 
Version Date: 
24 June 2019 
Current Version Date:  
30 June 2022 
 
 
Activation Date (OnCore):   
SRC approval Date: 
8 August 2015 
SRC approval Date:             1 February 2019 

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For Protocol Amendment of : LUN0071, Fresolimumab and Stereotactic Ablative Radiotherapy in  
Early Stage Non-Small Cell Lung Cancer (FRESO) 
 
Protocol Version Date: 26 March 2022 
 
Section 
Change 
Global 
The protocol version date is updated in the document 
footer. 
Genzyme replaced with Sanofi Genzyme 
Page 1, 2 
Updated personnel and version table 
Page 8, 38 
Accrual will occur over 60 months 
Page 9, 17 
Study duration updated 
Page 9, 11, 17, 18, 33 
Added SABR windows (-1/+5 days) 
Section 4.2.3, page 20 
Added follow up details 
Section 11.3, page 37 
Added “Case report forms will be developed using 
REDCap database system and will be maintained by 
the Clinical Research Coordinator assigned to this 
study” 
Page 7, 9, 10, 11, 14, 35, 36, 39 
Clarified that the primary endpoint is the severity of 
pulmonary fibrosis. 
Page 7, 9, 11, 15, 35, 39 
Clarified evaluation of severity vs. pattern. 
Page 35 
Added that scores will be assigned by consensus by at 
least two radiologists or radiation oncologists dedicated 
to the study. 
Page 35 
Added that in the phase 2 component of the study, the 
severity score of fibrosis in study subjects will be 
compared to historical controls.  Historical controls will 
consist of patients previously treated with the same 
dose of SABR (50 Gy in four fractions) at Stanford in 
the absence of fresolimumab. 
Page 35, 39 
Added that patients who are lost to follow up and who 
do not have a scan within +/-6 months of the 12-month 
time point will be excluded from analysis.  
Page 35, 39 
Added that patients who develop inflammatory lung 
conditions unrelated to radiotherapy (i.e. pneumonia, 
ARDS, drug-induced pneumonitis, etc.) will be 
excluded from the final endpoint analysis if the area of 
unrelated inflammation impedes scoring of fibrosis 
severity of the irradiated lesion. 
Page 39 
Added that our institutional experience revealed the 
presence of moderate-to-severe late radiation induced 
fibrosis in approximately 75% of SABR patients at 1 
year. 
Page 39 
Added that patients who are lost to follow up and who 
do not have a scan within +/-6 months of the 12-month 
time point will be excluded from analysis. Patients who 
develop inflammatory lung conditions unrelated to 
radiotherapy (i.e. pneumonia, ARDS, drug-induced 
pneumonitis, etc.) will be excluded from the final 
endpoint analysis if the area of unrelated inflammation 

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impedes scoring of fibrosis severity of the irradiated 
lesion 
Page 39 
Added that our institutional experience revealed the 
presence of moderate-to-severe late radiation induced 
fibrosis in ~75% of patients treated with SABR (50 Gy in 
4 fractions) at 1 year. 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS 
6 
SCHEMA: 
11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
12 
1. 
OBJECTIVES 
13 
2. 
BACKGROUND 
14 
2.1 
STUDY DISEASE 
14 
2.2 
STUDY AGENT/DEVICE/PROCEDURE 
14 
2.3 
RATIONALE 
16 
2.4 
STUDY DESIGN 
17 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
17 
3.1 
INCLUSION & EXCLUSION CRITERIA 
17 
3.2 
INFORMED CONSENT PROCESS 
17 
3.3 
RANDOMIZATION PROCEDURES 
17 
3.4 
STUDY TIMELINE 
17 
4. 
TREATMENT PLAN 
17 
4.1 
PRE-TREATMENT TESTS 
17 
4.2. 
DRUG THERAPY 
17 
4.3. 
PROCEDURES:  SABR ADMINISTRATION AND RADIATION TREATMENT PLANNING 
19 
5. 
INVESTIGATIONAL AGENT INFORMATION:  FRESOLIMUMAB 
23 
5.1 
DESCRIPTION/MECHANISM OF ACTION 
23 
5.2 
PHARMACOKINETICS 
23 
5.3 
HOW SUPPLIED / STORAGE 
24 
5.4 
MANUFACTURE 
25 
5.5 
ADVERSE REACTIONS 
25 
 
6. 
DOSE MODIFICATIONS 
26 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
26 
7.1 
POTENTIAL ADVERSE EVENTS 
26 
7.2  
DEFINITION OF AN ADVERSE EVENT 
27 

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7.3  
REPORTING ADVERSE EVENTS 
28 
7.4  
DEFINITION OF A SERIOUS ADVERSE EVENT 
29 
7.5  
IMMEDIATE REPORTING OF SERIOUS ADVERSE EVENTS 
29 
7.6  
SPECIAL CONSIDERATIONS 
29 
7.7  
DEFINITION OF REPORTABLE INFORMATION 
30 
7.8  
DEFINITION OF AN UNANTICIPATED PROBLEM  
30 
7.9 
REPORTING OF PREGNANCY 
30 
7.10 
DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL 
30 
7.11 
REPORTING OF OVERDOSE TO SANOFI GENZYME 
30 
7.12  STOPPING RULES 
31 
7.13  CONFIDENTIALITY 
31 
8. 
CORRELATIVE/SPECIAL STUDIES 
31 
8.1  
PHARMACOKINETIC ANALYSES  
31 
8.2 
CODING OF SPECIMENS FOR PRIVACY PROTECTSION  
32 
9. 
STUDY CALENDAR 
33 
10. MEASUREMENT OF ENDPOINT 
34 
10.1  SCORING OF POST-SABR RADIOLOGIC CHANGES  
34 
10.2 
ADDITIONAL SECONDARY ENDPOINTS 
35 
11. REGULATORY CONSIDERATIONS 
36 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL 
36 
11.2 
DATA AND SAFETY MONITORING PLAN 
36 
11.3 
DATA MANAGEMENT PLAN 
36 
12. STATISTICAL CONSIDERATIONS 
37 
12.1 
STATISTICAL DESIGN 
37 
12.2 
INTERIM ANALYSES 
37 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS 
37 
12.4 
PRIMARY AND SECONDARY ENDPOINTS 
37 
12.5  SAMPLE SIZE 
38 
13. INVESTIGATOR RESOURCES 
39 
13.1  QUALIFICATIONS  
39 
14. REFERENCES 
40 
APPENDIX A:  PARTICIPANT ELIGIBILITY CHECKLIST 
41 
 

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PROTOCOL SYNOPSIS 
Title of Study:  Fresolimumab and Stereotactic Ablative Radiotherapy in  
Early Stage Non-Small Cell Lung cancer 
Study Phase:  1-2 
Study Center(s):   Stanford University Hospital 
Indication:  
Stereotactic ablative radiotherapy (SABR) has emerged as an effective and safe 
treatment modality for early stage non-small cell lung cancer (NSCLC).  However, 
most patients develop significant fibrosis of lung tissue in the target region, which 
inhibits local lung function and complicates early diagnosis of possible tumor 
recurrence.  Additionally, the main pattern of failure after SABR for early stage 
NSCLC is regional/distant recurrence.  Thus, there is an unmet need for therapeutic 
strategies that can reduce post-treatment fibrosis and decrease regional/distant 
recurrence. 
Phase 1: 
Primary Objective:  
Evaluate the safe dose of fresolimumab in combination with SABR in patients 
Secondary Objectives:  
• 
Evaluate potential adverse events in patients receiving fresolimumab plus SABR 
• 
Evaluate post-treatment changes in pulmonary function  
• 
Evaluate recurrence rates and progression-free survival (PFS) 
• 
Assess pharmacokinetics (PK) of fresolimumab in combination with SABR 
(optional for patient) 
• 
Evaluate the rate and severity of radiation-induced pulmonary fibrosis after SABR 
plus fresolimumab 
Phase 2: 
Primary Objective:  
Evaluate the rate of moderate-to-severe radiation-induced pulmonary fibrosis after 
SABR plus fresolimumab 
Secondary Objectives:  
• 
Evaluate the pattern of radiation-induced pulmonary fibrosis after SABR plus 
fresolimumab 
• 
Evaluate potential adverse events in patients receiving fresolimumab plus SABR 
• 
Evaluate post-treatment changes in pulmonary function  
• 
Evaluate recurrence rates and progression-free survival (PFS) 
Hypothesis:  
We hypothesize that inhibition of TGFβ using fresolimumab will reduce the 
development of radiation-induced pulmonary fibrosis after SABR for early stage 
NSCLC.  
Phase 1 will help determine a safe and tolerable dose of fresolimumab in combination 
with SABR in patients with early stage NSCLC.  After the dose has been determined, 
we will then proceed to a single-arm, phase 2 study, in which patients will receive 
fresolimumab at the dose determined from Phase 1 in addition to SABR.  

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Study Design:  
We propose a prospective, phase 1-2 clinical trial to evaluate the evaluate the safety 
and efficacy of combining fresolimumab with SABR in the treatment of early stage 
NSCLC.   
Phase 1 will help determine a safe and tolerable dose of fresolimumab in combination 
with SABR in patients with early stage NSCLC.  After the dose has been determined, 
we will then proceed to a single-arm, phase 2 study, in which patients will receive 
fresolimumab at the dose determined from Phase 1 in addition to SABR.  
Comprehensive Safety Review  
The rate of NSCLC recurrence will be continuously evaluated for the 1st 10 subjects 
through 6 months follow-up.  In the event that there are ≥ 3 NSCLC recurrences in the 
first 10 subjects, enrollment will be paused, and a comprehensive safety review will 
be conducted, which will include the Stanford Cancer Institute Data Safety Monitoring 
Committee (DSMC).  If, after review, the DSMC recommends proceeding with the 
study, the report of the safety review will be submitted to the IND, and 
FDA’s concurrence will be sought before proceeding with enrollment.   
Similarly, development of new malignancies will be monitored for the first 10 patients 
through the 6 month follow-up time point [except keratoacanthomas / squamous cell 
carcinomas (SCC) of the skin].  Keratoacanthomas and SCC are not included 
because these are known events that regress after discontinuation of fresolimumab 
therapy, per the Investigator’s Brochure.  These lesions will be referred to a 
dermatologic oncologist or dermatologist for evaluation, treatment, and monitoring, 
but will not be tabulated towards the criteria for enrollment pause.  New malignancies 
are expected to be rare, and if more than 2 subjects develop new malignancies, 
enrollment would be similarly paused for a comprehensive safety review as above.  
Primary and Secondary Endpoint(s): 
Phase 1: 
Primary Endpoint 
Dose limiting toxicities (DLTs) of fresolimumab when combined with SABR 
Secondary Endpoint 
• 
Score the pattern of late radiation induced fibrosis at 12 months after SABR with 
and without fresolimumab 
• 
Evaluate pattern and severity of acute radiation-induced fibrosis in the first 6 
months after SABR 
• 
Score potential adverse events (AEs) of fresolimumab combined with SABR using 
CTCAE v4 
• 
Measure post-treatment changes in pulmonary function using pulmonary function 
test parameters at enrollment, 6-month, and 12-month follow-up 
• 
Evaluate recurrence and progression-free survival at 12 months 
• 
Measure blood pharmacokinetics (PK) of fresolimumab in combination with SABR 
(optional for patient)  
Exploratory Endpoint: 
• 
Assess extent of radiation-induced lung toxicity by quantitative imaging analysis 
of CT volumes and FDG uptake parameters 
 
 

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Phase 2 
Primary Endpoint 
Evaluate the presence of late moderate-to-severe radiation-induced fibrosis up to 12 
months after SABR with fresolimumab 
Secondary Endpoint 
• 
Score the pattern of late radiation induced fibrosis at 12 months after SABR with 
and without fresolimumab 
• 
Evaluate pattern and severity of acute radiation-induced fibrosis in the first 6 
months after SABR 
• 
Score potential adverse events (AEs) of fresolimumab combined with SABR using 
CTCAE v4 
• 
Measure post-treatment changes in pulmonary function using pulmonary function 
test parameters at enrollment, 6-month, and 12-month follow-up 
• 
Evaluate recurrence and progression-free survival at 12 months 
Exploratory Endpoint: 
• 
Assess extent of radiation-induced lung toxicity by quantitative imaging analysis 
of CT volumes and FDG uptake parameters 
Number of Patients:  55 to 60 
In 2014, ~80 lung SABR procedures were performed at Stanford Hospital.  It is estimated 
that 2 to 3 patients can reasonably be expected to accrue per month.  Accrual will occur over 
60 months. 
Inclusion Criteria: 
1. 
Newly diagnosed, histologically-proven T1-T2bN0M0 (Stage IA-IIA) NSCLC, with 
maximum tumor diameter ≤ 5 cm under consideration for stereotactic ablative body 
radiotherapy (SABR) as definitive primary treatment  
2. 
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 
3. 
ECOG PS 0 to 2  
4. 
Age greater than or equal to 18 years old and able to give informed consent  
5.   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: 
1. 
Significant anemia (hemoglobin < 9.0 g/dL) or neutropenia (ANC < 1000/mm3) 
2. 
Prior history of multifocal adenocarcinoma in situ (ie, classic or pure bronchioloalveolar 
carcinoma)  
3. 
Prior history of keratoacanthoma (well-differentiated squamous cell skin cancer variant, 
often centrally ulcerated).  History of basal cell cancer is allowed.  
4. 
Pre-malignant skin lesion(s) noted on prescreening skin exam, except for actinic (solar) 
keratosis  
5. 
Prior radiotherapy overlapping with high dose region of planned SABR course 
6. 
Prior history of head and neck; oral; or bladder cancer  
7. 
Prior receipt of systemic treatment (chemotherapy, targeted therapy, or immunotherapy) 
for the lesion under consideration of treatment  

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8. 
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  
9. 
Contraindication to receiving radiotherapy 
10.  Known allergy to components of fresolimumab 
11. 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.  
Intervention and Mode of Delivery: 
Phase 1 component: 
Fresolimumab will be administered intravenously (IV) at a dose of 3 mg/kg on Days 1, 
15, and 36 and SABR will be administered at 12.5 Gy/fraction in 4 fractions between 
Days 8 and 12 to a total of 5 patients who will be evaluated for safety, and additional 
patients will be enrolled if specific AE’s are observed.  A dose reduction may be 
implemented if excessive toxicity is observed. 
Phase 2 component: 
Fresolimumab will be administered IV at the dose selected in the preceding Phase 1 
component (3 mg/Kg) on Days 1, 15 (+ 6 days), and 36 (+/- 6 days) and SABR (-1/+5 
days) will be administered at 12.5 Gy/fraction in 4 fractions between Days 8 and 12. 
Duration of Intervention and Evaluation:  The study duration will be approximately 6 years 
(5 years for accrual and 1 year for follow-up) 
Statistical Methods:   
Definition of primary outcome/endpoint: 
Phase 1: 
DLT is defined as CTCAE grade 3 or higher radiation pneumonitis or bronchopulmonary 
hemorrhage  
Phase 2: 
Presence of radiation-induced pulmonary fibrosis is defined as presence of a moderate-
to-severe level of fibrosis in each patient by 12 months 
Definition of secondary outcomes/endpoints: 
Phase 1: 
• 
Potential adverse events is defined by CTCAE v4 
• 
Post-treatment changes in pulmonary function will be evaluated by changes in 
pulmonary function test at enrollment, 6-month, and 12-month follow-up 
• 
Recurrence is defined as presence of local, regional, and/or distant recurrence by 12 
month 
• 
Progression-free survival is time from time from study enrollment until the first 
documented date of disease progression. 
• 
Extent of radiation-induced lung toxicity is morphological changes on CT and PET 
after treatment 
• 
Presence of radiation induced pulmonary fibrosis is defined as presence of a 
moderate-to-severe level of fibrosis in each patient by 12 months 
• 
Severity of radiation induced pulmonary fibrosis is degree of fibrosis after SABR 
Phase 2: 
• 
Severity of radiation induced pulmonary fibrosis is degree of fibrosis after SABR 
• 
See Phase 1 definitions for the rest of the objectives 
Analytic plan for primary objective: 

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Phase 1: 
A safe dose of fresolimumab is reached when ≤10% of the patients receiving 
fresolimumab plus SABR develops DLTs, defined as CTCAE v4 grade 3 or higher 
radiation pneumonitis and bronchopulmonary hemorrhage.   
Phase 2: 
Rate of radiation-induced pulmonary fibrosis is defined as percentage of patients with a 
moderate-to-severe level of fibrosis.  Presence of fibrosis will be determined by CT 
imaging after treatment. 
Analytic plan for secondary objectives: 
Phase 1: 
• 
Potential adverse events will be monitored by treating physicians at each follow-up 
visit, and scored using CTCAE v4 with type and grade 
• 
Post-treatment changes in pulmonary function will be evaluated by changes in 
pulmonary function test (PFT) at enrollment, 6-month, and 12-month follow-up 
• 
Recurrence rates will be evaluated by follow-up CT imaging studies up to 1 year 
• 
Progression-free survival will be evaluated by following the above imaging results at 
each follow-up visit up to 1 year 
• 
Pharmacokinetics (PK) of fresolimumab will be determined by measurement of drug 
level in blood samples.  Blood sample will be collected once before fresolimumab 
administration and again within 1-4 hours post administration. 
• 
Rate of radiation induced pulmonary fibrosis is defined as percentage of patients with 
a moderate-to-severe level of fibrosis.  Presence of fibrosis will be determined by CT 
imaging after treatment. 
• 
Pattern of radiation-induced pulmonary fibrosis will be scored using the “Late 
Radiation Fibrosis Score” developed by Dahele, et al. [2] 
Phase 2: 
Please see Phase 1 definitions for the objectives 
Sample size justification: 
Phase 1: 
Post-SABR pneumonitis is expected to occur in ≤ 10% of patients with stage I disease.  
Based on this percentage, we propose to start out with a cohort of 5 patients at the 
pre-selected dose of 3mg/kg of fresolimumab.  If one patient develops DLT, then 5 more 
patients will be enrolled at the same dose to make a total of 10 patients.  If no more 
patients experience DLT, then the total percentage of patients experiencing DLT is 10% 
and is considered acceptable for toxicity. 
Phase 2: 
A sample of size 50 was chosen in order to have 80% power to detect a decrease in the 
incidence of post SABR moderate-to-severe fibrosis from 75% to 60% with a one sided 
significance level of 10%. 
Funding, Regulatory, and Feasibility Issues: 
This study is sponsored by Varian, Inc. and Sanofi Genzyme, Inc.  The fresolimumab used in 
this study will be provided by Sanofi Genzyme, Inc. Sanofi Genzyme has committed to 
providing the medication. 

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Patient Acceptability/Ethics and Consent Issues:
SABR is the definitive treatments for patients with stage I NSCLC who are unable or 
unwilling to undergo surgical resection.  This study involves adding fresolimumab to the 
above standard treatment.  The treatment is limited to three IV administrations of the 
medication, at the dose that is anticipated to be tolerable based on prior clinical trials.  We 
also structure the follow-up visits of the study to match those that would be needed following 
SABR treatment.  We believe with the above study design, we can increase patient 
acceptance and tolerability of the trial.
Sponsor Information
This study is sponsored by Varian, Inc., and Sanofi Genzyme, Inc.  The fresolimumab used 
in this study will be provided by Sanofi Genzyme, Inc.
Study Schema
Phase 1-2 Treatment Administration Schema:
        Phase 1 Schema:
Phase 2:

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Fresolimumab will be administered IV at the dose determined from Phase 1 on Days 1, 15 (+ 6 
days), and 36 (+/- 6 days), with SABR (-1/+5 days) being administered at 12.5 Gy/fraction in 
4 fractions between Days 8 and 12.  

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
AE 
Adverse event 
ANC 
Absolute neutrophil count 
BED 
Biologically equivalent dose 
CBC 
Complete blood count 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTV 
Clinical target volume 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DM 
Distant metastasis 
DNA 
Deoxyribonucleic acid 
DNF  
Distant nodal failure 
DMF  
Distant metastatic failure 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
EDTA 
Ethylenediaminetetraacetic acid 
EMT 
Epithelial mesenchymal transformation 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FEV-1 
Forced expiratory volume in 1 second 
FFF 
Flattening free filter mode  
FNA 
Fine needle aspirate 
GTV 
Gross tumor volume 
HNF 
Hilar node failure  
IDN 
Identification number 
ILF 
Involved lobe failure  
ITV 
internal target volume  
LC 
Local Control 
MF 
Marginal failure 
MNF 
Ipsilateral mediastinal nodal failure (MNF) 
NLF 
Non-primary lobe failure 
NSCLC 
Non-small cell lung cancer 
OS 
Overall Survival 
PFT 
Pulmonary function test 
PTF 
Primary tumor failure 
PTV 
Planning target volume 
QOL 
Quality of life 
RECIST 
Response evaluation criteria in solid tumors 
RC 
Regional control 
RPM 
Revolutions per minute 
RTOG 
Radiation Therapy Oncology Group 
SABR 
Stereotactic ablative radiotherapy  
SBRT 
Stereotactic body radiation therapy 
XRT 
External beam radiation therapy 

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1. 
OBJECTIVES 
Phase 1: 
Primary Objective:  
Evaluate the safe dose of fresolimumab in combination with SABR in patients 
Secondary Objectives:  
• 
Evaluate potential adverse events in patients receiving fresolimumab plus SABR 
• 
Evaluate post-treatment changes in pulmonary function  
• 
Evaluate recurrence rates and progression-free survival 
• 
Assess pharmacokinetics (PK) of fresolimumab in combination with SABR (optional 
for patient) 
• 
Evaluate the rate and severity of radiation-induced pulmonary fibrosis after SABR 
plus fresolimumab 
Phase 2: 
Primary Objective:  
Evaluate the rate of radiation-induced moderate-to-severe pulmonary fibrosis after 
SABR plus fresolimumab 
Secondary Objectives:  
• 
Evaluate the pattern of radiation induced pulmonary fibrosis after SABR plus 
fresolimumab 
• 
Evaluate potential adverse events in patients receiving fresolimumab plus SABR 
• 
Evaluate post-treatment changes in pulmonary function  
• 
Evaluate recurrence rates and progression-free survival 
2. 
BACKGROUND 
2.1 
Study Disease 
Lung cancer is the leading cause of cancer mortality worldwide, accounting for over 
1.3 million deaths each year, largely because it is most often diagnosed at advanced stages [1]. 
However, early stage non-small cell lung cancer (NSCLC) is often surgically curable with the 
appropriate resection, preferably lobectomy [2]. Unfortunately, a significant fraction of patients 
with early stage NSCLC cannot tolerate surgery owing to medical comorbidities.  
2.2 
Study Agent/Device/Procedure 
Stereotactic Ablative Radiotherapy 
In non-operable NSCLC patients, stereotactic ablative radiotherapy (SABR), also called 
stereotactic body radiation therapy (SBRT), has recently emerged as an important treatment 
option [3, 4].  A landmark prospective phase 2 clinical trial conducted by the Radiation Therapy 
Oncology Group, RTOG 0236, found that SABR resulted in outstanding local control (LC) and 
overall survival (OS) rates of 98% and 56% at 3 years in a cohort of strictly medically inoperable 
patients with peripherally located stage I NSCLC [5].  While extremely well tolerated, SABR 
almost always produces a significant fibrotic reaction in the targeted region of the lung.  These 
fibrotic reactions result in loss of function of the affected lung tissue and significantly complicate 
detection of post-SABR recurrences.  
Transforming growth factor-beta 
Transforming growth factor-beta (TGFβ) is a pleiotropic cytokine expressed as three isoforms; 
TGFβ1, TGFβ2, and TGFβ3 and belongs to a superfamily of ligands comprised of more than 
30 proteins such as bone morphogenetic proteins, activins, and inhibin. TGFβ isoforms are 
involved in a number of normal biologic and physiologic processes such as cell proliferation, cell 
differentiation, cell motility, apoptosis, angiogenesis, and extracellular matrix production [6]. In 
normal non-cancerous cells TGFβ limits the growth of epithelial, endothelial, neuronal, and 

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hematopoietic cells through induction of anti-proliferative and apoptotic responses but in cancer 
TGFβ has been shown to have growth promoting and prometastatic effects [7, 8]. 
TGFβ has been implicated in the growth, progression, and metastasis of cancer and is known to 
be a key mediator in epithelial homeostasis; controlling key events such as the differentiation, 
proliferation, growth and senescence of cells.  Typically, TGFβ suppresses the proliferation of 
cells and clear senesced cells through the induction of apoptosis [7, 8].  These antiproliferative 
effects are primarily mediated by mobilization of cyclin-dependent kinase inhibitors and 
suppression of c-Myc and in the absence of promitogenic gene mutations or other mitogenic 
stimuli, disruption of TGFβ signaling does not induce cell proliferation.  However, work of 
numerous investigators has revealed that mutations in TGFβ receptors or its signal transduction 
pathways, which abrogate the cytostatic activity of the growth factor in epithelial and 
hematopoietic cells, play a key role in tumor progression of many types of cancer [9].  
In addition, TGFβ has additional direct effects on tumor promotion by inducing 
epithelial-mesenchymal transformation (EMT), a morphologic and functional change for cancer 
cells.  Cancer cells which have undergone EMT are much more motile and invasive which leads 
to increased metastasis [10, 11]. 
In animal models, TGFβ has been implicated as a key regulator promoting the development of 
radiation-induced lung fibrosis.  In rodents, expression of TGFβ is induced after pulmonary 
irradiation and inhibition of TGFβ via monoclonal antibodies or small molecule inhibitors results 
in dramatically decreased development of fibrosis.  For example, in a study designed to 
determine if TGFβ neutralization ameliorates radiation-induced fibrosis in the lung, 
Fischer 344 rats were administered a single dose of 1D11 after receiving 5 fractionated doses of 
radiation.  Results demonstrated that a single dose of anti-TGFβ antibody significantly reduces 
inflammation, TGFβ activation and expression, and radiation-induced fibrosis [12].  Additionally, 
TGFβ inhibition has been show to radiosensitize various types of cancer cells.  For example, in 
studies involving syngeneic murine breast cancer and glioblastoma models TGFβ neutralization 
using a anti-TGFβ monoclonal antibody resulted in tumor growth delay [13, 14].  This suggests 
inhibition of TGFβ may be of therapeutic value in combination with radiotherapy. 
Description of Fresolimumab  
Fresolimumab is a fully human IgG4 kappa monoclonal antibody generated using recombinant 
technology in collaboration between Sanofi Genzyme Corporation and Cambridge Antibody 
Technology (Cambridge, UK).  Fresolimumab is capable of neutralizing all mammalian isoforms 
of TGFβ (ie, β1, β2, and β3).  Fresolimumab is a high-affinity antibody with dissociation 
constants (Kd) of 1.8 nM, 2.8 nM, and 1.4 nM for TGFβ1;  TGFβ 2, and TGFβ 3, respectively.  
Fresolimumab has entered clinical trials, including a recently completed multi-institutional 
phase 1 trial (NCI-06-C-0200) in patients with advanced malignant melanoma and renal cell 
cancer.  It is also being evaluated as an anti-fibrotic agent in patients with fibrotic conditions. 

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Previous clinical experience with Fresolimumab in Cancer Patients 
A first in human, single-dose multi-institutional phase 1 study of Fresolimumab was carried out 
in patients with idiopathic pulmonary fibrosis (clinicaltrials.gov: NCT00125385).  No drug-related 
serious adverse events (SAEs) were reported.  A single dose phase 1 trial of fresolimumab in 
patients with treatment resistant focal segmental glomerulosclerosis (clinical trials.gov: 
NCT00464321) has also been completed. 
A phase 1 multi-institution, dose-escalation trial of Fresolimumab in subjects with metastatic 
malignant melanoma and renal cell cancer was the lead institution was recently completed 
(NCI-06-C-0200). This protocol represented the first study of Fresolimumab in patients with 
cancer and the first to involve repeated doses of the antibody.  Cohorts of patients with 
advanced malignant melanoma and renal cell cancer that had failed at least 1 prior therapy 
were treated with intravenous Fresolimumab administered at 0.1, 0.3, 1, 3, 10 or 15 mg/kg in a 
3 + 3 dose-escalation design.  If no dose-limiting toxicity occurred within 28 days of the 
first dose (Day 0), 3 additional doses were administered 2 weeks apart (Days 28, 42 and 56).  
Patients achieving at least stable disease or better by RECIST criteria were eligible to receive 
Extended Treatment consisting of 4 doses of Fresolimumab at the highest dose level 
determined to be safe at the time every 2 weeks for up to 2 additional courses.  Twenty-two 
patients (21 with melanoma and one renal cell cancer patient) were treated in the initial 
dose-escalation component of the study and an additional 7 patients (all with malignant 
melanoma) were treated in a safety cohort expansion at the highest dose of 15 mg/kg.  
No dose-limiting toxicities were observed and the highest dose level of Fresolimumab, 
15 mg/kg, was determined to be safe.   
Evidence of clinical benefit (SD or better) was seen in 7 of 29 (24%) total patients enrolled in the 
study: PR (N = 1), SD (N = 3) and MR (N = 3).  Two of these 7 patients were determined to 
have met SD criteria per protocol but did not receive Extended Therapy. In the phase 1 study, 
for SD responses follow-up measurements had to meet the SD criteria at least once at a 
minimum interval of not less than 8 weeks.  The remaining 5 responses were observed in 
subjects receiving Fresolimumab at starting doses of 1 mg/kg or less.  Of these, 3 patients had 
mixed responses with shrinkage of metastases in the liver and at other sites, and one patient 
with skin disease achieved a PR with >89% reduction of target lesions lasting about one year.  
2.3 
Rationale 
Based on the clinical and preclinical data described above, we propose a prospective phase 1-2 
clinical trial that will test the hypothesis that TGFβ inhibition using fresolimumab will reduce the 
development of pulmonary fibrosis after SABR for early stage NSCLC.  Thousands of patients 
per year with early stage NSCLC are treated with SABR and all would benefit from the 
knowledge gained from this.  If successful, the addition of fresolimumab to SABR could increase 
the ease and speed with which local recurrence can be diagnosed, increasing the chance that 
additional local therapy could be used for salvage.  Additionally, proving that TGFβ inhibition 
can reduce or prevent radiation-induced fibrosis would serve as a proof-of-principle for applying 
this approach in other caner types where fibrosis is a significant side effect (eg, head and neck 
cancer, breast cancer, etc).  

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2.4 
Study Design 
Phase 1 component: 
Fresolimumab will be on Days 1, 15, and 36 and SABR will be administered at 
12.5 Gy/fraction in 4 fractions between Days 8 and 12 to a total of 5 patients who will be 
evaluated for safety, and additional patients will be enrolled if specific AE’s are 
observed.  A dose reduction may be implemented if excessive toxicity is observed.  
Blood would be collected for pharmacokinetic studies (only Phase 1).  This is a 
single-arm, open-label study 
Phase 2 component: 
Up to a total of 60 patients, including the Phase 1 portion.  Fresolimumab will be 
administered IV at the dose selected in the preceding Phase 1 (3 mg/Kg) component on 
Days 1, 15 (+ 6 days), and 36 (+/- 6 days) and SABR (-1/+5 days) will be administered at 
12.5 Gy/fraction in 4 fractions between Days 8 and 12. 
This is a single-arm, open-label study conducted under IND 125981 (Sponsor-
Investigator/ IND Holder: Maximilian Diehn, MD, PhD). 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion & Exclusion Criteria 
Inclusion Criteria: 
1. 
Newly diagnosed, histologically-proven T1-T2bN0M0 (Stage IA-IIA) NSCLC, with 
maximum tumor diameter ≤ 5 cm under consideration for stereotactic ablative body 
radiotherapy (SABR) as definitive primary treatment   
2. 
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 within 12 weeks 
3. 
ECOG PS 0 to 2 
4. 
Age greater than or equal to 18 years old and able to give informed consent 
5. 
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: 
1. 
Significant anemia (hemoglobin below 9.0 g/dL) or neutropenia (ANC < 1000/mm3) 
2. 
Prior history of multifocal adenocarcinoma in situ (ie, classic or pure bronchioloalveolar 
carcinoma)  
3. 
Prior history of keratoacanthoma (well-differentiated squamous cell skin cancer 
variant, often centrally ulcerated).  History of basal cell cancer is allowed.  
4. 
Pre-malignant skin lesion(s) noted on prescreening skin exam, except for actinic 
(solar) keratosis 
5. 
Prior radiotherapy overlapping with high dose region of planned SABR course 
6. 
Prior history of head and neck; oral; or bladder cancer  
7. 
Prior receipt of systemic treatment (chemotherapy, targeted therapy, or 
immunotherapy) for the lesion under consideration of treatment  
8. 
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  
9. 
Contraindication to receiving radiotherapy 

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10.  
Known allergy to components of fresolimumab 
11. 
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. 
3.2 
Informed Consent Process 
All participants will be provided with a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants will sign the IRB approved informed consent prior to participation in any study 
specific procedure.  The participant will receive a copy of the signed and dated consent 
document.  The original signed copy of the consent document will be retained in the medical 
record or research file.   
 
3.3 
Randomization Procedures 
Phase 1:  Single-arm, non-randomized  
Phase 2:  Single-arm, non-randomized 
3.4 
Study Timeline 
Estimated study length: 6 years consisting of 5 year(s) accrual + 1 year follow-up 
Primary Completion (for CT.gov): 
The study is expected to reach primary completion approximately 72 months from the time 
the study opens to accrual 
Study Completion: 
The study is expected to reach study completion approximately 72 months from the time the 
study opens to accrual.   Phase 1 is expected to be completed in approximately 18 months, 
and phase 2 in approximately 36 months 
4. 
TREATMENT PLAN 
4.1. Pre-treatment tests 
The following will be completed prior to treatment (for specifics see study calendar): 
a) Medical history and clinical examination, including a full skin exam by the investigators. 
b) Laboratory testing  
c) Baseline imaging- Acceptable to use simulation scans. 
d) Signed informed consent document. 
4.2. 
 Drug Therapy 
4.2.1 Fresolimumab Administration 
Fresolimumab will be administered IV at a dose of 3 mg/kg on Days 1, 15, and 36, with 
SABR (-1/+5 days) being administered at 12.5 Gy/fraction in 4 fractions between 
Days 8 and 12.  
 
 
 
 
Administration Schema:  

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Phase 1 (see study Schema, pg 9):
We will enroll 5 patients at 3 mg/kg of fresolimumab.
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:
1) Radiation pneumonitis, or
2) Bronchopulmonary hemorrhage 
Of the 5 patients, if none experience DLT, then 3 mg/kg will be the dose for the Phase 2
component. 
If one patient experiences DLT, an additional 5 patients will be enrolled at 3 mg/kg. If no 
more patients experiences DLT, then 3 mg/kg will be the dose for the Phase 2 component.  
If 2 or more patients experience 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.
At the lower dose (1 mg/kg), 5 more patients will be enrolled. If no more patients experience 
grade 3 or higher toxicity, then 1 mg/kg will be the dose for the Phase 2 component.
If one or more patients of 5 experience DLT at the reduced dose, the investigators will 
consider closing the study. 
Phase 2:
Fresolimumab will be administered IV at the dose determined from Phase 1 on Days 1, 15
(+ 6 days), and 36 (+/- 6 days), with SABR (-1/+5 days) being administered at 
12.5 Gy/fraction in 4 fractions between Days 8 and 12.
4.2.2 General Concomitant Medication and Supportive Care Guidelines
In general, concomitant medications and therapies deemed necessary for the supportive 
care and safety of the patient are allowed, provided their use is documented in the patient 
records. Patients must be instructed not to take additional medications including 
over-the-counter products and herbal/alternative medications during the study without prior 
consultation with the investigator.
Permitted treatments during the study include, but are not limited to the following:
•
Pain medication to allow the patient to be as comfortable as possible
•
Nutritional support or appetite stimulants (eg, megestrol)
•
Oxygen therapy and blood products or transfusions
The following concomitant treatments are not allowed during the study:
•
Concurrent use of other investigational drugs is not permitted.

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• 
The administration of other antineoplastic therapy (eg, chemotherapy, hormone therapy, 
immunotherapy, targeted therapy, and monoclonal antibodies) is not permitted.  
 
4.2.3 Duration of Therapy 
Patients will be seen on Days 1, 15, and 36 when they receive fresolimumab, and will be 
seen in follow-up at 3rd;  6th; 9th and 12th month from end of SABR completion (+/- 2 weeks).  
History and physical exam, ECOG PS, toxicity evaluation, CT Thorax (Chest) imaging, and 
labs will be evaluated at each of these visits.  Skin exams will be conducted at the 3rd month 
from end of SABR completion. PFTs will be completed at 6th and 12th month. PET/CT 
imaging will be evaluated at 6th month. The duration of the treatment phase of the study will 
be through the 1st follow-up visit, approximately 90 days after the SABR is completed.  
4.2.4 Duration of Follow-Up 
The follow-up portion of the study will begin approximately 90 days after SABR is completed 
through 12 months from enrollment.  Further follow-up information is on the study calendar.  
4.2.5 Criteria for Removal from Study 
Patients who develop the following conditions during the course of treatment will discontinue 
further planned study treatments (fresolimumab or SABR).  Long-term follow-up visits will 
still be performed as feasible unless patient completely withdraws consent (treatment and 
follow up). 
• 
Disease progression by RECIST or death 
• 
Unacceptable toxicity (Section 7.12) 
• 
Pregnancy 
• 
Patient request for no further treatment 
• 
Noncompliance 
• 
Lost to follow-up 
• 
Inability of subject to comply with study requirements 
• 
Any general or specific changes in the patient’s condition that render further treatment 
unacceptable in the judgment of the investigator 
4.2.6 Alternatives 
Alternative treatments include surgical resection, SABR alone, or no therapy. 
4.2.7 Compensation 
Patients will not be paid for their participation in the study.   
4.3. 
Procedures: SABR Administration and Radiation Treatment Planning  
4.3.1. 
Fiducials 
We may implant peri-tumoral metallic fiducial markers for image-guided tumor localization as 
needed, generally for lower lobe locations where the magnitude of tumor motion tends to be 
greatest.  The fiducials will be used as surrogates for targeting the daily tumor position during 
treatment.  The fiducials will be placed directly into the tumor and/or periphery under 
CT guidance.  Fiducials may be implanted prior to enrollment as this is a standard of care 
procedure for any patient receiving SABR for lung tumors. 
4.3.2. Simulation 
During radiotherapy simulation, customized immobilization devices will be formed for each 
patient, and 4-dimensional CT (4-D CT) will be acquired in the treatment position.  Acquisition of 
a PET-CT in the treatment position is encouraged but not required. 
4.3.3. Treatment planning 
The treating physicians will contour the gross tumor volume (GTV) on axial CT slices using lung 
windows for visualizing tumor/lung interfaces and mediastinal windows for tumor/soft tissue 

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interfaces, with the aid of fused PET.  No explicit expansion for microscopic extension will be 
added to form the clinical target volume (CTV), ie, CTV = GTV.  Breathing-induced tumor 
motion will be assessed using the 4-D CT data and managed by respiratory gating, dynamic 
tumor tracking, or motion-inclusive technique, and the internal target volume (ITV) will be 
designed accordingly.  A 0.5 cm setup margin will be added to the ITV to form the final planning 
target volume (PTV).  
Treatment will be delivered using 6 or 10 MV photons using a linear accelerator with daily 
kilovoltage (kV) X-ray portal imaging and/or daily cone-beam CT for anatomy-based matching.  
4.3.4. Dosimetry 
Treatment can be planned using forward or inverse planning.  In the case of the former, 
three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions.  For forward planned 3D 
conformal RT, when static beams are used, typically ≥ 10 (at least 7) non-opposing, 
non-coplanar beams of radiation will be used with roughly equal weighting.  Generally, more 
beams are used for larger lesion sizes.  Alternatively, dynamic conformal arcs (coplanar or 
non-coplanar) may be used.  In order to obtain acceptable coverage, field aperture size and 
shape should correspond nearly identically to the projection of the PTV along a beam’s eye view 
(ie, no additional “margin” for dose buildup at the edges of the blocks or MLC jaws beyond the 
PTV).  For inverse planning, volumetric modulated arc therapy or fixed beam IMRT will be 
performed.  In all cases, the treatment isocenter will be adjusted based on pre-treatment 
imaging.  
For purposes of dose planning and calculation of monitor units for actual treatment, this protocol 
will require tissue density heterogeneity corrections with algorithms that accurately model 
buildup and lateral electron scatter (eg, Monte Carlo, AAA, Acuros XB, 
superposition-convolution).  Simple pencil beam algorithms are not acceptable.  
4.3.5. Prescription dose constraints 
For all subjects, the decision of whether a treatment plan is acceptable will be made on a 
case-by-case basis by the treating radiation oncologist.  Successful treatment planning will 
require accomplishment of all of the following criteria:  
1.  Prescription dose: The prescription dose will be 50 Gray (Gy) in four 12.5 Gy fractions.  
2.  Maximum dose: The treatment plan should be created such that 100% corresponds to 
the prescription dose.  The maximum dose for the plan must be at least 110% and 
no more than 140% and this point must be located within the PTV and ideally within the 
GTV.  A maximum dose of 120 to 130% of the prescription dose centered in the GTV 
would be typical. 
3.  Planning Target Volume Coverage: 95% of the target volume (PTV) must be 
conformally covered by the prescription isodose surface (PTV V100%RX ≥ 95%) and 
99% of the target volume (PTV) receives a minimum of 90% of the prescription dose 
(PTV V90%RX > 99%). 
4.  High Dose Spillage: The cumulative volume of all tissue outside the PTV receiving a 
dose > 105% of prescription dose should be no more than 15% of the PTV volume.  The 
ratio of the volume receiving greater than or equal to the prescription dose to the PTV 
volume should ideally be < 1.2 (see table below).  These will not be required to be met in 
treating small tumors (< 2.5 cm axial GTV dimension or < 1.5 cm craniocaudal GTV 
dimension) in which the required minimum field size of 3.5 cm results in the inability to 
meet a conformality ratio of 1.2. 

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5.  Intermediate Dose Spillage: The falloff gradient beyond the PTV extending into normal 
tissue structures must be rapid in all directions and meet the following criteria: 
a. Location: The maximum total dose over all fractions in Gy to any point 
2 cm or greater away from the PTV in any direction must be no greater than is given 
by the table below.  
b. Volume: The ratio of the volume of 50% of the prescription dose isodose to the 
volume of the PTV must be no greater than is given in the table below. 
PTV 
(cc) 
Rx isodose vol / 
PTV 
50% Rx isodose vol 
/ PTV 
Maximum dose (% of Rx)  
@ 2 cm from PTV 
Deviation 
Deviation 
Deviation 
None 
Minor 
None 
Minor 
None 
Minor 
1.8 
< 1.2 
< 1.5 
< 5.9 
< 7.5 
< 50.0 
< 57.0 
3.8 
< 1.2 
< 1.5 
< 5.5 
< 6.5 
< 50.0 
< 57.0 
7.4 
< 1.2 
< 1.5 
< 5.1 
< 6.0 
< 50.0 
< 58.0 
13.2 
< 1.2 
< 1.5 
< 4.7 
< 5.8 
< 50.0 
< 58.0 
22 
< 1.2 
< 1.5 
< 4.5 
< 5.5 
< 54.0 
< 63.0 
34 
< 1.2 
< 1.5 
< 4.3 
< 5.3 
< 58.0 
< 68.0 
50 
< 1.2 
< 1.5 
< 4.0 
< 5.0 
< 62.0 
< 77.0 
70 
< 1.2 
< 1.5 
< 3.5 
< 4.8 
< 66.0 
< 86.0 
95 
< 1.2 
< 1.5 
< 3.3 
< 4.4 
< 70.0 
< 89.0 
126 
< 1.2 
< 1.5 
< 3.1 
< 4.0 
< 73.0 
< 91.0 
163 
< 1.2 
< 1.5 
< 2.9 
< 3.7 
< 77.0 
< 94.0 
Note:  Use interpolation if volume of PTV falls between table entries 
4.3.6. Prescription dose constraint tables 
The following tables list dose constraints to critical structures based on the number of fractions 
prescribed. Exceeding these dose limits by more than 5% constitutes an unacceptable protocol 
deviation. 
Critical structures with absolute volume and absolute point dose limits: Exceeding any of 
these limits constitutes a major protocol violation. 
Critical structure 
Volume dose limits (4 fractions) 
Maximum Point dose 
limit (< 0.035 mL) 
 
Dose 
Volume 
Dose 
Spinal cord 
20.8 Gy 
13.6 Gy 
< 0.35 mL 
< 1.2 mL 
26 Gy 
Brachial plexus 
23.6 Gy 
< 3 mL 
27.2 Gy 
Skin 
33.2 Gy 
< 10 mL 
36 Gy 
Lungs-GTV 
12.4 Gy 
11.6 Gy 
20 Gy 
< 1000 mL 
< 1500 mL 
< 10% (require < 15%) 
NA 
Stomach 
17.6 Gy 
< 10 mL 
27.2 Gy 
Small bowel* 
17.6 Gy 
12 Gy 
< 5 cc 
< 10 cc 
27.2 Gy 
* Avoid circumferential radiation 
 
Critical structures with relative volume and absolute point dose limits: The volume dose 
limits are suggested limits for these structures.  Exceeding these limits is not a protocol 
violation.  The recommended maximum point dose limits are also suggested limits that may not 

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be met.  However, exceeding any of the required maximum point dose limits constitutes a major 
violation.  Critical structure maximum doses may exceed the prescription dose as described 
below only when the PTV abuts or overlaps the structure.  
 
Critical 
structure 
Volume dose limits 
(4 fractions) 
Maximum point dose limit (<0.035 mL) 
 
Dose 
Volume 
Recommended 
Required 
Esophagus* 
18.8 
Gy 
< 5 mL 
30 Gy 
105% of PTV 
prescription dose 
Heart/pericardium 
28 Gy 
< 15 mL 
30 Gy 
105% of PTV 
prescription dose 
Great vessels* 
43 Gy 
< 10 mL 
49 Gy 
105% of PTV 
prescription dose 
Trachea and 
ipsilateral 
bronchus* 
15.6 
Gy 
< 4 mL 
34.8 Gy 
105% of PTV 
prescription dose 
Chest wall# 
33.6 
Gy 
< 10cc (< 30cc required) 
NA 
105% of PTV 
prescription dose 
Liver 
19.2 
Gy 
< 700 mL 
NA 
105% of PTV 
prescription dose 
* 
Avoid circumferential radiation 
# 
Chest wall limits (including “required” maximum point dose limit) may be exceeded for an 
otherwise excellent plan.  This will not be considered a violation. 
5. 
INVESTIGATIONAL AGENT INFORMATION:  Fresolimumab 
5.1 
 Description/Mechanism of Action   
Fresolimumab is an engineered human IgG4 kappa monoclonal antibody capable of neutralizing 
all mammalian isoforms of TGFβ (ie, TGFβ1;  TGFβ2;  and TGFβ3).  Fresolimumab is a 
high-affinity antibody. 
The structural formula for fresolimumab is depicted below: 
 
5.2 
Pharmacokinetics 
The pharmacokinetics of fresolimumab have been characterized in patients with advanced 
malignant melanoma and RCC, IPF, and FSGS in Phase 1 trials following single and multiple IV 
doses ranging from 0.1 mg/kg to 15 mg/kg.  Toxicology studies at doses of 0.1 to 50 mg/kg 
have been conducted in non-human primates and generally have had exposures 10-fold lower 
than the exposure levels seen with the corresponding dose in humans. 

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Dose-normalized values of Cmax were approximately similar among dose groups, regardless of 
patient disease.  Fresolimumab clearance showed no obvious dose-dependent trend, 
suggesting that the target antigen was not saturated in the studied dose range.  The overall 
terminal elimination half-life is approximately 2 to 3 weeks. 
Serum concentrations of fresolimumab from the phase 1 studies were pooled and analyzed 
using a non-linear mixed-effects modeling procedure.  The PK of fresolimumab was best 
described using a 2-compartment open model with first-order elimination from the central 
compartment.  The evaluation of covariate effects showed an effect of weight as the most 
important covariate using a full allometric model.  Over the range of body weights of 
50 to 100 kg, the typical value of clearance changed by no more than 30%.  There was no 
difference in the PK behavior of fresolimumab based on patient disease.  No other covariates 
were identified as being predictive of PK variability. 
5.3 
How Supplied/Storage 
Fresolimumab is supplied as a sterile lyophilized powder intended to be reconstituted with 
5.1 mL of sterile Water for Injection (sWFI).  The composition of the lyophilized powder is listed 
below: 
 
Prior to administration, lyophilized fresolimumab will be reconstituted with 5.1 mL (50 mg vial) of 
sWFI to result in a protein concentration of approximately 10 mg/mL in a 50 mM sodium 
phosphate buffer at pH 7.1, containing 25 mM sodium chloride, 3% mannitol, 1% sucrose, and 
0.01% polysorbate 80.  Filter needles must not be used to remove reconstituted drug product 
from the vial.  However, due to the nature of proteins and their ability to precipitate, the use of a 
0.22 μm low protein binding inline filter is required when administering this product (diluted as a 
solution for infusion).  The composition of reconstituted fresolimumab is listed below: 

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The lyophilized product is stored in clear glass vials of 5 mL capacity (nominal), which meet the 
USP standard for Type I glass, closed by a siliconized butyl rubber stopper. 
Fresolimumab vials must be stored at 2 to 8°C or 35.6 to 46.4°F until preparation for infusion.  
Reconstituted fresolimumab is stable for up to 24 hours after reconstitution with sWFI at either 
room temperature or under refrigeration (between 2 to 8°C or 35.6 to 46.4°F).  Although stable 
for up to 24 hours under these conditions, fresolimumab in sWFI should be used immediately.  
Reconstituted fresolimumab in sWFI that is further diluted in dextrose 5% in water at a 
concentration of 0.3 mg/mL to 7 mg/mL is stable for up to 24 hours at room temperature. 
Infusion bag should be administered over 30 mins using an intravenous infusion pump (through 
inline 0.22 micron low protein binding filter). Fresolimumab should not be infused in the same 
intravenous line with other products.  
 
5.4 
Manufacture 
To produce the antibody in sufficient quantities for clinical use, a mammalian cell line (derived 
from a murine myeloma) was constructed using the human deoxyribonucleic acid sequences for 
the anti-TGFβ antibody, selected by phage display technology, and the human IgG4 constant 
domains. This cell line enables manufacture of the human protein in large-scale fermenters.  
The protein is purified, filled into glass vials, and lyophilized. 
All reasonable care is taken during production to maintain product quality and integrity. The 
purification process (including 3 chromatography columns with different mechanisms for 
removal of contaminants, a low pH virus inactivation step and a virus retentive nano-filtration 
step) provides for the clearance of process-derived impurities and potential microbiological 
contaminants resulting in low impurity levels. Virus clearance studies have shown that the 
process is capable of clearing enveloped and nonenveloped viruses (murine leukemia virus and 
minute virus of mice). Purified drug substance, formulated bulk drug, and finished drug product 
fresolimumab are tested for identity, purity, potency, and stability against a set of release 
specifications that ensure that the product is suitable for parenteral use in the clinic. 
5.5 
Adverse Reactions 
Clinical experience with fresolimumab is limited.  Experience in the Phase 1 single-dose IPF 
study, the Phase 1 single-dose FSGS study, and the Phase 1 multiple-dose oncology study 
have demonstrated that fresolimumab is well tolerated at single doses up to 8 mg/kg in patients 
with IPF, at single doses up to 4 mg/kg in patients with FSGS, and at multiple doses up to 15 

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mg/kg in patients with advanced melanoma or renal cell carcinoma (RCC).  No dose limiting 
toxicities or acute infusion-associated events suggestive of cytokine release or hypersensitivity 
have been reported, although infusion reaction could still occur. 
5.6 
Contraindication 
There are no established contraindications to fresolimumab. 
6. 
DOSE MODIFICATIONS 
There will be no adjustments in radiation dose.  In the event a patient develops DLT prior to 
completion of SABR, efforts will be made to finish the remaining dose of radiation once the 
patient recovers adequately. 
Regarding fresolimumab, dose will be either administered on a given day or withheld.  If a 
patient develops dose limiting toxicity that has not resolved by Day 15 and/or 36, fresolimumab 
dose will be skipped for that dose number. 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
7.1.1.  Radiation 
The most common adverse events associated with SABR treatment are esophagitis, 
pneumonitis, and pulmonary fibrosis.  The complete list of known adverse events associated 
with SABR treatment is as follows: 
• Cardiac Disorders 
- Pericardial effusion 
- Pericarditis 
- Restrictive cardiomyopathy 
• Gastrointestinal Disorders 
- Dysphagia 
- Esophagitis 
- Esophageal fistula 
- Esophageal obstruction 
- Esophageal perforation 
- Esophageal stenosis 
- Esophageal ulcer 
- Esophageal hemorrhage 
• Injury, Poisoning, and Procedural Complications 
- Fracture (to be limited to rib fractures only) 
• Nervous System Disorders 
- Brachial plexopathy 
- Recurrent laryngeal nerve palsy 
- Myelitis 
• Respiratory, Thoracic, and Mediastinal Disorders 
- Atelectasis  
- Bronchopulmonary hemorrhage 
- Mediastinal hemorrhage 
- Pleural hemorrhage 
- Tracheal hemorrhage 
- Bronchial fistula 
- Pulmonary fistula 
- Bronchopleural fistula 
- Tracheal fistula 

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- Hypoxia  
- Bronchial obstruction 
- Tracheal obstruction 
- Pleural effusion 
- Pneumonitis 
- Pulmonary fibrosis 
• Skin and Subcutaneous Disorders 
- Skin ulceration (thorax only) 
7.1.2  Fresolimumab 
Clinical experience with fresolimumab is limited.  Most common adverse reactions reported from 
previous studies include fatigue, peripheral edema, nasopharyngitis, pustular rash, headache, 
bronchitis, diarrhea, and dyspnea.   
7.1.2.1 Skin 
Based on the clinical experience to date, the main epithelial adverse reaction to 
fresolimumab appears to be adverse events involving the skin, most notably 
keratoacanthoma and squamous cell carcinoma.  The development of these lesions 
appears to be related to both dose and duration of exposure.  Because of this potential 
risk, skin exams, evaluating for treatment emergent lesions such as KA and drug 
reactions should be performed in all patients receiving fresolimumab.  Patients who 
develop concerning treatment-emergent skin lesions should be referred to a 
dermatologic oncologist or dermatologist for evaluation within 2 weeks of reported 
symptoms. 
 
7.1.2.2 Acceleration of Neoplasia 
Available literature suggests neutralization of TGFβ does not cause de novo 
malignancies.  In advanced cancers, TGFβ neutralization may ameliorate cancer 
progression; however, in certain settings such as in the presence of premalignant 
lesions, it is possible that neutralization of TGFβ may contribute to 
premalignant/malignant transformation.  Long-term studies to investigate any 
carcinogenic or mutagenic effects of fresolimumab have not been conducted.  Patients 
receiving fresolimumab should be carefully monitored for the development of 
malignancies. 
7.1.2.3 Bleeding and Anemia 
Across the clinical studies, the majority of bleeding adverse events reported have been 
mild, self-limited events of gum bleeding without associated gingival lesions and nose 
bleeding without discrete nasal lesions.  Anemia in the absence of bleeding was seen in 
some patients in all of the phase 1 studies, but in the majority of cases was considered 
unrelated to study drug and could be explained by underlying diseases. 
Patients should be carefully monitored for the development of anemia and bleeding 
while receiving fresolimumab. 
7.1.2.4 Mouth Sores 
A small number of patients treated with fresolimumab have experienced mouth or gum 
sores.  Most of the sores were mild in nature.  Patients should be examined for mouth 
sores while taking fresolimumab.  
7.1.2.5 Immune Modulation 
No evidence of significant immune dysregulation has been seen in clinical studies to 
date.  Herpes Zoster, transient vitiligo, and hypopigmentation of the skin and/or hair 
have been reported before. 

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7.1.2.6 Reproductive Function 
The effects of fresolimumab on male and female reproductive function and/or fetal 
growth and development have not been investigated in formal toxicity studies.  
Fresolimumab is an antibody and is expected to be able to cross the placenta and enter 
the fetal circulation during pregnancy.  The effects of fresolimumab in this situation are 
unknown.  Pregnant or lactating women are excluded from clinical studies of 
fresolimumab.  Women who become pregnant or start lactating during the study will be 
discontinued from study treatment.  Sexually-active men or sexually active women of 
childbearing potential (last menstrual period within the previous 12 months and not 
surgically sterile) must use contraception or abstinence when being treated with 
fresolimumab. 
7.1.2.7 Overdose 
Animal studies have not clearly identified any acute dose related toxic effects. In the 
event of fresolimumab overdose, the administration should be immediately discontinued 
and appropriate precautions should be taken. 
7.2 Definition of an Adverse Event 
In the event of an adverse event the first concern will be for the safety of the subject.   
An adverse event is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless of whether it is 
considered related to the medical treatment or procedure (attribution of unrelated, unlikely, 
possible, probable, or definite).   
Changes resulting from normal growth and development which do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse experiences.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children, and onset of menses or menopause occurring at a physiologically appropriate time. 
If disease progression is noted during a protocol-specified reevaluation of the status of a 
patient’s cancer, and the progression is manifested solely by results of tumor markers and/or 
radiologic imaging, that occurrence of progressive disease will NOT be recorded as an adverse 
experience.  Progression of disease is not considered an adverse experience unless it results in 
hospitalization or death. 
7.3 Reporting Adverse Events 
Adverse events will be graded according to CTCAE v4. Adverse Events will be clearly noted in 
source documentation and listed on study specific Case Report Forms (CRFs).  The Protocol 
Director (PD) or designee will assess each Adverse Event (AE) to determine whether it is 
unexpected according to the Informed Consent, Protocol Document, or Investigator’s Brochure, 
and related to the investigation.  All AEs will be collected from signing of informed consent 
through 30 days after last study treatment.  Prior to Day 1, only Serious Adverse Events (SAEs, 
see below) deemed related to study procedures need to be collected.  All SAEs will be tracked 
until resolution, or until 30 after the last dose of the study treatment.  
Each occurrence of a given adverse event will be recorded.  Use of steroid as treatment for 
adverse event will be recorded.  Only the most severe grade over the course of a given episode 
will be recorded. 
Laboratory events defined as worsening of the laboratory value by one CTCAE v4 (Common 
Terminology Criteria for Adverse Events, version 4) grade or more from baseline value that 
meet the regulatory criteria for a serious adverse event (SAE) will be reported. 

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Note:  All deaths due to any cause must be reported immediately (within 24 hours) to Sanofi 
Genzyme. 
7.4 Definition of a Serious Adverse Event 
A serious adverse experience is any event which is fatal, life threatening, disabling, or 
incapacitating or results in hospitalization, prolongs a hospital stay or is associated with 
congenital abnormality.  In addition, any experience which the investigator regards as serious or 
which would suggest any significant hazard, contraindication, side effect or precaution that may 
be associated with the use of the drug should be reported as a serious adverse event.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
Life threatening definition: 
An adverse event is life threatening if the patient was at immediate risk of death from the event 
as it occurred (ie, it does not include a reaction that if it had occurred in a more serious form 
might have caused death).  For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life threatening even though drug-induced hepatitis 
could be fatal. 
Disability/incapacitating definition: 
An adverse experience is incapacitating or disabling if the experience results in a substantial 
and/or permanent disruption of the patient's ability to carry out normal life functions.  
Hospitalization definition: 
An adverse event that results in emergency department admission greater than 24 hours or 
requires general in-patient hospitalization.  Hospitalization for elective treatment of a 
pre-existing condition that did not worsen from baseline is not considered an AE. 
7.5 Immediate Reporting of Serious Adverse Events 
 Attribution of Adverse Events:  
Code  Attribution  
Definition  
1  
Unrelated  
The Adverse Event is clearly not related to the investigational agent(s)  
2  
Unlikely  
The Adverse Event is doubtfully related to the investigational agent(s)  
3  
Possible  
The Adverse Event may be related to the investigational agent(s)  
4  
Probable  
The Adverse Event is likely related to the investigational agent(s)  
5  
Definite  
The Adverse Event is clearly related to the investigational agent(s)  
All subjects/patients with serious adverse experiences must be followed up for outcome. 
All adverse events are serious and unexpected suspected adverse reactions, ie, serious and 
unexpected adverse events that are possibly, probably, or definitely related to the study drug 
fresolimumab, will be reported to the FDA via IND Safety Report [21CFR§312.32] within 
14 calendar days, or within 7 calendar days if the event is an unexpected fatal or life-threatening 
suspected adverse reaction.  
Any serious adverse experience, including death due to any cause, pregnancy, which occurs to 
any subject/patient treated on study or within 30 days following cessation of treatment, whether 
or not related to the investigational product, must be reported to Sanofi Genzyme and the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) within 2 working days. 
Additionally, any serious adverse experience considered by an investigator who is a qualified 
physician to be possibly, probably, or definitely related to the investigational product that is 

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brought to the attention of the investigator at any time outside of the time period specified in the 
previous paragraph also must be reported immediately.  
In addition, any SAEs which occur as a result of protocol specific diagnostic procedures or 
interventions must also be reported. 
The above should be reported to Stanford DSMC using the study specific case report form 
(CRF) regardless of the event’s relatedness to the investigation. Following review by the DSMC, 
events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the IRB using 
eProtocol within 10 working days of DSMC review, or within 5 working days for deaths or 
life-threatening experiences. 
Attribution of SAE to study drug should follow the standard attribution and grading system as 
specified by CTEP (http://ctep.cancer.gov/reporting/adeers.html, see table below).  
7.6 Special Considerations 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse or transmission 
of an infectious agent via a medicinal product.  
Serious adverse events occurring after a patient is discontinued from the study will NOT be 
reported unless the investigator feels that the event may have been caused by the study drug or 
a protocol procedure.  Study-specific clinical outcomes of death because of disease progression 
are exempt from serious adverse event reporting, unless the investigator deems them related to 
use of the study drug.  Hospitalization for study drug administration is not a serious adverse 
event. 
In general, serious adverse events assessed as clearly being due to disease progression and 
not due to study drug(s) should be excluded from adverse event reporting. However, in cases 
where the specificity or severity of an event is not consistent with the risk information, the event 
should be reported. 
7.7 Definition of Reportable Information 
In addition to the above events, the following information should be reported to Sanofi Genzyme 
and the Stanford DSMC:  
1. New information that indicates a change to the risks or potential benefits of the research, 
in terms of severity or frequency. 
2.  Complaints that are unresolved by the research team, or that indicate increased or 
unexpected risks. 
3.  Unanticipated adverse device effect.  New information about the effect on health or 
safety. 
7.8 Definition of an Unanticipated Problem    
Unanticipated problems involving risks to participants or others (UPs) are events (including 
internal or external events, death, life-threatening experiences, injuries, breaches of 
confidentiality, or other problems) that occur any time during or after the research study, which 
in the opinion of the PD are:  
1. Unexpected - not in the consent form, protocol, package insert, or label; or unexpected 
in its frequency, severity, or specificity, AND 

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2. Related to the research procedures – caused by, or probably caused by research 
activity, or, if a device is involved, probably caused by, or associated with the device, 
AND 
3. Harmful – caused harm to participants or others, or placed them at increased risk of 
harm (including physical, psychological, economic, or social harm). 
7.9 Reporting of Pregnancy 
If a patient or their partner inadvertently becomes pregnant while on treatment with 
fresolimumab, the patient will immediately be removed from the study. The site will contact the 
patient at least monthly and document the patient’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Sanofi Genzyme 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  If a male patient’s partner becomes pregnant on study, the pregnancy must be 
reported to Sanofi Genzyme.  The study investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn to 
Sanofi Genzyme.  
7.10 
Definition of an Overdose for This Protocol 
Overdose is defined as any dose more than 25% above the prescribed dose described in the 
study protocol. 
7.11 
Reporting of Overdose to Sanofi Genzyme 
If an adverse experience(s) is associated with (“results from”) the overdose of test drug, the 
adverse experience(s) is reported as a serious adverse experience, even if no other criteria for 
serious are met. 
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse experience must be reported within 
24 hours to Sanofi Genzyme. 
7.12 
Stopping Rules  
Crude rates of grade 3 or higher radiation pneumonitis or bronchopulmonary hemorrhage will be 
evaluated after 25 patients have finished treatment and completed 6 months of follow up. If a 
crude rate of >20% is observed, the study will be suspended to evaluate the likelihood of these 
toxicities being caused by the combination treatment and to decide whether to allow accrual of 
another test cohort. If a crude rate of ≤ 20% is observed, the study will proceed to primary 
completion. 
 
All outcome data (toxicity and efficacy) will be reviewed every 6 months by the Principal 
Investigators and key Co-Investigators.  This study will be monitored by the Stanford DSMC.  
All potential adverse events will be reported to the thoracic disease management group and the 
DSMC.  The study will terminate when the target accrual is met and all data are analyzed.   
Comprehensive Safety Review  
The rate of NSCLC recurrence will be continuously evaluated for the 1st 10 subjects through 
6 months follow-up.  In the event that there are ≥ 3 NSCLC recurrences in the first 10 subjects, 
enrollment will be paused, and a comprehensive safety review will be conducted, which will 
include the Stanford Cancer Institute Data Safety Monitoring Committee (DSMC).  If, 

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after review, the DSMC recommends proceeding with the study, the report of the safety review 
will be submitted to the IND, and FDA’s concurrence will be sought before proceeding with 
enrollment.   
Similarly, development of new malignancies will be monitored for the first 10 patients through 
the 6 month follow-up time point [except keratoacanthomas / squamous cell carcinomas (SCC) 
of the skin].  Keratoacanthomas and SCC are not included because these are known events 
that regress after discontinuation of fresolimumab therapy, per the Investigator’s Brochure.  
These lesions will be referred to a dermatologic oncologist or dermatologist for evaluation, 
treatment, and monitoring, but will not be tabulated towards the criteria for enrollment pause.  
New malignancies are expected to be rare, and if more than 2 subjects develop new 
malignancies, enrollment would be similarly paused for a comprehensive safety review as 
above.  
7.13  Confidentiality 
Study data will be maintained in protected patient binders.  Only research personnel listed on 
this protocol will have access to this information.  Only the patients unique IDN will be used.  
Specimens will be stored under the patient’s IDN.   
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 Pharmacokinetic Analyses 
Serum samples will be collected before and within 4 hours post each dose of fresolimumab for 
PK studies.  Instructions for collection are as follows: 
Group 
Name(s) 
Container(s) 
Collection Instructions 
 
SM/ GC1008 
Pre-infusion 
PK 
1- 5mL gold top 
serum 
separation tube 
 
1- 7mL clear 
cryovial 
One 5mL gold top serum separation tube.  Collect 5mL 
blood into the Serum Separator tube.  Fill tube completely. 
It is important to thoroughly mix the blood with the 
clotting activation agent by inverting the tube not less 
than five times.  Allow blood to clot for 30 minutes (tube 
standing upright).  Use pipette provided to transfer all of the 
serum into the appropriately labeled tubes.  Freeze 
immediately at -70ºC until shipment. Keep all samples 
frozen until ready to ship.  Ship frozen to Covance CLS 
Day of Collection 
 
SM/ GC1008 
Post-infusion 
PK 
1- 5mL gold 
top serum 
separation tube 
per timepoint 
 
1- 7mL clear 
cryovial per 
timepoint 
One 5mL gold top serum separation tube.  Collect 5mL 
blood into the Serum Separator tube.  Fill tube 
completely. It is important to thoroughly mix the 
blood with the clotting activation agent by inverting 
the tube not less than five times.  Allow blood to clot for 
30 minutes (tube standing upright).  Use pipette provided 
to transfer all of the serum into the appropriately labeled 
tube. Freeze immediately at -70ºC until shipment. Keep 
all samples frozen until ready to ship.  Ship frozen to 
Covance CLS Day of Collection 
 
8.2 Coding of specimens for privacy protection  
At the time of enrollment each patient will be given a specific confidential identification number 
(IDN). Specimens will be stored under the patient’s IDN. The information can be shared with 
other investigators listed on this protocol. Study data will be maintained in password protected 

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computer files (protected online database). Only research personnel will have access to this 
information. 

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9. 
STUDY CALENDAR 
Parameters 
Pre-Entry6 Day 1 Day 8-124 Day 157 Day 36 8 3 month 
9,10 
6 month10 9 month10 12 month 10 
History & Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
Complete skin exam 1 
X 
 
 
 
 
X 
 
 
 
ECOG PS 
X 
X 
 
X 
X 
X 
X 
X 
X 
Labs 2 
X 
X 
 
X 
X 
X 
X 
X 
X 
CT Thorax (Chest) 
X11 
 
 
 
 
X 
X 
X 
X 
PET/CT 
X11 
 
 
 
 
 
X 
 
 
Toxicity evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
PFT 3 
X 
 
 
 
 
 
X 
 
X 
SABR 4 
 
 
X 
 
 
 
 
 
 
Fresolimumab 5 
 
X 
 
X 
X 
 
 
 
 
1 To be performed by the investigators.  Suspect lesions will be referred for further evaluation to a dermatologic oncologist or dermatologist as 
appropriate  
2 Includes CBC with differential and complete metabolic panel.  Also urine or serum pregnancy test required for women of childbearing potential at 
pre-entry only 
3 Including DLCO, FEV1, and FVC 
4 12.5 Gy/fraction in 4 fractions between Days 8 to 12.  Minus 1 to + up to 5 days to allow for weekends and holidays and unforeseen 
circumstances. 
5 3 mg/kg IV (or other determined dose from Phase 1) given on days 1, 15, and 36  
6 All pre-entry assessment should be obtained within 4 weeks of enrollment  
7 3 days after completion of SABR, + up to 6 more days to allow for weekends and holidays and unforeseen circumstances 
8 Target 21 days after dose 2 of fresolimumab.  +/- 6 days to allow for weekends and holidays and unforeseen circumstances 
9 Needs to be at least 90 days after completion of SABR for safety analysis 
10  +/- 2 weeks to allow for weekends and holidays and unforeseen circumstances.  Date counted from completion of SABR.  
11 Acceptable to use non-diagnostic simulation planning scans for baseline imaging 
 
 
 
 

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10. 
MEASUREMENT OF ENDPOINT 
10.1 Scoring of post-SABR radiologic changes 
The extent of SABR-induced radiologic changes will be scored at each follow-up scan.  Scoring 
of radiologic changes will be performed by at least two radiologists or radiation oncologists 
dedicated to the study, who will be blinded to the treatments the patients receive. Scores will be 
assigned by consensus. 
Assessment of fibrosis will be performed based on three previously-published scales by Dahele, 
et al. [15]  In the phase 2 component of the study, the severity score of fibrosis in study subjects 
will be compared to historical controls.  Historical controls will consist of patients 
previously-treated with the same dose of SABR (50 Gy in four fractions) at Stanford in the 
absence of fresolimumab. 
 
Late Radiation Fibrosis Score (Pattern):  
Late CT changes will be defined as occurring at 12 months after enrollment and will consist of:  
1) “Modified conventional pattern” of fibrosis characterized by consolidation, volume loss, 
and bronchiectasis with or without GGO,  
2) Mass-like fibrosis characterized by a well-circumscribed focal consolidation limited to the 
tumor region but which is larger than the original tumor,  
3) “Scar-like fibrosis” consisting of a linear opacity in the tumor region with associated 
volume loss, or  
4) “No evidence of increasing density” including stable or regressing mass at the location of 
the treated tumor with no or minimal GGO or only normal appearing lung tissue.   
 
Acute Radiation Fibrosis Score (Pattern):  
The categories of acute findings (occurring in the first 6 months after enrollment) will be:  
1)  Diffuse consolidation,  
2)  Patchy consolidation,  
3)  Diffuse ground-glass opacities (GGOs),  
4)  Patchy GGO, or  
5)  No evidence of increasing density.  The term “diffuse” will apply to abnormalities that are 
at least 5 cm in maximum diameter and which contain more than 50% abnormal lung.  
Abnormalities not meeting these criteria will be termed “patchy”. 
Severity Score: 
We will assign an overall severity score of radiographic fibrosis at 6 and 12 months after 
enrollment using the categories:  
1)  “Severe” (much more extensive than usually seen after SABR),  
2)  “Moderate” (changes that are commonly seen after SABR),  
3)  “Mild”/“minor” (unusually slight changes compared to what is normally observed after 
SABR), or  
4)  “None.” 
“Presence of moderate-to-severe fibrosis” at 12 months will be defined as severity fibrosis 
scores 1 or 2 (ie, “Severe” or “Moderate”) .  This will serve as the primary endpoint for Phase 2. 
Pattern and severity of fibrosis at 6 months and pattern of fibrosis at 12 months will be 
evaluated as secondary endpoints for both Phase 1 and 2 of the study. 
Patients who are lost to follow-up and who do not have a scan within +/-6 months of the 12-
month time point will be excluded from analysis. Patients who develop inflammatory lung 
conditions unrelated to radiotherapy (i.e. pneumonia, ARDS, drug-induced pneumonitis, etc.) 

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will be excluded from the final endpoint analysis if the area of unrelated inflammation impedes 
scoring of fibrosis severity of the irradiated lesion. 
Quantitative image analyses: 
Finally, we will explore quantitative image analysis metrics for evaluating radiation fibrosis. This 
will include analyses such as contouring the region of fibrosis and quantifying its volume relative 
to the total lung volume and/or the original dose distribution.  Similarly, FDG-uptake metrics will 
be examined on the follow-up PET/CT. 
10.2 Additional Secondary Endpoints 
Patients will be evaluated for anti-tumor effect by follow-up imaging (lung protocol CT and/or 
PET-CT imaging) as outlined above.  Lung protocol CT scans (biphasic imaging, 1.25 mm cuts) 
and/or FDG PET-CT scans will be obtained at all follow-up intervals as described in the 
treatment calendar.  All subsequent scans (post-treatment) will be compared to the same 
pretreatment CT or PET/CT that was used in conjunction with radiation treatment planning.  
Patients will be evaluated for objective response at the follow-up intervals specified above. 
Response to SBRT will be assessed and reported according to RECIST Version 1.1 criteria. 
Evaluation of Target Lesions (Primary Tumor) 
Complete Response (CR):  Disappearance of target lesion.  
Partial Response (PR) :  t least a 30% decrease in the diameter of target lesion, taking 
as reference the baseline diameter. 
Progressive Disease (PD) :  At least a 20% increase in the diameter of the target 
lesion, taking as reference the smallest diameter on study (this includes the baseline 
diameter if that is the smallest on study). In addition to the relative increase of 20%, the 
diameter must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression).   
Stable Disease (SD) :  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest diameter while on study.   
Failure will be documented by biopsy when possible and otherwise will be defined as radiologic 
progression on CT and/or PET/CT that leads to a change in management, including institution 
of systemic or local anti-cancer therapy.  Failures will be categorized as follows: 
Type of Recurrence 
Description (after SABR treatment effects have subsided) 
Local Failure 
Primary tumor failure (PTF) Appearance of residual tumor located within the extent of the 
primary targeted tumor. 
Marginal failure (MF) 
Appearance of tumor ≤ 2 cm in any direction of the primary tumor 
or structures immediately adjacent to the primary tumor (lung/chest 
wall, mediastinum/diaphragm/spine). 
Involved lobe failure (ILF) 
Appearance of tumor > 2 cm in any direction of the primary tumor. 
Regional Failure 
Non-primary lobe failure 
(NLF) 
Appearance of tumor within another ipsilateral (non-primary) lobe. 

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Type of Recurrence 
Description (after SABR treatment effects have subsided) 
Hilar node failure (HNF) 
Appearance of tumor in ipsilateral hilar lymph nodes. 
Ipsilateral mediastinal 
nodal failure (MNF) 
Appearance of tumor in ipsilateral mediastinal and/or subcarinal 
lymph nodes. 
Distant Failure 
Distant nodal failure (DNF) 
Appearance of tumor in ipsilateral supraclavicular or contralateral 
lymph nodes. 
Distant metastatic failure 
(DMF) 
Appearance of tumor deposits characteristic of NSCLC metastasis 
(chest wall other than incision sites or immediately adjacent to 
primary, mediastinal structures/diaphragm, malignant pleural 
effusion/pericardial effusion), contralateral lung and/or other distant 
sites. 
Potential adverse events will be monitored by treating physicians at each follow-up visit, and 
scored using CTCAE v4 with type and grade.  
Post-treatment changes in pulmonary function will be evaluated by changes in pulmonary 
function test at enrollment, 6-month, and 12-month follow-up.  
Recurrence rate is determined by time from study enrollment to first documented date of 
recurrence.  
Progression-free survival (PFS) is time from time from study enrollment until the first 
documented date of disease progression.  
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol;  the proposed informed consent;  and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the protection of 
human subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
needed. 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study-specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms 
will be developed using REDCap database system and will be maintained by the Clinical 
Research Coordinator assigned to this study. CRFs will be kept in a locked cabinet, only 
accessible to the research team. 

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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
Rie von Eyben (Biostatistician at Stanford University) is the statistician for this study.  
12.1.1 Randomization 
This is a non-randomized study. 
12.2 
Interim analyses 
A review of the safety data will be completed every 6 months at the weekly Thoracic Radiation 
Oncology Team Meetings.  
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
See section 12.4.2. 
12.4 
Primary and Secondary Endpoints 
Phase 1: 
Primary Endpoint 
• 
Dose limiting toxicities (DLTs) of fresolimumab when combined with SABR 
Secondary Endpoint 
• 
Score the pattern of late radiation induced fibrosis at 12 months after SABR with and 
without fresolimumab 
• 
Evaluate severity and pattern of acute radiation-induced fibrosis in the first 6 months 
after SABR 
• 
Score potential adverse events (AEs) of fresolimumab combined with SABR using 
CTCAE v4 
• 
Measure post-treatment changes in pulmonary function using pulmonary function 
test parameters at enrollment, 6-month, and 12-month follow-up 
• 
Evaluate recurrence and progression-free survival at 12 months 
• 
Measure blood pharmacokinetics (PK) of fresolimumab in combination with SABR 
(optional for patient) 
Exploratory Endpoint: 
• 
Assess extent of radiation-induced lung toxicity by quantitative imaging analysis of 
CT volumes and FDG uptake parameters 
Phase 2 
Primary Endpoint 
Evaluate the presence of late moderate-to-severe radiation-induced fibrosis up to 
12 months after SABR with fresolimumab 
Secondary Endpoint 
• 
Score the pattern of late radiation induced fibrosis at 12 months after SABR with and 
without fresolimumab 
• 
Evaluate severity and pattern of acute radiation-induced fibrosis in the first 6 months 
after SABR 
• 
Score potential adverse events (AEs) of fresolimumab combined with SABR using 
CTCAE v4 
• 
Measure post-treatment changes in pulmonary function using pulmonary function 
test parameters at enrollment, 6-month, and 12-month follow-up 
• 
Evaluate recurrence and progression-free survival at 12 months 
Exploratory Endpoint: 

IRB-34863 
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• 
Assess extent of radiation-induced lung toxicity by quantitative imaging analysis of 
CT volumes and FDG uptake parameters 
12.4.1 Analysis Population 
Analysis will be carried out in all patients who complete protocol procedures. Patients who are 
lost to follow-up and who do not have a scan within +/-6 months of the 12-month time point will 
be excluded from analysis. Patients who develop inflammatory lung conditions unrelated to 
radiotherapy (i.e. pneumonia, ARDS, drug-induced pneumonitis, etc.) will be excluded from the 
final endpoint analysis if the area of unrelated inflammation impedes scoring of fibrosis severity 
of the irradiated lesion. 
 
12.4.2. Analysis Plan 
Approximately 60% of SABR patients develop acute radiologic changes in the lung at 3 months 
[16].  Late radiologic changes, reflecting fibrosis, are more frequent in SABR patients at 1 year 
[15]. Our institutional experience revealed the presence of moderate-to-severe late radiation 
induced fibrosis in ~75% of patients treated with SABR (50 Gy in 4 fractions) via VMAT 
technique at 1 year. 
Primary analysis: The outcome of moderate-to-severe radiologic fibrosis rate will be tested in 
evaluable patients in a one-sample one-sided test of proportion comparing the observed rate, 
which is expected to be at most 58%, to the historically observed rate of ~75%.  The observed 
rate and the 95% confidence interval calculated using the exact method will be reported. 
Secondary analysis: Local control at 12 months will be estimated along with a one-sided lower 
95% confidence bound to allow an informal assessment of the null hypothesis that the 
proportion is larger than 80%.  Patients with distant progression before local failure will be 
censored one day after the last imaging study;  patients who die before local control will be 
censored at the time of death.  These definitions are used for comparability.  Cumulative 
incidence estimates for local failure and other failure type will also be presented. 
Time to event data (local control, PFS, time to progression) will be evaluated using 
Kaplan-Meier estimates with 95% confidence intervals at multiples of 12 months based on 
Greenwood’s formula with a log transform.  Confidence intervals for median times to event, 
if relevant, will be constructed using the method of Brookmeyer and Crowley.  
Proportions (eg, proportion of patients with grade 4 or higher toxicity) will be estimated along 
with 95% exact confidence intervals.  Patient clinical and demographic characteristics will be 
reported with the appropriate summary statistic (mean, range, proportion, etc.)  Adverse events 
will be tabulated by organ system and severity. 
12.5 Sample Size 
12.5.1 Accrual Estimates 
Number of Patients: 55 to 60 
In 2014, ~80 lung SABR procedures were performed at Stanford Hospital.  It is estimated that 
2 to 3 patients can reasonably be expected to accrue per month.  Accrual will occur over 
60 months.  
12.5.2 
Sample Size Justification 
Phase 1: 
Post-SABR pneumonitis grade 3 or greater is expected to occur in ≤ 10% of patients with stage 
I disease.  Based on this percentage, we propose to start out with a cohort of 5 patients at the 
pre-selected dose of 3 mg/kg of fresolimumab.  If one patient develops DLT, then 5 more 
patients will be enrolled at the same dose to make a total of 10 patients.  If no more patients 

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experience DLT, then the total percentage of patients experiencing DLT is 10% and is 
considered acceptable for toxicity. 
Phase 2: 
A sample of size 50 was chosen in order to have 80% power to detect a decrease in the 
incidence of post-SABR moderate-to-severe fibrosis from 75% to 60% with a one-sided 
significance level of 10%. 

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13. 
INVESTIGATOR RESOURCES 
13.1 
Qualifications 
The study staff will include, but is not limited to, the Principal Investigators, Co-Investigators, 
research coordinators, research nurses, and any residents or fellows working with the 
physicians.  Also, laboratory personnel in the Principal Investigators’ laboratory will be involved 
in analyzing the plasma and tumor specimens collected from patients.  
All study staff have completed the required training specific for their responsibilities in this study.  
Furthermore, each member of the research team from each institution will be given a thorough 
explanation of the protocol and their responsibilities, including helping with scheduling, 
procedures, follow-up, data entry, or analysis.  All research investigators will be required to 
complete proper training through their institutional review boards.  

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14. 
REFERENCES 
1. Jemal, A., et al., Cancer statistics, 2010. CA Cancer J Clin, 2010. 60(5): p. 277-300. 
2. Ginsberg, R.J. and L.V. Rubinstein, Randomized trial of lobectomy versus limited resection 
for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg, 1995. 
60(3): p. 615-22; discussion 622-3. 
3. Hadziahmetovic, M., et al., Stereotactic body radiation therapy (stereotactic ablative 
radiotherapy) for stage I non-small cell lung cancer--updates of radiobiology, techniques, 
and clinical outcomes. Discov Med, 2010. 9(48): p. 411-7. 
4. Crabtree, T.D., et al., Stereotactic body radiation therapy versus surgical resection for stage 
I non-small cell lung cancer. J Thorac Cardiovasc Surg, 2010. 140(2): p. 377-86. 
5. Timmerman, R., et al., Stereotactic body radiation therapy for inoperable early stage lung 
cancer. JAMA, 2010. 303(11): p. 1070-6. 
6. Blobe, G.C., W.P. Schiemann, and H.F. Lodish, Role of transforming growth factor beta in 
human disease. N Engl J Med, 2000. 342(18): p. 1350-8. 
7. Derynck, R., R.J. Akhurst, and A. Balmain, TGF-beta signaling in tumor suppression and 
cancer progression. Nat Genet, 2001. 29(2): p. 117-29. 
8. Dumont, N. and C.L. Arteaga, Targeting the TGF beta signaling network in human 
neoplasia. Cancer Cell, 2003. 3(6): p. 531-6. 
9. Nagaraj, N.S. and P.K. Datta, Targeting the transforming growth factor-beta signaling 
pathway in human cancer. Expert Opin Investig Drugs, 2010. 19(1): p. 77-91. 
10. Caulin, C., et al., Chronic exposure of cultured transformed mouse epidermal cells to 
transforming growth factor-beta 1 induces an epithelial-mesenchymal transdifferentiation 
and a spindle tumoral phenotype. Cell Growth Differ, 1995. 6(8): p. 1027-35. 
11. Ellenrieder, V., et al., TGF-beta-induced invasiveness of pancreatic cancer cells is mediated 
by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J 
Cancer, 2001. 93(2): p. 204-11. 
12. Anscher, M.S., et al., Antitransforming growth factor-beta antibody 1D11 ameliorates normal 
tissue damage caused by high-dose radiation. Int J Radiat Oncol Biol Phys, 2006. 65(3): p. 
876-81. 
13. Bouquet, F., et al., TGFbeta1 inhibition increases the radiosensitivity of breast cancer cells 
in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res, 2011. 17(21): p. 
6754-65. 
14. Hardee, M.E., et al., Resistance of glioblastoma-initiating cells to radiation mediated by the 
tumor microenvironment can be abolished by inhibiting transforming growth factor-beta. 
Cancer Res, 2012. 72(16): p. 4119-29. 
15. Dahele, M., et al., Radiological changes after stereotactic radiotherapy for stage I lung 
cancer. J Thorac Oncol, 2011. 6(7): p. 1221-8. 
16. Palma, D.A., et al., Radiological and clinical pneumonitis after stereotactic lung 
radiotherapy: a matched analysis of three-dimensional conformal and volumetric-modulated 
arc therapy techniques. Int J Radiat Oncol Biol Phys, 2011. 80(2): p. 506-13. 
 

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APPENDIX A:  Participant Eligibility Checklist  
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist must be retained in the patient’s study 
file and the study’s Regulatory Binder.  
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records.  A description of the 
eligibility verification process should be included in the EPIC or other Electronic Medical Record 
progress note.  
Protocol Title: 
Fresolimumab and Stereotactic Ablative Radiotherapy in 
Early Stage Non-Small Cell Lung Cancer   
Protocol Number: 
IRB-34863 / LUN0071  
Principal Investigator: 
Max Diehn, MD, PhD  
II. Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV. Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation 
1. Newly diagnosed, histologically proven T1-T2bN0M0 
(Stage IA-IIA) NSCLC, with maximum tumor diameter ≤ 
5 cm under consideration for stereotactic ablative body 
radiotherapy (SABR) as definitive primary treatment.   
 
 
      
2.  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 
 
 
      
3. ECOG PS 0-2 
 
 
      
4. Age greater than or equal to 18 years old and able to 
give informed consent. 
 
 
      
5. 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 
(From IRB-approved protocol) 
 
1. Significant anemia (hemoglobin below 9.0 g/dL) or 
neutropenia (ANC < 1000/mm3) 
 
 
      
2. Prior history of multifocal adenocarcinoma in situ 
(ie, classic or pure bronchioloalveolar carcinoma) 
 
 
      
3. Prior history of keratoacanthoma (well-differentiated 
 
 
      

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squamous cell skin cancer variant, often centrally 
ulcerated).  History of basal cell cancer is allowed.  
4. Pre-malignant skin lesion(s) noted on prescreening skin 
exam, except for actinic (solar) keratosis 
 
 
      
5. Prior radiotherapy overlapping with high dose region of 
planned SABR course 
 
 
      
6. Prior history of head and neck;  oral;  or bladder cancer  
 
 
      
7. Prior receipt of systemic treatment (chemotherapy, 
targeted therapy, or immunotherapy) for the lesion 
under consideration of treatment 
 
 
      
8. 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  
 
 
      
9. Contraindication to receiving radiotherapy  
 
 
      
10. Known allergy to components of fresolimumab 
 
 
      
11. 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. 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology 
test results, subject self-report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: