Phase II Trial of Flaxseed to Prevent Pneumonopathy After Chemoradiation for Lung Cancer
Phase: PHASE2
Conditions: Lung Cancer
Sponsor: Abramson Cancer Center at Penn Medicine

 
PHASE II TRIAL OF FLAXSEED TO PREVENT PNEUMONOPATHY AFTER 
CHEMORADIATION FOR LUNG CANCER 
 
 
 
Principal Investigator 
Abigail T. Berman, MD 
Department of Radiation Oncology 
3400 Civic Center Boulevard, TRC 2 West  
Philadelphia, PA 19104 
215-662-2989 
 
Sub-Investigators 
 
Department of Radiation Oncology 
Keith Cengel, MD, PhD; 215-898-1035; 215-898-0838 
William P. Levin, MD; 215-614-0083 
Steven Feigenberg, MD; 215-662-2711 
 
Department of Pulmonary, Allergy, and Critical Care 
Melpo Christofidou-Solomidou, PhD; 215-573-9917   
 
Department of Biostatistics and Epidemiology 
Daniel F. Heitjan, PhD 
 
 
Funding Sponsor: 
N/A 
Study Product: 
Whole grain Flaxseed 
Protocol Number: 
IRB#: 821109   UPCC#: 28514 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Pennsylvania.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 
 
Version Date: 07/27/17 
                       10/24/14 
 
 
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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Table of Contents 
STUDY SUMMARY ..................................................................................................................... 1 
1 
INTRODUCTION................................................................................................................. 2 
2 
STUDY OBJECTIVES ......................................................................................................... 4 
3 
STUDY DESIGN ................................................................................................................... 4 
4 
SUBJECT SELECTION AND WITHDRAWAL .............................................................. 6 
5 
STUDY DRUG ...................................................................................................................... 7 
6 
STUDY PROCEDURES ...................................................................................................... 9 
7 
STATISTICAL PLAN ........................................................................................................ 11 
8 
SAFETY AND ADVERSE EVENTS ................................................................................ 12 
9 
PROTOCOL EXCEPTIONS AND DEVIATIONS……………………………………. 13 
10  DATA HANDLING AND RECORD KEEPING ............................................................. 14 
11 STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 15 
12 ETHICAL CONSIDERATIONS ....................................................................................... 15 
13 STUDY FINANCES............................................................................................................ 15 
14 REFERENCES .................................................................................................................... 16 
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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List of Abbreviations 
 
CRF: case report form 
 
CTCAE: Common Terminology Criteria for Adverse Events 
 
ED: enterodiol 
 
EL: enterolactone 
 
FS: flaxseed 
 
GCP: Good Clinical Practice 
 
GRAS:  Generally Recognized as Safe 
 
NCI: National Cancer Institute 
 
NSCLC: non-small cell lung cancer 
 
PI: principal investigator 
 
RILI: radiation-induced lung injury 
 
RNS: reactive nitrogen species 
 
ROS: reactive oxygen species 
 
RP: radiation pneumonitis 
 
SAE: serious adverse event 
 
SDG: secoisolariciresinol diglucoside  
 
WBC: white blood cells 
 
XRT: radiation therapy 
 
 
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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Study Summary 
Title 
PHASE 
II 
TRIAL 
OF 
FLAXSEED 
TO 
PREVENT 
PNEUMONOPATHY AFTER CHEMORADIATION FOR LUNG 
CANCER 
Short Title 
Dietary Flaxseed in NSCLC 
Protocol Number 
 
Phase 
Phase II 
Methodology 
Single-arm study, 40g flaxseed ingested per day 
Study Duration 
Two years 
Study Center(s) 
Single-center  
Objectives 
To establish the utility of FS supplementation in patients receiving 
chemoradiation therapy for lung cancer; To validate the ability to 
measure biomarkers of oxidative stress and active FS metabolites in 
these patients; to quantify oxidative stress.  
Number of Subjects 
48 subjects 
Diagnosis and Main 
Inclusion Criteria 
Patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) receiving chemoradiotherapy with definitive intent 
Study Product, Dose, 
Route, Regimen 
Whole grain flaxseed diet consisting of 40g flaxseed ingested per day 
Duration of 
administration 
Approximately eight to nine weeks 
Reference therapy 
none 
Statistical 
Methodology 
This is a single-arm phase II trial. The primary endpoint will be absence 
of radiation pneumonitis (RP) of grade 3 or above within 6 months from 
the end of XRT, according to the CTCAE v.4.0 scale. The most recent 
pooled Radiation Therapy Oncology Group analysis showed that the 
rate of > grade 3 RP was 18%51, so the null hypothesis “clinical 
response” rate for this study is 82%.  A sample size of n=39 achieves 
80% power to detect a response rate of 94.1% in a one-sided binomial 
exact test with target significance level no larger than α=0.1. The actual 
significance level achieved by this test is 0.062.  We will reject the null 
hypothesis that FS treatment has no effect on the RP rate if there are 3 
or fewer cases of RP in the 39 evaluable subjects.  Assuming a death 
rate of 10% prior to 6 months and a 10% inevaluable rate, we will seek 
to enroll 48 patients. 
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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1 
Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 
Background 
The effectiveness of radiotherapy for thoracic malignancies is limited by the high radiosensitivity 
of normal lung parenchyma 1, 2. Clinically significant radiation lung injury occurs in up to 30% 
of patients irradiated for lung cancer 3 and 10-15% of other thoracic oncology patients 4. A 
greater proportion of patients have subclinical adverse effects of radiation on the lung, 
identifiable by imaging and/or physiologic testing 5.  Highly reactive compounds known as 
reactive oxygen species (ROS) and reactive nitrogen species (RNS) are induced in large 
quantities by radiation therapy (XRT) and have been implicated in this form of lung injury 6.  
 
Two phases of radiation-induced lung injury have been described in humans 1. Acute radiation 
pneumonitis, thought to be largely inflammatory and exudative in nature, can occur several 
weeks to six months post-irradiation, and can be life threatening if a large volume of lung has 
been affected 7. In the second phase of radiation-induced lung injury that can occur months to 
years after irradiation, the lung tissue enters a fibrotic state in which the numbers of 
inflammatory cells decrease and a marked thickening of alveolar walls occurs due to collagen 
deposition.  
 
There is currently no known effective pharmacologic therapy for the prevention of acute or 
chronic radiation pneumonopathy. Systemic oral and intravenous corticosteroids are routinely 
used to treat clinically significant acute radiation pneumonitis, but the administration of these 
drugs does not alter the risk of developing late radiation fibrosis. The exact mechanism by which 
the acute radiation pneumonitis phase transitions to the late fibrotic phase is unclear. However, 
as recently reviewed by Robbins and Zhao 9, studies implicate a chronic state of oxidative 
stress in radiation-induced late fibrosis; it is widely recognized that irradiation is associated 
with both a rapid and a chronic increase in ROS/RNS production. This persistent state of 
oxidative stress may therefore be a target for inhibition of radiation injury and radioprotection of 
normal tissues 10 to allow for more effective radiotherapy and improved clinical outcomes. 
  
Currently the only means to avoid life-threatening or fatal radiation pneumonopathy is to 
minimize the amount of lung exposed to dangerous radiation levels. A safe and effective biologic 
radioprotector would thus be extremely useful. Preclinical data suggest that antioxidant 
molecules and/or enzymes might offer protection of the lung 11-13.  
 
FS has been piloted in multiple diseases at this institution39. We previously conducted a pilot trial 
of FS in NSCLC patients treated with chemoradiation by our team at the Pulmonary Division of 
the University of Pennsylvania, led by Dr. Christofidou-Solomidou PhD, and Dr. Berman and 
Dr. Rengan from the Department of Radiation Oncology as follows: 14 subjects were 
randomized to one FS or control muffin daily from start to 2 weeks after RT. Fourteen patients 
(control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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and control, respectively. Mean percentages of intended number of muffins consumed were 37% 
versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, 
confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend 
towards decreased rates of pneumonitis in FS. While FS in the administered muffin formulation 
did not meet tolerability criteria due to taste (not toxicity), we were able to show FS 
bioavailability and quantify oxidative stress markers.40 
1.2 
Investigational Agent 
Flaxseed (FS) is a non-toxic, whole grain commonly used as a nutritional supplement that has 
gained popularity because it is a rich source of natural antioxidants. FS is composed of high 
concentrations of omega-3 fatty acids and lignans. Omega-3 fatty acids reduce inflammation and 
may be helpful in treating a variety of autoimmune diseases 15-17.  Lignans, widely occurring 
plant compounds closely related to lignin (which forms the woody component of trees and other 
plants), possess antioxidant properties 18. The FS lignan precursor secoisolariciresinol 
diglucoside (SDG), isolated from FS, is metabolized in the mammalian intestine to the lignans 
enterodiol (ED) and enterolactone (EL). The oxygen radical scavenging properties of the FS 
lignans have been shown in vitro to act either by direct hydroxyl radical scavenging activity 19, 20 
or by inhibition of lipid peroxidation 21. In addition, the FS lignan SDG may exert antioxidant 
activity by inhibiting ROS produced by white blood cells (WBC) by acting as a platelet-
activating-factor antagonist 22. The antioxidant properties of FS lignans have been verified in 
animal models of endotoxic shock 22, diabetes 23 and in carbon tetrachloride-induced oxidative 
stress 24. Although ROS production and oxidant stress have been implicated in the etiology of a 
variety of acute and chronic lung injury forms, the therapeutic or preventive use of dietary FS or 
FS-derived lignans has not been extensively evaluated in pulmonary disease.  
1.3 
Preclinical Data 
Our group was the first to publish the use of FS in murine models of acute lung injury 
including hyperoxia and acid aspiration, and our data suggest the importance of its 
antioxidant properties 
25. Additionally, we have shown that FS can ameliorate 
ischemia/reperfusion lung injury in a murine model (manuscript under review). In a murine 
model of thoracic radiation induced lung fibrosis, dietary FS supplementation improves 
survival and overall health, and it reduces oxidative lung damage in mice receiving a single 
dose of thoracic radiation (manuscript under review). 
1.4 
Clinical Data to Date 
There is no available clinical research data on the use of dietary FS in the setting of thoracic 
radiation therapy in humans.  
1.5 
Dose Rationale and Risk/Benefits 
Dose Rationale: Previous studies have investigated dose of FS and have shown tolerability, 
increase in urinary lignan levels41-43, and decrease in diabetes and atherosclerotic disease for 
doses 15-50 g38,44,45. In this study, subjects will ingest 40g of FS per day in the form of ground, 
wholegrain FS, incorporated in the manner of their choice. The intolerability of the formulation 
in the NSCLC population39 prompted the switch to packets of ground FS, which has been shown 
to have excellent tolerability and is currently being utilized in pulmonary studies of cystic 
fibrosis and lung transplant patients40. 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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Potential Risks: Our original phase I studies shows that there is no significant safety issues with 
flaxseed ingestion during the prescribed time, although there is little data beyond six weeks of FS 
ingestion. There is no data on safety in children, nor in pregnancy and lactation.  There are 
isolated reports of FS induced contact allergy 27, 28. FS has not yet attained GRAS (Generally 
Recognized as Safe) status from the FDA. While 50g of ingested FS daily for one month has 
been well tolerated, subjects experienced up to a 30% increase in bowel movements 29. An upper 
total dose of 40g of FS daily was chosen to minimize its laxative effects. 
 
Potential Benefits: Subjects receiving study diet will receive close monitoring for toxicity. 
Subjects will be encouraged to continue a healthy diet in the setting of possible XRT induced 
esophagitis. In addition, flaxseed may reduce the risk of RILI; however, we do not know if this is 
the case and is the subject of research in this study.  
 
Risk Benefit Ratio: The potential benefits of this study outweigh the potential risks. Data from 
this study will provide evidence of efficacy of administering dietary FS in a phase II setting 
which will allow us to perform a larger, phase III clinical trial. It will be the first time markers of 
oxidative stress and FS metabolites will be systematically measured in this population. 
2 
Study Objectives 
Primary Objective: 
Determine in a phase II trial whether FS supplementation decreases the risk of RILI in patients 
receiving definitive chemoradiotherapy for locally advanced or metastatic NSCLC, and to collect 
additional toxicity and tolerability data from FS administration in this population. 
Secondary Objective: 
Determine how FS modulates the markers of inflammation and oxidative damage. 
1. Quantify the gene and protein expression levels of representative nrf2- regulated 
antioxidant enzymes HO-1 and NQO-1 from buccal swabs of NSCLC patients.  
2. Quantifying urinary markers of systemic oxidative stress including 8,12-iso-iPF2α-VI 
isoprostane (F2α-IsoPs) and 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGuo) and 
quantifying serum levels of FS lignans ED and EL. 
3 
Study Design  
3.1 
General Design 
See Table 1 (Study Flow Chart) 
 
This single arm Phase II trial will investigate the feasibility of dietary FS supplementation in a 
population of patients receiving definitive chemoradiotherapy for lung cancer. Subjects will be 
male or female with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
requiring irradiation of the mediastinum. 
 
 
We propose to have 48 subjects ingest FS starting approximately 1 week before their definitive 
XRT begins, and for the duration of their therapy (approximately 7-8 weeks). The subjects will 
be asked to stop eating the study FS after completion of their radiotherapy for a total of 
approximately 8-9 weeks of FS administration.  

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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Enrolled subjects will be seen at a pre-irradiation visit approximately one week prior to the start 
of XRT and weekly during the course of radiotherapy (approximately seven to eight weeks of 
therapy) and diet administration. Subjects will be assessed at each weekly visit for toxicity 
including measures of dermatitis, nausea, vomiting, diarrhea, esophagitis, cough, and dyspnea. In 
addition, at the visits as indicated in the study flow-sheet below, patients will complete a FACT-
L questionnaire, on specimen days, which has been shown to be correlative of lung-cancer 
specific patient-reported outcomes (Ring et al. 2008). This, along with the flaxseed logs, will be 
filled out by the patients in RedCap, which is a web-based secure portal used at the University of 
Pennsylvania for research and patient surveys and has been well-described in its use in the 
literature (Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel Gonzalez, 
Jose G. Conde, Research electronic data capture (REDCap) - A metadata-driven methodology 
and workflow process for providing translational research informatics support, J Biomed Inform. 
2009 Apr;42(2):377-81.). If a patient does not have computer access, the study coordinator will 
sit with the patient to enter the information into RedCap. Toxicity will be scored according to the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 for adverse event 
reporting. Research visits will be scheduled to coincide with subjects’ standard of care clinic 
visits whenever possible. 
 
Following completion of radiotherapy, subjects will be assessed at approximately one month and 
approximately six months. At approximately six months post XRT, subject involvement and 
study monitoring will be completed.  Due to unanticipated side-effects of treatment, scheduling 
issues or logistical difficulties, the specimen collection and/or visit schedule will be modified at 
the discretion of the principal investigator. 
 
Specimen collection will include obtaining blood, urine and buccal swabs at a total of five time 
points:  
1) At a pre-irradiation visit prior to starting the FS diet 
2) Approximately one week after starting the FS diet at the start of XRT  
3) At approximately 4 weeks following the start of XRT 
4)  At the conclusion of XRT therapy  
5) At approximately one month post XRT completion   
 
On the days of specimen sampling, subjects will be asked not to eat their daily FS until after 
sample collection, or at least 4 hours before their visit.  Collection of urine specimens and buccal 
swabs will be obtained by appropriately trained research study staff.  Collection of blood 
samples will be obtained by research staff appropriately trained in venipuncture techniques.  
 
The Investigational Drug Service (IDS) at the University of Pennsylvania will be responsible for 
flaxseed receipt, storage and dispensing to research staff. Subjects receiving radiotherapy will 
have daily visits to the radiation oncology department as standard of care for fractionated therapy 
and will be given FS as necessary by research staff after it is dispensed by IDS. 
3.2 
Primary Study Endpoints 
The primary endpoints to be measured in this study include: 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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• Rate of RILI after FS administration in a population of patients receiving definitive 
chemoradiotherapy for lung cancer. 
• Toxicity and tolerability data of dietary FS administration during chemoradiotherapy. 
3.3 
Secondary Study Endpoints 
The secondary endpoints to be measured in this study include: 
• Measures of biomarkers of oxidative stress in this population. 
• Measures of serum levels of FS metabolites. 
4 
Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
1. Male or female, ages 18 and older 
2. Current diagnosis of non-small cell lung cancer (NSCLC) including patients who 
have metastatic disease requiring definitive thoracic and mediastinal radiotherapy 
with concurrent chemotherapy. 
3. Able to provide written informed consent and comply with all study procedures 
4. Total planned radiation dose to gross disease 60-70 Gy.  
4.2 
Exclusion Criteria 
1. Current diagnosis of disease of the gastrointestinal system, liver, or kidneys which 
could result in altered metabolism or excretion of the study medication (history of 
major gastrointestinal tract surgery, gastrectomy, gastrostomy, bowel resection, etc.) 
or history of chronic gastrointestinal disorders (ulcerative colitis, regional enteritis, or 
gastrointestinal bleeding) 
2. Known hypersensitivity to flaxseed or any of its metabolites, or wheat products 
3. Taking or has taken an investigational drug within 14 days  
4. Taking or has taken Amifostine or Mucomyst (N-acetylcysteine) within 14 days 
5. Current or prior use of flaxseed, flax-containing products, soybeans, or soy-
containing products 
6. Current or prior use (limited to prior 14 days) of dietary supplements such as herbals 
or botanicals 
7. Prior thoracic and/or mediastinal radiation therapy  
4.3 
Subject Recruitment and Screening 
Subjects will be recruited from investigator clinical practices and include men and women who 
will be receiving chemoradiotherapy with definitive intent for non-small cell lung cancer 
(NSCLC) including patients with locally advanced or metastatic disease. Subjects will undergo 
an informed consent process in accordance with GCP (see section 11 Ethical Considerations). 
Informed consent will be obtained prior to the performance of any study procedures. Subjects 
must meet all of the inclusion and none of the exclusion criteria... 
Documentation of Eligibility: Screening assessments will be performed to determine subject 
eligibility criteria, which will be documented on a case report form. The PI will confirm and sign 
off on the inclusion and exclusion criteria on a case report form (CRF) prior to the patient being 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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formally enrolled in the study. (See sections 4.1 and 4.2 for complete listing of eligibility 
criteria). 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Any subjects experiencing a serious adverse event (SAE) felt to be related to study drug will be 
withdrawn from the study. Subjects will be withdrawn if discontinuation from the study is 
deemed by the principal investigator (PI) to be in their best interest, namely if an abnormal 
response of the subject’s malignancy to radiotherapy outside of normal limits is observed. 
Subjects may be withdrawn at any time at the discretion of the PI. Any subject withdrawing their 
consent to participate in the study or their authorization to use their protected health information 
will be withdrawn from the study. Subjects withdrawn may be replaced at the discretion of the 
principal investigator. 
Subjects may be withdrawn due to any of the following: 
1. Intolerable side effects 
2. Clinical deterioration 
3. Failure to attend outpatient and treatment visits 
4. Failure to provide lab specimens 
5. Failure to cooperate and provide toxicity and tolerability measures 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be withdrawn prematurely from the study, toxicity data will continue 
to be assessed as part of the normal radiotherapy protocol as determined by the investigator. 
Routine tests will be performed as standard of care as part of the ongoing radiotherapy.  
5 
Study Drug  
5.1 
Description 
(Also see section 1.2 Investigational Agent) 
Flaxseed is a non-toxic whole grain nutritional supplement with high content of natural 
antioxidants.  
5.2 
Treatment Regimen 
Subjects will be asked to eat FS daily starting approximately 1 week before of the initiation of 
radiotherapy. The subjects will be asked to continue eating FS for the duration of their therapy – 
approximately 7 to 8 weeks – for a total flaxseed administration of approximately 8 to 9 weeks.  
5.3 
Method for Assigning Subjects to Treatment Groups 
This is a single arm trial and all subjects will be assigned the same treatment regimen.  
5.4 
Preparation and Administration of Study Drug 
FS will be stored by the Investigational Drug Service at the University of Pennsylvania. FS will 
be dispensed to subjects on a weekly basis during radiation therapy. Dispensing will occur 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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during subjects’ daily visits for radiotherapy as part of standard of care on an as needed basis to 
allow for ingestion during the study treatment period.  
5.5 
Subject Compliance Monitoring 
Study subjects will be asked to complete a “FS log” during the study treatment period, and a 
research technician will assess treatment regimen compliance by determining quantities of FS 
eaten. This will occur on a weekly basis during subjects’ daily visits for radiotherapy. If a subject 
is deemed to be significantly non-compliant with the FS diet, the reason will be documented. 
This will be entered in RedCap by the Clinical Research Coordinator. Patients will also get text 
message or phone call reminders to take their flaxseed.  
5.6 
Prior and Concomitant Therapy 
A comprehensive medical history including medication history will be obtained prior to 
enrollment to determine if subjects meet eligibility criteria. (See sections 4.1 and 4.2 for 
complete listing of eligibility criteria). 
 
Prior therapy not permitted: 
1. Any dietary supplements such as herbals or botanicals within the prior 14 days. 
2. Prior flaxseed or flax-containing products, soybeans or soy-containing products. 
3. Prior thoracic radiotherapy. 
4. Any investigational agent within the prior 14 days. 
5. Amifostine or Mucomyst within the prior 14 days. 
 
Prior therapy permitted: 
1. Vitamins or multivitamins including calcium and vitamin D.  
 
Concomitant therapy not permitted: 
1. Flaxseed, flax-containing products, soybeans, or soy-containing products. 
2. Any herbals or botanicals. 
5.7 
Packaging 
FS grain will be will be packaged by the supplier in individual packets for daily consumption.   
The study subjects will be provided with instructions to ingest 40g of daily FS. 
5.8 
Blinding of Study Drug 
This is a single arm study and as such there will be no blinding of treatment assignment. 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Ground whole flaxseed will be manufactured, packaged and provided to the University of 
Pennsylvania by Golden Valley Flax by Hylden Farms of North Dakota, Park River, North 
Dakota.  It will be received by the Investigational Drug Service (IDS) at the University of 
Pennsylvania. 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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5.9.2 Storage 
Ground whole grain flaxseed will be stored by the Investigational Drug Service (IDS) at the 
University of Pennsylvania in a cool dry place per product instructions protected from direct 
light.  
5.9.3 Dispensing of Study Drug 
All FS will be dispensed in subject-specific packages in sufficient quantities to allow for the 
ingestion during the study treatment period. No extra FS will be provided. The subject will be 
provided with a one week supply of individually packaged FS with clear instructions given at the 
start of the treatment period to consume. Subjects will be given logs to track FS consumption.  
The Investigational Drug Service (IDS) at the University of Pennsylvania will dispense flaxseed 
to research staff that will provide it to the study participants. 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of study materials shipped, 
consumed, and remaining. This reconciliation will be logged on the reconciliation form, signed 
and dated. Any discrepancies noted will be investigated, resolved, and documented prior to 
return or destruction of unused study materials.  Materials destroyed on site will be documented 
in the study files. 
6 
Study Procedures 
See Table 1 (Study Flow Chart). 
6.1 
Visit 1: Pre-irradiation (Week -1) 
At Visit 1 (Pre-irradiation), subjects will receive information regarding the study and informed 
consent will be obtained. A baseline CTCAE toxicity evaluation will be performed. Flaxseed and 
FS log will be distributed to subjects. Subjects will be asked to start daily FS ingestion. A blood 
sample and urine sample will be obtained for baseline urinary isoprostanes (a marker of 
oxidative stress) and plasma lignan levels (flaxseed metabolites).  The blood sample obtained 
will be up to 15mL in volume. A buccal swab will also be obtained. 
 
Please note that radiation is not an experimental question. 
  
Standard pre-irradiation procedures will be performed as follows: 
 
The radiation dose will be prescribed at mid-separation on the central ray for two equally 
weighted beams.  For all other beam arrangements, the dose will be prescribed at the center of 
the target area or at the intersection of central rays of the beams. 
 
Simulation for all fields is required. CT-based treatment planning is required for all subjects and 
will be used to define the target volume. The gross tumor volume (GTV) will consist of all 
known sites of disease including the primary tumor and all pathologically enlarged (> 1 cm in 
short axis) or FDG-PET positive lymph nodes. Discontinuous volumes are allowed. Elective 
nodal irradiation is not allowed and therefore the GTV will be equal to the clinical target volume 
(CTV) for this study. The planning target volume (PTV) will be constructed from the GTV by an 
automatic margining tool supervised and edited by the treating radiation oncologist. The 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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irradiation target volume will be defined by shaped ports with custom-made blocks or multileaf 
collimation.  Portal verification shall be done for all treated fields.  Megavoltage equipment is 
required with minimum peak photon energies of 6 MV.  SAD techniques should be used.  Each 
field will be treated every session.  Interruptions in therapy should be discussed with the 
principal investigator but will be instituted at the discretion of the attending radiation oncologist. 
 
Dose calculation should be performed using inhomogeniety corrections to account for 
differences in tissue density across the thorax.  The total dose to gross disease will be 60-70 Gy. 
The prescribed dose will be constrained to keep the volume of lung receiving 20 Gy (V20) to be 
less than 35%. This will be administered in 2.0 Gy daily fractions without a planned treatment 
break.  Treatment will be continuous, 5 days per week for 7-8 consecutive weeks. 
 
Normal tissue doses:  Dose-volume histograms should be performed for spinal cord, lungs, and 
heart.  The maximal spinal cord dose should not exceed 45 Gy.  No more than 35% of the total 
lung volume should receive greater than 20 Gy.  No more than 50% of the total cardiac volume 
should receive greater than 40 Gy. The esophagus will be contoured on all patients and the 
dose volume parameters will be obtained. This is not a dose-limiting structure, and 
therefore no specific constraints will be mandated.  
6.2 
Visit 2: Start of Irradiation (Week 0) 
At Visit 2 (Start of Irradiation), toxicity evaluation will be performed and CTCAE scoring 
determined. Blood, urine, and buccal samples will be obtained. The blood sample obtained will 
be up to 15mL in volume.  Definitive radiation therapy will commence. 
6.3 
Visits 3 to 9(10): Radiation Weeks 1 through 7(8) 
Toxicity evaluation and CTCAE scoring will be obtained. FS compliance will be assessed once 
each week and FS log will be reviewed. 
 
At approximately 4 weeks following the start of XRT, blood urine, and buccal samples will be 
obtained.  Specimens will be obtained only once at this time point during the course of XRT.  
The blood sample obtained will be up to 15mL in volume 
 
Subjects will be instructed not to eat their FS within 4 hours before radiation, and preferably 
after radiation treatment on those days. Subjects will be instructed to stop eating FS at the 
completion of their prescribed radiotherapy. 
6.4 
Post Radiation 1 Month Follow-up  
Toxicity evaluation and CTCAE scoring will be performed, with bloodwork being performed as 
clinically indicated as part of standard of care. Urine and blood sampling for urinary isoprostanes 
and plasma FS lignan levels will be assessed.  A buccal swab will also be obtained. 
6.5 
Post Radiation 6 Month Follow-up 
Toxicity evaluation and CTCAE scoring will be performed, with blood work being performed as 
clinically indicated as part of standard of care.  Study cessation will be at the 6-month post XRT 
visit.  
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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Table 1. Study Flow Chart 
Event 
Pre-study 
Eligibility 
1 week 
prior to 
XRT 
Start of 
XRT 
Weekly during 
XRT 
End of 
XRT 
1 
month 
post 
XRT 
6 
months 
post 
XRT 
Visit 
Week 
 
Visit 1  
Week -1 
Visit 2 
Week 0 
Visits 3 to 8(9) 
Week 1 to 7(8) 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
FS 
Consumption 
 
X* 
X* 
X* 
X* 
 
 
FS Log 
Review 
 
X 
X 
X 
X 
 
 
Toxicity 
Evaluation 
 
X 
X 
X 
X 
X 
X 
FACT-L 
Questionnaire  
 
X 
X 
X*** 
X 
X 
X 
Specimen Collection 
Urine 
specimen 
 
X** 
X 
X*** 
X 
X 
 
Blood 
specimen 
 
X** 
X 
X*** 
X 
X 
 
Buccal Swab 
 
X** 
X 
X*** 
X 
X 
 
*FS consumption to begin after first specimens are obtained approximately 1 week prior to XRT and to continue 
every day during XRT and end at the end of XRT. 
** The first specimen collection can be done any time after consent but prior to first FS consumption. 
***Specimen collection and FACT-L questionnaires during XRT will occur at one time point only (approximately 4 
weeks following the start of XRT) 
7 
Statistical Plan 
7.1 
Study Design  
This is a single arm phase II flaxseed diet supplement for subjects with locally advanced or 
metastatic NSCLC who are scheduled to begin conventional chemoradiation therapy with 
definitive intent. Flaxseed is thought to be a protectant for radiation pneumonitis. Subjects will 
be told to ingest 40g of flaxseed daily.  
 
FS will be ingested daily for 8-9 weeks, including 7-8 weeks during radiation and for 1 week 
prior to radiation. Subjects will be queried weekly about their FS consumption while on the diet. 
Serial measurements of plasma levels of flaxseed metabolites, urine levels of oxidative stress 
markers, and buccal swabs will be obtained at 5 time points: baseline (prior to start of radiation), 
at week 0 of radiation, 4 weeks into radiation, at the end of radiation and at one month post-
radiation. This assessment is important because NSCLC subjects receiving radiation therapy 
often develop esophagitis and swallowing difficulties.  
 

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Protocol Short Title: Dietary Flaxseed in NSCLC 
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7.2 
Statistical Analyses and Decision-making  
Primary Objective: This is a single-arm phase II trial. The primary endpoint will be absence of 
radiation pneumonitis (RP) of grade 3 or above within 6 months from the end of RT, according 
to the CTCAE v.4.0 scale. The most recent pooled Radiation Therapy Oncology Group analysis 
showed that the rate of > grade 3 RP was 18%51, so the null hypothesis “clinical response” rate 
for this study is 82%.  A sample size of n=39 achieves 80% power to detect a response rate of 
94.1% in a one-sided binomial exact test with target significance level no larger than α=0.1. The 
actual significance level achieved by this test is 0.062.  We will reject the null hypothesis that FS 
treatment has no effect on the RP rate if there are 3 or fewer cases of RP in the 39 evaluable 
subjects.  Assuming a death rate of 10% prior to 6 months and a 10% inevaluable rate, we will 
seek to enroll 48 patients. As the Department of Radiation Oncology at Penn is one of the 
busiest centers in the country and currently treats approximately 235 patients daily, and the 
thoracic oncology service is the busiest clinic service within the Department and has exceptional 
rates of enrollment of patients onto investigator-initiated clinical trials, we expect to have no 
difficulty enrolling 48 patients in two years. 
 
Secondary Objective: We will analyze the continuous secondary endpoints (Aim 2) using mixed 
linear models that include random effects for subject.  We will inspect the data before analysis to 
identify a transformation to normality, if needed.  A simpler form of the analysis would be to 
conduct a paired t test comparing baseline to post-treatment values.  With n=39 evaluable 
subjects, we will be able to detect a change in the mean of 0.533 standard deviations with 90% 
power in a two-tailed test with type I error rate α=0.05.  We will collect blood and urine for 
markers of antioxidant activity and systemic inflammation, and buccal swabs for antioxidant 
enzyme epithelial gene expression at the specified time points. We will analyze the data using 
mixed linear models that include random effects for subject.  This will effectively be the same as 
a paired t-test on differences across the treatment periods.  
 
Multiplicity:  We will take an intermediate approach to avoid potential spurious claims of 
statistical significance due to the multiplicity of outcomes.  We will consider the sets of 
outcomes — antioxidant activity, epithelial gene expression, and clinical safety and efficacy — 
separately, adjusting for multiplicity as needed within each by the Simes procedure, which is 
more powerful than Bonferroni but provides the same level of control for the family-wise error 
rate. 
7.3 
Sample Size and Study Duration  
A maximum of 48 subjects with locally advanced or metastatic NSCLC who undergo definitive 
chemoradiation will be accrued over approximately two years. The study will close when the 
final subject has undergone the approximately 6-month post-radiation follow-up visit.  
7.4 
Subject Population(s) for Analysis 
The all-treated population will be used for all study analyses.  For purposes of this study, the all-
treated population is defined as the group of subjects ingesting at least 1 week of FS.  
8 
Safety and Adverse Events 
8.1 
Adverse Event Reporting 
Serious adverse events will be reported to the IRB and DSMC per institutional policy. 

Page 13 of 20 
Protocol Short Title: Dietary Flaxseed in NSCLC 
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All events meeting the DSMC reporting requirements will be entered into the mandatory Velos 
AE/SAE form. Once an event is entered, an e-mail alert to Doris Shank 
(doris.shank@uphs.upenn.edu) will be sent.  A study CRF will not replace the ACC central 
reporting form.  Information in Velos will be accurately maintained and updated in a timely 
manner.  If new/updated information is learned about the event, the event will be amended or 
corrected promptly.  An investigator will determine the grade, attribution and expectedness of all 
events. 
The following timeline will be adhered to for reporting events to the DSMC: 
1. All grade 3 or higher events (AE or SAE) within five business days of knowledge 
2. All unexpected deaths within 24 hours of knowledge. 
3. All other deaths within 30 days of knowledge. Deaths of subject’s off-study for greater 
than 30 days from the last study treatment/intervention are not reportable.   
8.2 
Stopping Rules 
If the subject develops adverse gastrointestinal complaints (Grade 3 or higher GI toxicity), or if 
the subject develops other significant side effects otherwise deemed unrelated to current 
radiotherapy, or if the subject displays unexpected lack of tumor responsiveness to radiotherapy, 
then the subject will be removed from the study. 
 
9  
Protocol Exceptions and Deviations 
9.1  
Protocol Exceptions  
A one time, intentional action or process that departs from the IRB and CTSRMC approved 
study protocol, intended for one occurrence. If the action disrupts the study progress, such that 
the study design or outcome (endpoints) may be compromised, or the action compromises the 
safety and welfare of study subjects, advance documented IRB and DSMC approval is required.  
9.2  
Protocol Deviations 
A one time, unintentional action or process that departs from the IRB and DSMC approved 
study protocol, involving one incident and identified retrospectively, after the event occurred. If 
the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or 
compromises the safety and welfare of the subjects, the deviation must be reported to the DSMC 
within 5 business days and the IRB within 10 business days.  
9.3  
Reporting of Protocol Exceptions and Deviations 
Protocol Exceptions and Protocol Deviations will be approved or reported to the IRB and DSMC 
per institutional requirements. 

Page 14 of 20 
Protocol Short Title: Dietary Flaxseed in NSCLC 
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10 
Data Handling and Record Keeping 
10.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following:  
 
 
• What protected health information (PHI) will be collected from subject(s) in this study  
 
• Who will have access to that information and why  
 
• Who will use or disclose that information  
 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period.  
 
10.1.1  Unintentional Disclosure 
 
Upon discovering that PHI may have been or has been disclosed to anyone not specified in the 
HIPAA disclosure consent, the investigator will report the disclosure to the Institutional Officer 
in the Office of Research Compliance and Integrity. The report should contain details about the 
type of data disclosed and the extent of the disclosure (number of subjects, who received it etc.).  
 
10.2  Source Documents  
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a research study necessary for the reconstruction and evaluation of the study. Source 
data are contained in source documents and may be paper, electronic or a combination of both. 
Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and CONFIDENTIAL. This material is the property of 
the University of Pennsylvania. Do not disclose or use except as authorized in writing by the 
study sponsor.  
 
10.3  Case Report Forms 
We will not use specific case report forms.  
 
 
 

Page 15 of 20 
Protocol Short Title: Dietary Flaxseed in NSCLC 
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10.4   HIPAA Retention Period (45 CFR164.530(j)) 
Protected Health Information (PHI) Research Requests (HIPAA1-008):  
Records documenting research requests, privacy board review or privacy officer expedited 
review, background material, and acceptance or denial of request. Retain 6 years after research 
completed.  
 
Protected Health Information Disclosure Records (HIPAA1-009):  
Documenting the release of PHI, including both authorized and unauthorized releases. 
Should include the date of release, to whom the information was released, and the 
circumstances of the release. Retain 6 years after research completed.  
 
Maintenance of HIPAA records is independent of the regulations for clinical study records. All 
records of PHI research requests and any type of release will maintained for 6 years after the 
research is fully terminated. 
11  
Study Monitoring, Auditing, and Inspecting 
11.1    Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Attachment 1.  The investigator 
will allocate adequate time for such monitoring activities.   
 
11.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
12 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.   
13 
Study Finances 
13.1 
Funding Source 
This study will be financed through a R21 grant through the National Institutes of Health (NIH). 
 

Page 16 of 20 
Protocol Short Title: Dietary Flaxseed in NSCLC 
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13.2 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All University of Pennsylvania investigators will follow the 
University conflict of interest policy. 
13.3 
Subject Stipends or Payments 
FS will be provided free of charge. Subjects will not be paid for their participation in this study.  
14 
References 
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Protocol Short Title: Dietary Flaxseed in NSCLC 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
Version Date:  07/27/2017 
 
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