Clinical trial NCT01869764
Conditions: Ductal Breast Carcinoma in Situ Lobular Breast Carcinoma in Situ Male Breast Cancer Stage IA Breast Cancer Stage IB Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2013-11-01; Completion date: 2018-07-01
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II clinical trial studies how well omega-3 fatty acid works in treating patients with stage I-III breast cancer. Studying samples of tissue and blood in the laboratory from breast cancer patients receiving omega-3 fatty acid may help doctors learn more about the effects of omega-3 fatty acid on tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if omega-3 dietary supplementation (omega-3 fatty acid) results in higher polyunsaturated fatty acids (PUFA) levels in surgical specimens of normal and malignant breast tissue in women who took omega 3 tablets in comparison to those who took placebo.

II. To determine if omega-3 dietary supplementation results in higher PUFA levels in plasma and red blood cells in women who took omega 3 tablets in comparison to those who took placebo.

III. To determine if omega-3 dietary supplementation affects the metabolites of omega-3 and omega-6 PUFA in surgical specimens of malignant and normal breast tissue in comparison to controls.

IV. To determine if women who take omega-3 dietary supplementation have less proliferation and greater apoptosis in malignant breast tissue in comparison to women who take placebo.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive omega-3 fatty acid orally (PO) daily for 7-14 days.

ARM II: Patients receive placebo PO daily for 7-14 days.

Arms: arm 1: Patients receive omega-3 fatty acid PO daily for 7-14 days. arm 2: Patients receive placebo PO daily for 7-14 days.
Interventions: intervention 1: omega-3 fatty acid intervention 2: placebo intervention 3: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
 
 
 
Co-Principal Investigators: 
Edward Levine, MD 
Department of General Surgery 
 
Greg Kucera, PhD 
Department of Internal Medicine – Hematology and Oncology 
Department of Cancer Biology 
 
Co-Investigator(s) 
Joseph O’Flaherty, MD 
Department of Internal Medicine – Infectious Diseases 
 
Marissa Howard-McNatt, MD 
Department of General Surgery 
 
Research Nurse: 
 
 
 
Michele Harmon, RN, BSN 
Comprehensive Cancer Center of Wake Forest University 
 
Statistician: 
Doug Case, PhD 
Department of Biostatistical Sciences 
Comprehensive Cancer Center 
 
Regulatory / Budget Contact: 
Megan Brown, BS 
Comprehensive Cancer Center of Wake Forest University 
 
Data Manager: 
Claire Kimbrough 
Comprehensive Cancer Center of Wake Forest University 
 
Drug Monitor: 
Sharon McFadden 
Comprehensive Cancer Center of Wake Forest University 
 
Participating Institution(s): 
Wake Forest School of Medicine 
 
Funding Sponsor: 
American Institute for Cancer Research  
 
Version Date: 
03.24.15 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
 
 
This document is proprietary property of the Comprehensive Cancer Center of Wake 
Forest University Health Sciences.  


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
i 
 
SCHEMA 
Objectives: 
 
 To determine if omega-3 dietary supplementation results in higher omega-3 PUFA levels in 
surgical specimens of normal and malignant breast tissue in women who took omega 3 
tablets in comparison to those who took placebo. 
 To determine if omega-3 dietary supplementation results in higher omega-3 PUFA levels in 
plasma and red blood cells in women who took omega 3 tablets in comparison to those who 
took placebo. 
 To determine if omega-3 dietary supplementation affects the metabolites of omega-3 and 
omega-6 PUFA in surgical specimens of malignant and normal breast tissue in comparison to 
controls. 
 To determine if women who take omega-3 dietary supplementation have less proliferation 
and greater apoptosis in malignant breast tissue in comparison to women who take placebo. 
 
 
Subject Eligibility: 
 
 Women scheduled to undergo surgical removal of newly diagnosed, histologically confirmed 
clinical stage I to III breast carcinoma and carcinoma in situ (including lobular carcinoma in 
situ and ductal carcinoma in situ). 
 Tumor measurement of at least 1 centimeter on imaging or physical exam 
 Age >18 years.  
 Ability to understand and the willingness to sign a written IRB-approved informed consent 
document. 
 No use of any NSAID or full-dose ASA-containing NSAID while taking study drug 
 No use of omega-3 fatty acid supplements within 1 month of enrollment 
 No patients with an allergy or known hypersensitivity to fish 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
ii 
 
Table of Contents 
SCHEMA ....................................................................................................................................................... i 
1.0 
Introduction and Background............................................................................................................ 1 
1.1 
Dietary sources of fatty acids ........................................................................................................ 1 
1.2 
Dietary n-3 PUFA and breast cancer ............................................................................................ 1 
1.3 
Rationale ....................................................................................................................................... 4 
2.0 
Objectives ......................................................................................................................................... 4 
3.0 
Patient Selection ................................................................................................................................ 4 
3.1 
Inclusion Criteria .......................................................................................................................... 4 
3.2 
Exclusion Criteria ......................................................................................................................... 5 
3.3 
Inclusion of Women and Minorities ............................................................................................. 5 
4.0 
Registration Procedures .................................................................................................................... 5 
5.0 
Treatment Plan .................................................................................................................................. 7 
5.1 
Study-Related Interventions .......................................................................................................... 7 
5.2 
Omega-3 PUFA Supplementation ................................................................................................ 7 
5.3 
General Concomitant Medication and Supportive Care Guidelines ............................................. 8 
5.4 
Duration of Subject Involvement .................................................................................................. 8 
6.0 
Adverse Events List and Reporting Requirements ........................................................................... 9 
6.1 
Adverse Event List for Omega-3 Fatty Acids ............................................................................... 9 
6.2 
Adverse Event Characteristics ...................................................................................................... 9 
6.3 
STRC SAE Reporting Requirements ............................................................................................ 9 
6.4  
WFUHS IRB AE Reporting Requirements................................................................................. 10 
7.0 
Pharmaceutical Information ............................................................................................................ 10 
7.1 
Pharmaceutical Information for PUFA Supplement ................................................................... 11 
7.2 
Pharmaceutical Information for Placebo ..................................................................................... 11 
8.0 
Correlative/Special Studies ............................................................................................................. 11 
9.0 
Statistical Considerations ................................................................................................................ 13 
9.1  Study Design/Endpoints ................................................................................................................... 13 
References ................................................................................................................................................... 15 
Appendix A – Eligibility and Source Document Checklists; Registration Form ....................................... 19 
Appendix B – Mandatory STRC SAE Notification Procedure ................................................................... 22 
Appendix C – Telephone Follow-up Data Collection Form ....................................................................... 25 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
iii 
 
Appendix E – CCCWFU Adverse Event Log ............................................................................................ 27 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
1 
 
1.0 
Introduction and Background 
1.1 
Dietary sources of fatty acids 
 
Saturated and monounsaturated fatty acids (FA) can be synthesized by human cells and 
obtained from diet.  By contrast, polyunsaturated fatty acids (PUFA) are essential FA that 
cannot be synthesized by mammals and must be obtained from diet. Thus the PUFA 
content of a tissue is dependent mainly on dietary intake. The shortest of the omega-6 
series of PUFA is linoleic acid (LA, 18:2, n-6) which is abundant in corn, sunflower, 
safflower, olive and other vegetable oils. Its 18 carbon omega-3 counterpart, α-linolenic 
acid (ALA, 18:3, n-3), is also a plant product found in leafy vegetables such as kale, 
spinach, broccoli and Brussels sprouts as well as walnuts and seeds such as flax and 
mustard. Both LA and ALA are converted through a series of enzymes to longer chain 
PUFA: LA to arachidonic acid (AA, 20:4, n-6), and ALA to eicosapentaenoic acid (EPA, 
20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3). LA is the most abundant FA in 
Western diets with consumption in the US that is 10-fold that of ALA (reviewed in (1)).  
Cell culture and animal studies have shown that that a high intake of LA lowers the 
conversion of ALA to EPA (2) and that the major source of EPA and DHA in humans is 
the dietary intake of salt water fish (3). 
1.2 
Dietary n-3 PUFA and breast cancer 
 
In human population studies, an inverse relationship has been observed between breast 
cancer incidence and calories from fish oil (4, 5). Nevertheless, current epidemiological 
literature on the association of marine PUFA and cancer remains controversial (6-8).  
One problem is that these studies have relied on data from self-reported dietary FA 
intakes or from estimates based on national consumption assessments that correlate 
poorly with direct measurements of FA in patient samples. The effect of n-3 PUFA 
depends on levels achieved in individuals and on the omega-3 PUFA content of the fish 
consumed. The EURAMIC study is one of the largest to use adipose tissue as a primary 
exposure measure for dietary fat intake (9). In this study, a lower ratio of n-6/n-3 PUFA 
was detected in adipose tissue of control compared to breast cancer subjects. A more 
recent study confirmed higher n-6 PUFA in adipose tissue of breast cancer patients 
compared to control individuals (10).  However outstanding gaps in existing knowledge 
of the potential benefit of n-3 PUFA in modifying breast cancer risk remains the lack of 
actual measurement of the PUFA and PUFA metabolites in malignant and normal 
breast tissues and an understanding of how dietary PUFA metabolism may contribute to 
and be altered in the neoplastic state.  
   
New data from the Women’s Intervention Nutrition Study (WINS) indicates that the risk 
of breast cancer recurrence can be reduced by a consuming a low fat diet (11). However, 
no attention was paid to specific FA species in the diet or how this might impact the FA 
content of breast tissue. Two earlier studies, one conducted with Japanese (12), the other 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
2 
 
with Finnish patients (13), identified increases in total PUFA in cancer compared to 
benign breast tissue. No such data are available for patients consuming “Western” diets.  
Finally, studies extant assume a tight or even 1:1 relation between PUFA in plasma, red 
blood cells (RBC), and breast cancer. Although many studies including our own in non-
human primates (14) have demonstrated that plasma FA profiles reflect dietary intake, 
our preliminary studies contradict the notion that RBC and to a lesser extent plasma 
measurements reflect the milieu in breast tissue. 
 
Mechanisms for modification of cancer risk by PUFA.  Studies in rodents strongly 
support a promoting role of omega-6 PUFA and a protective role of omega-3 PUFA in 
breast cancer (15-21): the growth of primary as well as metastatic tumors is inhibited by 
omega-3 PUFA-rich diets and promoted by omega-6 PUFA-rich diets. Several studies 
have suggested a potential use for omega-3 PUFA as a nutritional adjuvant therapy. In 
athymic nude mice with human breast cancer xenografts, lung metastases were inhibited 
by dietary supplementation with omega-3 PUFA initiated before or after surgical removal 
of the primary tumors (22). Dietary omega-3 PUFA also increased the efficacy of 
chemotherapeutic agents, doxorubicin (23) and mitomycin C, (24) in inhibiting tumor 
growth. These studies strongly suggest potential benefits of omega-3 PUFA 
supplementation at all levels of breast cancer. Although several mechanisms have been 
suggested by animal and cell culture studies, the most often cited mode for omega-3 
PUFA action is their ability to block metabolism of omega-6 PUFA, AA and LA (25-28).  
When AA and LA are released from cell membrane phospholipids, they are oxygenated 
by cyclooxygenases (COX)-1/2, 5-lipoxygenase (LOX), 12-LOX, and 15-LOX-1/2 to 
prostaglandin (PG)E2, 5-hydroxy-eicosatetraenoate (HETE), 12-HETE, 15-HETE, and 
13- hydroxy-octadecadienoic acid (HODE) (27, 29-32). These metabolites can promote 
breast cancer growth and the pathways making them may be overactive in breast cancer 
(27, 29-34). In contrast, omega-3 PUFA inhibit the release and metabolism of AA and 
LA to reduce formation of the omega-6 PUFA metabolites (27, 29-32, 35). Thus, the 
development and malignant behavior of breast cancer may reflect the overproduction of 
omega-6 PUFA-derived growth factors fueled by an omega-6 PUFA-rich diet and 
omega-3 PUFA-rich diets may inhibit this over-production. Our pilot data strongly 
support this concept. 
                     
Past studies on the effects of omega-6 PUFA metabolites and drugs that inhibit the 
oxygenases that make them have implicated the metabolites and oxygenases as growth 
factors. However, they varied widely as to which oxygenases and metabolites are critical 
to the proliferation and survival of cultured human breast cancer cells (29, 32, 35-37).  
Recent studies, including those in animals and humans, continue this disagreement.  
COX-2 and its PGE2 product are elevated in mouse models of breast cancer; COX-2 
over-expression induces breast tumors and Cox-2 knockout suppresses these tumors (33, 
34). Indeed, drugs that block COX-2 are associated with a reduced incidence of human 
breast cancer in human epidemiological studies (38) as well as mouse models of breast 
cancer (39-41). COX-1 may contribute to these effects or, in the absence of COX-2, 
mediate them (34, 35). On the other hand, 5-LOX inhibitors are particularly effective in 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
3 
 
stopping the growth of cultured human breast cancer cells, and 5-LOX metabolites 5-
HETE and 5-oxo-ETE (made from 5-HETE by a dehydrogenase; both act on cells 
through a common receptor, OXE (42)), are more effective than PGE2 in stimulating 
cultured human breast cancer cells to proliferate (43-47). Furthermore, mRNA for 5-LOX 
and its activating protein (FLAP) are increased in human malignant as opposed to normal 
breast tissue and in node (+) compared to node (-) disease; FLAP message levels 
correlate negatively with overall and disease-free survival (48, 49). Studies focusing on 
the 12-LOX/12-HETE axis find 12-HETE is somewhat weaker than 5-HETE in 
stimulating human breast cancer cell proliferation (47) but forced expression of 12-LOX 
stimulates the proliferation of human breast cancer cells in vitro and in mice (50).  12-
LOX-p message is over-expressed in malignant compared to normal human breast tissue 
and cell lines (32, 48, 51) and, when coupled with FLAP mRNA levels, provides a better 
prognostic indicator of overall and disease-free survival in breast cancer than FLAP 
mRNA alone (49).  Studies of 15-LOX find that 15-HETE and its hydroperoxy precursor, 
15-HpETE, may or may not inhibit the proliferation of breast cancer cells (46, 52) but 
mRNA and protein levels of their parent oxygenases, 15-LOX-1 and 15-LOX-2, are 
decreased in malignant compared to normal human breast tissue (48, 53).  Patients with 
low levels of message and protein for these oxygenases, or low 15-LOX-1/15-LOX-2 
message or protein ratios, have higher recurrence rates and shortened survivals (53).  
Thus, a 15-LOX, particularly 15-LOX-1, may suppress tumor growth.  Nonetheless, 
human breast cancer cells metabolize LA to 13-HODE through the action of 15-LOX’s 
(and COX-1/2) (54). 13-HODE is implicated in the proliferation, invasiveness, and 
metastatic behavior of breast cancer cells (54, 55). 
 
It is fair to say that the animal and human breast cancer studies to date have: 1) assigned 
multiple and often contradictory roles to the oxygenases and omega-6 PUFA metabolites 
in human breast cancer; 2) omitted companion studies on normal breast tissue; 3) not 
addressed the role of diet in modifying the lipid milieu of breast tissue; and most 
importantly, 4) focused on one or a limited range of oxygenases without measuring the 
metabolites per se. Because of the difficulty in measuring the metabolites, this last failure 
represents a critical barrier to progress in understanding the role(s) of PUFA in breast 
cancer. Studies typically identified one or two omega-6 PUFA metabolites using high 
performance liquid chromatography (HPLC) or immunoassays in animals or cultured 
cells but generally have not examined humans. HPLC assays do not distinguish between 
closely eluting metabolites (e.g. PGE2 versus PGE3) nor detect metabolites much below 
100 milligram levels. Immunoassays also do not distinguish omega-6 PUFA metabolites 
from their omega-3 PUFA counterparts and are not available for all the metabolites.  
Thus these methods are too insensitive and indiscriminant for human studies, particularly 
those analyzing the impact of omega-3 diets. In consequence, levels of the metabolites in 
malignant and normal breast tissue, the significance of their presence, and the impact of 
omega-3 PUFA diets on this presence are unknown. We have developed a multiple 
response monitoring-liquid chromatography-tandem mass spectroscopy (MRM-LC/ 
MS/MS) method that measures pg levels of PUFA metabolites in tissues to answer these 
vital questions.  


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
4 
 
1.3 
Rationale 
 
We hypothesize that omega-3 PUFA dietary supplementation will lead to a decrease in 
the omega-6 PUFA metabolite milieu in malignant breast tissue and will be associated 
with favorable prognostic markers. We will randomize women prior to definitive breast 
surgery to two grams of omega-3 fatty acid supplements daily or a matching placebo.  
We will measure the levels of omega-6 PUFA, omega-3 PUFA, and certain of their 
metabolites in the malignant breast tissue removed at surgery and compare the two 
groups. Further, we hypothesize that a defined level of omega-3 PUFA dietary 
supplementation will: 1) “reset” the PUFA metabolic pathway in malignant breast cells to 
one associated with a better prognosis by lowering the tumor load of omega-6 PUFA 
metabolites, and 2) fuel the production of omega-3 PUFA metabolites with anti-growth 
activity. For comparative purposes, we will pair these measurements to those made in 
nearby normal breast tissue. 
2.0 
Objectives 
 
2.1 To determine if omega-3 dietary supplementation results in higher PUFA levels in 
surgical specimens of normal and malignant breast tissue in women who took omega 
3 tablets in comparison to those who took placebo. 
 
2.2 To determine if omega-3 dietary supplementation results in higher PUFA levels in 
plasma and red blood cells in women who took omega 3 tablets in comparison to 
those who took placebo 
  
2.3 To determine if omega-3 dietary supplementation affects the metabolites of omega-3 
and omega-6 PUFA in surgical specimens of malignant and normal breast tissue in 
comparison to controls. 
 
2.4 To determine if women who take omega-3 dietary supplementation have less 
proliferation and greater apoptosis in malignant breast tissue in comparison to women 
who take placebo. 
3.0 
Patient Selection 
 
This clinical trial can fulfill its objective only if patients appropriate for this trial are 
enrolled. All relevant medical and other considerations should be taken into account 
when deciding whether this protocol is appropriate for a particular patient. Physicians 
should consider the risks and benefits of any therapy, and therefore only enroll patients 
for whom this treatment is appropriate. 
3.1 
Inclusion Criteria  
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
5 
 
 
 
 
3.1.1 
Newly diagnosed stage I to III breast cancer and carcinoma in situ (including 
lobular carcinoma in situ [LCIS] and ductal carcinoma in situ [DCIS])  
 
 
 
3.1.2 
Breast surgery (lumpectomy or mastectomy) is planned for at least 7 days 
from the day of enrollment.  
3.1.3  Age >18 years.   
3.1.4 
Ability to understand and the willingness to sign an IRB-approved written 
informed consent document. 
3.1.5 
Tumor measures at least 1 centimeter on imaging or physical exam 
 
  
3.2 
Exclusion Criteria  
 
3.2.1 Any patient with surgery scheduled < 7days after biopsy. 
3.2.2 Patients who are unable to refrain from the use of  any NSAID or full-dose 
ASA-containing NSAID while taking study drug. 
3.2.3 Patients who will receive neoadjuvant chemotherapy are not eligible. 
3.2.4 Patients who are currently taking omega-3 fatty acids, as they are unable to be 
randomized to placebo.  
3.2.5 Patients who have previously taken omega-3 fatty acid within 1 month prior to 
study enrollment 
3.2.6 Patients with an allergy or known hypersensitivity to fish 
3.2.7 Women who are pregnant or breastfeeding 
 
3.3 
Inclusion of Women and Minorities 
 
Women and members of all races and ethnic groups are eligible for this trial. 
4.0 
Registration Procedures 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer 
control trial, must be registered with the CCCWFU Protocol Registrar or entered into 
ORIS Screening Log within 24 hours of Informed Consent. Patients must be registered 
prior to the initiation of treatment.   
 
In order to ensure prompt registration of your patient, please: 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix A) 
3. Alert the WFUHS registrar by phone, and then send the signed Informed Consent 
Form, Eligibility Checklist and Protocol Registration Form to the registrar, either by 
fax or e-mail. 
 
 
Contact Information: 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
6 
 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
               
 
 
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Please fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 
Note:  If labs were performed at an outside institution, please provide a printout of the 
results.  Please ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will: 
 assign a patient study number 
 randomize the patient 
 register the patient on the study 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
7 
 
5.0 
Treatment Plan 
5.1 
Study-Related Interventions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients will be presented with the study and, if interested, provide written informed consent 
during their standard-of-care office visit. In addition, the routine physical conducted as standard 
of care during this visit will be used to obtain patients’ medical history, concurrent medications, 
and vital signs for the research study. 
5.2 
Omega-3 PUFA Supplementation 
 
Participants will be randomized to receive either two grams of omega-3 PUFA or 
placebo daily until the day before surgery. Omega-3 PUFA is supplied as a one 
gram capsule (see section 8.0 for a full description of the product). Placebos will 
be identical to the omega-3 supplements in size and color and will contain 99% 
soybean oil and less than 1% each of natural vitamin E, natural lemon flavor, 
marine lipid, and rosemary extract. PUFA and placebo capsules will be certified 
toxin-free products, and PUFA capsules will have verified EPA and DHA levels. 
 
Patients on both arms of the study will be instructed to take two capsules daily 
from the day after enrollment and the last two capsules the day prior to surgery.  
 
Baseline 
Intervention 
Periodd 
Day of Surgery 
Informed consent 
X 
 
 
Randomization 
X 
 
 
Demographics 
X 
 
 
Medical history 
X 
 
 
Concurrent meds 
X 
Xa 
 
Physical exam 
X 
 
 
Vital signs 
X 
 
 
Height, Weight, M2 
X 
 
 
Blood collection 
Xe 
 
Xe 
Specimen Collection 
 
 
X 
Adverse event evaluation 
 
X 
X 
Supplement Administration 
 
Xc 
 
Optional core biopsy for research purposes 
Xb 
 
 
a: Conducted via telephone for each patient on day 7 after enrollment. 
b: If available from clinically-obtained specimens. 
c: 2 grams of omega-3 PUFA or placebo PO daily during the intervention period. 
d: The intervention period is defined as the day after enrollment until the day prior to surgery. 
e: Whole blood; 4ml collected into EDTA tube 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
8 
 
The date that surgery is planned will be known at the time of randomization and 
an ample amount of the appropriate capsules will be supplied by the research 
nurse, plus four days’ worth of extra capsules. If there is a delay in the planned 
surgery, the patient will be told to continue taking the capsules as directed until 
the day prior to the revised surgery date.  
 
After one week of taking the capsules, the research nurse will call the patient to 
assess for adverse effects, self-reported compliance, confirm the surgery date, and 
address any other issues. In the event that the extra capsules are not sufficient to 
cover the remaining time until the scheduled date of surgery, additional capsules 
can be mailed to the patient’s home if needed. If the patient remains on study 
beyond 7 days, then additional phone calls will occur at day 14 and day 21 (and 
every seven days thereafter) until the patient undergoes surgery. Appendix C 
should be used to document the information obtained during these phone calls.  
 
5.3 
General Concomitant Medication and Supportive Care 
Guidelines 
 
The use of any NSAID or full-dose ASA-containing NSAID while taking study 
drug prohibited. Should the use of these agents be deemed necessary, the 
participant in question will be discontinued from the study.  Participants will be 
asked to use acetaminophen if needed during the study. 
 
All other medications and/or therapies during the intervention period will be 
performed as per standard of care, at the discretion of the participant’s physician. 
5.4 
Duration of Subject Involvement 
 
Subject participation extends from enrollment (at the clinic visit for the initial 
diagnosis) until the perioperative collection of study tissue specimens (usually 7-
14 days).  There will be no follow-up period, and the need for subject 
discontinuation is expected to be minimal. Nonetheless, participants will be 
withdrawn from the study in the event of any of the following: 
 
 Intercurrent illness that prevents further administration of treatment, 
 Patient decides to withdraw from the study,  
 Patient develops the need to use of any NSAID or full-dose ASA-containing 
NSAID between biopsy and surgery, or 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
9 
 
6.0 
Adverse Events List and Reporting Requirements 
6.1 
Adverse Event List for Omega-3 Fatty Acids  
 
Supplementation with omega-3 PUFAs is generally well-tolerated and safe. 
Theoretical concerns have been voiced regarding omega-3 PUFA 
supplementation aggravating bleeding; however, a recent study confirmed 
findings of prior smaller studies and failed to demonstrate any increased 
hemorrhagic risk across a variety of indices.(56)   
 
Possible adverse events include nausea, burping with fishy aftertaste, or 
gastrointestinal problems.(57) 
6.2 
Adverse Event Characteristics 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.   
 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
6.3 
STRC SAE Reporting Requirements 
 
The Safety and Toxicity Reporting Committee (STRC) is responsible for 
reviewing SAEs for CCCWFU Institutional studies as outlined in Appendix B. 
STRC currently requires that all unexpected 4 and all grade 5 SAEs on these trials 
be reported to them for review. All Clinical Research Management (CRM) staff 
members assisting a Principal Investigator in investigating, documenting and 
reporting an SAE qualifying for STRC reporting are responsible for informing a 
clinical member of the STRC as well as the entire committee via the email 
notification procedure of the occurrence of an SAE.  
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
10 
 
6.4  
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse 
events shall be promptly reported to the IRB, according to institutional policy.  
Reporting to the IRB is required regardless of the funding source, study sponsor, 
or whether the event involves an investigational or marketed drug, biologic or 
device.  Reportable events are not limited to physical injury, but include 
psychological, economic and social harm.  Reportable events may arise as a result 
of drugs, biological agents, devices, procedures or other interventions, or as a 
result of questionnaires, surveys, observations or other interactions with research 
subjects. 
 
All members of the research team are responsible for the appropriate reporting to 
the IRB and other applicable parties of unanticipated problems involving risk to 
subjects or others.  The Principal Investigator, however, is ultimately responsible 
for ensuring the prompt reporting of unanticipated problems involving risk to 
subjects or others to the IRB.  The Principal Investigator is also responsible for 
ensuring that all reported unanticipated risks to subjects and others which they 
receive are reviewed to determine whether the report represents a change in the 
risks and/or benefits to study participants, and whether any changes in the 
informed consent, protocol or other study-related documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a 
site where the study has been approved by the WFUHS IRB (internal events) 
must be reported to the WFUHS IRB within 7 calendar days of the investigator or 
other members of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at 
another site conducting the same study that has been approved by the WFUHS 
IRB (external events) must be reported to the WFUHS IRB within 7 calendar 
days of the investigator or other members of the study team becoming aware of 
the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential 
benefit of the research and as a result warrants a substantive change in the 
research protocol or informed consent process/document in order to insure the 
safety, rights or welfare of research subjects. 
7.0 
Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.1. 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
11 
 
7.1 
Pharmaceutical Information for PUFA Supplement  
 
Product description:  The omega-3 supplements used in this study will be 
provided by Nordic Naturals. The specific omega-3 formulation to be used in this 
study is ProOmega®, a marine oil concentration containing omega-3 PUFA, 
eicosapentaenoic acid (EPA) and doxosahexaenoic acid (DHA), supplied in 
triglyceride form. Each 2 capsule dose contains 650 EPA / 450 DHA per 2 soft 
gels. 
 
Route of administration:  Patients will take two capsules by mouth per day. 
7.2 
Pharmaceutical Information for Placebo 
 
Placebos used in this study will also be supplied by Nordic Naturals. Each capsule 
will be identical in size and shape to the PUFA supplements; however they will 
contain 99% soybean oil and less than 1% each of natural vitamin E, natural 
lemon flavor, marine lipid, and rosemary extract.  Patients randomized to receive 
placebo will take two capsules by mouth per day. 
8.0 
Correlative/Special Studies 
 
Between 5 and 100mg of tumor tissue and a similarly-sized section of adjacent normal 
tissue (obtained from sites equidistant from the site of prior fine needle aspiration) will be 
retrieved at surgery and immediately divided into sections for separate analyses of the 
metabolites and PUFA. For metabolites, a section is placed in 1 ml of tris-buffered saline 
(4 ºC, pH 7.4) containing 100 μM diethylenetriaminepentaacetic acid to chelate metals 
that attack alkenes, 80 μM of butylated hydroxytoluene to prevent oxidation, and 5 ng of 
each deuterated metabolite to serve as internal standards.  For PUFA, a section will be 
suspended in ethanol (4 ºC) containing 80 μM butylated hydroxytoluene and 100 μM 
triphenyl-phosphine. Samples on ice will be transported to our lab. Metabolite samples 
will be extracted with hexane: ethyl acetate (1:1). Extracts will be blown dry under a 
stream of N2, taken up in methanol, and stored under Argon at -80 ºC. PUFA samples 
will be stored at -80º under Argon in their original ethanol-inhibitor solution and 
extracted immediately before GC analysis.  
 
All tissues will be coded with a unique identifier so that patient identities cannot be 
discerned. 
 
Whole blood (4 ml) will be drawn into EDTA-containing tubes from patients both at 
baseline and immediately before surgery; placed on ice; adjusted to 100 μM in 
diethylenetriamine-pentaacetic acid and 80 μM butylated hydroxytoluene; transported on 
ice to our lab (Hanes 4032, contact Tiffany Walker-West at 336-716-3443 who will 
transport samples from OR to the lab); and centrifuged (1000g, 5 min, 4 º).  RBC will be 
washed with tris-buffered saline (pH 7.4) and suspended in buffer containing 80 μM 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
12 
 
butylated hydroxytoluene and 100 μM triphenylphosphine. RBC and plasma (1 ml) are 
stored at -80 ºC under Argon and extracted immediately before GC. In general, samples 
are placed in storage within 90 min of procurement.   
 
Our Institution performs Mib1 on all patients undergoing breast cancer surgery. Tissue 
blocks will be obtained from the Department of Pathology archives for the preparation of 
slides for cleaved caspase-3 immunostaining in our laboratory.  
 
For MRM-LC/MS/MS, breast tissues will be spiked with deuterated standards (5 ng) of 
each metabolite at the time of extraction except d4-PGE2 and d8-5-HETE will be used as 
the internal standard for PGE3 and 5-HEPE, respectively. We have synthesized d5-17-
OH-DHA for use as the internal standard for 17-OH-DHA. Extracts will be assayed for 
the daughter ion of each deuterated and non-
deuterated species, all of which have unique 
LC elution times, M-1 masses, and/or M-1 
breakdown ion masses (Table 1) relative to 
other monitored and unmonitored metabolites.   
 
Data are converted to pg/mg wet tissue weight 
and then corrected for processing losses by 
comparison to the recovery of their respective 
deuterated analogs.  We validated the 
accuracy and precision of this method and 
determined the linearity of recoveries over 1 
pg-100 ng of each metabolite in cultured 
mouse prostate cancer cells.  Our MS system 
is a Waters Quatro II with a Z-spray interface 
and automated by a Spark Holland LC and a 
Reliance Autosampler and Conditioned 
Staker maintained at 4 ºC.  We use a cone voltage of 35V and a capillary voltage of 2.4 
kV for HETE, HODE, and DHA metabolites and 50V and 3.5 kV for PG metabolites.  
The LC system for the latter three types of metabolites is a Waters Corp YMC ODS-AQ 
1.00 mm I.D.x100 mm length column eluted at 0.05 ml/min with 2 mM NH4OAc, pH 
8.0, as solvent A and MeOH as solvent B in the following gradients: 0 min, 70% B; 0-4 
min to 90% B; 4-5 min, 90% B; 5-6 min to 70% B; 6-30 min, 70% B.  The HETEs elute 
with complete baseline separation in this system.  The LC system for PGs is a 
Phenomenex Luna Phenyl-Hexyl 1.00 mm I.D. x 150 mm length column eluted at 0.07 
ml/min with H2O as solvent A and CH3CN, 0.1% formic acid, as solvent B in the 
following stepwise gradients: 0 min, injection; 0-6 min, 20% B; 6-6.1 min to 45% B; 6.1-
7.1 min, 45% B; 7.1-7.2 min to 65% B; 7.2-9.2 min, 65% B; 9.2-9.3 min to 20% B; 9.3-
15 min, 10 % B, 15 min.  
 
We will study a total of 60 patients, analyzing the PUFA in their plasma before and after 
dietary supplementation, breast cancer, and normal breast tissue and the PUFA 
Table 1 
 
Molecular weight of M-1 and daughter ions of 
species detected by MRM-LC/MS/MS 
Species 
M-1 
daughter ion 
PGE2 
351 
271 
d4-PGE2 
355 
275 
PGE3 
349 
269 
5-HETE 
319 
115 
5-HEPE 
317 
115 
d8-5-HETE 
327 
115.8 
15-HETE 
319 
218.8 
d8-15-HETE 
327 
225.7 
12-HETE 
319 
179 
d8-12-HETE 
327 
184 
13-HODE 
295 
194.7 
d4-13-HETE 
299 
197.7 
17-HDHA 
343 
207.5 
d5-17-HDHA 
348 
200.85 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
13 
 
metabolites in their breast cancer and normal breast tissue as described in Table 2.  In 
some patients we may have the opportunity to collect a specimen at study enrollment for 
research purposes only. In that small subset we will have an additional core biopsy 
available for research purposes. We will evaluate the FAs pre-surgery and pre-
intervention. We anticipate that approximately 10-20 patients will be appropriate for a 
core biopsy for research purposes only.    
 
 
Table 2 – Samples to be Collected 
 
PUFA 
Plasma
/RBC 
Breast, 
tumor1 
Breast, 
normal 
Metabolites 
Breast, 
tumor1 
Breast, 
normal 
 
 
FA pre-study 
60 
 
 
OH  #1 
60 
60 
FA at surgery 
60 
60 
60 
OH #2 
60 
60 
 
 
 
 
PGE’s 
60 
60 
1Includes 30 patients with invasive ductal cancer in each dietary treatment group.  PUFA are analyzed by GC, 
metabolites by MRM-LC/MS/MS; OH (i.e. HETE/ HODE/HDHA) metabolites require two separate MRM-
LC/MS/MS runs. 
 
   
9.0 
Statistical Considerations 
9.1  Study Design/Endpoints 
 
This is a randomized, placebo controlled phase II trial assessing the effect of omega-3 
dietary supplementation on PUFA levels (LA, AA, EPA, DHA, total omega-6 PUFA, 
total omega-3 PUFA and n-6/n-3 PUFA ratios), metabolites of omega-3 and omega-6 
PUFA (see Table 1), and proliferation and apoptosis in women with stage I-III breast 
cancer. Patients who meet the eligibility criteria will be randomized to omega-3 dietary 
supplementation or a matching placebo with equal probability. Randomization will occur 
following the diagnosis of breast cancer and at least one week prior to the scheduled 
surgical resection. Patients will take two capsules per day from the time of randomization 
through the day before surgery.  The primary objective is to assess the effect of omega-3 
supplementation on PUFA levels in normal and metastatic breast tissue and in plasma 
and red blood cells. Secondary objectives include assessing the effect of the omega-3 
supplementation on the metabolites of omega-3 and omega-6 PUFA in malignant and 
normal breast tissue and assessing the effect of the supplementation on proliferation and 
apoptosis in malignant breast tissue. 
 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
14 
 
9.2  Analyses 
Descriptive reports will consist of summary statistics (means, standard deviations, 
proportions, etc.) for patient characteristics and outcome measures (including toxicities) 
by treatment arm. Tables, graphs, and charts will be used to illustrate the data when 
appropriate. Accrual and toxicity are followed by the Safety and Toxicity Review 
Committee, and adverse events will be reported to the IRB.  
Analysis of variance (ANOVA) will be used to assess the effect of omega-3 dietary 
supplementation on PUFA levels separately in normal and malignant breast tissue.  
Additionally, we will fit the normal and malignant breast tissue jointly as repeated 
measures to see if there are PUFA differences by tissue type and to determine if the 
omega-3 effect differs in the two tissue types (tissue type by treatment interaction). Since 
we will have pretreatment PUFA levels in the serum, we will use analysis of covariance 
(ANCOVA) to assess the omega-3 effect in plasma and RBC, where the baseline levels 
of the PUFAs will be included as covariates.  In all analyses, residuals will be assessed to 
determine if the assumptions of variance homogeneity and normality (and linearity for 
the ANCOVA models) are met, and transformations will be used if needed. The 
secondary outcomes will be analyzed using the same methods as described for the 
primary outcomes. 
9.3  Sample Size/Power 
Sixty patients will be accrued to this study, approximately 30 in each arm. This sample 
size will allow us to detect a one standard deviation (SD) difference between treatment 
groups in PUFA levels with 80% power at the 5% overall level of significance (allowing 
for multiple comparisons by using a Bonferroni correction – each test done at the 0.05/7 
level of significance), assuming a 10% drop-out rate. The anticipated accrual rate for this 
study is two patients per month. 
9.4  Stratification/Randomization 
There are no strata in this study. All eligible patients will be randomized to omega-3 
supplementation or a matching placebo with equal probability using a variably sized 
permuted block randomization scheme. Block sizes will be chosen randomly to ensure 
that future randomizations cannot be inferred from past assignments.   
 
 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
15 
 
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Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
16 
 
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CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
17 
 
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Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
18 
 
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CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
19 
 
Appendix A – Eligibility and Source Document Checklists; 
Registration Form 
 
REGISTRATION GUIDELINES 
 
The following guidelines have been developed in order to ensure timely registration of your 
patient. 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 
trial, must be registered with the CCCWFU Protocol Registrar or entered into ORIS Screening 
Log within 24 hours of Informed Consent.  Patients must be registered prior to the initiation of 
treatment.   
 
In order to ensure prompt registration of your patient, please: 
1. Complete the Eligibility Checklist (attached) 
2. Complete the Protocol Registration Form (attached) 
3. Alert the WFUHS registrar by phone, and then send the signed Informed Consent Form, 
Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or 
 e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
              *Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
4. Please fax/e-mail ALL eligibility source documents with registration.  Patients will not be 
registered without all required supporting documents. 
Note:  If labs were performed at an outside institution, please provide a printout of the 
results.  Please ensure that the most recent lab values are sent. 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
20 
 
CCCWFU #  98113  
 
Eligibility Checklist                                              Page 1                            
 
Yes No 
N/A Inclusion Criteria (All responses must be YES in order to enter study) 
Eligibility 
Confirmation 
(registrar) 
 
 
 
Does the patient have newly diagnosed stage I to III breast cancer 
and carcinoma in situ (including lobular carcinoma in situ [LCIS] and 
ductal carcinoma in situ [DCIS])? 
 
 
 
 
Is the patient scheduled to undergo breast surgery (lumpectomy or 
mastectomy) at least 7 days from the day of enrollment? 
 
 
 
 
Is the patient >18 years of age? 
 
 
 
 
Is the patient able to understand and willing to sign an IRB-approved 
written informed consent document? 
 
 
 
 
Does the patient’s tumor measure at least 1 centimeter on imaging or 
physical exam? 
 
 
 
 
Yes No 
N/A Exclusion Criteria (All responses must be NO in order to enter study) 
 
 
 
 
 
 
 
 
 
Is the patient scheduled for breast surgery sooner than 7 days after 
biopsy? 
 
 
 
 
Will the patient require the use of any NSAID or full-dose ASA-
containing NSAID while taking study drug? 
 
 
 
 
Is the patient scheduled to receive neoadjuvant chemotherapy? 
 
 
 
 
Is the patient currently taking omega-3 fatty acids? 
 
 
 
 
Has the patient previously taken omega-3 fatty acid within 1 month 
prior to study enrollment? 
 
 
 
 
Does the patient have an allergy or known hypersensitivity to fish? 
 
 
 
 
Is the patient pregnant or breastfeeding? 
 
 
 
 
Signature: ______________________________ Date: _________________ 
 
Please send source documentation with Eligibility Form.  
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
21 
 
CCCWFU # 98113 Protocol Registration Form                               Page 2 
 
DEMOGRAPHICS 
Patient: Last Name: 
_____________________ 
First Name: 
____________________________ 
MRN:   ___ ___ ___ ___ ___ ___ ___ ___ 
DOB (mm/dd/yy): __ __ / __ ___ / __ __ 
SEX:   
  Male             Female 
Ethnicity (choose one):   
 Hispanic     Non-Hispanic  
Race (choose all that apply): 
 WHITE    BLACK     ASIAN      PACIFIC ISLANDER     NATIVE AMERICAN  
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Zip Code:  ___ ___ ___ ___ ___ 
Primary Diagnosis: 
_____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
Date of scheduled surgery:  ___ ___ / ___ ___ / ___ ___ 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 
PM, Monday – Friday. 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, 
faxed or e-mailed to the registrar at 336-7136772 or registra@wakehealth.edu. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES 
  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
22 
 
Appendix B – Mandatory STRC SAE Notification Procedure 
 
Mandatory Safety and Toxicity Review Committee (STRC) Serious Adverse Event (SAE) 
Reporting Requirements – Revised 6/05/2012 
 
This document describes STRC reporting and use of the electronic submission form that is 
submitted for unexpected grade 4 and any grade 5 (death during protocol intervention) 
SAEs on CCCWFU Institutional interventional trial patients. There are multiple entities that 
require reporting of SAEs. Each entity has different rules for what is reported, and how it is 
reported.  
 
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) 
should NOT be used to evaluate whether an event should be reported to STRC. Only the rules for 
reporting described in this document should be considered. 
 
As defined in the NCI summary IV reporting guidelines, CCCWFU Institutional studies 
covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in which 
the center is a primary contributor to the design, implementation, and monitoring of the 
trial, or participation in a multi-site trial initiated by an institutional investigator at 
another center.  Institutional trials are almost always authored by a researcher here at 
CCCWFU. Institutional protocols are labeled NCI Code=”I” for Institutional on the protocol 
screen in ORIS. Cooperative group protocols are not considered Institutional, but Research Base 
trials are classified as Institutional. 
 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional studies, as defined 
above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these trials be 
reported to them for review. All Clinical Research Management (CRM) staff members assisting 
a PI in documenting and reporting an SAE that qualifies for STRC reporting are responsible for 
informing a clinical member of the STRC by phone, followed by informing the entire committee 
via the required email notification. 
 
THESE REPORTING REQUIREMENTS APPLY TO EVERYONE WORKING WITH 
CANCER CENTER INSTITUTIONAL PROTOCOLS. 
 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event not including routinely experienced events per protocol (e.g. 
myelosuppression) and all grade 5 events (death during protocol intervention) should be 
reported. The patient is considered “on-treatment” as defined in the protocol, which can extend 
days/weeks/months past the last date of actual protocol intervention.  
 
 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
23 
 
 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2 and 
Phase 3 Interventional Trials 
 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 3 
 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated Not 
Required 
Not Required REPORT 
TO STRC 
Not 
Required 
REPORT 
TO STRC 
REPORT 
TO STRC 
Unlikely 
Not 
Required 
Not Required REPORT 
TO STRC 
Not 
Required 
REPORT 
TO STRC 
REPORT 
TO STRC 
Possible 
Not 
Required 
Not Required REPORT 
TO STRC 
Not 
Required 
REPORT 
TO STRC 
REPORT 
TO STRC 
Probable 
Not 
Required 
Not Required REPORT 
TO STRC 
Not 
Required 
REPORT 
TO STRC 
REPORT 
TO STRC 
Definite 
Not 
Required 
Not Required REPORT 
TO STRC 
Not 
Required 
REPORT 
TO STRC 
REPORT 
TO STRC 
 
STRC reporting may not be appropriate for specific expected adverse events for protocols. In those 
situations the adverse events that will not require STRC reporting must be specified in the text of 
the approved protocol. 
 
STRC notification responsibilities of the person handling the reporting/documenting of the 
SAE: 
1. Make a phone call to the appropriate clinical member of the STRC as listed below (page if 
necessary)—see note 2 below 
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. 
This form is found at either the ORIS main menu page or by going to 
http://ccc.wfubmc.edu/oris/strc.aspx. 
This will ensure that all persons that the event applies to will be notified; remember to file a 
copy of your confirmation. (Form instructions will walk you through the required fields, 
consult the help page for further instructions.) 
3. Ensure that you document that the appropriate persons on the STRC has been contacted. 
4. Follow up with/update the clinical member of STRC regarding any new developments or 
information obtained during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the electronic STRC form: 
1. ORIS Patient ID (PID) 
2. Name of STRC Clinician notified/Date/Time/Comments. 
3. Grade of event. 
4. Is this related to protocol intervention or treatment? 
5. Is suspension of the protocol needed? 
6. Is any change to consent or protocol needed? 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
24 
 
7. Was the nature or severity of the event unexpected? 
8. Date of the event. 
9. Brief description of the event using approved CTC version terminology. 
10.  Date of last study dose before event. 
11. Relevant tests/labs. 
12. Most importantly make sure that the Investigator assigns attribution to the reported 
 
event (grade) using the appropriate CTCAE version for the protocol. 
 
The Clinical Members of STRC to Notify by Phone or Page: 
 
Bayard Powell, MD – Director-at-Large, CCCWFU; Chair, PRC; Section Head,  
Glenn Lesser, MD – Hematology Oncology  
Kathryn Greven, MD – Vice Chair –  
Marissa Howard-McNatt, MD – General Surgery  
 
Definition of Unavailable: As a general guideline if the first clinician that is contacted does not 
respond to the phone call or page within a reasonable amount of time, then initiate contact with 
their backup.  Give the back-up a reasonable amount of time to respond to a phone call or page 
before contacting another member. This is a general guideline.  You must use your best 
judgment as a clinical research professional given the time of day, severity of the SAE, and other 
circumstances as to when it is appropriate to contact backup clinicians.  If the event occurs near 
the end of day, then leave messages (voice or email) as appropriate and proceed with submitting 
your STRC notification form.  The important criteria is that have taken reasonable steps to notify 
and document that you have initiated some type of contact to one or more of the clinical 
members of STRC. 
 
STRC CLINICAN RESPONSIBILITY: 
 
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as 
they are reported; and communicate a response to the Investigator, event reporter and the 
members of STRC. The review will include but not be limited to the information reported; there 
may be times when additional information is needed in order for an assessment to be made 
further communication directly with the investigator may be warranted. STRC reserves the right 
to agree with the investigator’s assessment if STRC does not agree with the investigator STRC 
reserves the right to suspend the trial pending further investigation. 
 
AMENDMENTS TO PREVIOUS REPORTS 
 
If you are not able to supply all pertinent information with the initial submission, once the 
additional information is available do not submit a new report. Go to the original email that 
was received by STRC and others “reply to all” and entitle your email “Amendment for (list 
date of event and patient ID) this will avoid duplications of the same event. List the additional 
information which you are reporting. 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
25 
 
Appendix C – Telephone Follow-up Data Collection Form 
 
ORIS PID:  _____________ Initials of person completing form:  ____________ 
Date of call:  
 
____ ____ / ____ ____ / ___ ____ 
 
Omega-3 PUFA Supplementation: 
Date patient began taking capsules:  ____ ____ / ____ ____ / ____ ____ 
Original date of surgery: 
____ ____ / ____ ____ / ____ ____ 
Has the patient’s surgery been rescheduled? Yes  
  No 
    
 
If Yes, indicate new date: ____ / ____ / ____ 
 
If Yes, does patient have ample capsules to last until surgery? Yes  
  No 
   
 
If No, indicate the # of additional capsules mailed to patient and the date of shipment: 
 
# capsules:  _________________  Date shipped:  ____ ____ / ____ ____ / ____ ____ 
 
Compliance:  
Does the patient report compliance with taking capsules? Yes  
  No 
    
If No, how many doses of medication were missed? _________ 
 
Adverse Events: 
Have any adverse events been identified?    Yes  
  No 
    
If Yes, Have they been recorded on the CCCWFU AE Log (Appendix F)? Yes 
 No 
 NA 
 
Have the adverse events been documented in the medical record?  Yes  
  No 
   NA 
 
 
Other issues noted during phone call: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in 
Patients with Stage I-III Breast Carcinoma 
 
26 
 
Appendix D – Tissue Procurement Form 
 
 
 
 A minimum of 5mg and maximum of 100mg of tissue will be obtained from tumor and 
normal breast tissue.  
 Antioxidant solution will be provided by the Edwards or Kucera lab. 
 Divide samples into two sections, record weights and place in labeled eppendorf tubes 
containing the antioxidant solution.  
 
 
                                                Tumor                                                              Normal 
 
    Section/tube#                 1                         2                                               3                        4                
 
    % of total mass           ~40%                 ~60%                                      ~40%                    ~60%          
 
    Weight in mg            _______            _______                                    _______            _______     
  
    Antioxidant                  1ml                    1ml                                             1ml                   1ml             
 
 
 
Blood 
 
 Collect in 4ml purple vacutainer tube.  
 Invert 8-10 times. Store on ice for immediate pick up by Tiffany Walker-West (6-3443) 
 
 
 
 
 
 
Patient identification # ____________________                           Date _________________ 
 
 
 
 
 


CCCWFU 98113 
Comprehensive Cancer Center of Wake Forest University 
A Randomized, Placebo-Controlled Phase II Clinical Trial of Omega-3 PUFA Dietary Supplementation in Patients with Stage I-III Breast Carcinoma 
 
27 
 
Appendix E – CCCWFU Adverse Event Log 
Adverse 
Event 
Descriptio
n 
Start 
Date 
 
Stop 
Date 
 
AE Type 
Grade (1-5) 
per CTC v. 
4.0 
 
 
Attribution 
 
 
 
Serious 
 
 
 
Action Taken 
 
 
 
Treating 
Physician 
Initials/ 
Date 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 

ICF_001.pdf: