Conditions: Advanced Malignant Neoplasm Fatigue
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well ethyl icosapentate and physical activity work in treating fatigue in patients with cancer that has spread from where it started to other places in the body. Ethyl icosapentate and physical activity may provide more robust and clinically effective improvement of cancer related fatigue, which may facilitate patients continuing cancer therapy since it would be tolerated and effective in controlling disease.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the effect of the combination of ethyl icosapentate (icosapent ethyl) 2 gm orally daily plus physical activity (PA) for the reduction of cancer related fatigue (CRF) (Functional Assessment of Chronic Illness Therapy - Fatigue \[FACIT-F\] subscale) at the end of 8 weeks in patients with advanced cancer by comparing the difference between the FACIT-F subscale score at baseline and at 57 +/- 5 days, between patients who will receive either Icosapent ethyl plus physical activity and placebo plus physical activity.

SECONDARY OBJECTIVES:

I. To determine the feasibility, adherence, and satisfaction of using the combined intervention for the reduction of cancer related fatigue in advanced cancer.

II. To explore the effects of the combination of Icosapent ethyl 2 gm orally daily plus physical activity on quality of life (QOL)-related variables, mood (HADS - Hospital Anxiety and Depression Inventory), quality of life domains (Functional Assessment of Cancer Therapy - General \[FACT-G\]), cancer related symptoms (Edmonton Symptom Assessment Scale - ESAS) in these patients.

III. To explore the effects of combined intervention on serum C - reactive protein and intracellular cytokine levels (IL-6, TNF-a, IL-10, IL-1RA) before and after treatment.

IV. To explore its side effects and tolerability of the combined study interventions in these patients.

V. To explore the effect of multimodal therapy on body composition. VI. To explore the effect of the proposed treatment in this study on the overall survival time in patients.

OUTLINE: Patients are randomized to 1 of 3 groups.

GROUP I: Patients receive ethyl icosapentate orally (PO) twice daily (BID) for 8 weeks. Patients complete resistance exercises 3 days per week and undergo walking program at least 5 days per week for 8 weeks. After 8 weeks, patients may optionally continue to receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks.

GROUP II: Patients receive placebo PO BID for 8 weeks. Patients complete resistance exercises 3 days per week and undergo walking program at least 5 days per week for 8 weeks. After 8 weeks, patients may optionally receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks as in Group I.

GROUP III: Patients receive placebo PO BID for 8 weeks. Patients meet with an exercise specialist during the first week to learn different stretching exercises and complete the stretching exercises 3 days per week for 8 weeks. After 8 weeks, patients may optionally receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks as in Group I.

After completion of study treatment, patients are followed up at 1 month.

Arms:
arm 1: Patients receive ethyl icosapentate PO BID for 8 weeks. Patients complete resistance exercises 3 days per week and undergo walking program at least 5 days per week for 8 weeks. After 8 weeks, patients may optionally continue to receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks. arm 2: Patients receive placebo PO BID for 8 weeks. Patients complete resistance exercises 3 days per week and undergo walking program at least 5 days per week for 8 weeks. After 8 weeks, patients may optionally receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks as in Group I. arm 3: Patients receive placebo PO BID for 8 weeks. Patients meet with an exercise specialist during the first week to learn different stretching exercises and complete the stretching exercises 3 days per week for 8 weeks. After 8 weeks, patients may optionally receive ethyl icosapentate, complete resistance exercises, and undergo walking program for 4 weeks as in Group I.

Interventions: intervention 1: Ethyl Icosapentate intervention 2: Exercise Intervention intervention 3: Exercise Intervention intervention 4: Laboratory Biomarker Analysis intervention 5: Placebo intervention 6: Quality-of-Life Assessment intervention 7: Questionnaire Administration
Intervention descriptions: intervention 1: Given by mouth 2 gm orally daily plus physical activity intervention 2: Complete resistance exercises and undergo walking program intervention 3: Meet with exercise specialist and complete stretching exercises intervention 4: Correlative studies intervention 5: Given PO intervention 6: Ancillary studies intervention 7: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2016-0348 
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 Title page  
 
EFFECTS OF FISH OIL AND PHYSICAL ACTIVITY ON FATIGUE IN PATIENTS WITH ADVANCED 
CANCER  
Study Interventions:  
Icosapent ethyl, matching placebo, and 
standardized Physical Activity  
[Study purpose:]  
Phase II preliminary efficacy trial  
Clinical study phase:  
II 
Principal Investigator:  
Sriram Yennu, MD, MS  
Associate Professor  
University of Texas M.D. Anderson Cancer Center  
Department of Palliative, Rehabilitation, and 
Integrative Medicine – Unit 1414  
1515 Holcombe Blvd, Houston, TX 77030  
713-792-3938  
 
Co-Principal Investigator:  
 
Eduardo Bruera, MD  
Professor and Chair  
University of Texas M.D. Anderson Cancer Center  
Department of Palliative, Rehabilitation, and 
Integrative Medicine – Unit 1414  
1515 Holcombe Blvd, Houston, TX 77030  
713-792-6084  
 
Co-Investigators:  
 
Cathy Eng MD, Professor ; David Fogelman MD, 
Assistant Professor; Department of GI Medical 
Oncology; University of Texas M.D. Anderson 
Cancer Center  
Karen Basen-Engquist PhD, Professor, 
Department of Behavioral Science, University of 
Texas M.D. Anderson Cancer Center  
Kenneth Hess PhD, Professor; Diane Liu, Principal 
Statistical Analyst, Department of Biostatistics, 
University of Texas M.D. Anderson Cancer Center  
James Reuben PhD, Professor, Department of 
Hematopathology – Research, University of Texas 
M.D. Anderson Cancer Center  
Rony Dev MD, Associate Professor, Department 
of Palliative, Rehabilitation and Integrative 
Medicine  
 


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Data Manager:  
 
Janet L. Williams, MPH  
Supervisor, Data Analysis  
University of Texas M.D. Anderson Cancer Center  
Department of Palliative, Rehabilitation and 
Integrative Medicine – Unit 1414  
1515 Holcombe Blvd, Houston, TX 77030  
713-792-9153  
 
Statistician:  
 
Kenneth Hess, PhD  
Professor  
University of Texas M.D. Anderson Cancer Center  
Department of Biostatistics – Unit 1411  
1515 Holcombe Blvd, Houston, TX 77030  
713-794-4157  
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Synopsis 
Title  
Effects of fish oil and physical activity on fatigue in Patients with Advanced Cancer  
Clinical study phase : II  
 
Study objective(s)  
 
Primary Objective: 1. To determine the effect of the combination of Icosapent ethyl 2 gm orally daily 
plus physical activity for the reduction of cancer related fatigue [FACIT-F subscale] at the end of 8 weeks 
in patients with advanced cancer by comparing the difference between the FACIT-F subscale score at 
baseline and at 57±5 days, between patients who will receive either Icosapent ethyl plus physical activity 
and placebo plus physical activity.  
 
Secondary Objectives:  
 
1. To determine the feasibility, adherence, and satisfaction of using the combined intervention for the 
reduction of cancer related fatigue in patients with advanced cancer.  
 
2. To explore the effects of the combination of Icosapent ethyl 2 gm orally daily plus physical activity on 
quality of life-related variables, mood (HADS – Hospital Anxiety and Depression Inventory), quality of life 
domains (FACT-G), Cancer related Symptoms (Edmonton Symptom Assessment Scale – ESAS) in these 
patients.  
 
3. To explore the effects of combined intervention on serum C - reactive protein and intracellular 
cytokine levels [IL-6, TNF-α, IL-10, IL-1RA] before and after treatment.  
 
4. To explore its side effects and tolerability of the combined study interventions in these patients.  
 
5. To explore the effect of multimodal therapy on body composition.  
 
6. To explore the effect of the proposed treatment in this study on the overall survival time in patients.  
 
We hypothesize that:  
• 
The combination of Icosapent ethyl plus physical activity is capable of significantly reducing the 
severity of CRF between baseline and end of week 8 [FACIT-F subscale].  
• 
Physical activity is capable of reducing the severity of CRF between baseline and end of week 8.  
 
Background  
 
Cancer-related fatigue (CRF) is the most frequently reported symptom associated with cancer and its 
treatment. CRF is more severe and debilitating in patients with advanced cancer than in those with early 
cancer or in cancer survivors. Its frequency ranges from 60% to 90% in patients who are receiving 
palliative care. As a result of improved therapy, patients with advanced cancer are living longer, and due 
to advances in treatment for pain and nausea, clinicians are more frequently recognizing CRF as an 
important symptom that negatively affects quality of life (QOL), interferes with daily activity, has 


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potentially devastating social and economic consequences, and affects the ability to receive palliative 
cancer therapy. However, only few studies have been conducted to determine whether established 
therapies for CRF such as physical activity are effective in palliative care patients. In addition, prior 
pharmacological studies for CRF in palliative care have shown mixed results. Given the high frequency of 
adverse effects of CRF and the limited treatment options in advanced cancer patients, further research 
on new treatment strategies is greatly needed. The rationale for the proposed study is that, CRF is a 
frequent and serious consequence of cancer and cancer related treatment. As palliative care moves to 
early integration, palliative care is increasingly been provided in an outpatient setting, a vast majority of 
advanced cancer patients are receiving some form of active therapy such as targeted therapy. CRF is 
common, limits the use of targeted therapy in advanced cancer patients and significantly impacts QOL. 
Several strategies have been proposed for management of CRF, none of these strategies result in 
clinically relevant improvement (defined as at least 10 point improvement in the Functional Assessment 
of Cancer Illness Therapy-Fatigue (FACIT-F) scores or equivalent in other validated scales) of CRF despite 
showing modest benefit as compared to placebo. The most plausible reason is that these interventions 
have been unable to target the multifactorial target mechanisms that cause CRF. Our group has shown 
that dexamethasone results in improvement of fatigue; however, these agents may be useful only for a 
short duration due to the side-effect profile. On the basis of previously described mechanisms and the 
results of pilot studies, Ecosapentaenoic Acid (EPA) or fish oil has beneficial effect on fatigue in patients 
with cancer. Previous fish oil studies however had several limitations including the dose (low dose 
<2gm), short duration of treatment (~3 weeks), number of capsules (>10), and no validated measure for 
fatigue such as FACIT-F. The duration of efficacy, and possible mechanisms EPA in reduction of CRF, has 
not been characterized. In addition, not all assessment tools used in previous studies were validated, 
and there was no attempt to understand the pathophysiologic characteristics of EPA using laboratory 
correlates in fatigued cancer patients. The effects of EPA on CRF and cytokine levels must be defined 
through randomized controlled studies using validated tools and laboratory correlates. In cancer 
patients receiving treatment and in cancer survivors, physical activity (PA) or exercise has been shown to 
improve CRF. Randomized clinical trials among cancer patients who participated in an physical activity 
program showed significant increases in cardiovascular capacity; improved overall health-related QOL; 
less fatigue; fewer sleeping problems; and increased self-reported physical functioning, general well-
being, self-esteem, and energy. A recent Cochrane meta-analysis of 28 clinical trials that included more 
than 2,000 cancer patients confirmed these findings. However, the evidence suggests that physical 
activity has a very modest benefit (effect size 0.23) in improving CRF. This lack of robust response 
(defined as >/=10 points on the FACIT-F subscale) to these treatments may be due to a lack of effect on 
the multidimensional and multifactorial nature of CRF. Hence there is a need to test combined therapies 
for CRF such as fish oil plus physical activity, since these treatments individually target the 
multidimensional causative factors contributing to CRF in advanced cancer. 
 
Indication Cancer Related Fatigue  
 
Diagnosis and main criteria for inclusion  
 
Inclusion:  
 
1) Diagnosis of advanced cancer  
2) Patients should describe fatigue as being present for a minimum of 2 weeks 


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3) Patients should rate the severity of fatigue as 4/10 in a 0-10 ESAS scale, where 0=no fatigue, 10= 
worse fatigue possible 
4) If patients are on opioids for the treatment of cancer pain, they must have had no major dose change 
(>25%) for at least 48 hours prior to study entry. Change in opioid dose after study entry is allowed  
5) Presence of relatively intact cognition defined by normal memorial delirium assessment scale (<7/30); 
sign written informed consent  
6) Patients must be 18 years or older  
7) Patient willing to keep a daily diary, engage in telephone follow up with a nurse  
8) Patient must have telephone access to be contacted by the research nurse  
9) Hemoglobin of >/=10 g/dl within 2 weeks of enrollment. If the patient has not had blood drawn for a 
hemoglobin level in the past two weeks, one will be done to determine the eligibility  
10) Patients should have a Zubrod </= 1  
 
Exclusion:  
 
1) Major contraindication to fish oil i.e. hypersensitivity to fish/oil or physical activity  
2) Currently on fish oil or has been on fish oil within the last 10 days  
3) Inability to complete the baseline assessment forms or to understand the recommendations for 
participation in the study  
4) Pregnant or lactating women. Childbearing age women are not on birth control  
5) Reports a fall in the past 30 days  
6) Patient reported regular participation in moderate- or vigorous-intensity physical activity for at >/=30 
minutes at least 5 times a week and strength training for >/=2 days/week  
7) Active or clinically significant cardiac disease (e.g., New York Heart Association functional class II or 
more)  
8) Signs of third spacing as determined by the treating physician (e.g., pedal edema, pleural effusion, 
ascites)  
 
Study design  
 
We will randomize 96 eligible patients in the Biostatistics Clinical Trial Conduct website to receive either 
Icosapent ethyl 2 gm orally daily plus physical activity, or placebo plus physical activity, or placebo plus 
control physical activity (1:1:1) for 8 weeks  
 
Type of control  
 
In this randomized controlled study, patients will be randomized to either combination of Icosapent 
ethyl 2 gm orally daily plus physical activity; or placebo plus physical activity or placebo plus control 
physical activity for 8 weeks. The placebo will appear identical to the drug, but will contain 
methylcellulose as the inert ingredient. Assessment will be performed at baseline to Day 57±5 ±5 as per 
Table 4. In the proposed study we plan to use fish oil preparation, Icosapent ethyl [an ethyl ester of EPA] 
0.5 gram capsules [Amarin Pharma Inc, Bedminster, NJ, 2012]. The objective of 8 weeks of treatment is 
to evaluate the efficacy of the combined intervention for cancer related fatigue.  
 


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The rationale for placebo and control arm for physical activity is to control for placebo effect, attention 
to participants’ expectation and the subjective elements of diagnosis or assessment. See Table 4 for the 
study assessments. All patients at the primary end point (8 weeks) will have an option to receive 
Icosapent ethyl 2 gm orally daily plus physical activity for 4 more weeks in an open label basis.  
 
Number of subjects  
96 patients  
 
Plan for statistical analysis  
 
The primary objective is to study is to determine the difference between the FACIT-F subscale score at 
baseline and at Day 57±5 ± 5 days, between patients who will receive either fish oil and exercise and 
placebo and exercise.  
 
In a recent cancer related intervention study by our team using oral dexamethasone (DM) compared to 
placebo was associated with improvement in FACIT-F subscale scores (mean, SD) of 9.6 (11) vs. 3.1 (9.7) 
(p=0.005) at day 15. However, we are investigating a different intervention (combination of fish oil and 
physical activity) and therefore we propose to detect a FACIT-F subscale change of 9.5 (standard 
deviation of 10) in Icosapent ethyl 2 gm orally daily plus physical activity group against 3 (standard 
deviation of 10) in placebo plus physical activity group, with 30 patients in each group, we have an 80% 
power to detect this difference (effect size 0.65) using a two-sided t-test with a significance level of 0.10. 
We will also collect information regarding the change in FACIT-F subscale score in 30 patients with 
placebo plus control physical activity, although not being compared with patients on fish oil and 
exercise. With a total of 30 patients in this group, we will have an 80% power to detect an effect size of 
0.465 in the change in FACIT-F subscale score using a single group t-test with a 0.100 two-sided 
significance level. We will enter a total of 96 patients to allow for possible 5% dropout rate. For the 
primary endpoint, we will compare the difference between the FACIT-F subscale score at baseline and at 
57±5 days, between patients who will receive Icosapent ethyl plus physical activity and placebo plus 
physical activity using t-test. Wilcoxon rank sum test may be considered if the distribution of the data is 
not normal. We will also compare the change of FACIT-F subscale scores among all three groups using 
ANOVA or Kruskal-Wallis test, whichever appropriate. At the end of the study, overall survival time in 
each group will be estimated using Kaplan-Meier method and may be compared among three treatment 
groups using log-rank test.  
 
Adherence will be calculated as the % of total prescribed strength training sessions, the % of total 
prescribed walking regimen minutes completed (physical activity), and the percentage of total 
prescribed pills taken (study medication). The adherence rate, as defined, is a continuous variable. At 
the end of the study, we will estimate the average adherence of prescribed strength, of total prescribed 
walking regimen minutes and of total prescribed pills taken separately using mean, standard deviation, 
median, and range. The adherence rate can also be compared among all three groups using Kruskal-
Wallis test. We will estimate 95% confidence intervals for the proportion of patients completing the 
intervention, the adherence rate, and the proportion of patients with a satisfaction over time. With 30 
patients in each arm, a 95% confidence interval for a proportion of 73% (22/30), for example, can be 
estimated as (54%, 88%).  
 


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Data of variables of interest will be summarized using standard descriptive statistics, such as mean, 
standard deviation, median, and range for continuous variables, frequency and proportion for 
categorical variables. Correlation will be assessed among continuous variables using Pearson or 
Spearman correlation coefficient, whichever is appropriate. Association between categorical variables 
will be examined by Chi-Squared test or Fisher’s exact test when appropriate. Boxplot and histogram will 
be applied to demonstrate distribution of variables of interest.  
 
Since FACIT-F scores will be obtained at 0, 15, 29, 43 and 57±5 days, and other QOL variables and 
cytokine markers will also be obtained repeatedly over time, we will also evaluate the effect of 
treatment on the changes of these measured over time using repeated measure analysis in which intra-
patient correlation of the measures are accounted for. However due to the small scale and exploratory 
nature of the study, we will report p-value as is without adjusting for multiplicity.  
 
To address issues related to missing data, we may perform multiple imputation analyses. If the data 
does not appear to be normally distributed, transformation may be employed to the data, or 
appropriate nonparametric methods will be used for data analysis.  Toxicity data will be summarized by 
treatment, grade and relationship using frequencies and cross-tabulation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of abbreviations  
ADL  
Activities of Daily Living  
AE 
Adverse Events 
ALT  
Alanine aminotransferase  
Ang  
Angiopoietin  
aPTT  
Activated partial thromboplastin time  
AST  
Aspartate aminotransferase  
BID  
bis in die, twice daily  
BUN  
Blood Urea Nitrogen  
c-KIT  
Stem Cell Factor Receptor Tyrosine Kinase  
CAM 
Complementary and Alternative Medicine 
CR  
Complete Response  
C-RAF  
C isoform of Rapidly Accelerated Fibrosarcoma protein  
CRF  
Cancer-related Fatigue  
CRP 
C-Reactive Protein 
CTCAE  
Common Terminology Criteria for Adverse Events  
DCE  
Dynamic Contrast Enhanced  
DM 
Dexamethasone 
ECOG  
Eastern Cooperative Oncology Group  
EGFR  
Epidermal growth factor receptor  
EORTC-QLQ-
30  
 
European Organization for Research and Treatment of Cancer – Quality of Life 
Questionnaire  
EPA 
Ecosapentaenoic Acid  
ERK  
Extracellular Signal-regulated Kinases  
FACIT-F  
 
Functional Assessment of Chronic Illness Therapy – Fatigue  
FACT-G  
Functional Assessment of Cancer Therapy -- General  
FDA  
Food and Drug Administration  
FGFR  
Fibroblast Growth Factor Receptor  
FLT3  
FMS-like Tyrosine Kinase 3  
GCP  
Good Clinical Practice  
GMP  
Good Manufacturing Practice  
HCC  
Hepatocellular Carcinoma  
HFSR  
Hand-foot-skin reaction  
 
 
 
 
 


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IB  
Investigator’s Brochure  
IC50  
Half Maximal Inhibitory Concentration  
HADS 
Hospital Anxiety and Depression Inventory 
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonisation  
IR  
Immediate Release  
IRB  
Institutional Review Board  
MAPK  
Mitogen Activated Protein Kinase  
mCRC  
Metastatic colorectal cancer  
MEK  
MAP Kinase / ERK Kinase 1  
MFSI-SF 
Multidimensional Fatigue Symptom Inventory-Short Form 
NM  
Nano molar  
NYHA  
New York Heart Association  
PA  
Physical Activity  
PD  
Progressive Disease  
PFS  
Progression free survival  
PO  
per oris, oral  
PR  
Partial Response 
PROMIS  
Patient Reported Outcomes Measurement Information System  
PS  
PSQI  
Performance Status  
Pittsburgh Sleep Quality Index  
PTT  
Partial thromboplastin time  
QD  
 
quaque die, once daily  
 
QOL 
Quality of Life 
RAF  
Rapidly Accelerated Fibrosarcoma  
RAS  
Rat sarcoma  
RCC  
Renal Cell Carcinoma  
RECIST  
Response Evaluation Criteria for Solid Tumors  
RET  
Rearranged during transfection  
RTK  
Receptor Tyrosine Kinase  
SAE  
Serious Adverse Event  
SD  
Stable Disease  
SUSARs  
Suspected Unexpected Serious Adverse Reactions  
TIE2  
Tyrosine kinase with Immunoglobulin and Epidermal Growth Factor (EGF) homology 
domain 2  
TTP  
Time to Progression  
UTMDACC  University of Texas M.D. Anderson Cancer Center  
VEGF  
Vascular Endothelial Growth Factor  
VEGFR  
Vascular Endothelial Growth Factor Receptor  
 
 
 


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1. Introduction  
1.1 Background  
Cancer related fatigue (CRF) is a frequent and serious consequence of cancer and cancer related 
treatment (Yennurajalingam et al. 2010; 2012). As a result of improved therapy, patients with advanced 
cancer are living longer, and due to advances in treatment for pain and nausea, clinicians are more 
frequently recognizing CRF as an important symptom that negatively affects quality of life (QOL), 
interferes with daily activity, has potentially devastating social and economic consequences, and affects 
the ability to receive palliative cancer therapy.6 CRF is common, limits the use of targeted therapy in 
advanced cancer patients and significantly impacts QOL An explorative study indicate that compared 
with cancer survivors, patients with advanced cancer had higher levels of physical fatigue. 12 Several 
strategies have been proposed for management of CRF including physical activity, erythropoietin 
stimulating agents and psychostimulants.1 However, none of these strategies result in clinically relevant 
improvement (defined as at least 10 point improvement in the Functional Assessment of Cancer Illness 
Therapy-Fatigue (FACIT-F) scores or equivalent in other validated scales) of CRF despite showing modest 
benefit as compared to placebo (Reddy S et al. 2007). The most plausible reason is that these 
interventions have been unable to target the multifactorial target mechanisms that cause CRF. 
 


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Figure 1. Conceptual Model (adaptation of the integrated Fatigue Model) shows various causative 
factors of multidimensional fatigue and potential targets of the study interventions, darker lines 
indicate stronger relationship.  
 
In cancer patients receiving treatment and in cancer survivors, PA or exercise has been shown to 
improve CRF (Cramp F et al. 2012). Randomized clinical trials among cancer patients who participated in 
an PA program showed significant increases in cardiovascular capacity; improved overall health-related 
QOL; less fatigue; fewer sleeping problems; and increased self-reported physical functioning, general 
well-being, self-esteem, and energy 17, 18. Published data from studies by Bourke et al.(n=18) 19, Valence 
et al. (n=178) 20, and Shariah et al.(n=36)21 support beneficial effects of PA in patients colorectal cancer. 
A recent Cochrane meta-analysis (Cramp F et al. 2012) of 28 clinical trials that included more than 2,000 
cancer patients confirmed these findings. However, the evidence suggests that PA has a very modest 
benefit (effect size 0.23) in improving CRF 22. This lack of robust response (defined as ≥10 points on the 
FACIT-F subscale) 13 to these treatments may be due to a lack of effect on the multifactorial nature of 
CRF 23. Hence there is a need to test combined therapies for CRF such as fish oil with physical activity, 
since these treatments individually target the multidimensional causative factors contributing to CRF in 
advanced cancer.  
 
Conceptual Model: We adapted the Integrated Fatigue Model (Fig. 1) for this study to explain the 
complex multifactorial etiology of CRF and its treatments.24, 25 Physical, behavioral, affective, and 
physiological/biochemical factors are the manifestation of multidimensional CRF in advanced cancer. PA 
or Exercise uniquely affects health-related fitness outcomes, anxiety, depression, inflammation and 
cognition that have been shown to mediate CRF.3, 26 Fish Oil has direct central nervous system effects, 
pain, mood, cachexia inflammation, which can affect CRF.8, 27 Exercise modulates the effect of the 
inflammatory cytokines that are significantly associated with moderate to severe CRF.3, 28, 29 
Therapies combining exercise with fish oil have the potential to improve CRF directly, but they may also 
improve CRF through their joint effects.  
 
1.2 Rationale of the study  
 
Our group has shown that anti-inflammatory agents such as dexamethasone results in clinically 
significant improvement of fatigue; however, these agents are useful only for a short duration due to 
the side-effect profile (Yennurajalingam et al. 2013). On the basis of previously described mechanisms 
and the results of pilot studies, Ecosapentaenoic Acid (EPA) or fish oil has a beneficial effect on fatigue, 
primarily in the general population and in patients with cancer. 15, 16 Previous fish oil studies had several 
limitations including the dose (low dose <2gm), short duration of treatment (2-3 weeks), number of 
capsules (>10), and no validated measure for fatigue such as FACIT-F. The duration of efficacy, and 
possible mechanisms Icosapent ethyl [an ethyl ester of EPA] in reduction of CRF, has not been 
characterized. In addition, not all assessment tools used in previous studies were validated, and there 
was no attempt to understand the pathophysiologic characteristics of Icosapent ethyl using laboratory 
correlates in fatigued cancer patients. The effects of Icosapent ethyl on CRF and cytokine levels must be 
defined through randomized controlled studies using validated tools and laboratory correlates.  
 
Significance: CRF is more severe and debilitating in patients with advanced cancer than in patients with 
early cancer or in cancer survivors.1, 3, 30 However, because of the limited number of clinical trials 


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studying CRF in advanced cancer as a primary outcome, few standard treatment options currently 
exist.3, 8, 31, 32 Recently, the National Institutes of Health state-of-the-science Conference issued a 
statement that calls for the development of new treatments for CRF.3, 23, 33 They stated that “Studies are 
needed to investigate the effectiveness of combinations of both pharmacologic and non-pharmacologic 
treatments.” The results of the proposed project would help us prescribe a safe and effective 
intervention, treatments that have shown preliminary evidence of efficacy in improving CRF in advanced 
cancer patients.3 The proposed research is significant because it will be the first to test the effects of the 
combination of Icosapent ethyl 2 gm orally daily plus PA in advanced cancer patients, a group that is 
living longer as more treatments are available yet experience the most severe levels of CRF among 
cancer patients because of the lack of effective treatment options.1, 6 As preliminary studies22, 34-36 
indicate, we anticipate that this combination therapy, if effective, will provide more robust and clinically 
effective improvement of CRF,13 which would facilitate patients continuing cancer therapy since it would 
be tolerated and effective in controlling disease. This study will provide important evidence to show the 
joint effects of fish oil and PA in improving CRF. Other important benefits of this study are that it will 
provide important data on the role of combination intervention in other QOL measures such as anxiety, 
depression, and the role of combined interventions on objective measures of physical activity, strength, 
and pro-inflammatory cytokines.  
 
1.4. Preliminary Studies  
 
Pharmacologic Treatment of Fatigue: Our team’s studies in patients with advanced cancer allowed us to 
establish the high frequency, severity and multifactorial nature of fatigue.4, 34-37, 40, 44-48 We conducted 
studies of various assessment methods for fatigue and were able characterize fatigue in this patient 
population.4, 49-52 In a preliminary study of 31 advanced cancer patients, we found that 
methylprednisolone 32mg/day significantly improved CRF (p<0.01) compared with placebo with no 
significant differences in side-effects between groups.35 As shown in Table 1, this study was unable to 
detect sustained responses to Day 33 perhaps due to low doses, type of the steroid, and lack of 
validated tools. In a recently published36 RCT study of 84 patients with advanced cancer, oral 
Dexamethasone (DM) at 8 mg/day for 14 days was found to be effective in alleviating CRF compared 
with placebo. The mean improvement in the FACIT-F subscale at Day 15 was significantly higher in the 
DM group than in the placebo (9 [10.3] vs. 3.1 [9.59], P=0.008).36  
 
Prior EPA (fish oil) study by our team in advanced cancer patients:  
 
Our team conducted a study in 60 advanced cancer patients with decreased weight and appetite who 
were randomly assigned to fish oil capsules or placebo (daily dose of 18 gelatin capsules containing 
either 1,000 mg of fish oil (Marine Lipid Concentrate Capsule [Banner Pharmacaps, Halifax, Canada] 
containing 180 mg of EPA, 120 mg of docosahexaenoic acid [DHA], and 1 mg of vitamin E) or 1,000 mg of 
a placebo (olive oil) 16. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and 
function were prospectively assessed at days 1 and 14. Fish oil did not significantly influence appetite, 
tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with 
placebo in patients with advanced cancer and loss of both weight and appetite. The tiredness or fatigue 
improved significantly (p= 0.04) in patients who received higher dosage (Table 1). However the dose 
(1.8gm of EPA, short duration of treatment (2 weeks), number of capsules, and no validated measure for 
fatigue were the limitations of this study.  


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Table 1. Differences between Placebo and Fish Oil group at Baseline and Day 14  
 
 
Prior PA Studies by our team:  
 
Prior studies led by Dr. Basen-Engquist tested interventions in patients with highly symptomatic prostate 
cancer (TPRB-98-103-01-PBP)53, mCRC, and in breast cancer (CA89519).54 The breast cancer study 
showed improved 6-minute walk performance and QOL.54 In an R01-funded study of PA in endometrial 
cancer survivors,55 the intervention was completed with a high percentage and was well received among 
the participants. The same methods will be used in the proposed study. In the next few months, a 154 
person trial comparing a home-based PA intervention to a relaxation intervention for improving physical 
functioning and managing symptoms in advanced colorectal cancer patients (R21 CA137333) will be 
completed. To date only 5 patients in the PA arm have experienced adverse events (AE; 9 AE total, 1 
definitely attributable to physical activity, 8 possibly attributable. All AE were grade 1 (5) or grade 2 (4). 
None of the AEs were due to falls.  
 
An ongoing study in highly symptomatic prostate cancer patients, NCT01410942, conducted by the same 
team as that in the proposed study (PI: Yennu; Dr. Basen-Engquist (Co-I), uses the same standardized 
exercise regimen in combination with study drug. Table 2 shows the adherence rates and safety data of 
the first 12 patients enrolled (blinded). The enrolled patients in this ongoing study had no difficulty in 
completing all the assessments. Based on the preliminary data presented, we conclude that this 
proposed PA would be feasible and safe. 
 
 
 
 
 
 


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Table 2. Preliminary adherence rates and safety data of first 12 patients (blinded) 
 
Prior Inflammatory cytokine and CRF studies by our team:  
Prior studies 56-59 by our group showed wide variability in serum cytokine levels in patients with 
advanced cancer and hence the need to assess cytokines levels in LPS activated monocytes. PA results in 
modulation of TNF-α, IL-1β, and IL-6,60 interleukin-1 receptor antagonist (IL-1RA), TNF-receptors (TNF-R), 
and IL-10 levels.61 Since most of these factors are produced by activated monocytes/macrophages, we 
propose to assess the synthesis of these factors by resting (unstimulated) as well as LPS-activated 
peripheral blood monocytes isolated from patients before and after study treatment.  
 
Figure 2 shows the synthesis of TNF-α by LPS-activated monocytes isolated from patients at baseline 
(D0) and at weeks 1- 5 after treatment with dexamethasone (DM). In patients treated with 8 mg DM 
daily (dark histograms), the percentage of LPS-activated monocytes that synthesized TNF-α decreased, 
whereas in patients receiving placebo (light histograms) for the first 2 weeks there was no change in the 
percentage of LPS-activated monocytes that synthesized TNF-α from D0 until week 2. Thereafter, when 
placebo patients (light histograms) switched to open-label DM, there was a decrease in the percentage 
of LPS-activated monocytes that synthesized TNF-α. Hence analyses of the levels of cytokines from 
induced monocytes would help to determine their association with change CRF and treatment, as shown 
in our previous studies.34, 57, 62 
Change in TNF-α production by LPS-activated monocytes from dexamethasone-treated patients and 
placebo-treated patients in double-blind phase (Days 8 and 15) and in dexamethasone-only open-
label phase (Days 29 and 35). 


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2. Study objectives  
 
Primary Objective: 1. To determine the effects of the combination of Icosapent ethyl 2 gm orally daily 
plus PA for the reduction of cancer related fatigue [FACIT-F subscale] at the end of 8 weeks in patients 
with advanced cancer by comparing the difference between the FACIT-F subscale score at baseline and 
at 57±5 days, between patients who will receive either Icosapent ethyl plus PA or placebo plus physical 
activity.  
 
Secondary Objectives:  
 
1. To determine the feasibility, adherence, and satisfaction of using the combined intervention for the 
reduction of cancer related fatigue in patients with advanced cancer.  
 


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2. To explore the effects of the combination of Icosapent ethyl 2 gm orally daily plus PA on quality of 
life-related variables, mood (HADS – Hospital Anxiety and Depression Inventory), quality of life domains 
(FACT-G), Cancer related Symptoms (Edmonton Symptom Assessment Scale – ESAS) in these patients. 
3. To explore the effects of combined intervention on serum C - reactive protein and intracellular 
cytokine levels [IL-6, TNF-α, IL-10, IL-1RA] before and after treatment.  
 
4. To explore its side effects and tolerability of the combined study interventions in these patients.  
 
5. To explore the effect of multimodal therapy on body composition.  
 
6. To explore the effect of the proposed treatment in this study on the overall survival time in patients  
 
We hypothesize that:  
• 
The combination of Icosapent ethyl plus PA is capable of significantly reducing the severity of 
CRF between baseline and end of week 8 [FACIT-F subscale].  
• 
Physical activity is capable of reducing the severity of CRF between baseline and end of week 8.  
 
3. Investigator[s] and other study participants  
 
Principal Investigator: Sriram Yennu MD, MS, UT MD Anderson Cancer Center (UTMDACC)  
 
Co- Principal Investigator: Eduardo Bruera MD, UT MDACC;  
 
Co- Investigators: Cathy Eng MD; David Fogelman MD; Karen Basen-Engquist PhD;  
 
Rony Dev MD, James M Reuben PhD, Kenneth Hess, and Diane Liu MS, UT MDACC.  
 
4. Study Design  
 
4.1 Study population  
 
Patients with advanced cancer will be recruited from UTMDACC. At UTMDACC, patients will be recruited 
from medical oncologists working in outpatient clinics, and in our own outpatient supportive care 
center. Patients will be screened for eligibility criteria. Patients who are eligible and who provide written 
informed consent to participate in this research study will be admitted to the double-blind phase of the 
study described below. Consent forms and assessments will be available and administered by the study-
assigned research nurse. Feasibility: Is based on the prior successful accrual in similar symptom control 
trials by our group in these sites and great interest in Complementary and Alternative Medicine (CAM) in 
this population (48%).  
 
5. Eligibility  
 
5.1.1 Inclusion criteria  
 
Inclusion Criteria:  


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a) Diagnosis of advanced cancer   
 
b) Patients should describe fatigue as being present for a minimum of 2 weeks; 
 
c) Patients should rate the severity of fatigue as 4/10 in a 0-10 ESAS scale, where 0=no fatigue, 10= 
worse fatigue possible; 
 
d) If patients are on opioids for the treatment of cancer pain, they must have had no major dose change 
(>25%) for at least 48 hours prior to study entry. Change in opioid dose after study entry is allowed;  
 
e) Presence of relatively intact cognition defined by normal memorial delirium assessment scale (<7/30); 
sign written informed consent;  
 
f) Patients must be 18 years or older. The questionnaires used in this study have been validated only in 
the adult population;  
 
g) Patient willing to keep a daily diary, engage in telephone follow up with a nurse;  
 
h) Patient must have telephone access to be contacted by the research nurse;  
 
i) Hemoglobin of >/=10 g/dl within 2 weeks of enrollment. If the patient has not had blood drawn for a 
hemoglobin level in the past two weeks, one will be done to determine the eligibility.  
 
j) Patients should have a Zubrod </= 1.  
 
k) Life expectancy of >/= 4 months.  
 
l) Subjects must be able to understand and be willing to sign the written informed consent form. A 
signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific 
procedure.  
 
m) Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements:  
 
• 
Total bilirubin ≤ 1.5 x the upper limits of normal (ULN)  
• 
Alanine aminotransferase (ALT) and aspartate amino-transferease (AST) ≤ 2.5 x ULN (≤ 5 x ULN 
for subjects with liver involvement of their cancer)  
• 
Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their 
cancer)  
• 
Serum creatinine ≤ 1.5 x the ULN  
• 
International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x ULN. (Subjects 
who are prophylactically treated with an agent such as warfarin or heparin will be allowed to 
participate provided that no prior evidence of underlying abnormality in coagulation parameters 


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exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable 
based on a measurement that is pre-dose as defined by the local standard of care. (See Section 
3.3)  
• 
Platelet count > 100000 /mm3, hemoglobin (Hb) >/= 10 g/dL, absolute neutrophil count (ANC) 
1500/mm3. Blood transfusion to meet the inclusion criteria will not be allowed.  
 
n) Women of childbearing potential must have a negative serum pregnancy test performed within 7 
days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) 
and surgically sterilized women are not required to undergo a pregnancy test. The definition of 
adequate contraception will be based on the judgment of the investigator.  
 
o) Subjects (men and women) of childbearing potential must agree to use adequate contraception 
beginning at the signing of the ICF until at least2 months after the last dose of study drug. The definition 
of adequate contraception will be based on the judgment of the principal investigator or a designated 
associate.  
 
p) Subject must be able to swallow and retain oral medication.  
 
q) Patients on pain medications (non-opioids), including NSAIDS and acetaminophen, may be enrolled as 
long as they have been using it chronically, at least more than 2 weeks.  
 
5.1.2 Exclusion criteria  
 
Exclusion Criteria:  
 
a) Major contraindication to fish oil i.e. hypersensitivity to fish/ fish oil or physical activity;  
 
b) Currently on fish oil or has been on fish oil within the last 10 days;  
 
c) Inability to complete the baseline assessment forms or to understand the recommendations for 
participation in the study.  
 
d) Pregnant or lactating women. Childbearing age women are not on birth control.  
 
e) Reports a falls in the past 30 days;  
 
f) Patient reported regular participation in moderate- or vigorous-intensity PA for at ≥30 minutes at least 
5 times a week and strength training for ≥2 days/week;  
 
g) Signs of third spacing as determined by the treating physician (e.g., pedal edema, pleural effusion, 
ascites)  
 
h) Previous assignment to treatment during this study. Subjects permanently withdrawn from study 
participation will not be allowed to re-enter study.  


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i) Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg [NCI-
CTCAE v4.0] on repeated measurement) despite optimal medical management.  
 
j) Active or clinically significant cardiac disease including:  
 
• 
Congestive heart failure – New York Heart Association (NYHA) > Class II.  
• 
Active coronary artery disease.  
• 
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.  
• 
Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before 
randomization, or myocardial infarction within 6 months before randomization.  
 
k) Evidence or history of bleeding diathesis or coagulopathy. 
  
l) Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study 
medication.  
 
m) Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident 
(including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of 
start of study treatment within 6 months of informed consent.  
 
n) Patients with any previously untreated or concurrent cancer that is distinct in primary site or 
histology except cervical cancer in-situ, treated ductal carcinoma in situ of the breast, curatively treated 
nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder tumor. 
Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 
years before registration are allowed. All cancer treatments must be completed at least 3 years prior to 
registration.  
 
o) Patients with phaeochromocytoma.  
 
p) Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis 
B or C infection requiring treatment with antiviral therapy.  
 
q) Ongoing infection > Grade 2 NCI-CTCAE v4.0.  
 
r) Symptomatic metastatic brain or meningeal tumors.  
 
s) Presence of a non-healing wound, non-healing ulcer, or bone fracture.  
 
t) Major surgical procedure or significant traumatic injury within 28 days before start of study 
medication  
 
u) Renal failure requiring hemo-or peritoneal dialysis.  


Pr ot oc ol 2 0 1 6 -0 3 4 8  
R e v. M arc h 1 4, 2 0 1 8  
V ersi o n 1 0  
P a g e 2 0  of 4 7  
 
 
v) D e hy dr ati o n Gr a d e > 1 N CI -C T C A E v 4. 0.  
 
w) P ati e nts wit h s eiz ur e dis or d er r e q uir i n g m e dic ati o n.  
 
x) Hist or y of P ersist e nt pr ot ei n uri a 
 Gr a d e  3  N CI
-C T C A E v 4. 0  
 
y) I nt erstiti al l u n g dis e as e wit h o n g oi n g si g ns a n d sy m pt o ms at t h e ti m e of i nf or m e d c o ns e nt.  
z) Pl e ur al eff usi o n or ascit es t h at c a us es r es pir at or y c o m pr o mis e ( ≥ N CI -C T C A E v ersi o n 4. 0 Gr a d e 2 
dys p n e a).  
 
a a) Hist or y of or g a n all o gr aft (i ncl u di n g c or n e al tr a ns pl a nt).  
b b) K n o w n or s us p ect e d all er gy or hy p ers e nsitivity t o a ny of t h e st u dy dr u gs, st u dy dr u g cl ass es, 
or exci pi e nts of t h e f or m ul ati o ns giv e n d uri n g t h e c o urs e of t his tri al.  
cc) A ny m al a bs or pti o n c o n diti o n.  
d d) W o m e n w h o ar e pr e g n a nt or br e ast -f e e di n g.  
e e) A ny c o n diti o n w hic h, i n t h e i nv esti g at or’s o pi ni o n, m a k es t h e s u bj ect u ns uit a bl e f or tri al 
p artici p ati o n.  
ff) S u bst a nc e a b us e, m e dic al, ps yc h ol o gic al or s oci al c o n diti o ns t h at m ay i nt erf er e wit h t h e 
s u bj ect’s p artici p ati o n i n t h e st u dy or ev al u ati o n of t h e st u dy r es ults.  
 
5. 1. 3 E xcl u d e d t h er a pi es a n d m e dic ati o ns, pr e vi o us a n d c o nc o mit a nt  
 
 
•  
C o nc urr e nt us e of a n ot h er i nv esti g ati o n al dr u g or d evic e t h er a py (i. e., o utsi d e of st u dy  
tr e at m e nt) d uri n g, or wit hi n 4 w e e ks of tri al e ntry (si g ni n g of t h e i nf or m e d c o ns e nt f or m).  
 
•  
M aj or s ur gic al pr oc e d ur e, o p e n bi o psy, or si g nific a nt tr a u m atic i nj ur y wit hi n 2 8 d a ys b ef or e 
st art of st u dy m e dic ati o n.  
 
•  
T h er a p e utic a ntic o a g ul ati o n wit h Vit a mi n- K a nt a g o nists ( e. g., w arf ari n) or wit h h e p ari ns a n d 
h e p ari n oi ds.  
•  
 
o  H o w ev er, pr o p hyl actic a ntic o a g ul ati o n as d escri b e d b el o w is all o w e d:  
•  
L o w d os e w arf ari n ( 1 m g or all y, o nc e d aily) wit h P T -I N R ≤ 1. 5 x UL N is 
p er mitt e d W e will m o nit or t h e P T/I N R w e e kly f or p ati e nts o n w arf ari n a n d li v er 
f u ncti o n t est e v er y 2 w e e ks ( T ot al bilir u bi n, a n d A S T (S G O T) a n d AL T ( S G P T) if 
h e p atic m et ast as es ar e pr es e nt or if p ati e nts ar e o n p ot e nti all y h e p at oxic 
a g e nts s uc h as ac et a mi n o p h e n or st ati ns.  
•  
L o w d os e as piri n ≤ 1 0 0 m g d ail y).  
•  
Pr o p hyl actic d os es of h e p ari n.  
•  
Us e of a ny h er b al r e m e dy ( e. g. St. J o h n’s w ort [ Hy p eric u m p erf or at u m])  
 
•  
Us e of D ex a m et h as o n e f or c a nc er r el at e d f ati g u e  


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5.2 Withdrawal of subjects from study  
 
5.2.1 Withdrawal  
 
Subjects must be withdrawn from the trial (treatment and procedures) for the following reasons:  
• 
Subject withdraws consent from study treatment and study procedures. A subject must be 
removed from the trial at his/her own request or at the request of his/her legally acceptable 
representative. At any time during the trial and without giving reasons, a subject may decline to 
participate further. The subject will not suffer any disadvantage as a result.  
• 
Pregnancy. Pregnancy will be reported as an SAE. (Note: subjects who have been withdrawn 
from treatment with study drug because of pregnancy should not undergo CT scans [with 
contrast]/MRI or bone scans while pregnant.)  
• 
If, in the investigator's opinion, continuation of the trial would be harmful to the subject's well-
being.  
• 
Subject is lost to follow-up.  
• 
Death.  
 
Subjects may be withdrawn from the study for the following reasons:  
• 
The subject is non-compliant with study drug, trial procedures, or both; including the use of 
anti-cancer therapy not prescribed by the study protocol.  
• 
Severe allergic reaction to fish oil.  
• 
The development of a second cancer.  
• 
Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints.  
• 
Deterioration of ECOG performance status to 4.  
• 
Use of illicit drugs or other substances that may, in the opinion of the investigator, have a 
reasonable chance of contributing to toxicity or otherwise skewing trial result.  
 
Any subject removed from the trial will remain under medical supervision until discharge or transfer is 
medically acceptable.  
 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's medical records.  
Details for the premature termination of the study as a whole (or components thereof [e.g. centers, 
treatment arms, dose steps]) are provided in Section 10 ( Premature termination of the study).  
 
5.2.2 Screen Failures/Dropouts  
 
A subject who discontinues study participation prematurely for any reason is defined as a “dropout” if 
the subject has already been randomized; assigned to treatment/run-in/wash-out; administered at least 
one dose of study drug.  
 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the study before 
the time point used for the definition of “dropout” (see above) is regarded a “screening failure”.  
 


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5.2.3 Replacement  
 
No withdrawn subjects will be replaced.  
 
6. Treatment[s]  
 
We will randomize 96 eligible patients in the Biostatistics Clinical Trial Conduct website to receive either 
Icosapent ethyl (Vascepa) 2 gm orally daily plus physical activity, or placebo plus physical activity, or 
placebo plus control PA(1:1:1) for 8 weeks (see treatment schema below).  
 
6.1 Treatments to be administered  
 
In this study, patients will be randomized to either combination of Icosapent ethyl 2 gm orally daily plus 
physical activity; or placebo plus PA or placebo plus control PA for 8 weeks (See Fig. 3 below for the 
treatment schema). The placebo will be identical to the drug, but will contain methylcellulose as the 
inert ingredient. Assessment will be performed at baseline to Day 57±5 as per Table 4.  
 
Icosapent ethyl (Vascepa)  
 
In the proposed study we plan to use fish oil preparation, Icosapent ethyl [an ethyl ester of EPA] 0.5 
gram capsules [Amarin Pharma Inc, Bedminster, NJ, 2012]. The placebo will be identical to the drug, but 
will contain methylcellulose as the inert ingredient. Assessment will be performed at baseline to Day 
57±5. The objective of 8 weeks of treatment is to evaluate the efficacy of the combined intervention for 
cancer related fatigue. 
 
The rationale for placebo and control arm for PA is to control for placebo effect, attention to 
participant’s expectation and the subjective elements of diagnosis or assessment. See Table 4 for the 
study assessments. All patients at the primary end point (8 weeks) will have an option to receive 
Icosapent ethyl 2 gm orally daily plus PA for 4 more weeks in an open label basis. 


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Figure 3  
Exercise Prescription.  
For this study, we plan to use an exercise intervention based on the American College of Sports 
Medicine (ACSM) exercise recommendations for cancer survivors. 64 The exercise intervention will 
include resistance training 3 days/week and moderate intensity walking for upto150 minutes per week.  
 
Participants will have weekly supervised (in person or by telephone) sessions with an ACSM-certified 
cancer exercise specialist. At the supervised, in person session the patient will perform the resistance 
exercise and moderate intensity walking up to 30 minutes, depending on the patient’s tolerance.  
 
The goal of the resistance exercises is to enhance the individual’s ability to go from a seated to standing 
position independently. The resistance exercise program has been designed to strengthen the major 
muscles of the lower body, including the quadriceps, hamstrings, gluteus maximus, and hip flexor group.  
 
These exercises will include (but will not be limited to) squats, lunges, leg extensions, leg curls, and hip 
extensions. We focus on the lower body to simplify the exercise plan, given the short timeframe of the 
intervention, and because lower body strength is critical to patient mobility and functioning. We will use 
resistance tubes as our mode of resistance. These tubes are color-coded to indicate their specific 


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resistance level: light, moderate, or hard. The resistance exercise sessions are to be completed 3 days a 
week, allowing at least 48 hours between each session. This allows the muscles adequate time for rest 
and prevents overtraining. The participant will begin with 1 set of 10 to 12 repetitions at lightest 
resistance progressing to 2 sets of 12 repetitions as exercise tolerance increases. Resistance will then be 
increased as the participant’s endurance and strength progresses. The graded resistance program will be 
designed so that the individual begins with a lighter resistance and progresses to heavier resistance once 
a level has been mastered. Since the level of aerobic fitness will vary among participants, the frequency 
and duration of the walking program will be established based on exercise physiologist’s assessment of 
the participant’s baseline aerobic fitness level (six-minute walk test). For example, the recommendation 
may be to walk 10 minutes 1-3 times a day or up to a 30-minute walk once a day at a moderate intensity 
level. Participants will work toward the goal of 150 minutes of moderate intensity walking per week.  
 
To encourage and monitor adherence to the walking program, we will provide participants with a 
pedometer and an exercise log to record their resistance exercise sessions, time spent in moderate 
intensity walking, and the number of steps they take each day. Participants will be asked to walk a 
minimum of 5 days a week at the duration established by the exercise physiologist. In the first week of 
the intervention, the exercise physiologist will meet with each participant to evaluate his or her current 
strength and aerobic fitness level and to teach the assigned exercises. Each week the exercise 
physiologist will assess their progress and help them identify and overcome any barriers to completing 
the exercise program, and to evaluate for adverse events or health problems. The frequency, intensity, 
and duration of the assigned exercises will also be evaluated and adjusted as necessary.  
 
The participants will be randomized to either the intervention described above or a control exercise 
program consisting of stretching exercises only. Participants in the control exercise intervention will 
meet with the exercise physiologist in the first week of the intervention in order to learn the stretches 
and receive written instructions on how they should be done. Participants will have weekly supervised 
sessions with an ACSM-certified cancer exercise specialist. With use of an outcome measures outlined in 
Table 1, we will analyze differences between participants receiving the exercise intervention and the 
control physical activity.  
 
To ensure adherence to the exercise protocol, video recordings will be made. Dr. Basen-Engquist will 
randomly review sessions to evaluate the exercise physiologist’s adherence to the protocol.  
 
 
 
6.2 Blinding  
 
In compliance with applicable regulations, in the event of a SUSARs, the patient’s treatment code will 
usually be unblinded before reporting to the health authorities, ethic committees and investigators (see 
Section 7.3.3.3) if the SUSAR was related to the blinded treatment.  
Emergency unblinding by the investigator  
 
Unblinding may occur for emergency purposes only. Investigators should note that the occurrence of a 
serious adverse event or progressive disease should not routinely precipitate the immediate unblinding 
of the label. If unblinding is necessary for the treatment of a subject for a serious adverse event, every 


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attempt should be made to contact the Principal Investigator prior to unblinding. If this is not feasible, 
then Principal Investigator must be contacted within 24 hours of unblinding.  
 
6.4. Drug logistics and accountability  
 
All study drugs (Icosapent ethyl/Placebo) will be stored at the investigational site in accordance with 
Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the Institution and will be inaccessible to 
unauthorized personnel.  
 
6.5. Accountability  
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using the NCI Drug 
Accountability Record or another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for Accountability and 
Storage of Investigational Agents” or to obtain a copy of the drug accountability form.)  
 
6.6. Destruction and Return  
 
At the end of the study, unused study medication (Icosapent ethyl/Placebo) should be destroyed 
according to institutional policies.  
 
Treatment compliance  
 
An adequate record of receipt, distribution, and return of all study drugs (Icosapent Ethyl/Placebo) must 
be kept in the form of a Drug Accountability Form.  
 
Subject compliance with the treatment and protocol includes willingness to comply with all aspects of 
the protocol, and to have blood collected for all safety evaluations. At the discretion of the principal 
investigator, a subject may be discontinued from the trial for non-compliance with follow-up visits or 
study drug.  
 
6.7. Prior and concomitant therapy  
 
All medication that is considered necessary for the subject’s welfare, and which is not expected to 
interfere with the evaluation of the study treatment, may be given at the discretion of the investigator.  
 
All medications (including contrast media) taken within 2 weeks prior to the start of the study and 
during the study must be recorded in the subject’s source documentation and in the CRF (including 
start/stop dates, dose frequency, route of administration, and indication). Specific caution should be 
taken when considering or administering a concomitant medication that is metabolized by the 
cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9. Such concomitant medication should be avoided, if 
possible.  
 


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Permitted concomitant therapy includes:  
• 
Standard therapies for concurrent medical conditions.  
• 
Supportive care for any underlying illness.  
• 
Palliative radiation therapy is allowed if the target lesion(s) are not included within the 
radiation field and no more than 10% of the bone marrow is irradiated.  
• 
Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors may be 
used in the management of acute toxicity, such as febrile neutropenia, when clinically indicated 
or at the investigator’s discretion. However, they may not be substituted for a required dose 
reduction. Subjects are permitted to take chronic erythropoietin.  
• 
Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided that they do not interfere with the study endpoints, in the 
opinion of the investigator.  
• 
Bisphosphonates  
• 
Subjects who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and INR/PTT are stable. Close 
monitoring (day5 of cycle 1 and day 1 of each cycle) is mandatory. If either of these values are 
above the therapeutic range, the doses should be modified and the assessments should be 
repeated weekly until they are stable.  
 
The following are not permitted:  
• 
Other investigational treatment during or within 30 days before starting study treatment  
• 
Systemic antitumor therapy, including cytotoxic therapy, signal transduction inhibitors, 
immunotherapy, and hormonal therapy  
• 
Bone marrow transplant or stem cell rescue  
• 
Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum])  
• 
Please note: Patients should be seen frequently / early during treatment as per Prescribing 
Information  
• 
Monitor blood pressure weekly for the first 6 weeks of treatment and every cycle or more 
frequently as clinically indicated.  
 
 
 
 
 
 
 


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7.0. Outcome Measures/Planned Assessments  
7.1. Timing of assessments 
 
 
Table 4. Study assessments for Icosapent ethyl/Placebo. 
ASSESSMENTS  
Baseline  Day 8*  
(± 3)  
Day 
15*  
(± 3)  
Day 
21*  
(± 3)  
Day 
29  
(± 3)  
Day 
36*  
(± 5)  
Day 
43*  
(± 5)  
Day 
50*  
(± 5)  
Day  
57  
(± 5)  
1 month post 
open label 
phaseǂ  
(± 5)  
History/ Physical exam  
X  
 
 
 
X  
 
 
 
X  
 
Zubrod score  
X  
 
 
 
 
 
 
 
 
X  
Medication review  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
FACIT-F subscale, FACT-G, 
MFSI-SF, PROMIS-Fatigue, 
HADS, PSQI  
X  
 
X  
 
X  
 
X  
 
X  
X  
ESAS  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Physical Performance Tests  
(30 second chair stand test 
six-minute walk test, 
accelerometer, Godin 
leisure-time PA 
questionnaire)  
X  
 
 
 
X  
 
 
 
X  
X  
Body composition Body 
Mass Index (Bio Impedence), 
Resting energy expenditure 
using indirect calorimetry§  
X  
 
 
 
X  
 
 
 
X  
X  
Cytokines (CRP, Serum IL-1b, 
TNF-α, IL-6; Intracellular 
cytokines IL-6 R; TNF R, IL-
1R, IL-10)  
X  
 
 
 
X  
 
 
 
X  
 
Electrolytes liver function 
tests, PT/INR**, CBC**  
X  
 
X  
 
X  
 
X  
 
X  
X  
Toxicity evaluation  
 
X 
X  
X  
X  
X  
X  
X  
X  
X  
Global Symptom Evaluation  
 
 
 
 
 
 
 
 
X 
 
ǂ patients in control arm and the intervention arm will have an option of treatment in drug or placebo +exercise arms  
*Assessment by phone or in person  
** PT/INR at baseline only unless patient is being treated with prophylactic anticoagulants. CBC at baseline only unless 
more frequently testing is clinically indicated.  
-Assessments are performed by the Palliative Care team and complements the standard of care provided by the GI 
medical oncologists  
 
 
 
 
 


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7.2. Assessments  
 
7.2.1 Physical Activity/ Function:  
 
We will use the 30 second chair stand test, six-minute walk test and an accelerometer. A self-report 
exercise questionnaire, the Godin leisure-time PA questionnaire, will be used to complement the 
objective measures. IM Systems-three dimensional accelerometers (“Biotrainer-Pro”) will be used to 
objectively measure physical activity. These accelerometers complement the self-report for estimating 
PA and can record PA in 15-second increments for 5 days. Patients will wear the accelerometer for 5 
days during the week before each assessment. When participants return the accelerometers the data 
will be uploaded into the project database, and the amount of time spent in moderate to vigorous 
activity will be calculated.  
 
30 second chair stand test: The 30 second sit-to-stand task assesses lower body strength.65 A standard 
chair without arms with an approximate height of 17 inches will be used. After a demonstration, a 
practice trial of one repetition will be done to check for proper form. On the start signal, the participant 
rises to a full stand and then returns to a fully seated position. The patient completes as many full stands 
as possible within a 30 second period.  
 
In the six-minute walk test, participants are asked to walk as fast and as far as they can for six minutes, 
and the distance walked is measured. The test will be conducted in an area with a 250 foot hallway and 
minimal traffic. The six-minute walk test has high test-retest and inter-tester reliability, and its validity is 
supported by correlations with self-report measures of fatigue and functional status. 66 The patient will 
be strongly encouraged to give a maximum effort.  
 
7.2.2 Patient-reported outcomes  
 
Functional Assessment of Cancer Illness Therapy (FACIT-F): is a well-validated QOL instrument.67 This 
FACIT-F fatigue subscale was chosen as the primary outcome measure since it has been widely used in 
CRF treatment trials by our team and by others.34, 37, 40, 45, 68 The 13-item fatigue subscale is a patient-
rated assessment of intensity of fatigue and its related symptoms on a scale of 0 to 4. This scale has 
been shown to have strong internal consistency (α = 0.93–0.95), sensitivity of 0.92, and specificity of 
0.6923.  
 
Pittsburg Sleep Quality Index (PSQI): This instrument provides a brief, clinically useful assessment of a 
variety of sleep disturbances that might affect sleep quality. 69  
 
Patient-Reported Outcomes Measurement Information System (PROMIS): measures key symptoms 
and health concepts applicable to advanced cancer, enabling efficient and interpretable clinical trial 
research and clinical practice application of patient-reported outcomes (PROs).70, 71 The PROMIS fatigue 
measure used in the study was found to be highly correlated with the legacy measures.23  
 
Multidimensional Fatigue Symptom Inventory (MFSI-SF) consists of 30 items designed to assess the 
multidimensional nature of fatigue.72 Ratings are summed to obtain scores for 5 subscales (general 
fatigue, physical fatigue, emotional fatigue, mental fatigue, and vigor).  


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Hospital Anxiety Depression Scale (HADS): This 14-item questionnaire has been validated in a number 
of clinical situations and has been widely used in medically ill patients.73  
 
The Edmonton Symptom Assessment Scale (ESAS) measures 10 common symptoms in the past 24 
hours (pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and 
feeling of well-being) during the previous 24 hours; This questionnaire has been found to valid and 
reliable in cancer populations.74  
Please see Table 4 for the timing of the assessments  
 
7.2.3. Cytokine assessments: Peripheral blood will be collected at baseline, Day 29 and Day 57±5 (Table 
4). On completion of the study, the change in levels of synthesis of cytokines in LPS-induced monocytes 
will be correlated with the proportion of patients with decreased fatigue and with those who have no 
decrease in fatigue. Methods: Briefly, 1 mL of peripheral blood will be incubated with 10 μg/mL LPS for 5 
h and with brefeldin A for the last 3 h of incubation to block the intracellular transport of the de novo 
cytokine synthesis from the Golgi. Thereafter, LPS-activated monocytes will be stained for surface 
expression of CD14 and CD33 and for the presence of cytoplasmic cytokines, as previously described,56 
by using a panel of cytokine-specific monoclonal antibodies conjugated with phycoerythrin to detect 
one of the cytokines. The cytokine assessments will be performed in Dr. James Reuben’s laboratory.  
 
7.2.4. Body Composition: Cancer induced lean body mass loss/ fat loss occurs in a higher frequency in 
advanced cancer patients resulting in severe CRF, functional impairment and their inability to tolerate 
therapy. Resting energy expenditure, at baseline and Day 57±5. However all patients will be assessed for 
body mass index, phase angle evaluation using Bio electric impedance [Tanita bioelectrical impedance 
analysis body composition scale].75-78  
 
7.2.5. Medical history  
 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria listed below 
will be collected:  
• 
Not pertaining to the study indication.  
• 
Start before signing of the informed consent.  
• 
Considered relevant to the study.  
 
7.2.6. Blood Collection  
 
Patients who completed questionnaires over the telephone but are unable to return to UTMDACC will 
have their blood collected by their local physician and the results sent to the UTMDACC study team. 
 
7.2.7. Patient Remuneration  
 
After completion of the study assessments, patients will receive parking reimbursement for up to $12.00 
at baseline, Day 29 (± 3 days), and Day 57 (± 3 days) for a total of up to $36.00.  
 


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7.3. Safety  
 
All subjects who receive at least one dose of study treatment will be valid for the safety analysis.  
All observations pertinent to the safety of the study treatment will be recorded and included in the final 
report.  
 
Safety variables include the following: AEs, laboratory changes (complete blood counts, electrolytes, 
chemistry, and coagulation), changes in vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) and ECG and, in some instances, changes in chest x-ray images, as produced at the 
investigator’s discretion (e.g., for evaluation for pneumonia).  
 
All AEs whether considered drug-related or not, will be reported in with a diagnosis, start/stop dates, 
action taken, whether treatment was discontinued, any corrective measures taken, outcome, and other 
possible causes. For all events, the relationship to treatment and the intensity of the event will be 
determined by the investigator.  
 
This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity and SAE reporting with regard to 
toxicity grade.  
 
7.3.1. Adverse events  
 
Definitions  
 
Definition of adverse event (AE)  
 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.  
 
A surgical procedure that was planned prior to the start of the study by any physician treating the 
subject should not be recorded as AE (however, the condition for which the surgery is required may be 
an AE if worsens compared to baseline).  
 
• 
Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history (e.g. 
seasonal allergy without acute complaints).  
• 
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are recorded 
as medical history (e.g. allergic pollinosis).  
 
• 
Conditions that started or deteriorated after signing of informed consent will be documented as 
adverse events.  
 


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Definition of serious adverse event (SAE)  
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the following 
criteria (a – f):  
 
a. Results in death.  
b. Is life-threatening.  
 
The term ‘life-threatening’ in the definition refers to an event in which the patient was at risk of 
death at the time of the event, it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
 
c. Requires inpatient hospitalization or prolongation of existing hospitalization.  
 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at least one 
of the following exceptions is met:  
- The admission results in a hospital stay of less than 12 hours.  
- The admission is pre-planned. (i.e. elective or scheduled surgery arranged prior to the 
start of the study)  
- The admission is not associated with an AE. (e.g. social hospitalization for purposes of 
respite care).  
 
However, it should be noted that invasive treatment during any hospitalization may fulfill the criterion 
of ‘medically important’ and as such may be reportable as an SAE dependent on clinical judgment. In 
addition, where local regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedence.  
 
d. Results in persistent or significant disability / incapacity.   
     Disability means a substantial disruption of a person’s ability to conduct normal life’s functions.  
 
e. Is a congenital anomaly / birth defect.  
f. Is another medically important serious event as judged by the investigator.  
 
7.3.2. Classifications for adverse event assessment  
 
All AEs will be assessed and documented by the investigator according to the categories detailed below.  
 
7.3.2.1. Seriousness  
 
For each AE, the seriousness must be determined according to the criteria given in Section 7.3.1  
 
7.3.2.2. Intensity 
 


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The intensity of the AE is classified according to the CTCAEv4.0. Grade refers to the severity (intensity) of 
the AE: 
 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention is not indicated. 
 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; limiting to 
age-appropriate instrumental activities of daily living (ADL; instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc). 
 
CTCAEv4 Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self-care ADL 
(self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
 
CTCAEv4 Grade 5: death due to an AE. 
 
7.3.2.3. Causal relationship 
 
The assessment of the causal relationship between an AE and the administration of treatment is a 
clinical decision based on all available information. 
The causality assessment should be done separately for each study treatment. 
 
The assessment is based on the question whether there was a “reasonable causal relationship” to the 
study treatment in question. 
 
Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical site. 
 
Or 
 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no indication that 
the drug caused disorientation that may have caused the event; cancer developing a few 
days after the first drug administration. 
 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated with the 
use of the study treatment. 
 
Factors to be considered in assessing the relationship of the AE to study treatment include: 
 


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- The temporal sequence from drug administration: The event should occur after the drug is 
given. The length of time from drug exposure to event should be evaluated in the clinical 
context of the event. 
 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge): 
 
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases: Each event should be evaluated in the context 
of the natural history and course of the disease being treated and any other disease the subject 
may have. 
- Concomitant medication or treatment: The other drugs the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them may be suspected 
to cause the event in question. 
- The pharmacology and pharmacokinetics of the study treatment: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the study treatment, coupled 
with the individual subject’s pharmacodynamics should be considered. 
[Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-required procedure(s) is 
based on the question whether there was a “reasonable causal relationship” to protocol-required 
procedure(s). 
Possible answers are “yes” or “no”. 
7.3.3. Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories listed below. 
The study treatment action should be recorded separately for each study treatment. 
 ־Drug withdrawn 
 ־Drug interrupted 
 ־Dose reduced 
 ־Dose not changed 
 ־Dose increased 
 ־Not applicable 
 ־Unknown 


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7.3.3.1.1. Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
7.3.3.1.2. Outcome 
The outcome of the AE is to be documented as follows: 
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 
7.3.3.2. Assessments and documentation of adverse events 
7.3.3.3. Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 7.3.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission of 
updated reports to the designated person. An isolated laboratory abnormality that is assigned grade 4, 
according to CTC definition, is not reportable as an SAE; unless the investigator assesses that the event 
meets standard ICH criteria for an SAE. CTC grade 4 baseline laboratory abnormalities that are part of 
the disease profile should not be reported as an SAE, specifically when they are allowed or not excluded 
by the protocol inclusion/exclusion criteria. 
Throughout the course of the STUDY, the Principal Investigator and study personnel agree to comply 
with the obligations of adverse event reporting as set forth below, ‘Safety Reporting Requirements’ and 
with FDA regulations. 
SPONSOR/ INSTITUTION is responsible for all the pharmacovigilance obligations and safety reporting 
pursuant to the applicable law and regulations in the country where the STUDY is performed. 
Additionally, the SPONSOR/INSTITUTION shall immediately, within 24 hours at the latest, report to  
IRB/DSMB by fax or and/or email. Safety Reporting Requirements 
The PRINCIPAL INVESTIGATOR must accept full responsibility for the trial and the safety of the subjects 
participating in the trial. The PRINCIPAL INVESTIGATOR is responsible for the ongoing safety evaluation 
of the study and shall provide to IRB/DSMB all Serious Adverse Events (SAEs) within 24 hours of the 
PRINCIPAL INVESTIGATOR’S awareness. 
Definitions: 


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The following definitions, which are consistent with FDA and ICH regulations/guidance, will be used: 
Adverse Event (AE): 
An adverse event is any adverse event associated with the use of a drug in humans, whether or not 
considered drug related, including the following: An adverse event occurring in the course of the use of 
a drug in professional practice; an adverse event occurring from drug overdose whether accidental or 
intentional; an adverse event occurring from drug withdrawal; and any failure of expected 
pharmacological action. 
Serious Adverse Event (SAE): 
A serious adverse event includes any event that: 
Results in death. 
Is life-threatening. 
NOTE: The term ‘life-threatening’ refers to an event during which the subject was at 
immediate risk of death from the adverse event. It does not refer to an event which 
hypothetically might have caused death if it had been more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization means that the subject has been detained at the 
hospital or emergency ward for observation or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious. Hospitalization for 
elective treatment planned prior to study enrollment is neither an SAE nor an AE. 
Results in persistent or significant disability or incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly or birth defect. 
Is an important medical event. 
An event may be considered an important medical event when, based upon appropriate 
medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 


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emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Adverse Drug Reaction (ADR): 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. The phrase “responses to a medicinal product” means in 
view of the investigator and/or company that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility and that the adverse event is associated 
with the use of the drug. 
Serious Adverse Drug Reaction (SADR): 
A Serious Adverse Drug Reaction is an event that meets any of the criteria for seriousness as 
previously defined and has a possible causal relationship to the study drug. 
Requirements for Reporting of Serious Adverse Events: 
All SAEs must be reported to IRB/DSMB within 24 hours of the Principal Investigator’s 
awareness and must include the following minimum information: 
1. The name and contact information of the reporter 
2. The name of the study drug(s) 
3. A description of the reported SAE 
4. A patient identified by one or more of the following: 
a. Patient initials 
b. Patient number 
c. Knowledge that a patient who experienced the adverse event exists 
d. Age 
e. Sex 
5. An investigator assessment of study drug causality. For studies with combination therapy, a 
separate causality assessment should be provided for each study drug. 
Additional data which would aid the review and causality assessment of the case include but are 
not limited to: 
The date of onset 
The severity 
The time from administration of study drug(s) to start of the event 
The duration and outcome of the event 


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Any possible etiology for the event 
The final diagnosis or syndrome, if known 
Action(s) taken, if any 
For blinded studies, the Principal Investigator will provide the treatment assignment upon request for 
patients who experience SAEs. The Principal Investigator will provide the final treatment assignment 
immediately after the end of the study. 
Expedited Reporting of Other Safety Information: 
The Investigator/ Sponsor shall report to IRB/DSMB within 24 hours of the investigator’s awareness of 
other events such as: 
An adverse event related to study specific procedures 
Any new and important event related to treatment with the study drug(s). 
Any pregnancy during which a female patient was exposed to the study drug(s) 
Any pregnancy in the partner of a male patient, where the male patient was exposed to study 
drug at the time of conception or conception occurred within two weeks of the last dose of 
study drug(s). 
Any other relevant safety information including but not limited to reports on drug interaction, 
overdose, drug abuse or misuse, drug dependency, withdrawal syndrome, medication error, 
occupational exposure and lack of drug effect (LODE) occurring at any time during the treatment 
phase; 
Any communication concerning safety related information to regulatory authorities or ethics 
committees including but not limited to: 
- Development Safety Update Reports (DSUR) / relevant parts of IND reports for the 
STUDY; 
- Any other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees; 
The Investigator/Sponsor may report SAEs using: 
A MedWatch form available at http://www.fda.gov/medwatch/ 
7.3.3.4. Expected adverse events due to Icosapent ethyl 
Below is the overview of the known side-effects reported by the use of study drug. 
• 
Musculoskeletal: Arthralgia (2.3% ) 
 


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7.3.4. Pregnancies 
The investigator must report to IRB/DSMB any pregnancy occurring in a study subject, or in his partner, 
during the subject’s participation in this study. The report should be submitted within the same 
timelines as an SAE, although a pregnancy per se is not considered an SAE. 
For a study subject, the outcome of the pregnancy should be followed up carefully, and any abnormal 
outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar information 
on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
Progressive disease 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE (i.e., hospitalization, 
disability, death, or important medical event), the signs and symptoms should be reported as an SAE and 
not the underlying progressive disease. 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the investigator will 
inform IRB/DSMB and record the cause of death in detail (using the SAE Form) within 24 hours. 
8. Statistical methods and determination of sample size 
The primary objective is to study is to determine the difference between the FACIT-F subscale score at 
baseline and at Day 57± 5 days, between patients who will receive either fish oil and PA and placebo and 
PA. 
Interim Analysis Plan 
We plan to implement the Bayesian toxicity monitoring rule for severe toxicity (defined as any Grade 3 
or 4 toxicity that is attributable to the FISH OIL treatment regimen as per NCI CTCAE V4 criteria) 
separately for each arm. We will stop the treatment arm if there is an 85% posterior probability to 
observe a larger than 30% severe toxicity rate in that arm, i.e., Pr(Ptox > 0.3 | data) > 0.85, given that 
the prior of severe toxicity rate follows a beta distribution, beta(0.3, 0.7)79,80. The cohort of monitoring 
will be every 5 patients starting from the first 10 patients. Given this rule, the accrual for a specific arm 
will be stopped if [# severe toxicities/Total # of patients treated]>=5/10, 7/15, 9/20, 11/25, 12/30, 
13/32. Given these boundaries, we will have a 5%, 27% and 67% chance to stop an arm early if the true 
severe toxicity rate is 20%, 30% and 40% for that arm, respectively. 
Sample size calculation: 
In a recent cancer related intervention study by our team using oral dexamethasone (DM) 
[Yennurajalingam, S., S. Frisbee-Hume, et al. (2013)] compared to placebo was associated with 
improvement in FACIT-F subscale scores (mean, SD) of 9.6 (11) vs. 3.1 (9.7) (p=0.005) at day 15. 


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However, we are investigating a different intervention (combination of fish oil and physical activity) and 
therefore we propose to detect a FACIT-F subscale change of 9.5 (standard deviation of 10) in Icosapent 
ethyl 2 gm orally daily plus PA group against 3 (standard deviation of 10) in placebo plus PA group, with 
30 patients in each group, we have an 80% power to detect this difference (effect size 0.65) using a two-
sided t-test with a significance level of 0.10. We will also collect information regarding the change in 
FACIT-F subscale score in 30 patients with placebo plus control physical activity, although not being 
compared with patients on fish oil and exercise. With a total of 30 patients in this group, we will have an 
80% power to detect an effect size of 0.465 in the change in FACIT-F subscale score using a single group 
t-test with a 0.10 two-sided significance level. We will enter a total of 96 patients to allow for possible 
5% dropout rate. 
For the primary endpoint, we will compare the difference between the FACIT-F subscale score at 
baseline and at 57±5 days, between patients who will receive Icosapent ethyl plus PA and placebo plus 
PA using t-test. Wilcoxon rank sum test may be considered if the distribution of the data is not normal. 
We will also compare the change of FACIT-F subscale scores among all three groups using ANOVA or 
Kruskal-Wallis test, whichever appropriate. At the end of the study, overall survival time in each group 
will be estimated using Kaplan-Meier method and may be compared among three treatment groups 
using log-rank test. 
This study is considered feasible if patient is adherent to the study. Adherence will be calculated as the 
mean of the percentage of total prescribed strength training sessions, the percentage of total prescribed 
walking regimen minutes completed (PA), and the mean (across all patients) percentage of total 
prescribed pills taken (study medication). The adherence rate, as defined, is a continuous variable. At 
the end of the study, we will estimate the average adherence of prescribed strength, of total prescribed 
walking regimen minutes and of total prescribed pills taken separately using mean, standard deviation, 
median, and range. This study intervention of combination of Icosapent Ethyl and Physical activity will 
be considered feasible as evidenced by adherence rate is >/=75% to daily combined therapy during the 
8-week intervention. The adherence rate can also be compared among all three groups using Kruskal-
Wallis test. We will estimate 95% confidence intervals for the proportion of patients completing the 
intervention, the adherence rate, and the proportion of patients with a satisfaction over time. With 30 
patients in each arm, a 95% confidence interval for a proportion of 73% (22/30), for example, can be 
estimated as (54%, 88%). 
Data of variables of interest will be summarized using standard descriptive statistics, such as mean, 
standard deviation, median, and range for continuous variables, frequency and proportion for 
categorical variables. Correlation will be assessed among continuous variables using Pearson or 
Spearman correlation coefficient, whichever is appropriate. Association between categorical variables 
will be examined by Chi-Squared test or Fisher’s exact test when appropriate. Boxplot and histogram will 
be applied to demonstrate distribution of variables of interest. 
Since FACIT-F scores will be obtained at 0, 15, 29, 43 and 57±5 days, and other QOL variables and 
cytokine markers will also be obtained repeatedly over time, we will also evaluate the effect of 
treatment on the changes of these measured over time using repeated measure analysis in which intra-


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patient correlation of the measures are accounted for. However due to the small scale and exploratory 
nature of the study, we will report p-value as is without adjusting for multiplicity. 
To address issues related to missing data, we may perform multiple imputation analyses. If the data 
does not appear to be normally distributed, transformation may be employed to the data, or 
appropriate nonparametric methods will be used for data analysis. 
Toxicity data will be summarized by treatment, grade and relationship using frequencies and cross-
tabulation. 
9. Data handling and quality assurance 
The Data safety monitoring board at MD ACC will review and handle the data safety and quality 
assurance. 
9.1 Audit and inspection 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) are possible.  
9.2 Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they are 
readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. 
10. Premature termination of the study 
• 
If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies (on e.g. toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity). 
• 
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) 
does not suggest a proper completion of the trial within a reasonable time frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• 
Closures should occur only after consultation between involved parties. 
• 
All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; head of study 
center) must be informed as applicable according to local law. 


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• 
In case of a partial study closure, ongoing subjects, including those in post study follow-up, 
must be taken care of in an ethical manner. 
 
Details for individual subject's withdrawal can be found in Section 5.2.1. 
11. Ethical and legal aspects 
11.1 Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of 
this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) guidelines 
and under the guiding principles detailed in the Declaration of Helsinki. The study will also be carried out 
in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers before 
start of the study, according to GCP, local laws, regulations and organizations. When necessary, an 
extension, amendment or renewal of the EC/IRB approval must be obtained. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
The investigator may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial subjects without prior IEC/IRB approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the proposed 
protocol amendment should be submitted to the IEC/IRB/head of medical institution. Any deviations 
from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and properly documented. 
11.2 Subject information and consent 
See attached UT MD Anderson Cancer Center consent document. 
11.3. Publication policy 
The Principal Investigator should ensure that the information regarding the study be publicly available 
on the internet at www.clinicaltrials.gov. 
11.4. Confidentiality 


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All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the subject’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
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13. Amendments N/A 
14. Appendices: See attachment 
14.3. Examples of a low fat meal 


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Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 ounces 
of skim milk. (Approximately 319 calories and 8.2 grams of fat) 
One cup of cereal (i.e. Special K), 8 ounces of skimmed milk, one piece of toast with jam (no butter or 
marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g of carbohydrate, 520 
calories).