Conditions: Cancer-related Cognitive Difficulties
Keywords: Cancer Cognitive difficulties
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 110
Healthy volunteers: no

Brief summary:
This research seeks to determine if a combination of low-dose ibuprofen along with a structured home-based walking and progressive resistance exercise program, EXCAP, will be effective in reducing cognitive difficulties among cancer patients receiving chemotherapy.

Detailed description:
To conduct a feasibility pilot to assess preliminary efficacy of a 6 week course of ibuprofen (200 mg BID with does 8 hours apart) and a structured home based walking/progressive resistance program, EXCAP, alone or together, on cognitive function and levels of inflammatory molecules among cancer patients receiving chemotherapy (beginning at cycle 2). If these interventions prove to be useful and have potential benefit, they could have a substantial impact on treating cognitive difficulties experienced by cancer patients as well as improve quality of life. Moreover, if there is an effect of these interventions on cognitive functioning and inflammation, we will gain more knowledge of a possible mechanism of chemotherapy-related cognitive difficulties.

Arms:
arm 1: 200mg placebo (taken twice a day at least 8 hours apart) for a period of 6 weeks and a progressive walking and resistance band exercise program called Exercise for Cancer Patient (EXCAP) for a period of 6 weeks. arm 2: 200mg ibuprofen (taken twice a day at least 8 hours apart) and a progressive walking and resistance band exercise program called Exercise for Cancer Patient (EXCAP) for a period of 6 weeks. arm 3: 200mg placebo (taken twice a day at least 8 hours apart) for a period of 6 weeks. arm 4: 200mg ibuprofen (taken twice a day at least 8 hours apart) for a period of 6 weeks.

Interventions: intervention 1: Ibuprofen intervention 2: Home-Based Exercise intervention 3: Placebo
Intervention descriptions: intervention 1: 200 mg BID and 8 hours apart intervention 2: A progressive walking and resistance band exercise program called Exercise for Cancer patient (EXCAP) for a 6 week period intervention 3: 200mg BID and 8 hours apart

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: A Phase II Study of the Effects of Physical Activity and Low-Dose 
Ibuprofen on Cognitive Function in Cancer Patients Undergoing 
Chemotherapy 
NCT Number: NCT01238120    
Document Date: January 31, 2018 
 


 
UNIVERSITY OF ROCHESTER CANCER CENTER
A Phase II Study of the Effects of Physical Activity and Low-Dose Ibuprofen 
on Cognitive Function in Cancer Patients Undergoing Chemotherapy 
STUDY CHAIR/PI:  
Michelle C. Janelsins, Ph.D.
STUDY CO-CHAIRS/Co-I: Gary R. Morrow, Ph.D., M.S.
Karen M. Mustian, Ph.D., M.P.H.
Deborah A. Cory-Slechta, Ph.D. 
Michelle Shayne, M.D.
Supriya G. Mohile, M.D. 
Jacqueline P. Williams, Ph.D.
Charles E. Heckler, Ph.D. 
Mohamed Tejani, M.D.


RSRB # 31416                                        Page 2 of 46          Version Date: January 31, 2018
TABLE OF CONTENTS
Section 
  Page
Study Schema........................................................................................................3
1.0  Background.....................................................................................................3
2.0  Objectives .......................................................................................................9
3.0  Subject Eligibility...........................................................................................10
4.0  Treatment Assignment..................................................................................12
5.0  Treatment Protocol .......................................................................................13
6.0  Treatment Evaluation....................................................................................27
7.0  Statistical Considerations..............................................................................34
8.0  Schedule of Activities....................................................................................37
9.0   Patient Consent and Peer Judgment...........................................................39
10.0  References..................................................................................................40
 


RSRB # 31416                                        Page 3 of 46          Version Date: January 31, 2018
Study Schema 
1.0  Background
1.1 Cognitive Impairment in Cancer Patients as a Public Health Problem
Due to the decreasing mortality rate of cancer, there are more than 10 million 
cancer survivors in the United States.[1, 2] Because many of these survivors do 
not succumb to cancer, other health problems, including cognitive difficulties due 
to treatment, are a major concern. 
Up to 75% of cancer patients will experience some form of cognitive impairment 
(e.g. problems with memory, attention, and executive functioning) during the 
treatment of their cancer and, for many, this impairment will persist for many 
months or years following treatment.[3-7] Cognitive problems in those who receive 
chemotherapy are more severe than in those who receive locoregional therapy 
(e.g. radiation, surgery).[5] These cognitive problems can negatively impact 
activities of daily living such as 1) performance at work, 2) caring for family 
members and 3) accessing necessary medical and other health services. Until 
the past decade, this condition was largely under-studied, and no effective 


RSRB # 31416                                        Page 4 of 46          Version Date: January 31, 2018
treatment exists. 
1.2 The Etiology of Chemotherapy-Related Cognitive Impairment: A Possible 
Link Between Cognitive Impairment and Inflammation   
The etiology of cognitive impairment in cancer patients receiving chemotherapy 
is unknown, but some clues have been identified. Findings from a small number 
of neuroimaging studies have shown that chemotherapy affects specific brain 
regions. Location-specific brain dysfunction is supported by Magnetic Resonance 
Imaging (MRI) studies that have identified abnormalities in brain metabolism and 
blood flow in areas involved in cognition including the prefrontal lobe, 
hippocampus, parahippocampal gyrus, cingulate gyrus, and precuneus regions.[8, 
9] Whether chemotherapeutic agents can enter the brain at high enough levels to 
cause direct neurotoxicity leading to these abnormalities—or whether these 
effects on metabolism are indirect—is unknown.
Recent literature suggests that elevated levels of pro-inflammatory cytokines may 
be causally related to cognitive problems in cancer patients.[10] Over three 
decades ago, the brain was considered an immune-privileged organ due to tight 
regulation by the blood brain barrier and lack of brain-resident lymph nodes. 
Now, we appreciate an immunological capacity within the brain. For instance, 
although at low levels, cytokine-producing T lymphocytes can be identified within 
the brain,[11] and neurons, astrocytes, and microglia have all been found capable 
of pro-inflammatory cytokine production.[12] We also know that interaction occurs 
between the peripheral blood and the CNS; increased levels of pro-inflammatory 
molecules in the peripheral blood can induce CNS glial changes, subsequent 
cytokine production, and cognitive problems (e.g. memory).[13-16] Many of the 
pioneering studies linking inflammation to cognitive problems were conducted in 
the context of neurodegenerative diseases; [17] inflammatory processes are now 
implicated in a number of these disorders including Alzheimer’s disease (AD), 
Parkinson’s disease (PD), multiple sclerosis (MS), and human immunodeficiency 
type 1 dementia. For example, a recent small-scale prospective clinical study 
revealed that high peripheral blood mononuclear cell (PBMC) production of IL-1 
and TNF- correlates with a higher risk of the subsequent development of AD.[18] 
Additionally, traumatic brain injury (TBI) early in life—with the consequent 
elevation of inflammatory mediators—and the later development of AD are 
positively correlated in some studies,[19] suggesting that a heightened 
inflammatory status may contribute to cognitive difficulties. 
Recent studies have shown that elevated levels of inflammatory cytokines are a 
consequence 
of 
immunotherapy, 
immunotherapy 
in 
combination 
with 
chemotherapy, and chemotherapy alone, and it is therefore plausible that these 
elevated levels of cytokines play a role in cognitive difficulties in cancer patients. 
For example, studies in cancer patients who have received high doses of IL-2 
and IFN-alpha,[20] or interferon-alpha and chemotherapy[21] for treatment of 
cancer have been conducted; both of these studies revealed associations of 


RSRB # 31416                                        Page 5 of 46          Version Date: January 31, 2018
treatment with cognitive problems in this population. Interleukin-2 immunotherapy 
leads to impairments in spatial working memory and IFN-alpha immunotherapy 
leads to impairments in reaction time,[20] while IFN-alpha plus chemotherapy 
leads to problems in spatial working memory.[21] Chemotherapy has also been 
associated with increased levels of pro-inflammatory cytokines, IL-1β [22], and 
alterations in IL-6, IL-8, and TNF- levels.[23] 
My data from mice show that cyclophosphamide chemotherapy increased blood 
levels of the inflammatory molecule MCP-1 (Fig. 1A), increased microglial 
activation (indicating brain inflammation, Fig. 1C) and reduced neural precursor 
proliferation (implicating impaired memory processes, Fig. 1B, [24]). Collectively, 
these data from human and animal studies suggest that chemotherapy elicits an 
inflammatory response that might produce neural cell damage and impaired 
cognitive functioning.   These studies support our hypothesis that inflammation 
may contribute to chemotherapy-related cognitive difficulties in cancer patients. 
Possible mechanisms for explaining how heightened levels of pro-inflammatory 
cytokines due to cancer and cancer treatment may contribute directly to 
problems in cognitive functioning include 1) activation of the blood brain barrier to 
induce glial changes and subsequent cytokine production in the CNS, 2) creation 
of leakiness in the blood brain barrier causing increased concentrations of toxic 
substances to enter the brain, and 3) interaction with the vagus nerve triggering 
central nervous system induced inflammatory signals. 
We propose a model whereby the combined insult of cancer and cancer 
chemotherapy leads to heightened levels of pro-inflammatory molecules that 
activate the blood brain barrier, allowing for brain inflammation and associated 
problems in cognition. Moreover, interventions (e.g. exercise, anti-inflammatory 
medication) aimed at dampening chronic inflammation will alleviate cognitive 
problems experienced by those receiving chemotherapy (Figure 2)
*p < 0.005
Figure 1
0
5
10
15
20
25
30
35
40
Control
(Saline)
Chemotherapy
*
Number of Positive BrdU Cells Per 
Dentate Gyrus Section 
B
2000
2500
3000
3500
4000
4500
Control 
(Saline)
Chemotherapy
Pixel Intensity
*
A
*
*
0
10
20
30
40
50
60
70
80
90
Resting
Microglia
Active 
Microglia
Saline
Chemotherapy
C
Increased Systemic 
MCP-1 ChemokineLevels
Reduced Neural Cell 
Birthing
Increased Brain 
Inflammation
Percent of Positive BrdU Cells Per 
Dentate Gyrus Section 


RSRB # 31416                                        Page 6 of 46          Version Date: January 31, 2018
Figure 2: Proposed model for chemotherapy-related cognitive difficulties 
and interventions to inhibit inflammation. 
Model: Chemotherapy likely leads to heightened peripheral blood levels of 
cytokines causing sustained inflammation which, in turn, activates the blood brain 
barrier and causes CNS inflammation. Chronic CNS inflammation leads to 
neurotoxicity and cognitive difficulties. Interventions that reduce inflammation, 
such as exercise and ibuprofen, can dampen the inflammatory response caused 
by chemotherapy leading to an improvement in cognitive functioning.  
1.3 Exercise as an intervention to reduce inflammation and treat cognitive 
impairment
Increasing evidence suggests that exercise improves functional capacity and 
quality of life (QOL) in cancer survivors [25-27] and may provide a useful 
intervention for reducing symptom burden resulting from treatment in this 
population. These positive outcomes may be linked in part to the overall anti-
inflammatory effects of exercise. For example, exercise may help to maintain or 
reduce body fat, a source of highly inflammatory adipose tissue.[28, 29] Regular 
aerobic exercise can reduce levels of circulating cytokines (e.g. IL-6, CRP) and 
both aerobic exercise and resistance training each can reduce TNF-alpha [30] in 
older adults. A ten-week walking program also demonstrated a reduction in IL-6 
and psychological stress.[31]   
Exercise may particularly be a good intervention to reduce inflammation in 
women receiving chemotherapy. These women tend to gain weight, which is 
largely attributed to an increase in fat mass (adiposity) [32-34]. Increases in 
adiposity lead to increases in inflammation within the body that we hypothesize 
contribute to cognitive difficulties in cancer patients.  
Ibuprofen
Chemotherapy
Peripheral blood 
pro-inflammatory 
cytokines and 
inflammation 
(TNF-α, IL-1β, 
MCP-1 
Activation of 
blood brain barrier
CNS Pro-
inflammatory 
cytokines and 
inflammation 
(TNF-α, IL-1β, 
MCP-1, activated 
microglia)
Neurotoxicity,
Cognitive difficulties
and/or
Moderate 
Exercise
Dampens
Ibuprofen
and/or
Moderate 
Exercise
Improves


RSRB # 31416                                        Page 7 of 46          Version Date: January 31, 2018
Studies have shown the beneficial effects of aerobic exercise and strength 
training on cognitive functioning in older adults with and without cognitive decline, 
as reviewed in a recent meta-analysis. [35] Moreover, physical activity may be 
related to decreased risk of developing cognitive problems. A recent randomized 
controlled trial examined the effects of a 6-month home-based exercise 
intervention in 170 subjects on problems in memory and found improvements in 
memory which persisted for one year post-intervention. [36]  
Exercise interventions in cancer patients are feasible and safe. Mustian and 
colleagues,[37]   Cramp and colleagues, [38]  Galvao and Newton,[39]  Stevinsen 
and colleagues, [40]  and Knols and colleagues [41] report on the benefits of 
exercise among cancer survivors during and after treatment.  Exercise has been 
shown to improve Cancer-Related Fatigue (CRF), QOL, emotional distress, 
immunological parameters, aerobic capacity, strength, flexibility, and body 
composition in these studies.  Fourteen of these studies by nine different 
research groups assessed the beneficial effects of exercise interventions 
specifically during chemotherapy.  
We performed secondary analyses on a pilot RCT originally conducted by Dr. 
Mustian, a Co-Investigator on this study, that compared the effects of a 12-week 
exercise (Tai Chi Chuan)  intervention to a non-exercise control group on 
functional capacity and quality of life in 21 breast cancer survivors.[25] In this 
study, subjects were also asked about forgetfulness on a 5-point scale (0 = not at 
all to 4 = extremely) prior to the intervention, halfway through the intervention, 
and post-intervention. While significance was not reached, a trend toward 
improvement (p=0.12) was observed from the pre-intervention to post-
intervention time-points (see Figure 3 below) for the exercise group. 
Figure 3
1.3.1 The home-based exercise program, EXCAP, used in the proposed study, 
and developed by Dr. Mustian, has been validated and safety-tested in 
cancer patients undergoing radiation treatment and is associated with 
improved functional capacity, reduced fatigue, and altered cytokine levels 


RSRB # 31416                                        Page 8 of 46          Version Date: January 31, 2018
[42-45] compared to standard care.  This intervention is now being tested in 
a multi-center clinical trial for effects on fatigue in cancer patients 
undergoing chemotherapy through the URCC NCORP and affiliates. 
1.4 Ibuprofen as an intervention to reduce inflammation and treat cognitive 
impairment
Ibuprofen is a non-selective non-steroidal anti-inflammatory agent (NSAID) that is 
FDA-approved for treatment of numerous conditions including pain, headache, 
fever, and inflammation. Ibuprofen inhibits cyclooxygenase 1 and 2 activity, 
thereby inhibiting the synthesis of prostaglandins (e.g. PGE2) and consequently 
down-regulating inflammatory pathways involving IL-1β, TNF-, MCP-1 and other 
pro-inflammatory signaling pathways. 
NSAIDs have been associated with reduced odds of cognitive problems, 
especially with long-term usage. Low-dose ibuprofen also may have positive 
effects on cognitive functioning in the setting of neurodegenerative disease.  A 
recent case-control study assessing the effects of anti-inflammatory medication 
on risk of Alzheimer’s disease revealed a 44% reduction in risk with long-term 
usage (> 2 years), although prospective studies have been inconsistent. [46]
Long-term NSAID usage, particularly ibuprofen, also has been associated with 
better cognitive performance and lower rates of cognitive decline in a study of 
healthy older adults. [47]
1.4.1. The value of low-dose, short-term usage of an anti-inflammatory on 
cognitive function has not been investigated, and assessing such usage 
for preliminary effectiveness in cancer patients is the primary goal of this 
study.   
1.5 Summary
Exercise and ibuprofen usage have been associated with the maintenance 
of proper cognitive functioning among the general population compared to 
non-users. Little research has been done on the effects of exercise on 
cognitive functioning in cancer patients undergoing treatment and no 
research has been done to test ibuprofen for effects on cognitive 
functioning in cancer patients undergoing treatment. This pilot study 
serves as a feasibility trial for ibuprofen, exercise, and combined 
intervention arms in cancer patients undergoing chemotherapy. Both the 
ibuprofen and exercise interventions are aimed at maintaining cognitive 
functioning by reducing inflammation within the body and brain, thereby 
reducing cognitive difficulties due to chemotherapy. 
We propose to conduct a feasibility pilot to assess preliminary efficacy of a 
6-week course of ibuprofen (200 mg BID with doses 8 hours apart) and a 


RSRB # 31416                                        Page 9 of 46          Version Date: January 31, 2018
structured home-based walking/progressive resistance exercise program, 
EXCAP, alone or together, on cognitive function and levels of 
inflammatory molecules (MCP-1, TNF-, IL-1, IL-6, IL-8, PGE2) among 
cancer patients receiving chemotherapy.  If these interventions prove to 
be useful and have a potential benefit, they could have a substantial 
impact on treating cognitive difficulties experienced by cancer patients 
ultimately leading to improved performance in activities of daily living, at 
work, and in interpersonal relationships. Moreover, if there is an effect of 
these interventions on cognitive functioning and inflammation, we will gain 
more knowledge of a possible mechanism of chemotherapy-related 
cognitive difficulties. 
2.0  Objectives
2.1 Study hypotheses
A combination of low-dose ibuprofen (200 mg BID with doses 8 
hours apart) along with a structured home-based walking and 
progressive resistance exercise program, EXCAP, will be 
efficacious in reducing cognitive difficulties among cancer patients 
receiving chemotherapy, as assessed 1) objectively by a validated 
computerized cognitive (memory) test (CANTAB), 2) subjectively by 
a psychometrically validated self-report instrument (FACT-COG) 
and 3) biologically by cytokine and receptor levels (e.g. MCP-1, 
TNF-α, IL-1, IL-6, IL-8, PGE2). 
2.1.1.  Primary Objective
To collect preliminary efficacy data on a 6-week course of ibuprofen 
(200 mg BID) and a structured home-based walking/progressive 
resistance exercise program, EXCAP, combined or alone, for 
improving cognitive functioning in cancer patients receiving 
chemotherapy, as assessed objectively by a validated 
computerized cognitive (memory) test (CANTAB). 
Hypothesis 1: Exercise and ibuprofen (combined or alone) will lead 
to higher memory performances (percent correct across delays) as 
assessed by the objective CANTAB delayed matching to sample 
task in cancer patients receiving adjuvant chemotherapy. 
2.1.2 Secondary Objective 
To collect preliminary efficacy data on a 6-week course of ibuprofen 
(200 mg BID) and a structured home-based walking/progressive 
resistance exercise program, EXCAP, combined or alone, for 


RSRB # 31416                                        Page 10 of 46          Version Date: January 31, 2018
improving cognitive functioning in cancer patients receiving 
chemotherapy, as assessed subjectively by a psychometrically 
validated instrument (FACT-COG).
Hypothesis 2: Exercise and ibuprofen (combined or alone) will lead 
to higher cognitive functioning score as assessed subjectively by a 
psychometrically validated instrument (FACT-COG). 
2.1.3 Tertiary Objective
To collect preliminary data on the effect of a 6-week course of 
ibuprofen (200 mg BID) and a structured home-based 
walking/progressive resistance exercise program, EXCAP, 
combined or alone, on cytokines and their receptors (e.g. MCP-1, 
TNF-α, IL-1, IL-6, IL-8, PGE2) in cancer patients receiving 
chemotherapy.   
 
Hypothesis 3: Exercise and ibuprofen (combined or alone) will lead 
to reduced levels of inflammatory cytokines and their receptors 
((e.g. MCP-1, TNF-α, IL-1, IL-6, IL-8, PGE2). 
3.0  Subject Eligibility
Inclusion Criteria:
3.1     Must report cognitive difficulties of 3 or higher (on a scale of 0 = “Not
           Present” to 10 = “As Bad As You Can Imagine”) on our adapted
           Symptom Inventory question, “Are you currently experiencing any
           cognitive (e.g. in memory, attention, concentration) problems since your 
           cancer diagnosis?” at the start of or after their first cycle of chemotherapy.
3.2      Must provide informed consent.
3.3 
Be able to read English (since the assessment materials are in English). 
3.4      Have a primary diagnosis of cancer. 
3.5
Be able to swallow medication.
3.6      Women of child-bearing potential (i.e. women who are pre-menopausal or 
not surgically sterile) must not be pregnant or become pregnant during the 
6-week study. 
3.7
Agree not to take a daily dosage of an NSAID over 200 mg during the 6-
week intervention period. (Higher doses of an NSAID on an ‘as needed’ 


RSRB # 31416                                        Page 11 of 46          Version Date: January 31, 2018
basis are OK but should not exceed more than 1000 mg for one day per 
week; higher doses of acetaminophen are OK for pain management.) 
3.8 
Be scheduled to receive at least 2 additional cycles of oral or IV 
chemotherapy over the 42-day study period. 
3.9 
Must have the approval of their treating physician (or physician’s nurse 
practitioner or physician’s assistant) to participate in exercise testing 
(i.e.VO2max test and handgrip test) and a low to moderate home-based 
walking and progressive resistance exercise program.
3.10 Must have the approval of their treating physician (or physician’s nurse 
practitioner or physician’s assistant) to receive the 6 week 
ibuprofen/placebo regimen (200 mg BID and doses 8 hours apart).  
3.11
Must be at least 18 years of age.  
Exclusion Criteria:
3.12
Currently taking a consistent dosage (at least 3 days a week) of a NSAID 
for the last 3 months that is over 400 mg daily. 
3.13
Have an allergy to ibuprofen.
3.14 Be identified as in the active or maintenance stage of exercise behavior as 
assessed by the single-item Exercise Stages of Change Short Form.
3.15
Have physical limitations (e.g. cardiorespiratory, orthopedic, central 
nervous 
system) 
that 
contraindicate 
participation 
in 
sub-maximal 
physiological fitness testing or a low to moderate home-based walking and 
progressive resistance program, as assessed by the oncologist (or 
physician’s designee).  
3.16    Have a history of peptic ulcer disease within the last 12 months unless 
adequately treated, as assessed by the patient’s primary care physician or 
medical oncologist.
3.17
Diagnosed with a neurodegenerative disease.
3.18
Had a myocardial infarction within the past 6 months.
3.19    Patients with a neutropenic episode (characterized by neutropenic fever) 
during the first cycle of chemotherapy or at high risk for a neutropenic 
episode during future chemotherapy cycles at the treating physician’s 
discretion.  


RSRB # 31416                                        Page 12 of 46          Version Date: January 31, 2018
3.20
Have confirmed metastatic disease to the central nervous system. 
3.21
Have been diagnosed with a major psychiatric illness within the last five 
years.
4.0  Treatment Assignment
4.1
All patients who meet the eligibility criteria, sign the patient informed 
consent form, obtain physician consent, and complete baseline 
assessments will be randomized to one of four treatment arms.  
Randomization will be determined by means of a computer-generated 
random number table. 
4.1.1 This study will use a permuted block-randomized scheme with 
block sizes of 4 or 8 with equal probability to ensure an equal 
distribution among the four arms.
4.1.2 Participants will be stratified by gender (female, male) and tumor 
site (Breast, GI, Other). 
4.1.3 A total enrollment of 116 patients is planned (29 in each treatment 
arm).
4.1.4 All patients will receive usual care monitoring. 
4.1.5 Treatment sequence in the four trial arms will be as follows:
Treatment Arm 
Condition
1
Placebo:  Patients will be given a 200 mg placebo to 
be taken BID by mouth and 8 hours apart, beginning 
on Day 1 of the next on-study chemotherapy cycle for 
a period of 6 weeks. 
 
2
Ibuprofen 200 mg BID:  Patients will be given 200 mg 
of ibuprofen to be taken BID by mouth and 8 hours 
apart, beginning on Day 1 of the next on-study 
chemotherapy cycle for a period of 6 weeks.
3
Placebo and Home-Based Exercise (EXCAP):  
Patients will be given 200 mg placebo to be taken BID 
by mouth and 8 hours apart beginning on Day 1 of the 
next on-study chemotherapy cycle for a period of 6 
weeks along with a progressive walking and 
resistance band exercise treatment for a period of 6 


RSRB # 31416                                        Page 13 of 46          Version Date: January 31, 2018
weeks.
4
Ibuprofen 200 mg BID and Home-Based Exercise 
(EXCAP):  Patients will be given 200 mg of ibuprofen 
to be taken BID by mouth along with a progressive 
walking and resistance band exercise treatment 
beginning on Day 1 of the next on-study 
chemotherapy for a period of 6 weeks.
5.0  Treatment Protocol
5.1
This will be a four-arm feasibility clinical trial of an intervention examining 
the preliminary efficacy of ibuprofen 200 mg BID alone, a structured 
home-based walking/progressive resistance exercise program alone, and 
the combination of ibuprofen 200 mg BID and a structured home-based 
walking/progressive resistance exercise program for reducing cognitive 
difficulties during chemotherapy.  
5.2
Recruitment, Screening, and Eligibility 
5.2.1   Potentially eligible subjects at the University of Rochester Medical 
Centers will be identified by their physician or other physician-
designated clinical personnel.  The study coordinator can contact 
the physician or physician-designated clinical personnel about 
potentially eligible subjects and the physician or physician-
designated clinical personnel can verify that they are ok to 
approach.  
Subjects may also be recruited through the use of study posters, 
flyers, and brochures. The URMC PEAK Laboratory staff will share 
information about this study on the laboratory’s social media page 
located at www.facebook.com/URMCPEAKLAB. All study related 
information posted on the PEAK Lab social media page will be 
obtained from IRB approved study recruitment materials.
The initial contact will assess whether the patient has any interest 
in participating in a clinical trial to reduce cognitive difficulties at the 
start of or after their first chemotherapy treatment.  If interested, 
patients will be screened to determine their eligibility for the study.  
Screening will be done in a closed room or private area at Wilmot 
Cancer Institute locations or in our Cancer Control Research 
Department. Recruitment and screening will be carried out at 
Wilmot Cancer Institute sites including, but not limited to, Wilmot 
Cancer Center, Wilmot Cancer Institute's Pluta Cancer Center, 
Wilmot Cancer Institute at Highland Hospital, Wilmot Cancer 


RSRB # 31416                                        Page 14 of 46          Version Date: January 31, 2018
Institute at Park Ridge, and the Wilmot Cancer Institute at Strong 
West. During screening a patient must report cognitive difficulties of 
3 or higher (on a scale of 0 = “Not Present” to 10 = “As Bad As You 
Can Imagine”) adapted from a similar Symptom Inventory question, 
“Are you currently experiencing any cognitive (e.g. in memory, 
attention, concentration) problems since your cancer diagnosis?” 
If the patient then meets eligibility criteria, study personnel will 
explain the details of the study and obtain informed consent from 
patients who agree to participate. For subjects that are recruited 
and enrolled, study personnel will complete basic medical history 
questionnaires with the subjects, show them how to use the 
pedometer and how to correctly record their steps.  Study 
coordinator will verify at this time that the study subject is not 
pregnant from their medical record.  
Ideally, screening will occur by in-person contact. Screening may 
also occur by answering to a score of 3 or higher on a written form 
containing the screening question that has been provided to the 
patient (e.g. at appointment check-in given by the 
secretary/administrator or in person with study staff) at the start of 
or after their first chemotherapy treatment. Only patients that are to 
be receiving chemotherapy will be provided with this form. The 
coordinator will follow-up with interested participants to tell them 
about the study after physician or physician designee approval is 
granted for study personnel to approach the patient.  
5.3
Consent Process, Baseline Assessments, Co-Enrollment, and Participant 
Compensation
5.3.1 Cancer patients who are scheduled to receive at least 2 additional 
cycles of chemotherapy or 6 weeks of active chemotherapy 
treatment who meet the eligibility criteria including approval from 
their physician will be invited to participate in the trial.
Upon consent, with help from the study coordinator, the patient will 
complete an On-Study Data Form and a Medication Form to 
provide clinical and demographic data.  Questions concerning the 
patient’s medical history, supplement and prescription drug usage 
history, and exercise history are included.
The study coordinator will obtain information necessary to complete 
these forms from the patient’s medical records when the patient is 
unable to provide this information in sufficient detail (e.g., staging, 
Karnofsky Performance Scale or ECOG Performance Status, 
surgical procedures, types and doses of treatments).  


RSRB # 31416                                        Page 15 of 46          Version Date: January 31, 2018
5.3.2 Co-Enrollment in RSRB 54027 and RSRB 31416
Patients receiving cancer treatments at Wilmot Cancer Institute 
sites that meet inclusion and exclusion criteria for RSRB 54027 and 
RSRB 31416 are eligible to co-enroll in both RSRB 54027 and 
RSRB 31416.The principal investigator and study team have 
determined co-enrollment will not compromise the scientific merit or 
integrity of the observational study RSRB 54027 or the 
interventional study RSRB 31416. RSRB 54027 participants that 
meet all eligibility criteria for RSRB 31416 will be screened and 
offered the opportunity to co-enroll.
To minimize the burden on study participants co-enrolled in RSRB 
54027 and RSRB 31416 redundant study assessments will be not 
be duplicated for overlapping time points. Study assessments 
required at both Assessment 5 in RSRB 54027 and the Baseline 
visit in RSRB 31416 will be completed one time and the data 
utilized in both studies. Study assessments scheduled at 
Assessment 5 in RSRB 54027 and at the Baseline assessment for 
RSRB 31416 are shaded in the Co-Enrollment Assessments Table.
Co-Enrollment Assessments Table
Procedure/Form
RSRB 54027
Assessment 5
RSRB 31416
Baseline Visit
On Study Data
Done at 
Assessment 1
X
Medication Form
X
X
Blood Draw
X
X
PBMC Collection
X
FACT-G
X
X
FACT-COG
X
X
Computerized CANTAB Tests
X
X
WRAT-4
Done at 
Assessment 1
X
HVLT-R Form 3
X
X
CTMT
X
X
COWA
X
X
POMS
X
X
FSCL
X
X
PSQI
X
X
CES-D
X
MFSI
X
ACLS
X
Symptom Inventory
X
Cancer Treatment Dosage Form
X
Toxicity Outcome Form
X


RSRB # 31416                                        Page 16 of 46          Version Date: January 31, 2018
Cancer Therapy Treatment Notes
X
5.3.3 Baseline measures of physical activity involve fitting each 
participant with a Pedometer for a 3-day baseline assessment prior 
to their next on-study chemotherapy. At baseline, patients will also 
complete brief and validated measures of cognitive functioning 
(FACT-COG), quality of life (FACT-G), sleep (PSQI), fatigue 
(FSCL), anxiety (STAI), mood (POMS), and depression (CESD). 
These forms will take approximately 15-20 minutes for the patients 
to complete.
Fasted blood samples (4-6 hours prior to blood draw with 
encouragement to maintain hydration) will be drawn by URMC-
approved phlebotomists (URMC Labs) or by a Wilmot Cancer 
Institute phlebotomist or nurse. Blood samples may also be 
obtained at the Clinical Research Center (CRC) located in Strong 
Memorial Hospital by a CRC phlebotomist or nurse. If the blood 
sample is not fasted, we will still collect the blood sample and note 
the last time the person ate in the research record. All subjects will 
be offered a light snack upon completion of the blood draw and 
provided with a $5 gift card for a café at URMC.
In a cancer control designated laboratory (e.g. Dr. Mustian’s 
Physical Exercise, Activity and Kinesiology laboratory), patients will 
complete computerized and paper-based cognitive tests of 
memory, executive function and processing speed/attention that will 
total 60 minutes of time. 
Patients will then be evaluated on vitals (Resting Heart Rate, 
Height, Weight & Blood Pressure), aerobic capacity (VO2max 
Treadmill Test), muscular strength (Handgrip Dynamometry test 
and upper and lower body fitness testing), body composition 
(bioelectrical impedance) and physical activity.  All exercise testing 
will be conducted in the Physical Exercise, Activity, and Kinesiology 
(PEAK) Laboratory. The Physical Activity Readiness Questionnaire 
(PAR-Q) will be used by the clinical exercise physiologist prior to 
fitness testing to make sure that patients are ready to perform 
fitness tests and to guide any modifications.   
 
5.3.4 Participants will be paid for participating in this study. Each 
participant will receive $40.00 upon completion of the baseline 
study visit assessments, $50.00 upon the completion of the post-
intervention visit assessments, and will be provided with a $5 gift 
card for a café at URMC upon completion of each study blood 
draw. Participants will not be paid for visits that they do not 
complete. Participants can be paid up to $100.00 for taking part in 


RSRB # 31416                                        Page 17 of 46          Version Date: January 31, 2018
this study.
If participants will be traveling greater than 25 miles round trip to 
attend the Baseline and Post-Intervention office visits at the PEAK 
Laboratory (located at 250 Crittenden Boulevard, Rochester, NY 
14642), they will be provided with travel compensation. Distance 
based compensation will be provided as follows:  

Less than 25 miles round trip = $0

Between 25-50 miles round trip = $10

Greater than 50 miles round trip = $20 
Participants will be reimbursed for travel expenses up to a 
maximum amount of $40 during the study. Distance based 
compensation will not be provided if a participant’s research study 
visit corresponds with a clinic visit. Travel compensation and 
participant payment costs will be paid from funds from Dr. 
Janelsins’ NCI K07 Award and her other research funds.  
Participants that are co-enrolled in RSRB 54027 and RSRB 31416 
will receive compensation as scheduled for the Baseline study visit 
in RSRB 31416 in addition to the compensation scheduled for 
Assessment 5 in RSRB 54027.
5.3.2 Patients will be randomized to one of four treatment arms.  Study 
medication (provided by the University of Rochester Investigational 
Drug Service (IDS)) and instructions for ibuprofen/placebo 200 mg 
BID will be given and reviewed with all patients in a cancer control 
designated laboratory.  Study personnel will bring the medication to 
the cancer control laboratory at the time of randomization. Drug 
provided by the IDS is stored in a secured location within the 
Cancer Control Unit at URMC that is locked at all times and only 
accessible by approved study personnel.  Ibuprofen/placebo pills 
will be over encapsulated in gelatin capsules so that patients will 
not know whether they have ibuprofen or placebo. Arm 3 and arm 4 
patients will also receive instructions and an Exercise Kit for the 
home-based walking and progressive resistance exercise program. 
(Note: Patients not randomized to an exercise arm will receive the 
exercise kit at the end of the study at no cost.) 
5.3.2.1
Patients assigned to Treatment Arm 1 will receive a 6-
week supply of placebo, which consists of 84 pills of placebo 
to be taken twice daily (BID) and at least 8 hours apart.  
5.3.2.2
Patients assigned to Treatment Arm 2 will receive a 6-
week supply of ibuprofen, which consists of 84 pills of 
ibuprofen to be taken twice daily (BID) and at least 8 hours 
apart.


RSRB # 31416                                        Page 18 of 46          Version Date: January 31, 2018
5.3.2.3
Patients assigned to Treatment Arm 3 will receive a 6-
week supply of placebo, which consists of 84 pills of placebo 
to be taken twice daily (BID) and at least 8 hours apart and a 
home-based walking and progressive resistance exercise 
regimen to follow for a total duration of 6 weeks. Participants 
assigned to Treatment Arm 3 will wear the pedometer and 
Garmin DAT and pedometer daily during the study intervention 
period.
5.3.2.4
Patients assigned to Treatment Arm 4 will receive a 6-
week supply of ibuprofen, which consists of 84 pills of 
ibuprofen to be taken twice daily (BID) and at least 8 hours 
apart and a home-based walking and progressive resistance 
exercise regimen to follow for a total duration of 6 weeks.  
Participants assigned to Treatment Arm 3 will wear the 
pedometer and Garmin DAT and pedometer daily during the 
study intervention period.
5.4
Physiological and Psychological Assessments
5.4.1 Baseline assessments will be completed prior to the initiation of the 
next chemotherapy cycle. Post assessments will occur most often 
on Day 42 of the intervention. Because scheduling issues can 
occur, the post assessment may not always be completed on Day 
42, and therefore, the post assessment may be performed during 
the last week on study up until the subject’s last on-study 
chemotherapy. ] In the instance of an adverse event, assessments 
may be delayed.
5.4.2 Fasting blood draws at 2 time-points (baseline and post-
intervention) will be done to measure cytokine, chemokine and 
receptor levels by appropriate ELISA/multiplex methods. These 
time-points coincide with baseline and post-intervention 
assessments but are not always on the same day. We often, at the 
request of the patient, will collect blood along with pre-
chemotherapy labs.
Blood draws will be performed by a nurse or phlebotomist in the 
Wilmot Cancer Institute and or by a nurse from the Clinical 
Research Center (CRC) at Strong Memorial Hospital prior to the 
patient’s chemotherapy appointment (within 5 days before or the 
morning/afternoon of). The time of day will be noted, with future 
assessments at approximately the same time of day during post-
testing.  


RSRB # 31416                                        Page 19 of 46          Version Date: January 31, 2018
The blood sample (35 ml) for cytokine measurements will be drawn 
in 2 red (for serum), 2 paxgene (for RNA), and 1 purple EDTA tube 
(for whole blood) vacutainers and will be transported by a member 
of the research team to Dr. Janelsins’ Laboratory in the Department 
of Surgery for immediate spinning, processing, and storing (at -20° 
or -80° C) of serum/whole blood/RNA. All human biological 
materials will be handled in adherence with the University of 
Rochester Office of Environmental Safety Biosafety Level II 
requirements.  Dr. William’s laboratory is a back-up site should that 
laboratory be needed for any processing. Dr. William’s and Dr. 
Janelsins’ laboratories have received appropriate biosafety 
certifications by the University of Rochester Institutional Biosafety 
Committee and undergoes routine inspections.  Samples not 
included in the immunological analyses of this project will be stored 
for future research by Dr. Janelsins and her team (if the patient has 
consented that we can use their samples for future research).  
5.4.3 Blood Samples for Participants Co-enrolled in RSRB 31416
For participants co-enrolled in RSRB 54027 and RSRB 31416, 
blood sample collection will occur once for Assessment 5 in RSRB 
54027 and the Baseline visit in RSRB 31416. After processing, 
blood samples will be split equally between the two studies. The 
total volume of blood collected from participants co-enrolled in 
RSRB 54027 and RSRB 31416 for both RSRB 54027 Assessment 
5 and RSRB 31416 Baseline assessment will be approximately 50 
mL.
BLOOD COLLECTION  FOR PARTICIPANTS CO-ENROLLED
IN RSRB 31416 and RSRB 54027
RSRB 54027
Assessment 5
RSRB 31416
Baseline Visit
Co-Enrolled
Serum (Red 
Top)
2 tubes (20mL)
2 tubes (20mL)
2 tubes (20mL)
Whole Blood 
(Purple Top)
1 tube (10 mL)
1 tube (10 mL)
1 tube (10 mL)
Paxgene
1 tube (2.5 mL)
2 tubes (5 mL)
2 tubes (5 mL)
PBMC (Green 
top)
2 tubes (10mL + 
5mL)
Not collected
2 tubes (10mL + 
5mL)
Approximate 
Total Volume
48 mL
35 mL
50 mL
5.4.3 Blood counts measured by standard CBC with differential 
procedures will be abstracted from the patient’s medical record. 
5.4.4 All patients will be given a measure of cognitive functioning 
(Functional Assessment of Cancer Therapy with Cognition (FACT-


RSRB # 31416                                        Page 20 of 46          Version Date: January 31, 2018
Cog)), Functional Assessment of Cancer Therapy (FACT-G), 
Pittsburgh Sleep Quality Index (PSQI), Fatigue Symptom Checklist 
(FSCL),  Spelberger State/Trait Anxiety Inventory (STAI), Profile of 
Mood States (POMS), and Center for Epidemiological Studies 
Depression Scale (CES-D), to complete at home at the appropriate 
times (i.e. during baseline, and at post-intervention). FACT-COG 
and FACT-G will be completed at pre- and post-intervention and at 
week 3 (during the intervention). Additionally, each patient will 
complete a daily diary which includes questions about symptoms, 
daily exercise, and drug usage. The exercise daily diary will also be 
used to measure adherence and compliance to the exercise 
intervention (if randomized to those arms). Participants assigned to 
the exercise program will wear the Garmin DAT and pedometer 
daily during the study intervention period. Participants assigned to 
non-exercise treatment arms will receive a Garmin DAT at the post-
intervention visit. 
5.4.5 All patients will be evaluated on aerobic capacity (VO2max 
Treadmill Test and Resting Metabolic Rate Test), and muscular 
strength (handgrip dynamometry).  All physiological fitness testing 
will be administered according to the Guidelines for Exercise 
Testing and Prescription (GETP) as outlined by the American 
College of Sports Medicine (ACSM).  
5.4.6 All patients will be evaluated for cognitive performance on the 
CANTAB computerized neuropsychological assessment of memory 
performance on a delayed matching to sample task. This 
assessment measures memory across delay times (0, 4, 12 
seconds) as well as reaction time. This assessment is non-invasive 
and only requires touching a computer screen. This assessment 
takes less than 10 minutes to complete. Three other CANTAB tests 
will be included for secondary/exploratory analyses: Verbal 
Recognition Memory (Immediate and Delayed memory; ten 
minutes), Rapid Visual Information Processing (a short 10 minute 
test of attention and working memory) and One Touch Stockings of 
Cambridge (OTS) (a short ten-minute test of frontal lobe executive 
functioning).  Paper-based assessment with the WRAT, HVLT-R, 
COWA, and TMT A/B will also be conducted for secondary 
analyses.      
5.5
Ibuprofen 200 mg (Arms 2 & 4) or placebo 200 mg (Arms 1 & 3)
5.5.1 The ibuprofen arms 2 & 4 will follow the guidelines listed below:
5.5.1.1
The ibuprofen 200 mg pills will be supplied by the 
University of Rochester Medical Center Investigational Drug 


RSRB # 31416                                        Page 21 of 46          Version Date: January 31, 2018
Service and will be over-encapsulated. The pills will be given 
to the subjects in a plastic vial by the study coordinator and 
will receive a full 6-week supply as prepared by the IDS.  
Research subjects will be instructed to take the ibuprofen 
once in the morning and once in the evening as long as the 
doses are at least 8 hours apart.  Subjects will take 2 
capsules /day for duration of 6 weeks.   (Note: Study 
medication is prepared by the IDS and stored in the Cancer 
Control Unit per section 5.3.2). 
5.5.1.2
The placebo 200 mg pills will be supplied by the 
University of Rochester Medical Center Investigational Drug 
Service and will be over-encapsulated and given to the 
subjects in a plastic vial with a six week supply by the study 
coordinator.  Research subjects will be instructed to take the 
ibuprofen once in the morning and once in the evening as 
long as the doses are at least 8 hours apart.  Subjects will 
take 2 capsules/day for a duration of 6 weeks.  Note: Study 
medication is prepared by the IDS and stored in the Cancer 
Control Unit per section 5.3.2). 
5.5.1.3
The study coordinator will contact each subject 
weekly. The study coordinator will use this opportunity to 
assess any potential complications or toxicities due to the 
intervention.
5.6
Walking and Progressive Resistance Exercise Arms 3 & 4
5.6.1 The Home-Based Walking and Progressive Resistance Exercise 
Program, EXCAP, is designed by an Exercise Scientist certified by 
the American College of Sports Medicine (ACSM) and is in 
accordance with the guidelines for exercise testing and prescription 
as set forth by the ACSM.  EXCAP has been tested by Dr. Mustian 
in a pilot study with cancer patients receiving radiation treatment. A 
large randomized controlled trial of EXCAP is currently being 
conducted by Dr. Mustian with URCC NCORP and affiliates in 
patients receiving chemotherapy. 
5.6.2 The Home-Based Walking and Progressive Resistance Exercise 
Program, EXCAP, will follow the guidelines listed below.
5.6.2.1
The Home-Based Walking Prescription will be based 
on a patient’s baseline pedometer assessment.  Subjects will 
be encouraged to increase their total steps walked by a 
minimum of 5% a week, while maintaining a moderate 
intensity, during the 6-week intervention.  [Note: Walking 


RSRB # 31416                                        Page 22 of 46          Version Date: January 31, 2018
intensity will be monitored via the Revised Rating of 
Perceived Exertion (RPE) Scale, which is a visual analog 
scale ranging from 0 = No exertion to 10 = Maximal exertion; 
and part of the daily diary that participants will keep.  An 
RPE between 3-7 corresponds to a heart rate reserve of 40-
70%] 
5.6.2.2
The Home-Based Progressive Resistance 
Prescription will be based on a patient’s optimal level of 
challenge.  Subjects will be instructed on the proper use of 
resistance bands.  Subjects will then be instructed to choose 
a resistance band with which they can perform 8-15 
repetitions of various upper body resistance exercises (bicep 
curl, tricep extension, chest press, rows, overhead press)  
and lower body resistance exercises (leg curl, leg extension, 
squat, toe raises, side bends).  The resistance will be 
determined via the Revised Rating of Perceived Exertion 
(RPE) Scale.  Participants will choose a resistance level that 
corresponds to an RPE between 3-7.  Subjects will be 
instructed to begin with 1 set of 8-15 repetitions at a 
moderately challenging level daily.  Patients will be 
instructed to progressively increase to four (4) sets for each 
exercise daily with 15 repetitions.  Participants will be 
instructed to use a 3-4 second eccentric movement and a 3-
4 second concentric movement.  Each resistance training 
session will last between 30 – 45 minutes.  (Note: Patients 
will be instructed in the proper methods for performing each 
exercise and will be able to call the coordinator or exercise 
trainer if questions arise).  The resistance band training 
program is a mild to moderate progressive resistance 
program designed to maintain strength, muscle mass and 
function, not a vigorous weight training program designed to 
substantially increase strength and muscle mass.  The dose 
of resistance exercise is very similar to programs used in 
rehabilitation.  It is common and safe to prescribe resistance 
exercises like these on a daily basis to maintain strength, 
muscle mass and function. 
5.6.2.3
The study coordinator will talk with each patient 
on a weekly basis.  He/she will answer any questions 
the patient may have regarding the exercise program 
in order to facilitate proper adherence and compliance 
to the exercise intervention.  
5.6.3 All Walking and Progressive Resistance Exercises will be 
performed off-site from the University of Rochester Cancer Institute 


RSRB # 31416                                        Page 23 of 46          Version Date: January 31, 2018
in a home-based patient-selected environment.  
5.6.4 There will be no costs to the patient for the physiological 
assessments (e.g. serum collection and muscular strength), 
resistance bands, pedometer, Garmin digital activity tracker, or 
Home-Based Walking and Progressive Resistance Exercise 
Prescription.  All costs will be paid from funds from Dr. Janelsins’ 
NCI K07 Award and her other research funds.  
5.7
Toxicity Monitoring:
Removal from study:  Patients can be removed from the study for any of 
the following reasons:
1.
Any grade ≥ 3 toxicity related to the study drug.
2.
A grade 2 toxicity that persists for more than 2 weeks.
3.
Withdrawal of consent.
For any clinically adverse event, the toxicity grading scale 
established by the FDA will be used.  It is as follows:
Grade 1 toxicity (Mild): No interference with activity
Grade 2 toxicity (Moderate): Some interference with activity not 
requiring medical intervention.
Grade 3 toxicity (Severe): Prevents daily activity and requires 
medical intervention.
Grade 4 toxicity (Potentially Life Threatening): ER visit or 
hospitalization.
5.7.1 Any grade 3 toxicity or persistent grade 2 toxicity reported to Dr. 
Janelsins and Dr. Janelsins’ research team will be reviewed 
immediately by one of the medical monitors (Dr. Mohile (primary), 
Dr. Tejani (secondary), all other protocol oncologists (tertiary)) to 
determine whether the toxicity is related to the study interventions 
or to chemotherapy. If the toxicity is at least possibly due to the 
study interventions, the participant will be removed from the study. 
If a study participant is removed from the study, the research team 
may continue to follow the study participant for assessment data if 
the participant agrees and medical monitors feel it is safe for the 
participant to perform study assessments. 
5.7.2 Ibuprofen
The potential risks and side effects of ibuprofen include: 


RSRB # 31416                                        Page 24 of 46          Version Date: January 31, 2018
Side effects can include headaches, dizziness, drowsiness, rash, 
abdominal pain, nausea, diarrhea, constipation, and heartburn.  
Since ibuprofen reduces the ability of blood to clot, bleeding may be 
increased after injury. Studies of high doses of ibuprofen (800 mg 3 
times per day) have been associated with low incidence of 
gastroduodenal and gastric ulcers.[48, 49] The low dose for the 
proposed studies is not likely to cause ulcers; as a precaution, we 
are excluding those who have a history of ulcer disease during the 
past year. 
NSAIDs (e.g. ibuprofen) have been used in clinical studies in 
cancer patients receiving chemotherapy and have been safe and 
have not altered chemotherapy pharmacokinetics[50]. The doses of 
ibuprofen and time-frame of ibuprofen that we have chosen are 
similar to other ongoing studies of NSAIDs given in combination 
with chemotherapy (clinicaltrials.gov identifiers: NCT00520091, 
NCT00300729, NCT00064181, NCT00135018). 
5.7.3  Exercise 
Commencement of a low to moderate walking and progressive 
resistance exercise program is not associated with any severe side 
effects, and risks are minimal for individuals with no 
cardiopulmonary, orthopedic, or age-identified high risk factors as 
determined by the patient’s treating physician (or designee).  
The chance of a cardiac event is rare once coronary disease has 
been excluded with reasonable certainty.  Approximately 1 death 
per 15,000-20,000 healthy men per year occurs during jogging; this 
risk is much lower in women.  A transient increase in blood 
pressure may occur with all types of exercise.  Although unlikely, 
the risks involved in a low to moderate walking and progressive 
resistance exercise program are musculoskeletal— possibly mild 
muscle soreness, a muscle strain, or related injuries such as 
tripping.  Overall, the risk level for participation in a low to moderate 
Home-Based Walking and Progressive Resistance program is 
minimal.  
Risks associated with a VO2max test or 6-minute walk test are 
similar to participation in a low to moderate walking exercise 
program and are minimal for individuals with no cardiopulmonary, 
orthopedic, or age-identified high risk factors as determined by the 
patient’s doctor.    The nature of these assessments will require a 
level of exertion causing temporary changes such as an increase in 
heart rate and blood pressure, both of which are normal responses 
to moderate exercise.  Seven-to-ten Repetition Maximum Tests for 


RSRB # 31416                                        Page 25 of 46          Version Date: January 31, 2018
strength may cause minor stiffness and/or tenderness in muscles 
for a couple of days following testing.  The nature of these 
assessments will require a level of exertion causing temporary 
changes like an increase in heart rate and blood pressure, both of 
which are normal responses to moderate exercise.  There is a 
small risk of irritation to the skin from the electrodes used for the 
BIA analysis.  
Every effort will be made to minimize the risks for all study 
procedures through the approval of the treating physician to enter 
the study, supervision of all testing and exercise prescription by an 
American College of Sports Medicine certified Health and Fitness 
Instructor or a physician (or physician’s designee) when necessary 
according to American College of Sports Medicine Guidelines, the 
use of standardized guidelines for exercise testing and prescription 
provided by the American College of Sports Medicine and resting 
metabolic rate testing. Risks will also be minimized by following the 
documented and approved procedures for the tests that are 
performed in the NIH-funded and approved University of Rochester 
Clinical Research Center, and trained staff will perform these tests. 
Dr. Mustian has found the intervention to be safe in breast and 
prostate cancer patients undergoing radiation treatment [45]; 
additional approved study with EXCAP in cancer patients receiving 
chemotherapy and/or radiation therapy is being conducted at the 
University and through the University of Rochester NCORP 
program.  
5.7.4 There is a chance of bruising and a very slight chance of infection 
with blood collection.  This will be minimized through the use of 
standardized hospital procedures for blood collection, use of a 
trained phlebotomist and sterile materials.  
5.8
Adverse Events
5.8.1   A research coordinator will call each patient weekly to assess side 
effects.  The coordinator will record any adverse events (AE) and/or 
serious adverse events (SAE).  All patients are routinely 
undergoing close supervision by their oncologist and medical team 
and often, these AEs and SAEs are addressed during the patients 
clinic visit as part of the standard of care. If any follow-up 
appointment is needed regarding the AE or SAE, the patient will 
follow-up as directed by their oncologist and this will be 
documented in the research record.  Reports regarding potential 
toxicities, patient safety, and outcomes will be submitted to the 
University of Rochester Medical Center Research Subjects Review 


RSRB # 31416                                        Page 26 of 46          Version Date: January 31, 2018
Board (RSRB).
5.8.1.1 An adverse event (AE) is any untoward medical 
occurrence in a patient administered a pharmaceutical 
product, which does not necessarily have a causal 
relationship with the treatment.  An adverse event can be 
any unfavorable and unintended sign (eg, including an 
abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the drug, whether or 
not it is considered to be drug related.  This includes any 
newly occurring event or previous condition that has 
increased in severity or frequency since the administration of 
drug.
5.8.1.2A serious adverse event (SAE) is any adverse event, 
occurring at any dose and regardless of causality that:

Results in death.

Is life-threatening.  Life-threatening means that the patient 
was at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a 
more severe form.

Requires inpatient hospitalization or prolongation of 
existing hospitalization.  Hospital admissions and/or 
surgical operations scheduled to occur during the study 
period but planned prior to study entry are not considered 
AEs if the illness or disease existed before the patient was 
enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (eg, surgery performed 
earlier than planned).

Results in persistent or significant 
disability/incapacity.  Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life 
functions.

Is a congenital anomaly/birth defect.

Is an important medical event.  An important medical event 
is an event that may not result in death, be life-threatening, 
or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may 
jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in 
the definitions for SAEs.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment 
in an 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.  


RSRB # 31416                                        Page 27 of 46          Version Date: January 31, 2018
5.8.1.3 An unexpected adverse event is any drug/intervention 
experience, the specificity or severity of which is not 
consistent with the risk information described in the 
investigators brochure or general investigational plan. 
Unexpected as used in this definition refers to an adverse 
drug event that has not been previously observed rather 
than from the perspective of such experience not having 
been anticipated from the pharmacological properties of the 
drug/intervention.
5.8.2 Adverse Event Reporting
Serious adverse events that are associated with the study and 
occur while a subject is on study until 14 days after the date the 
subject goes off study must be reported in writing to the Strong 
Memorial Hospital IRB within 10 working days. They are also 
reported to the Data Safety Monitoring Committee within the same 
time frame. Adverse events that are both unexpected fatal or life-
threatening events must be reported immediately to the IRB.
5.8.3 Data Safety Monitoring Plan
Investigators will conduct continuous review of data and patient 
safety.  The review will include for each treatment arm level:  the 
number of patients, significant toxicities as described in the 
protocol, dose adjustments, and responses observed.  The 
Investigator will submit twice yearly summaries of this data to the 
Clinical Trials Monitoring Committee for review.  
Clinical Trials Data Safety Monitoring Committee:  The Director 
of the Cancer Institute delegates responsibility for continued review 
and monitoring of all clinical trials conducted by the URCC to the 
Clinical Trials Data Safety Monitoring Committee.  This committee 
provides oversight of study progress and safety by review of 
accrual and adverse events at biannual meetings. Any adverse 
event requiring expedited review per protocol will be submitted to 
the Data Safety Monitoring Committee (DSMC) for determination as 
to whether further action is required.  The study PI and the study 
medical monitor determine if the adverse event requires expedited 
review.  Interim meetings are scheduled, as needed, to address 
specific issues that require immediate attention to assure patient 
safety.  
The Committee:  


RSRB # 31416                                        Page 28 of 46          Version Date: January 31, 2018
a)
Reviews assigned clinical trials conducted at the URCC for 
progress and safety.
b)
Reviews all adverse events requiring expedited reporting as 
defined in the protocol.
c)
Reviews reports generated by the URCC data quality control review 
process.
d)
Submits recommendations for corrective actions to the Protocol 
Review Committee and the PI
e)
In general, outcome data is not made available to individuals 
outside of the DSMC until accrual has been completed and all 
patients have completed their treatment.  At this time, the DSMC 
may approve the release of outcome data on a confidential basis to 
the trial PI for planning the preparation of manuscripts and/or to a 
small number of other investigators for purposes of planning future 
trials.  Any release of outcome data prior to the DSMC’s 
recommendation for general dissemination of results must be 
reviewed and approved by the DSMC.
Safety Coordinator:  The Medical Director of the Cancer Center 
Clinical Trials Office appoints the Safety Coordinator.  The Safety 
Coordinator monitors adverse event rates utilizing the URCC 
Clinical Trials database.  If any assigned study has had two or more 
of the same SAEs reported in a month or more than six of the same 
SAEs in six months, the DSMC will review the summary of SAEs, 
discuss events with the Study Chair, and conduct a more detailed 
review with the Study Chair.  The Data Safety Monitoring Chair will 
determine if further action is required.
5.8.4 All study drugs will be dispensed and all biological specimens will 
be collected at the University of Rochester Medical Center 
locations.
6.0  Treatment Evaluation
6.1
Measures
6.1.1 Cognitive Assessments – Computerized (~35 minutes)
6.1.1.1 
CANTAB was developed for assessment and 
evaluation of cognitive function. CANTAB tests are reliable and 
validated and have been reported in over 600 publications, 
including those by Co-Investigator on this protocol, Dr. Deborah 


RSRB # 31416                                        Page 29 of 46          Version Date: January 31, 2018
Cory-Slechta. 
The administrator will closely follow the provided script. The primary 
outcome measure will be short-term memory (percent correct) 
performance across a delay series as assessed by the delayed 
matching to sample task. This test takes approximately 10 minutes 
to complete, and a total of three data points is obtained (at 0, 4, and 
12 seconds). A subject is shown a complex visual pattern and then, 
after a brief delay (4 and 12 seconds), is shown four similar 
patterns. The subject is instructed to touch the pattern on the 
computer screen which exactly matches the sample. Speed to 
complete the task (latency in ms) is also assessed within the same 
measure which may indicate attention/motivation contributions to 
performance on the task. 
6.1.1.2
Memory (verbal) will also be assessed by the Verbal 
Recognition Memory (VRM) Task. In this task, the subject is asked 
to remember a list of words (presented to them on a screen) and 
then immediately recall them verbally. The subject is then asked to 
recall from a list if they previously saw the word (pressing yes or 
no). Following the next two tasks (i.e. the executive function and 
attention task) approximately 20 minutes later, the subject is then 
asked to recall whether or not they recognize the word (pressing 
yes or no) from the original list of words.    
6.1.1.3
 Attention will be assessed by the Rapid Visual 
Information Processing (RVP) task. The second secondary 
outcome measure will be total latency (ms). Errors will also be 
recorded. A white box is displayed in the center of the computer 
screen, inside which digits, from 2 to 9, are displayed in a pseudo-
random order, at the rate of 100 digits per minute. The subject must 
detect consecutive odd or even sequences of digits (for example, 2-
4-6) and respond by pressing the touch pad.  
6.1.1.4 
Executive function will be assessed by the One 
Touch Stockings of Cambridge (OTS) planning task (total percent 
correct). Percent correct based on the number of necessary moves 
involved will also be assessed. The subject is shown two displays 
containing three colored balls. The displays are presented in such a 
way that they can easily be perceived as stacks of colored balls 
held in stockings or socks suspended from a beam. There is a row 
of boxes containing numbers at the bottom of the screen, from one 
upwards. The test administrator first demonstrates to the subject 
how to use the balls in the lower display to copy the pattern shown 
in the upper display. The balls may be moved one at a time by 
touching the required ball, then touching the position to which it 


RSRB # 31416                                        Page 30 of 46          Version Date: January 31, 2018
should be moved. The subject is shown one demonstration 
problem, then must solve three further problems. These problems 
increase in complexity, from one move to four moves. Next the 
subject is shown more problems and must work out how many 
moves the solutions require in his/her head, then touch the 
appropriate box at the bottom of the screen to indicate the number 
of moves required.  
6.1.1.5
All patients will complete the 50-item Functional 
Assessment of Cancer Therapy with Cognition (FACT-Cog) 
questionnaire.  The FACT-Cog addresses a wide range of cognitive 
functioning domains which allows one to separate specific domains 
of cognition. It was developed by Wagner and colleagues[6] and is 
currently undergoing validation in studies with cancer patients.[51] 
6.1.2   Cognitive Assessment – Paper Based (~25 minutes)
6.1.2.1 
Basic academic skills/cognitive reserve will be 
measured with the Wide Range Achievement Test-Third Edition 
(WRAT-4). This test has been validated for individuals aged 5-
75.[49] Three subtests are included: reading, spelling, and 
arithmetic. The reading test includes the recognition and naming of 
letters and pronunciation of words out of context. The spelling test 
includes the subject writing his/her name and then writing letters 
and words as dictated. The arithmetic involves counting, reading 
number symbols, solving oral problems, and doing written 
computations. 
6.1.2.2 
Short-term memory will be assessed by the 
Hopkins Verbal Learning and Memory Test-Revised (HVLT-
R).[50, 51] In this test, the administrator reads a list of 12 words to the 
subject three times. Immediate recall is assessed after each time. 
After 20 minutes, the participant is asked to recall the 12 words. 
The administrator records the number of correct and incorrect 
words. The score is the number of correct words in both the 
immediate (3 trials) and delayed recall (after 20 min).  For the 
delayed recall, the number of correct words minus the number of 
incorrect words will also be recorded. 
6.1.2.3 
Attention/scanning, speed/sequencing, and 
executive function will be assessed by the Trail Making Test 
(Comprehensive Trail Making Test Trails 1 and 5).[52, 53] In part 
A/Trail 1, participants draw a line connected to each number in 
sequential order. In part B/Trail 5, participants draw a line to 
connect numbers and letters in sequential order. Time to complete 


RSRB # 31416                                        Page 31 of 46          Version Date: January 31, 2018
the test (in seconds) is recorded for both parts A and B.  Part A is 
stopped after 3 min, and Part B is stopped after 5 minutes.  
6.1.2.4 
Verbal fluency/executive function will be assessed 
by the Controlled Oral Word Association Test (COWA).[54] 
Designed by Benton and colleagues, this test assesses fluency with 
naming words with C, F, and L.  Subjects are asked to tell the 
administrator as many words as possible beginning with the letter 
C, excluding proper nouns, numbers, and the same word with a 
different suffix. The subject has 60 seconds to list as many words 
as possible. The number of correct words, incorrect words, and the 
number of repeats will be recorded. This test takes less than five 
minutes to administer. Trials are repeated for the letter F and L. 
6.1.3 Inflammation markers 
Cytokines and their receptors (e.g. IL-1, TNF-α, IL-6), 
Chemokines (e.g. MCP-1 and IL-8) prostaglandins (i.e. PGE2) can 
be easily measured in the serum with reliable results. Serum is 
aliquoted into microfuge tubes to minimize freeze/thaw cycles that 
could result in protein degradation. Cytokine levels will be assessed 
using a colorimetric ELISAs from R & D Systems in Dr. Janelsins’ 
Laboratory or by Luminex at the URMC Human Immunology Center 
Core. Inflammation marker RNA levels and genotyping will be 
analyzed by qRT-PCR at the URMC Genomics Core.
6.1.4 Physical Activity
Physical activity will be assessed by questions on the daily 
journal.  In addition, objective assessments of physical activity will 
be obtained via the pedometer.
The Pedometer devices will be used to assess duration of physical 
activity via steps walked during the time out of bed. Participants 
NOT assigned to the exercise arm will give back their pedometer 
after the 3-day baseline measure and will have the pedometer and 
reissued for the 3-day measure at the end of the trial. Permission 
will be obtained to mail the pedometer to the subject if necessary. 
The Garmin Digital Activity Tracker will be used to evaluate the 
feasibility and preliminary efficacy of a wrist-worn digital activity 
tracker for assessing the duration of physical activity via steps 
walked during the time out of bed.  Participants assigned to the 
exercise intervention will wear the Garmin DAT daily during the 
study intervention period. Participants not assigned to the exercise 


RSRB # 31416                                        Page 32 of 46          Version Date: January 31, 2018
intervention will receive a Garmin DAT at the post-intervention visit.
6.1.5 Aerobic Capacity
Aerobic capacity will be assessed using a VO2max Treadmill Test 
as a measure of compliance using a modified “Branching Treadmill 
Protocol”. Participants begin at a normal walking speed (2.5 mph) 
and 0% grade. After 2 min. the speed is increased to a faster 
walking speed (3.0 mph) and 0% grade. After 2 min, the speed is 
increased to 3.5 mph and 2% grade. Thereafter, only the grade is 
increased by 2% every 2 min. Oxygen consumption (VO2), carbon 
dioxide production (VCO2), and flow rate will be measured 
continuously. The test is ended when the participant wants to stop. 
An MD is available onsite in the hospital during all tests as outlined 
by the ACSM fitness testing guidelines.  In preparation for the 
exercise treadmill test, subjects have the option to fast for 4 hrs 
prior to the test and they will be asked to rest quietly on a bed in a 
quiet room for 30 minutes under a clear canopy which is placed 
over their head.  During this 30 minute period, they will have their 
resting metabolic rate measured for 30 minutes using continuous, 
computerized open-circuit indirect calorimetry (Sensormedics® 
Vmax).  A 6-Minute walking test may be substituted for the treadmill 
test in the event the person is not able to complete it.  This is a sub 
maximal measurement using a 6 minute walk protocol.  Participants 
are given a short warm up and cool down walking protocol in the 
test walking area in the University of Rochester.  Participants walk 
for a total of 6 minutes and cover as much distance as they can 
during this time.  Upon completion of the test, the total distance 
walked is used to calculate an estimate of aerobic capacity 
(VO2max:Maximal Oxygen Consumption).
6.1.6 Muscular Fitness
Muscular fitness will be assessed using a handgrip dynamometer 
test and the 7-10 repetition maximum dynamic strength testing 
protocol. 
The Handgrip Dynamometer Test is a grip strength test used to 
assess the maximal voluntary contraction generated by the arm 
muscles.  The test is administered with the patient standing in 
anatomical position; the elbow joint angle will be held constant at 
180 degrees with the medial distal humeral epicondyl held 2 inches 
from the torso.  Trials will be performed in an alternating bilateral 
sequence for a total of six attempts (three with each arm).  The best 
score of the three trials will be used for right and left limbs to 
calculate static strength.  The surgically involved arm(s) will be 


RSRB # 31416                                        Page 33 of 46          Version Date: January 31, 2018
noted for data analysis.  The handgrip dynamometer test has been 
previously used in a number of URCC NCORP protocols and has 
shown to be a reliable clinical method of assessing strength. [52] 
The standard 7-10 Repetition Maximum Dynamic Strength 
Testing Protocol will be used to estimate patients’ 1-repetition 
maximums for the leg extension (quadriceps) and bench press 
(pectoralis and deltoid). The patients will receive a full orientation 
to the fixed resistance machines and proper lifting form by a 
certified (e.g., ACSM) exercise testing professional.  Participants 
will perform a light warm up consisting of 8 lift repetitions employing 
the lightest weight on the machine.  After the warm up, patients will 
be given a 2-3 minute rest break.  A weight will be selected by the 
exercise testing staff based on the ease or difficulty of completing 
the warm up for each patient and this weight will be lifted until 
subjective fatigue.  Alternating rest breaks (2-3 minutes) and lifting 
bouts will continue with the resistance weight being adjusted by the 
exercise testing staff until the patient reaches a level of resistance 
that results in subjective fatigue between 7-10 repetitions.   
Established algorithms employing the weight lifted and the number 
of repetitions completed will then be used to estimate the patients’ 
1-repetition maximum.[53] 
6.1.7 Muscle Mass
The RJL Bioelectrical Impedance System is a non-invasive, 
easy-to administer and safe method of assessing lean body mass.  
BIA involves passing a small electrical current through the body 
and evaluating the reactance and resistance to flow, which are 
related to fat-free mass (FFM) and total body water.  Prediction of 
lean body mass from BIA is as reliable as skin-fold measurements 
and hydrostatic weighing.  Participants have the option to be 4 
hours fasted, although it is not required. Participants need to be 
abstained from alcohol and diuretics (unless prescribed) for 48 
hours, well hydrated (water only), and voided completely prior to 
assessment.  We will also document whether participants exercised 
within the last 12 hours or not. Participants lie supine on a flat 
surface for approximately 5 minutes prior to the test, to ensure a 
resting metabolic state.  Electrodes are attached to the right hand 
(distal end of the 3rd and 4th metacarpal and distal end of the ulnar 
and radius), and the right foot (distal end of the 3rd and 4th 
metatarsal and distal end of the tibia and fibula).  Skeletal muscle 
mass will then be calculated from the lean body mass. [54] 
6.1.8 Daily Diaries 


RSRB # 31416                                        Page 34 of 46          Version Date: January 31, 2018
Participants will be asked to complete daily diaries each night. All 
participants will complete the Daily Symptom Diary. Participants 
assigned to the exercise intervention will be asked to record step 
counts measured via pedometer and Garmin digital activity tracker, 
number of minutes they exercised that day (aerobic and resistance 
training), perceived exertion during exercise, and severity of eight 
symptoms assessed on 11-point scales anchored by 0 = “Not 
Present” and 10 = “As Bad As You Can Imagine” on the Exercise 
Daily Diary. The symptoms queried about at their worst on a daily 
basis are fatigue, sleep, stress, depression, concentration, memory, 
pain and anxiety. The diary takes 2-3 minutes to complete. 
Questions about daily exercise and daily NSAID usage are also 
included. Note: When patient diaries are returned to us they the 
symptom section will be reviewed for indications of problems and 
the patient’s medical team will be notified if any symptom is 
consistently scored as 4 or higher throughout the study period. The 
study coordinator will ask about symptoms during weekly phone 
calls and will contact the subject’s medical team if a severe 
complaint (scored as 8 or greater and out of the ordinary for the 
patient) is made. 
6.1.9 Quality of Life
The Functional Assessment of Cancer Treatment-General (FACT-
G) is a 27-item assessment of four domains of well-being: 
physical, social/family, emotional, and functional. Subjects are 
asked questions related to domains of well-being on a five point 
scale (0-4) with 0 being a score of “not at all” and 4 being a score of 
“very much”. This questionnaire is a well-validated test for 
assessment of quality of life for cancer patients receiving 
treatment.[55, 56]
       6.1.11 Mood
General mood will be assessed using the short form of the Profile 
of Mood States (POMS).  The POMS consists of 30 adjectives in 6 
subscales (e.g., anxiety, depression), which subjects rate on a five-
point scale with “1” = “Not at all” and”5” = “Extremely” to describe 
their moods over the past week.  The POMS has been used 
extensively in research with cancer patients and has demonstrated 
reliability and validity. [57, 58]
6.1.12
Fatigue
The Fatigue Symptom Checklist (FSCL)[59] will be administered to 
measure fatigue. This instrument consists of 30 items in three 


RSRB # 31416                                        Page 35 of 46          Version Date: January 31, 2018
subscales that have been associated with fatigue: drowsiness and 
dullness, difficulty of concentration, and projection of physical 
impairment. Subjects are asked to indicate the presence and 
intensity of each item on a five-point scale. Both the number and 
intensity of fatigue symptoms can be calculated for this scale. 
6.1.13
Anxiety 
Anxiety will be measured using the Spielberger State/Trait 
Anxiety Inventory (STAI Form X-1).  In order to reduce the overall 
patient burden, we will use only the state portion of the 
questionnaire.  This one-page, self-administered questionnaire 
consists of 20 short statements which people may use to describe 
their feelings.  Participants are asked to fill in a numbered circle to 
indicate the degree to which they generally experience the 
particular feeling, ranging from 1 = “Not at all” to 4 = “Very much so” 
at that time.  It is one of the most widely-used assessments of 
anxiety.  Internal consistency coefficients > 0.90 have been shown, 
along with test/retest reliability coefficients > 0.70.  Concurrent, 
construct, convergent and divergent validity have also been 
demonstrated. [63]  We have successfully implemented this measure 
in previous studies.
6.1.14
Sleep 
The Pittsburgh Sleep Quality Inventory (PSQI), a commonly
used, 25 item psychometrically sound measure scored for both
global severity and subscale scores, will assess sleep initiation and
maintenance problems and possible etiologic factors (e.g., pain,
nightmares, hot flashes).[64]  This measure has been implemented
in other NCORP studies conducted by our group.  
6.1.15
Depression 
Depressive symptoms will be measured with the Center for 
Epidemiological Studies Depression Scale (CES-D).  The CES-
D is a 20-item depression scale developed and validated for use 
with a variety of populations.  It is in a format similar to that of the 
Beck Depression Inventory, but with less emphasis on physical 
symptoms of depression that may be confounded with disease 
symptoms or treatment side effects.  It has been shown to reliably 
and validly measure depression in cancer populations,[65] and we 
have successfully used this measure in previous studies.  
Note: Because cognitive difficulties, depression, anxiety, mood 
disruption, sleep disturbance and fatigue are often present as 


RSRB # 31416                                        Page 36 of 46          Version Date: January 31, 2018
symptom clusters, measures of depression, anxiety, mood, sleep 
and fatigue have been carefully selected to minimize potential 
confounding and enable assessment of possible confounds 
between these concepts.  
6.1.16
Feedback Questionnaire
At the post-intervention assessment, we will ask patients to 
complete a 3-item questionnaire about the usefulness and 
acceptability of the study treatments.
6.1.17
Disclosure of Physical Activity Results
After completion of study participation and upon request, results of 
physical activity testing may be shared with the patient by the 
coordinator and exercise physiologist. If requested, A Summary of 
Physical Activity Testing sheet will be completed by the study 
coordinator and mailed to the patient. The sheet will contain results 
of the patient vitals (pulse, blood pressure, height, weight), body 
composition, and metabolic, strength, and cardiopulmonary 
assessment results. The study coordinator or exercise physiologist 
will discuss the results provided on the Summary of Physical 
Activity Testing sheet over a follow-up phone call with the subject or 
in person in the PEAK lab.
7.0  Statistical Considerations
7.1
Primary analyses: The primary purpose for conducting this Phase II 
pilot study is to gather preliminary efficacy data for the development 
of a larger R01-level investigator-initiated grant submission of 
efficacy. The primary analyses will consist of calculating means, 
standard deviations and effect sizes for each of the objectives at 
pre-intervention and post-intervention in each of the 4 study arms.  
These analyses will be interpreted as providing preliminary effect 
size estimates for an R01 submission. The main analyses are 
described individually below for each of the study hypotheses. 
Stratification: All models will have gender and site as additional 
covariates. 
7.1.1 Hypothesis 1 (Primary Objective): Exercise and ibuprofen 
(combined or alone) will lead to higher short-term memory 
performances (percent correct across delays) as assessed by the 
objective CANTAB delayed matching to sample task in cancer 
patients receiving adjuvant chemotherapy. The mean effect of 


RSRB # 31416                                        Page 37 of 46          Version Date: January 31, 2018
treatment arm scores will be assessed by ANCOVAs, using the 
longest delay on this task (1200 ms), with baseline as a covariate. 
Interaction terms may be included but removed if not significant. 
We will also assess other covariates that may influence cognitive 
function, including age, education level, menopausal status (if 
applicable), and WRAT-4 reading score. Additionally, repeated 
measures ANOVAs using mixed modeling across sessions (0,4,12 
second delays) will be used. To model the response (Post-
intervention – Baseline), the fixed effects will be delay, arm, and 
delay x arm interaction. Random effects will be patient to patient 
and within patient variability. All main effects will be studied by post-
hoc tests. In all cases, p values of ≤ 0.05 will be considered 
statistically significant.  
7.1.2 Hypothesis 2 (Secondary Objective): At post-intervention, the 
effects of exercise and ibuprofen (combined or alone) on quality of 
life as assessed by the FACT-COG self-reported cognitive 
performance after completion of all chemotherapy compared to the 
control. The mean effects of treatment arm scores will be assessed 
by ANCOVA incorporating baseline as a covariate. Interaction 
terms will be incorporated initially but removed if not significant. We 
will also assess other covariates that may influence cognitive 
function, including age, education level, menopausal status (if 
applicable), and WRAT-4 reading score.
7.1.3 Hypothesis 3 (Tertiary Objective): At post-intervention assessment, 
exercise and ibuprofen (combined or alone) will lead to reduced 
immune marker levels compared to standard care in cancer 
patients receiving adjuvant chemotherapy. The mean effects of 
treatment arm scores will be assessed by ANCOVA incorporating 
baseline as a covariate. Interaction term between baseline and arm 
will be included initially, but removed from the model if not 
significant. We will also assess other covariates that may influence 
cognitive function, including age, education level, menopausal 
status (if applicable), and WRAT-4 reading score.
7.1.4 Exploratory Hypotheses: Additional analyses will examine between 
group differences in the other outcome measures.  These will 
include performance on CANTAB attention and executive 
functioning tests, paper-based tests of attention, reading, executive 
function and verbal memory, Physical Activity (Pedometer), aerobic 
capacity (VO2max treadmill test, Resting metabolic Rate), muscular 
strength (handgrip dynamometry and 7-10 Rep. Max Tests), body 
mass (BIA), other disease or cognitively related biomarkers, and 
self-reported measures (i.e. cognitive functioning, quality of life, 
fatigue, anxiety, depression, sleep, mood). These exploratory 


RSRB # 31416                                        Page 38 of 46          Version Date: January 31, 2018
analyses may be useful in refining or adding to the follow-up larger 
study. Preliminary analyses of the relationships to these outcomes 
and biomarkers will be conducted. 
   
 
7.2
Sample Size
7.2.1 116 is the target accrual for this Phase II study and was selected as 
an adequate size to provide pilot data for effect size determination 
for subsequent R01-level studies.
7.2.2   It is possible that 20% of patients will not provide evaluable data 
leaving approximately 23 evaluable patients per treatment 
condition. This number of patients will be adequate to meet our 
primary objective of ascertaining the appropriateness of our 
procedures and methods and to provide data to generate a sample-
size estimate for a R01-level investigator-initiated grant, especially 
considering that we will be able to take advantage of the 2x2 
factorial design in determining the intervention effectiveness.  We 
have been able to determine preliminary power based on Dr. 
Janelsins’ feasibility research with the CANTAB cognitive battery. 
Using our preliminary CANTAB DMS data, the standard deviation 
of percent correct for all delays was 11.3.  Assuming 23 evaluable 
subjects per arm (21% attrition), alpha=0.05, and 80% power, 
ANCOVA should be able to detect a change of 7%.  This assumes 
a correlation of about 0.8 between baseline and post-intervention.  
This is based on the effect size for the most conservative pattern of 
four means: (0, d/2, d/2, d) where d is the largest difference existing 
among the means.  The power curve is shown in the figure, with a 
vertical line marking ½ SD. 
Power Across Possible Detectable Differences of 
Primary Outcome Measure
0
2
4
6
8
10
0.2
0.4
0.6
0.8
1.0
Difference
Power


RSRB # 31416                                        Page 39 of 46          Version Date: January 31, 2018
7.2.3 Based on Dr. Janelsins’ preliminary research with co-investigators 
and oncologist collaborators on this project, it will take 
approximately 4 years to enroll 116 participants
8.0  Schedule of Activities 
Procedure
Time Since Randomization
0
21 Days
42 Days
Eligibility Interview
X
Informed Consent
X
Clinical Record Information
X
X*
On Study Data
X
X*
Medication Form
X
X*
Blood Collection Information (e.g. Date, 
Time, Volume)
X
X
Blood CBC Levels
X
X
Inflammation Markers (Protein, RNA, DNA)
X
X
Phone Calls
Weekly
Weekly
Weekly
Daily Diary
Daily
Daily
Daily
FACT-G
X
X
X
FACT-COG
X
X
X
CANTAB Cognitive Tests
X
X
Paper-Based Cognitive Tests
X
X
Resting Metabolic Rate
X
X
VO2max Treadmill Tests
X
X
Pedometer
X
X
Handgrip Dynamometer
X
X
BIA
X
X
7-10 Repetition Maximum Test
X
X
POMS
X
X
FSCL
X
X
PSQI
X
X
CES-D
X
X
*Update 


RSRB # 31416                                        Page 40 of 46          Version Date: January 31, 2018
8.1
All hardcopy research records will be stored onsite in the University of 
Rochester Medical Center, in the Behavioral Medicine Unit of the 
Saunders Research Building and the Wilmot Cancer Institute. The Cancer 
Institute is secured by electronic key cards.  Offices within the Cancer 
Institute are again secured by key and data is kept in locked file cabinets.  
Electronic research records are stored on the University of Rochester 
Medical Center’s password secured and firewall protected networks. 
These are the same methods of security used for patient medical records.  
Human serum samples and biopsy samples are stored in locked freezers, 
within locked and alarmed laboratories that are accessible by key codes 
and electronic card swipes.  All final files, databases and blood samples 
that are stored after study completion will remain on secured servers or in 
locked freezers, respectively, and all information will be de-identified.  
8.2
All data (information, human blood samples, and human tissue samples) 
collected for the current study will be used in post hoc analyses as 
appropriate.    The patient indicates on the consent form whether their 
blood is allowed to be used for future research. If a patient does not allow 
their blood to be used for future research, their blood will not be banked. 
Patients also are provided the opportunity to be contacted for future 
research studies in the informed consent.  The patient’s individual 
research record will not be shared with their treating physician, unless 
they provide consent or the patient’s treating physician is a study 
physician, in which case they will have access to study data as a study co-
investigator. A short letter with feasibility findings and notice of extension 
of the study due to federal grant funding will be provided to the 36 
participants accrued before 2/2013. Overall study results will be presented 
to participants, faculty and staff at the University of Rochester Medical 
Center. Study results will be presented at professional meetings and 
published.  
8.3
The study coordinator will assign a numerical Study ID to each participant 
once they have signed the consent form.  Questionnaires will use this 
number and the participant’s first, middle, and last initials as identifiers, to 
ensure data integrity.  Other identifying information will not exist on these 
forms.  A complete list of study participants with study ID, name, and 
contact information will be maintained separately. This linkage information 
will only be accessible to the study coordinator, study investigators, and 
the individual responsible for maintaining the database.
9.0   Patient Consent and Peer Judgment
9.1
Current, state, federal, and institutional regulations concerning informed 
consent will be followed.  Participation in this study is voluntary.  
Participants are free not to take part or to withdraw at any time, for 
whatever reason, without risking loss of present or future care they would 
otherwise expect to receive.  In the event that a patient does withdraw 


RSRB # 31416                                        Page 41 of 46          Version Date: January 31, 2018
from the study, the information they have already provided will be kept in a 
confidential manner.  Participants may discontinue participation in the 
study at any time if they decide they do not wish to take part any longer.  
Participants may be withdrawn from the study by research personnel if it is 
deemed in their best interest to no longer participate.
10.0  References
1.
Cancer Facts and Figures, in American Cancer Society 2008: Atlanta, GA.
2.
Ganz, P.A., A teachable moment for oncologists: cancer survivors, 10 
million strong and growing! J Clin Oncol, 2005. 23(24): p. 5458-60.
3.
Janelsins, M., Roscoe, JA, Jean-Pierre, P, Morrow, GR. Cognitive 
Functioning in Breast Cancer Patients During and Following Chemotherapy in 
American Society of Clinical Oncology. 2009.
4.
Brezden, C.B., et al., Cognitive function in breast cancer patients receiving 
adjuvant chemotherapy. J Clin Oncol, 2000. 18(14): p. 2695-701.
5.
Ahles, T.A., et al., Neuropsychologic impact of standard-dose systemic 
chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin 
Oncol, 2002. 20(2): p. 485-93.
6.
van Dam, F.S., et al., Impairment of cognitive function in women receiving 
adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose 
chemotherapy. J Natl Cancer Inst, 1998. 90(3): p. 210-8.
7.
Wefel, J.S., et al., The cognitive sequelae of standard-dose adjuvant 
chemotherapy in women with breast carcinoma: results of a prospective, 
randomized, longitudinal trial. Cancer, 2004. 100(11): p. 2292-9.
8.
Inagaki, M., et al., Smaller regional volumes of brain gray and white matter 
demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. 
Cancer, 2007. 109(1): p. 146-56.
9.
Saykin, A.J., T.A. Ahles, and B.C. McDonald, Mechanisms of 


RSRB # 31416                                        Page 42 of 46          Version Date: January 31, 2018
chemotherapy-induced cognitive disorders: neuropsychological, 
pathophysiological, and neuroimaging perspectives. Semin Clin Neuropsychiatry, 
2003. 8(4): p. 201-16.
10.
Ahles, T.A. and A.J. Saykin, Candidate mechanisms for chemotherapy-
induced cognitive changes. Nat Rev Cancer, 2007. 7(3): p. 192-201.
11.
Hickey, W.F., Basic principles of immunological surveillance of the normal 
central nervous system. Glia, 2001. 36(2): p. 118-24.
12.
McGeer, E.G. and P.L. McGeer, Inflammatory processes in Alzheimer's 
disease. Prog Neuropsychopharmacol Biol Psychiatry, 2003. 27(5): p. 741-9.
13.
Sparkman, N.L. and R.W. Johnson, Neuroinflammation associated with 
aging sensitizes the brain to the effects of infection or stress. 
Neuroimmunomodulation, 2008. 15(4-6): p. 323-30.
14.
Sparkman, N.L., et al., Interleukin-6 facilitates lipopolysaccharide-induced 
disruption in working memory and expression of other proinflammatory cytokines 
in hippocampal neuronal cell layers. J Neurosci, 2006. 26(42): p. 10709-16.
15.
Abraham, J. and R.W. Johnson, Central inhibition of interleukin-1beta 
ameliorates sickness behavior in aged mice. Brain Behav Immun, 2009. 23(3): p. 
396-401.
16.
Henry, C.J., et al., Minocycline attenuates lipopolysaccharide (LPS)-
induced neuroinflammation, sickness behavior, and anhedonia. J 
Neuroinflammation, 2008. 5: p. 15.
17.
Wyss-Coray, T. and L. Mucke, Inflammation in neurodegenerative 
disease--a double-edged sword. Neuron, 2002. 35(3): p. 419-32.
18.
Tan, Z.S., et al., Inflammatory markers and the risk of Alzheimer disease: 
the Framingham Study. Neurology, 2007. 68(22): p. 1902-8.
19.
Van Den Heuvel, C., E. Thornton, and R. Vink, Traumatic brain injury and 
Alzheimer's disease: a review. Prog Brain Res, 2007. 161: p. 303-16.
20.
Capuron, L., A. Ravaud, and R. Dantzer, Timing and specificity of the 
cognitive changes induced by interleukin-2 and interferon-alpha treatments in 
cancer patients. Psychosom Med, 2001. 63(3): p. 376-86.
21.
Scheibel, R.S., et al., Cognitive dysfunction and depression during 
treatment with interferon-alpha and chemotherapy. J Neuropsychiatry Clin 
Neurosci, 2004. 16(2): p. 185-91.
22.
Villani, F., et al., Serum cytokine in response to chemo-radiotherapy for 
Hodgkin's disease. Tumori, 2008. 94(6): p. 803-8.


RSRB # 31416                                        Page 43 of 46          Version Date: January 31, 2018
23.
Pusztai, L., et al., Changes in plasma levels of inflammatory cytokines in 
response to paclitaxel chemotherapy. Cytokine, 2004. 25(3): p. 94-102.
24.
Janelsins, M.C., Roscoe, J.A., Berg, M.J., Thompson, B.D., Gallagher, 
M.J., Morrow, G.R., Opanashuk, L.A., and R.A. Gross, IGF-1 Partially Restores 
Chemotherapy-induced Reductions in Neural Cell Proliferation in Adult C57BL/6 
mice. Cancer Invest, 2010. In Press.
25.
Mustian, K.M., J.A. Katula, and H. Zhao, A pilot study to assess the 
influence of tai chi chuan on functional capacity among breast cancer survivors. J 
Support Oncol, 2006. 4(3): p. 139-45.
26.
Mustian, K.M., et al., Tai Chi Chuan, health-related quality of life and self-
esteem: a randomized trial with breast cancer survivors. Support Care Cancer, 
2004. 12(12): p. 871-6.
27.
Knobf, M.T., R. Musanti, and J. Dorward, Exercise and quality of life 
outcomes in patients with cancer. Semin Oncol Nurs, 2007. 23(4): p. 285-96.
28.
Stewart, L.K., et al., The influence of exercise training on inflammatory 
cytokines and C-reactive protein. Med Sci Sports Exerc, 2007. 39(10): p. 1714-9.
29.
Rotter, V., I. Nagaev, and U. Smith, Interleukin-6 (IL-6) induces insulin 
resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, 
overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem, 
2003. 278(46): p. 45777-84.
30.
Kohut, M.L., et al., Aerobic exercise, but not flexibility/resistance exercise, 
reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and 
psychosocial factors in older adults. Brain Behav Immun, 2006. 20(3): p. 201-9.
31.
Starkweather, A.R., The effects of exercise on perceived stress and IL-6 
levels among older adults. Biol Res Nurs, 2007. 8(3): p. 186-94.
32.
Nichols, H.B., et al., Body mass index before and after breast cancer 
diagnosis: associations with all-cause, breast cancer, and cardiovascular disease 
mortality. Cancer Epidemiol Biomarkers Prev, 2009. 18(5): p. 1403-9.
33.
Tredan, O., et al., Body weight change in women receiving adjuvant 
chemotherapy for breast cancer: A French prospective study. Clin Nutr, 2009.
34.
Demark-Wahnefried, W., et al., Changes in weight, body composition, and 
factors influencing energy balance among premenopausal breast cancer patients 
receiving adjuvant chemotherapy. J Clin Oncol, 2001. 19(9): p. 2381-9.
35.
van Uffelen, J.G., et al., The effects of exercise on cognition in older adults 
with and without cognitive decline: a systematic review. Clin J Sport Med, 2008. 
18(6): p. 486-500.


RSRB # 31416                                        Page 44 of 46          Version Date: January 31, 2018
36.
Lautenschlager, N.T., et al., Effect of physical activity on cognitive function 
in older adults at risk for Alzheimer disease: a randomized trial. JAMA, 2008. 
300(9): p. 1027-37.
37.
Mustian, K.M., et al., Integrative nonpharmacologic behavioral 
interventions for the management of cancer-related fatigue. Oncologist, 2007. 12 
Suppl 1: p. 52-67.
38.
Cramp, F. and J. Daniel, Exercise for the management of cancer-related 
fatigue in adults. Cochrane Database Syst Rev, 2008(2): p. CD006145.
39.
Newton, R.U. and D.A. Galvao, Exercise in prevention and management 
of cancer. Curr Treat Options Oncol, 2008. 9(2-3): p. 135-46.
40.
Stevinson, C., D.A. Lawlor, and K.R. Fox, Exercise interventions for 
cancer patients: systematic review of controlled trials. Cancer Causes Control, 
2004. 15(10): p. 1035-56.
41.
Knols, R., et al., Physical exercise in cancer patients during and after 
medical treatment: a systematic review of randomized and controlled clinical 
trials. J Clin Oncol, 2005. 23(16): p. 3830-42.
42.
Mustian, K.M., Griggs, J., Bukata, S., Podgorski, C., Morrow, G. A 
randomized controlled pilot of home-based exercise (HBEX) versus standard 
care (SC) among breast (BC) and prostate cancer (PC) patients receiving 
radiation therapy (RTH) in American Society of Clinical Oncology. 2006.
43.
Mustian, K.M., Fisher, S., Adams, J. Janelsins, M., Palesh, O., Darling, T., 
Peppone, L., Heckler, C., Williams, J., Morrow, G. . Cytokine-mediated changes 
associatted with imporvements in cancer-related fatigue induced by exercise: 
Results from a randomized pilot study of cancer patients receiving radiotherapy. . 
in American Society of Clinical Oncology. 2009: Journal of Clinical Oncology.
44.
Mustian, K.M., Palesh, O., Heckler, C., Morrow, G. R. (2008) Exercise, 
Quality of Life and Cancer-Related Fatigue Among Cancer Patients Receiving 
Radiation. in Journal of Supportive Care in Cancer. 2008.
45.
Mustian, K.M.P., L., Darling, T., Palesh, O., Heckler, C., Morrow, G.R., A 
4-Week Home-Based Aerobic and Resistance Exercise Program During 
Radiation Therapy: A Pilot Randomized Clinical Trial. The Journal of Supportive 
Oncology, 2009. In Press.
46.
Vlad, S.C., et al., Protective effects of NSAIDs on the development of 
Alzheimer disease. Neurology, 2008. 70(19): p. 1672-7.
47.
Hee Kang, J. and F. Grodstein, Regular use of nonsteroidal anti-
inflammatory drugs and cognitive function in aging women. Neurology, 2003. 
60(10): p. 1591-7.


RSRB # 31416                                        Page 45 of 46          Version Date: January 31, 2018
48.
Hawkey, C., et al., Comparison of the effect of rofecoxib (a 
cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal 
mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-
controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study 
Group. Arthritis Rheum, 2000. 43(2): p. 370-7.
49.
Laine, L., et al., A randomized trial comparing the effect of rofecoxib, a 
cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal 
mucosa of patients with osteoarthritis.Rofecoxib Osteoarthritis Endoscopy Study 
Group. Gastroenterology, 1999. 117(4): p. 776-83.
50.
Sweeney, C.J., et al., Two drug interaction studies evaluating the 
pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or 
Ibuprofen in patients with advanced cancer. Clin Cancer Res, 2006. 12(2): p. 
536-42.
51.
Vardy, J., et al., Assessing cognitive function in cancer patients. Support 
Care Cancer, 2006. 14(11): p. 1111-8.
52.
Peolsson, A., R. Hedlund, and B. Oberg, Intra- and inter-tester reliability 
and reference values for hand strength. J Rehabil Med, 2001. 33(1): p. 36-41.
53.
Dohoney, P., Chromiak, J.A., Lemire, D., Abadie, B.R., Kovacs, C. , 
Prediction of one repetition maximum (1-RM) strength from a 4-6 RM and a 7-10 
RM submaximal strength test in healthy young adult males. Journal of Exercise 
Physiology Online, 2002. 5(3).
54.
Janssen, I., et al., Estimation of skeletal muscle mass by bioelectrical 
impedance analysis. J Appl Physiol, 2000. 89(2): p. 465-71.
55.
Cella, D.F. and D.S. Tulsky, Quality of life in cancer: definition, purpose, 
and method of measurement. Cancer Invest, 1993. 11(3): p. 327-36.
56.
Cella, D.F., et al., The Functional Assessment of Cancer Therapy scale: 
development and validation of the general measure. J Clin Oncol, 1993. 11(3): p. 
570-9.
57.
Meek, P.M., et al., Psychometric testing of fatigue instruments for use with 
cancer patients. Nurs Res, 2000. 49(4): p. 181-90.
58.
Shacham, S.A., A shortened version of the Profile of Mood States. J. Pers. 
Assess., 1983. 47: p. 305-306.
59.
Yoshitake, H., Three caracteristic patterns of subjective fatigue symptoms. 
Ergonomics, 1978. 21(3): p. 231-3.
60.
Smets, E.M., et al., The Multidimensional Fatigue Inventory (MFI) 
psychometric qualities of an instrument to assess fatigue. J Psychosom Res, 


RSRB # 31416                                        Page 46 of 46          Version Date: January 31, 2018
1995. 39(3): p. 315-25.
61.
Stein, K.D., et al., Further validation of the multidimensional fatigue 
symptom inventory-short form. J Pain Symptom Manage, 2004. 27(1): p. 14-23.
62.
Stein, K.D., et al., A multidimensional measure of fatigue for use with 
cancer patients. Cancer Pract, 1998. 6(3): p. 143-52.
63.
Spielberger, C.D., Sydeman, S.J, Owen, A.E., Marsh, B.J. , ed. Measuring 
anxiety and anger with the State-Trait Anxiety Inventory (STAI) and the State-
Trait Anger Expression Inventory (STAXI). 2 ed. The use of psychological testing 
for treatment planning and outcomes assessment, ed. M.E. Maruish. 1999, 
Lawrence Erlbaum Associates, Inc. : Mahwah, NJ. 993-213.
64.
Buysse, D.J., et al., The Pittsburgh Sleep Quality Index: a new instrument 
for psychiatric practice and research. Psychiatry Res, 1989. 28(2): p. 193-213.
65.
Eaton, W.W. and L.G. Kessler, Rates of symptoms of depression in a 
national sample. Am J Epidemiol, 1981. 114(4): p. 528-38.
66.
Robbins, T.W., et al., Effects of scopolamine on delayed-matching-to-
sample and paired associates tests of visual memory and learning in human 
subjects: comparison with diazepam and implications for dementia. 
Psychopharmacology (Berl), 1997. 134(1): p. 95-106.