Feasibility Study of a Home-Based Exercise Intervention Program for Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Androgen Deprivation Therapy (ADT)
Phase: NA
Conditions: Castration-resistant Prostate Cancer, Androgen Deprivation Therapy
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC  1613:  Feasibility Study of a Home-based Exercise Intervention Program for 
Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Androgen-
Deprivation Therapy (ADT) 
 
Principal Investigator 
Erik D. Hanson, PhD 
Assistant Professor, Exercise and Sport Science 
Department of Exercise & Sport Science 
315 Woollen Gym – CB # 8605 – UNC-CH 
Chapel Hill, NC 27599 
(Tel) 919-962-0816 
(Fax) 919-962-0489 
Email: edhanson@email.unc.edu 
 
Co-Investigator(s)  
Claudio Battaglini, PhD 
 
 
 
Matthew Milowsky, MD 
 
 
 
Young Whang, MD, PhD 
 
 
 
Ethan Basch, MD 
William Kim, MD 
William Wood, MD, MPH 
Mary Dunn, NP 
Tracy Rose, MD 
Rhonda Bitting, MD, Wake Forest 
 
Biostatistician  
Allison M Deal, MS 
Lineberger Comprehensive Cancer Center 
PO Box 7295 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7295 
Email: allison_deal@med.unc.edu 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source: Physical Activity and Cancer Survivorship Pilot Grant (2016) 
Version Date:  October 23, 2019 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
--LCCC  1613:  Feasibility Study of a Home-based Exercise Intervention Program 
for Patients with Metastatic Castration-Resistant Prostate Cancer Receiving 
Androgen-Deprivation Therapy (ADT) 
 
 
Principal Investigator 
Erik D. Hanson, PhD 
Assistant Professor, Exercise and Sport Science 
Department of Exercise & Sport Science 
315 Woollen Gym – CB # 8605 – UNC-CH 
Chapel Hill, NC 27599 
(Tel) 919-962-0816 
(Fax) 919-962-0489 
Email: edhanson@email.unc.edu 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Principal Investigator (PI) Name: __Erik Hanson______________________________ 
 
PI Signature: _______________________________________________________ 
 
Date:___October 23, 2019_________ 
 
 
 
Version Date: October 23, 2019 
 

LCCC 1613 
 
CONFIDENTIAL 
PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE .................................................................1 
1.1 
Study Synopsis .....................................................................................................1 
1.2 
Prostate Cancer ....................................................................................................1 
1.3 
Purpose and Rationale..........................................................................................3 
1.4 
Future Work .........................................................................................................4 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................4 
2.1 
Primary Objective ................................................................................................4 
2.2 
Secondary Objectives...........................................................................................4 
2.3 
Exploratory Objectives ........................................................................................5 
3.0 
PATIENT ELIGIBILITY .....................................................................................5 
3.1 
Inclusion Criteria .................................................................................................5 
3.2 
Exclusion Criteria ................................................................................................5 
4.0 
STUDY PLAN ........................................................................................................6 
4.1 
Schema .................................................................................................................6 
4.2 
Recruitment of mCRPC patients receiving ADT.................................................6 
4.3 
Exercise Intervention ...........................................................................................7 
4.4 
Study Measures ....................................................................................................8 
4.5 
Removal of Patients from Protocol ....................................................................11 
4.6 
Study Withdrawal ..............................................................................................11 
5.0 
EXPECTED RISKS/UNANTICIPATED PROBLEMS/DATA AND 
SAFETY MONITORING ...............................................................................................12 
5.1 
Expected Risks ...................................................................................................12 

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5.2 
Unanticipated Problems .....................................................................................12 
5.3 
Reporting............................................................................................................12 
6.0 
STATISTICAL CONSIDERATIONS ...............................................................13 
6.1 
Study Design ......................................................................................................13 
6.2 
Sample Size and Accrual ...................................................................................13 
6.3 
Data Analysis Plans ...........................................................................................14 
6.4 
Data Management/Auditing ...............................................................................14 
7.0 
STUDY MANAGEMENT ...................................................................................14 
7.1 
Institutional Review Board (IRB) Approval and Consent .................................14 
7.2 
Required Documentation ...................................................................................15 
7.3 
Registration Procedures .....................................................................................15 
7.4 
Adherence to the Protocol ..................................................................................15 
7.5 
Amendments to the Protocol ..............................................................................16 
7.6 
Record Retention ...............................................................................................16 
7.7 
Obligations of Investigators ...............................................................................17 
7.8 
REFERENCES ..................................................................................................17 

LCCC 1613 
 
CONFIDENTIAL 
PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
1 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This single arm, multi-site pilot study aims to evaluate the feasibility of recruiting 
and adherence to a 12 week home-based exercise intervention to be conducted in 
men with metastatic castration resistant prostate cancer (mCRPC) receiving 
androgen deprivation therapy (ADT). Thirty patients will be enrolled, with the 
expectation that 20-25 will complete all follow-up measures.  
 
The secondary objective of this study are to compare the changes in body 
composition (e.g., percent body fat, bone mineral content, lean mass), muscle 
strength, cardiovascular and overall physical function, and patient reported 
outcomes (quality of life (QoL), fatigue, depression) before and after the 12 week 
exercise intervention as a means of attenuating the declines in these outcomes 
typically seen with ADT. We hypothesize that exercise training will improve (post 
value > baseline value) strength and cardiovascular and physical function while 
body composition will remain unchanged. Finally, the effects of exercise on 
markers of inflammation and their relationship with changes in physical function 
and body composition will also be examined as exploratory outcomes. Data from 
this study will be used to determine feasibility (successfully able to recruit these 
individuals) and adherence to a home-based exercise intervention in men with 
mCRPC receiving ADT as well as the ability to refine the exercise intervention 
with plans to evaluate it in future larger trials in this population. 
1.2 
Prostate Cancer 
Prostate cancer is the most commonly diagnosed cancer among men and the second 
leading cause of cancer related deaths in men in the United States. An estimated 
220, 800 men in the U.S will be diagnosed with prostate cancer in 2016 with an 
estimated 27,540 prostate cancer related deaths (Cancer Facts & Figures 2015).  
Since prostate cancer is stimulated to grow by the male hormone, testosterone, 
medications that shut off the normal production of testosterone referred to as ADT 
represent the first-line (primary) treatment for patients with advanced disease.   
 
Unlike cancers arising from other organs such as lung and pancreas cancer, the life 
expectancy for patients with advanced prostate cancer is measured in years.  Thus, 
side effects of treatment that impact on quality of life are extremely important to 
consider in men with prostate cancer. Loss of testosterone is associated with many 
side effects including those related to negative changes in body composition 
(increase fat mass, loss of muscle mass) (Galvao et al., 2008; Smith et al., 2002), 
male menopause symptoms including hot flashes, loss of sexual drive, 
osteoporosis, high cholesterol, cardiovascular disease and diabetes (Braga-Basaria 
et al., 2006; Smith et al., 2002, 2006), and severe fatigue.  These side-effects, if not 
treated, may contribute to the development of other co-morbidities as well as lead 
to an inability to function at pre-cancer levels with the potential for a major impact 
on quality of life.) (Galvao et al., 2008; Smith et al., 2002)  

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PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
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1.2.1 Androgen Deprivation Therapy (ADT) 
Primary ADT usually refers to surgical castration (orchiectomy) or medical 
castration using a gonadotropin-releasing hormone (GnRH) agonist or antagonist.  
The onset of ADT is associated with a number of adverse events, including loss of 
muscle strength, altered body composition, higher fatigue, poor physical function, 
and QoL (Galvao et al. 2008, Hanson and Hurley 2011). Prostate cancer that 
progresses on ADT is referred to as castration resistant, despite its continued 
reliance on androgens.  This reliance is evidenced by the benefits reported with the 
androgen synthesis inhibitor, abiraterone acetate, and the potent androgen receptor 
inhibitor, enzalutamide, in metastatic CRPC (de Bono et al. 2011; Ryan et al. 2013; 
Scher et al. 2012; Beer et al. 2014). Based on these data, abiraaterone and 
enzalutamide represent the standard of care in men with mCRPC in the pre- and 
post-chemotherapy settings. However, additional androgen suppression beyond 
castration (sometimes referred to as androgen annihilation (Rove and Crawford 
2013) or “super-castration” (Pezaro et al.  2013) may exacerbate the symptoms of 
primary ADT. For example, 7.5 months of abiraterone alone significantly 
decreased lean mass at 6 months by -4.3%, particularly in those with a body mass 
index (BMI) >30. While these additional castration agents (including but not 
limited to abiraterone and enzalutamide) are prolonging survival during mCRPC, 
it becomes increasingly important to examine ways to mitigate the ADT-related 
side effects such that both quantity and quality of life are maintained at the highest 
possible levels. 
1.2.2 Exercise Training in Prostate Cancer 
One possible remedy for the complications associated with ADT use in mCRPC 
patients is to prescribe exercise training. Exercise in men on primary ADT who 
were not yet castration resistant has been shown to improve muscle mass, strength, 
and physical function (Galvao et al. 2007, Galvao et al. 2010, 2009; Newton et al., 
2009) but has yet to be examined as a potential complementary therapy in mCRPC. 
Specifically, Galvao and colleagues (2010) conducted a randomized controlled trial 
of twice weekly resistance (weights and abdominal crunches) and aerobic exercise 
(15-20 minutes of cycling and walking/jogging at 65 to 80% maximum heart rate) 
for 12 weeks versus usual care in men on ADT for at least 2 months prior to 
enrollment. The study reported significant differences between the two groups for 
muscle strength, lean mass, and several physical function tasks, all favoring the 
exercise group. Using the SF-36 QoL tool, significant improvements were reported 
for general health and fatigue, again favoring the exercise group. No adverse events 
were reported secondary to the exercise interventions, or to the testing procedures. 
More recently, a resistance training study in prostate cancer patients with bone 
metastases showed similar findings with gains in strength, physical function, and 
lean mass all favoring the exercise group (Cormie et al. 2013). No adverse events 
were reported in this study as well. Considering the current evidence of the positive 
effects of exercise in men with earlier stage prostate cancer and also those with 
more advanced disease, it is possible that the same benefits may also be achievable 
in mCRPC. Since many aspects of the proposed study are modeled after Galvao 

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February 15, 2017 
 
3 
and Cormie’s earlier work in prostate patients, the safe use of and execution of the 
current protocol by mCRPC patients is highly expected. In addition, the American 
Cancer Society recently convened a group of experts to address physical exercise 
in cancer survivors (Schmitz et al. 2010). These guidelines recommend exercise in 
cancer survivors, including those with bone metastases provided appropriate 
support is available during exercise, and attention paid to issues such as balance 
(Rock et al. 2012).  
 
In addition to these data, a systematic review of 10 studies evaluating the impact of 
exercise in prostate cancer patients undergoing ADT was recently published 
(Gardner et al 2013). The majority of study participants (>80%) did not have 
metastatic disease, although patients with non-bone metastases were included in 
some of the trials. The authors of this review concluded that exercise is safe in 
prostate cancer, and leads to similar benefits as those reported in otherwise healthy 
adults.   
1.3 
Purpose and Rationale 
The purpose of our trial is to evaluate the feasibility and adherence to a home-based 
12 week exercise intervention in mCRPC patients receiving ADT. We will also 
examine if a home-based exercise intervention can improve muscle strength, body 
composition, physical function, cardiopulmonary function fatigue, and patient 
reported outcomes (fatigue, depression, QoL). Finally, we will also explore the 
effects of the exercise training on biomarkers of inflammation-hormonal status and 
their potential association with changes in body composition, physical function, 
fatigue, depression, and QoL.  
 
Most exercise studies in cancer patients have been conducted within exercise 
facilities, and ones conducted in prostate cancer report adherence rates >90%, 
(Galvao et al. 2006, 2009; Hanson et a. 2013), even in men with bone metastases 
(Cormie et al. 2013). However, this limits the benefits of exercise to individuals 
who live in close proximity to sites where these programs are offered. Recently, 
there are several reports on home-based exercise interventions. Findings from these 
studies have shown good adherence in addition to improvements in various 
outcomes such as cardiorespiratory function, fatigue, QoL and avoidance of weight 
gain and increases in body fat (Ligibel, et al. 2010; {Pinto, 2005 #78}, et al. 2007; 
Pinto, et al. 2005). This marks an important next step in expanding the number 
patients who can successful access exercise and is particularly relevant for 
advanced diseases (i.e. mCRPC) where patients may travel long distances to be 
seen in clinic but would not be able to regularly attend exercise training programs. 
As the North Carolina Cancer Hospital is a tertiary referral center, this limits the 
number of mCRPC patients who are local. The regimen to be used in the present 
study will include strength training and aerobic exercise 2-4x times per week, 
building up both components over time, following recommendations from the 
American College of Sports Medicine and utilizing a similar home-based exercise 
training program employed by Spector et al. (2014) in African America breast 
cancer patients. As relatively few studies to date have examined home-based 

LCCC 1613 
 
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February 15, 2017 
 
4 
training program in more advanced disease states, feasibility programs are an 
important next step in expanding the outreach of exercise interventions. In addition, 
adaptations will be made throughout the training program to accommodate 
potential physical limitations and to account for the individual training response 
with the intent of maximizing feasibility and adherence and while simultaneously 
attempting to improve physical and psychological characteristics that are adversely 
affected during treatment for metastatic prostate cancer.  
 
1.4 
Future Work 
Given the relative paucity of home based interventions in the mCRPC population, 
this work will determine if recruiting these men for exercise interventions is 
feasible. Moreover, it will also provide insight if the exercise adherence rates 
approach the levels seen in laboratory based exercise interventions. With this 
information in hand, the proposed project will provide the preliminary data to 
justify a randomized control trial to further investigate the role of home-based 
exercise in these patients. Finally, as future randomized control trials will likely 
need to be multi-site, similar projects are being developed at separate sites as 
parallel trials (Duke University, University of Alabama Birmingham) to 
demonstrate collaboration between these institutes and to be in position to generate 
the necessary accrurual numbers for the randomized trials. 
2.0 
STUDY OBJECTIVES AND ENDPOINTS  
2.1 
Primary Objective 
To estimate the feasibility of a 12 week, home-based exercise intervention in 
mCPRC patients undergoing androgen deprivation therapy by reporting the 
percentage of patients who complete the pre/post exercise intervention testing. 
2.2 
Secondary Objectives 
2.2.1 To report the level of adherence to the exercise intervention  
2.2.2 To report the change in measurements of overall physical function (6 meter (m) 
usual and rapid walk, timed up and go, chair stands, and stair climb tests, 400m 
walk) in mCPRC patients before and after undergoing a home-based 12-week 
exercise intervention   
2.2.3 To report the changes in patient reported outcomes including fatigue, depression 
and overall QoL in mCRPC patients before and after a home-based intervention  
2.2.4 To report the change in total and regional lean, fat, and bone mass (e.g., upper limb, 
lower limb) in mCRPC patients before and after a home-based intervention  
2.2.5 To report the changes in muscle function including muscle strength, endurance, and 
muscle architecture in mCRPC patients before and after a home-based intervention  

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2.2.6 To report the change in cardiopulmonary function (peak oxygen uptake) in mCRPC 
patients before and after a home-based intervention 
2.3 
Exploratory Objectives 
2.3.1 To report changes in relevant biomarkers and immune function after exercise 
training, and explore the association of these changes with changes in physical 
function and lean mass. Biomarkers including but not limited to  testosterone, lipid 
profile, PSA, stromal cell derived factor [SDF]-1α, IL-6, IL1β, IL-8 and IL-10 and 
IFN- cytokines will be explored. Immune function will be assessed by complete 
white blood cell counts and cell counts and function of specific subpopulations via 
flow cytometry. 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subject must meet all of the inclusion criteria to participate in this study:  
3.1.1 ≥18 years of age  
3.1.2 Metastatic disease that has progressed despite castrate levels of testosterone 
(surgically or medically castrated, with testosterone levels of < 50 ng/dL) receiving 
ADT. This will be verified by assessing total testosterone levels within 4 weeks 
prior to enrollement. 
3.1.3 No current chemotherapy 
3.1.4 Patients may be receiving additional hormonal therapy agents including but not 
limited to antiandrogens (e.g. bicalutamide, enzalutamide) and CYP17 inhibitors 
(e.g. abiraterone). 
3.1.5 Ability to engage safely in moderate exercise as determined by their treating 
physician 
3.1.6 Not previously engaged in regular exercise training (<3 or more d/wk for > 30 
min/d or <90 mins per week total including strength training, aerobic training, or 
walking) in the past 6 months 
3.1.7 Access to a computer or a smart phone for syncing and uploading wearable activity 
data 
3.1.8 Be able to speak and read English 
3.2 
Exclusion Criteria 
All subjects meeting any of the exclusion criteria at baseline will be excluded from 
study participation 

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UNIVERSITY OF NORTH CAROLINA 
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3.2.1 Any condition that causes severe pain with exertion 
3.2.2 History of bone fractures 
3.2.3 Active cardiovascular disease including any of the following: 
• New York Heart Association (NYHA) Grade II or greater congestive heart 
failure  
• History of myocardial infarction or unstable angina within 6 months prior 
to Day 1 
• History of stroke or transient ischemic attack within 6 months prior to Day 
1 
3.2.4 Acute or chronic respiratory disease that is severe enough to compromise the ability 
of the participant to safely engage in exercise training protocol 
3.2.5 Acute or chronic bone/joint/muscular abnormalities compromising their ability to 
exercise 
3.2.6 Neurological conditions that affect balance and, or muscle strength 
3.2.7 Dementia, altered mental status or any psychiatric condition prohibiting the 
understanding or rendering of informed consent 
4.0 
STUDY PLAN 
4.1 
Schema 
 
 
 
Participants with mCRPC receiving ADT will be recruited for involvement in a 
single-arm prospective 12-week exercise intervention study.  
4.2 
Recruitment of mCRPC patients receiving ADT 
Thirty men with mCRPC receiving ADT will be recruited for this study and will 
engage in a home-based intervention. Men with mCRPC will be approached by 
their treating oncologist at UNC-Chapel Hill or Wake Forest and informed of the 
study. All patients who are interested in participating will be provided informed 
consent.  
 

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7 
4.2.1 Overseeing Site 
At UNC, recruiting prostate cancer patients undergoing ADT +/- additional 
hormonal therapies will be done in close collaboration and with the support of 
physicians (see co-investigators) from the UNC Lineberger Comprehensive Cancer 
Center (LCCC). In 2015, LCCC saw approximately 485 prostate cancer, of which 
~125 were mCRPC. Over the past 3-year period, 124 men (16%) have enrolled in 
various cooperative group, pharmaceutical sponsored, or investigator-initiated 
studies. All eligible patients will be enrolled and track reasons for dropout, should 
they not complete all aspects of study.  
4.2.2 Participating Sites 
At Wake Forest, study activities will be led by Dr Rhonda Bitting, an Assistant 
Professor of Medicine in Hematology and Oncology and Alexander Lucas, PhD, a 
Research Fellow in the School of Medicine. 
 
All patients from all sites will be requested to maintain their pre-study level of 
physical activity and diet (Appendix 0) during the duration of the study beyond the 
addition of the prescribed exercises. A 24 hour dietary recall the day before the 
baseline and post-training assessments will be completed to estimate total caloric 
intake at each time point and to help ensure that patients have eaten similarly prior 
to each testing session. This will help to ensure the validity of the secondary 
outcomes and also the testing assessments themselves. Physical activity levels will 
be screened during the introduction and consent process, with thresholds for 
inclusion defined in 3.1.6.   
4.3 
Exercise Intervention 
The exercise intervention will consist of a combination of aerobic (cardiovascular 
exercise) and strength training (emphasis of the intervention) ~3 times per week for 
12 weeks with each session lasting 1 hour. The home-based exercise intervention 
will begin with a low intensity walking and resistance (ie, strength) training, which 
progressed to follow the previously tested and successful home-based program 
demonstrated by Spector et al. (2014) [and designed by Co-Investigator Battaglini]. 
The combined aerobic and resistance training protocol will follow the guidelines 
set forth by the American College of Sports Medicine. The progressive 
standardized aerobic exercise plan will involve walking. Resistance training 
included upper, lower, and abdominal core strengthening exercises. Upper body 
strength exercises included lateral and front raises, wall or modified floor push-ups, 
chest press, bent row, arm curls, and triceps stretches. Lower body strength 
exercises included chair squats, chair leg raises, hamstring curls, and calf raises. 
The four core strengthening exercises were the bridge, crunches, reverse crunches, 
and obliques. Upper and lower body exercises will be done with elastic resistance 
bands. All exercises will be demonstrated to the participants during their initial 
exercise testing session. Participants will be also instructed to perform stretching 
exercises of major muscle groups after the walking component of their exercise 
program. Participants will be given an exercise training workbook that included 

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UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
8 
weekly exercise logs, the exercise training plan, illustrations of resistance exercises 
and stretches (Appendix 1). Participants will be given activity monitors to wear 
which will record heart rate, activity minutes and calories expended (these are small 
wrist watch-like devises that are easily operated). This information will be recorded 
by the participants and regularly synced with a computer so that weekly exercise 
totals (number of aerobic sessions, amount of time per session) along with the 
exercise intensity can be determined. To stimulate a training effect following 
recommendations from the American College of Sports Medicine, from week 1 to 
completion of the study, walking will be increased from 15 to 30 minutes and 
intensity from 40% to 65% of heart rate reserve. Therabands elastic bands will be 
used for the resistance training. Participants will be instructed to perform 12 to 15 
repetitions per exercise beginning with the light- or medium-strength band and 
progressing to the heaviest strength band as ability permitted. Once a participant 
can comfortably complete 15 repetitions for all prescribed sets, they will increase 
resistance by moving up to the next band. The training volume increased from 1 set 
per exercise on week 1 to 3 sets by week 12 (see table below). 
 
Week 
Walking 
Sessions 
Per Week 
Walking 
Sessions 
Minutes 
Per Week 
Resistance 
Training 
Sets  
Per Week 
Resistance 
Training 
Sessions 
Per Week 
Target 
Heart Rate 
Reserve 
1 
2 
15 
1 
1 
40-50 
2 
2 
15 
1 
2 
40-50 
3 
3 
20 
2 
2 
50-60 
4 
4 
30 
2 
3 
50-60 
5-6 
4 
22 
2 
3 
50-60 
6-8 
4 
25 
2 
3 
55-65 
10-12 
4 
30 
3 
3 
55-65 
 
To facilitate the engagement of the patients and to help with adherence, weekly 
contact will be made by a member of the research team. This will involve either a 
phone call, Skype, or an email contact, based upon the patient’s preference. This 
follow up will allow for answering of any questions related to the study, including 
proper exercise technique, activity levels, or using/syncing the wearable device. 
4.4 
Study Measures 
All testing procedures will be completed at baseline and 12 weeks after exercise 
training. All testing will be completed in a single baseline or post-training session 
lasting between 2-3 hours, including rest breaks. Pilot testing of the protocol has 
shown that these tests can be completed in this time frame. Standardized rest 
periods have been included and the testing order has been designed to allow for 
patients that meet the inclusion criteria to be able to perform all tests within a single 
session. The single session will also be more convenient for participants travelling 
longer distances to come to the UNC or Wake Forest Cancer Hospitals, which may 
help with the primary outcome (feasibility). 

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Testing Task 
Time (mins) 
Body Composition (DXA) 
10 
Ultrasound for Muscle Size/Quality 
10 
Muscle Function 
40-50 
Break (sitting) 
10 
Physical Function 
30-40 
Break (sitting) 
5 
Cardiopulmonary Testing 
30 
Total 
135-155 
Patient reported outcome questionnaires will be given out prior for the patients to 
complete at home and to bring into the respective testing sessions. 
4.4.1 Physical Function 
• Overall functionality will be assessed using standard simulated activates 
of daily living (Hanson et al. 2009, 2013), including the 6m usual and rapid 
walk tests, the timed up and go test, chair stands, and stair climb tasks and 
400m walk test (Appendix 2). 
• The short physical performance battery (5 chair stands, 8 foot usual walk, 
and side by side, tandem, and semi-tandem 10 second balance tests) will 
also determined (Guralnik et al. 1994). 
• Body Composition to measure lean and fat mass and bone mineral density 
will be completed using dual-energy x-ray absorptiometry (DXA). Both 
total body and regional scans will be performed.  
• Muscle size and quality of the quadriceps muscles will be measured using 
portable ultra-sound technology to determine cross-sectional area (size) 
and echo intensity (quality). The ultrasound CSA measurement will be 
performed on the right Vastus Lateralis via manual movement of the 
transducer slowly and continually from lateral to medial along an upper leg 
template suitable for each subject. The purpose of the template is to ensure 
precise measurement and reproduction of the same muscle area for the 
comparison of pre- and post-intervention CSA images. In the 
musculoskeletal mode of the device, gain and frequency will be 
standardized between tests and across subjects in order to optimize image 
quality.  Depth will be adjusted between participants to ensure both deep 
and superficial fascia remain visible in the field-of-view. Hypoallergenic 
water-soluble transmission gel (1 - 2 oz.) will be applied to the skin to 
reduce possible near field artifacts and enhance acoustic coupling 
(Aquasonic 100, Parker Laboratories, Inc., Fairfield, NJ, USA).  
LogicView™ software (General Electric Company, Milwaukee, WI, USA) 
will be used to generate real-time panoramic cross-sectional images of the 
muscles. Three scans will be performed and an average of the three will be 
recorded in order to reduce the likelihood of technician error. Following 
each scan, each image will be reviewed to ensure appropriate image 
quality. If a scan is does not produce a clean image of CSA, additional 

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scans will be performed. All ultrasound imaging analyses will be 
performed using Image-J software (version 1.46r, National Institutes of 
Health, USA). Prior to analysis, each image will be individually scaled 
from area in pixels to centimeters using the straight-line function.  CSA of 
VLs will be determined using the polygon function by selecting a region of 
interest that includes as much of the muscle as possible without any 
surrounding fascia.   
• Muscle function in the forms of muscle strength, power, and endurance 
will be assessed using several different techniques. Upper and lower body 
muscle strength will be assessed on the chest press, knee extension, and leg 
press. Patients will be familiarized prior to undergoing baseline testing to 
minimize the risk of injury and to improve the validity of the testing 
outcome. Patients will complete sets of a single repetition with increasing 
resistance until they are no longer able to move the weight throughout the 
full range of motion (Hanson et al. 2009, 2013). The maximal amount of 
resistance lifted is their maximal strength. Muscle endurance will be 
determined using a repetitions test. Participants will complete as many 
consecutive repetitions as possible at 70% of their maximal strength for the 
chest and leg press (Hanson et al. 2013). The total number of successful 
repetitions will be used to determine endurance capabilities. Knee extensor 
muscle power, which is affected by both force and velocity, will be 
assessed on an isokinetic dynamometer. Patients will be asked to extend 
their leg as quickly as possible against a fixed resistance load to determine 
power and rate of force development (Appendix 3).  
• Cardiopulmonary function (VO2 peak) will be assessed using a graded 
exercise test on a treadmill. Patients will begin the test walking slowly on 
the treadmill and every two minutes, the grade and speed of the treadmill 
will be increased in a progressive manner until fatigue occurs. Respiratory 
gases will be collected throughout the test and analyzed using a metabolic 
cart to determine oxygen utilization and carbon dioxide production. The 
maximal oxygen uptake that is recorded will be used as a marker of aerobic 
fitness (Appendix 4).  
4.4.2 Quality of Life (QoL) 
QoL questionnaires will be completed at baseline and after exercise training. 
• Fatigue (FACIT- Fatigue, Appendix 5). Fatigue will be measure using the 
FACIT-Fatigue, a 1 page form that uses a rating scale that goes from 0 (no 
fatigue) to 10 (severe fatigue). It assesses the patient’s fatigue levels in the 
last 7 days. It also measures how usual activities, performing work, 
walking, relationship, and enjoyment of life are affected by fatigue. 
• Depression will be measured using the Hospital Anxiety and Depression 
Scale (HADS; Appendix 6), a concise, self-administered 1 page form that 
categorizes anxiety and depression.  The total score goes from 0-21, and 
scores are categorized from minimal to severe depression/anxiety. 

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• QoL will be measured using the Functional Assesment of Cancer Therapy-
Prostate (FACT-P; Appendix 7).  The FACT-P is composed of both multi-
item scales and single-item measures. These include physical, social, 
emotional, and functional well-being, along with an assessment of prostate-
specific health status. five functional scales, three symptom scales, a global 
health status / QoL scale, and six single items. All of the scales score from 
0-4 and and a high scale score represents a higher response level. 
 
We recognize that any changes in QoL, depression, and fatigue will be 
difficult to attribute to exercise alone. 
4.4.3 Laboratory Measures 
Fasted blood draws will occur at baseline and after exercise training. 
• Select laboratory measures (testosterone, lipid profiles, prostate specific 
antigen, stromal cell derived factor (SDF)-1α) and inflammatory markers 
(IL-6, IL-1β, IL-8, IL-10 and IFN-) will be measured using Enzyme-
Linked Immunosorbent Assay (ELISA) from serum and plasma collected 
in the fasted, resting state at the beginning and end of the exercise 
intervention using analysis procedures appropriate for exercise studies 
(Hackney & Viru 2008). Any excess serum/blood remaining after protocol-
dictated studies are complete will be destroyed.  
4.5 
Removal of Patients from Protocol  
Participants will be removed from the study intervention if they indicate they no 
longer wish to participate and if they are not able to complete the exercise 
intervention due to disease/treatment complications. Additionally, subjects will be 
removed if their physician-oncologist request that their patient is excluded from the 
study for any medical or emotional concerns. 
 
In case a patient decides to prematurely discontinue the protocol intervention, the 
patient should be asked if he may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be documented in both the 
medical records and in the study data collection forms. 
4.6 
Study Withdrawal 
If a patient decides to withdraw from the study all efforts should be made to 
complete and report study assessments as thoroughly as possible. The investigator 
should contact the patient or a responsible relative by telephone or through a 
personal visit to establish as completely as possible the reason for the study 
withdrawal. A complete final evaluation at the time of the patient’s study 
withdrawal should be made with an explanation of why the patient is withdrawing 
from the study. If the reason for removal of a patient from the study is an adverse 
event, the principal specific event will be recorded on study data collection forms.  

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5.0 
EXPECTED RISKS/UNANTICIPATED PROBLEMS/DATA 
AND SAFETY MONITORING 
5.1 
Expected Risks 
5.1.1 Exercise 
There should be no psychological or physiological harm caused by the research, 
and thus this will not cause the patient any emotional or physical loss. In the 
unlikely event of injury during the fitness assessments and the exercise portion of 
this study, such as muscle distensions and joint trauma, medical professionals on 
the research team will provide the appropriate care. Also, due to the stringent 
criteria for participation in the study, only subjects deemed capable by their 
oncologists will be enrolled in the study. 
5.1.2 Whole Body DXA Scan 
The amount of radiation from exposure to a DXA scan is low, 0.008 mSv (0.8 
mrem), equivalent to the radiation exposure everyone receives in one day from 
background radiation. 
5.1.3 Ultrasound 
There are no anticipated safety concerns associated with the use of ultrasound. 
5.2 
Unanticipated Problems 
As defined by UNC’s IRB, unanticipated problems involving risks to study subjects 
refers to any incident, experience, or outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• 
Is related or possibly related to a subject’s participation in the research; and  
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
5.3 
Reporting 
Any unanticipated problem that occurs during the conduct of this study and that 
meets at least the first two criteria listed in section 5.3 must be reported to the UNC 
IRB (overseeing site) using the IRB’s web-based reporting system.   
 
 

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6.0 
STATISTICAL CONSIDERATIONS 
6.1 
Study Design 
This study will recruit patients with metastatic CRPC to undergo a home-based 
exercise intervention in order to establish feasibility in this patient population.  
Secondary objectives include evaluating its impact on changes in physical function, 
body composition, muscle function, cardiopulmonary function, fatigue, depression, 
quality of life, and biomarkers. Evaluations will be done at baseline and after the 
12-week intervention. It is hypothesized that the exercise intervention will increase 
function relatively to baseline in these men.  
6.2 
Sample Size and Accrual 
Previous exercise intervention studies have shown that attrition rates in healthy 
controls are between 20-30% (Hanson et al. 2009; Walts et al. 2008). Surprisingly, 
attrition rates are lower in prostate cancer patients on ADT at between 2-10% 
(Hanson et al. 2013; Galvao et al. 2006, 2011). However, prostate patients with 
bone metastases experienced higher drop out rates (25% (Cormie et al. 2013)). 
Because no study has examined the effects of exercise on metastatic CRPC patients, 
we want to confirm that patients will participate and complete pre/post study 
measures.  We anticipate that recruiting 30 men should yield a final sample size of 
20-25 subjects. The table below shows the percentage, along with exact 95% 
binomial confidence interval for possible results.  If we retain 20/30 patients, our 
fesibility estimate will be 67%, with a 95% CI ranging from 47%-83%. 
 
% 
n/N 
Estimate (95% CI) 
50% 
(15/30) 
50.0% (31.3%,68.7%) 
60% 
(18/30) 
60.0% (40.6%,77.3%) 
67% 
(20/30) 
66.7% (47.2%,82.7%) 
70% 
(21/30) 
70.0% (50.6%,85.3%) 
80% 
(24/30) 
80.0% (61.4%,92.3%) 
83% 
(25/30) 
83.3% (65.3%,94.4%) 
90% 
(27/30) 
90.0% (73.5%,97.9%) 
100% 
(30/30) 
100.0% (88.4%,100.0%) 
 
For seconadary objectives comparing changes over time, a sample size of 25 will 
have 80% power to detect an effect size of 0.584 using a paired t-test with a 0.050 
two-sided significance level.  For example, for the 400m walk test - This effect size 
may be seen if the difference from pre to post if -5 seconds with a standard deviation 
is 8.56 seconds. If only 20 patients per group complete the post measures, there will 
be 80% power to detect an effect size of 0.66, which may be seen if the mean 
difference is 5.65 with a common standard deviation of 8.56. 

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Accrual of these patients will occur over the span of 24 months. Should sufficient 
recruitment (~30 men) not be obtained in that time period, the research team may 
conclude that exercise interventions in this population and setting appear not to be 
feasible. 
6.3 
Data Analysis Plans  
Descriptive statistics including means, standard deviations, medians, ranges, and 
percentages, will be used to report on all measures at baseline and post intervention 
and changes in measures over time. Changes in continuous measures will be 
compared between groups using two group t-tests or Fisher’s Exact tests for 
categorical variables.   
 
Associations of changes in biomarkers with changes in physical function or body 
composition measures will be explored using correlation coefficients.  Associations 
of other measures will be explored using two group t-tests for continuous and 
categorical variables or Fisher’s Exact tests for two categorical variables.   
 
As sample size permits, analyses will be repeated with stratification based on 
treatment type, treatment duration, or age.  This will be purely exploratory. 
 
All analysis will be performed by the statistician of record. 
6.4 
Data Management/Auditing  
Data will be managed the PI and his designated staff, and it will be entered into an 
REDCcap database designed by the PI’s staff, with input from the statistician of 
record. Co-investigators Lucas and Bitting at Wake Forest University will access 
REDCap for secure data entry. As an investigator initiated study, this trial will also 
be audited by the Lineberger Cancer Center audit committee every six or twelve 
months, depending on the participation of affiliate sites. 
7.0 
STUDY MANAGEMENT 
7.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, patient will be asked to give 
verbal consent so that the medical history screening can be completed over the 

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phone. At the initial visit, patients will be given a full explanation of the study and 
will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and 
local or state regulations. Once this essential information has been provided to the 
patient and the investigator is assured that the patient understands the implications 
of participating in the study, the patient will be asked to give consent to participate 
in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
7.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
placed on file at the University of North Carolina. 
• A copy of the official IRB approval letter for the protocol and informed 
consent 
• CVs and medical licensure for the principal investigator and any 
associate investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
7.3 
Registration Procedures 
All patients will be registered with Oncore™ by the Study Coordinator/PI.  This 
will allow the cancer center to track accrual onto this important trial.  Contact Paul 
Jones (paul_e_jones@med.unc.edu) for any questions on Oncore, and for Oncore 
training. 
7.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   
7.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior UNC IRB approval.  
 
For any such emergency modification implemented, a UNC IRB modification form 
must be completed by PI/UNC Research Personnel within five (5) business days of 
making the change.   
7.4.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB as the overseeing site.  

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7.4.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the UNC IRB. According to UNC’s IRB, a protocol 
deviation is any unplanned variance from an IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®, and 
report to any sponsor or data and safety monitoring committee in accordance with 
their policies.  Deviations should be summarized and reported to the IRB at the time 
of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
7.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator.  It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk 
to the patient, a revised consent form might be required.   
 
The written amendment, and if required the amended consent form, must be sent to 
UNC’s IRB for approval prior to implementation.   
7.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 

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logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study 
investigator.  In the case of a study with a drug seeking regulatory approval and 
marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization 
(ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
7.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of 
data. At the completion of the study, all case report forms will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy 
of the data.  
 
7.8 
REFERENCES  
1. Hanson, E.D., S.R. Srivatsan, S. Agrawal, K.S. Menon, M.J. Delmonico, M.Q. 
Wang, and B.F. Hurley, Effects of strength training on physical function: 
influence of power, strength, and body composition. J Strength Cond Res, 2009. 
23(9): p. 2627-37. 
 
2. Walts, C.T., E.D. Hanson, M.J. Delmonico, L. Yao, M.Q. Wang, and B.F. 
Hurley, Do sex or race differences influence strength training effects on muscle 
or fat? Med Sci Sports Exerc, 2008. 40(4): p. 669-76. 
 
3. Hanson, E.D., A.K. Sheaff, S. Sood, L. Ma, J.D. Francis, A. Goldberg, and B.F. 
Hurley, Strength Training Induces Muscle Hypertrophy and Functional Gains 

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in Black Prostate Cancer Patients Despite Androgen Deprivation Therapy. J 
Gerontol A Biol Sci Med Sci, 2013. 68(4):490-8. 
 
4. Galvao, D.A., K. Nosaka, D.R. Taaffe, N. Spry, L.J. Kristjanson, M.R. 
McGuigan, K. Suzuki, K. Yamaya, and R.U.Newton, Resistance training and 
reduction of treatment side effects in prostate cancer patients. Med Sci Sports 
Exerc, 2006. 38(12): p. 2045-2052. 
 
5. Segal, R.J., R.D. Reid, K.S. Courneya, S.C. Malone, M.B. Parliament, C.G. 
Scott, P.M. Venner, H.A. Quinney, L.W. Jones, M.E. D'Angelo, and G.A. 
Wells, Resistance exercise in men receiving androgen deprivation therapy for 
prostate cancer. J Clin Oncol, 2003. 21(9): p. 1653-1659. 
 
6. Galvao, D.A., D.R. Taaffe, N. Spry, D. Joseph, and R.U. Newton, Combined 
resistance and aerobic exercise program reverses muscle loss in men 
undergoing androgen suppression therapy for prostate cancer without bone 
metastases: a randomized controlled trial. J Clin Oncol, 2010. 28(2): p. 340-7. 
 
7. Evans, E.S., C.L. Battaglini, D.G. Groff, and A.C. Hackney, Aerobic exercise 
intensity in breast cancer patients: a preliminary investigation. Integr Cancer 
Ther, 2009. 8(2): p. 139-47. 
 
8. Evans E.S., Hackney A.C., McMurray R.G., Randell S.H., Muss H.B., Deal 
A.M., Battaglini C.L. Impact of acute intermittent exercise on natural killer 
cells in breast cancer survivors. Integr Cancer Ther. 2015 14(5):436-45. 
 
9. Hanson E.D., Sakkal S., Baindur-Hudson S., Violet J., Battaglini C.L., 
McConell G.K., Hayes A. Cytotoxic lymphocyte response to moderate intensity 
aerobic exercise in prostate cancer survivors. Med Sci Sport Exerc. 2015. 
47(5): S2659, 2015. 
 
10. Battaglini, C.L., A.C. Hackney, R. Garcia, D. Groff, E. Evans, and T. Shea, The 
effects of an exercise program in leukemia patients. Integr Cancer Ther, 2009. 
8(2): p. 130-8. 
 
11. Warburton, D.E., C.W. Nicol, and S.S. Bredin, Health benefits of physical 
activity: the evidence. CMAJ, 2006. 174(6): p. 801-9. 
 
12. Lakoski, S.G., N.D. Eves, P.S. Douglas, and L.W. Jones, Exercise 
rehabilitation in patients with cancer. Nat Rev Clin Oncol, 2012. 9(5): p. 288-
96. 
 
13. Galvao, D.A. and R.U. Newton, Review of exercise intervention studies in 
cancer patients. J Clin Oncol, 2005. 23(4): p. 899-909. 
 

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14. De Backer, I.C., G. Schep, F.J. Backx, G. Vreugdenhil, and H. Kuipers, 
Resistance training in cancer survivors: a systematic review. Int J Sports Med, 
2009. 30(10): p. 703-12. 
 
15. Loprinzi, P.D., B.J. Cardinal, K. Winters-Stone, E. Smit, and C.L. Loprinzi, 
Physical activity and the risk of breast cancer recurrence: a literature review. 
Oncol Nurs Forum, 2012. 39(3): p. 269-74.  
 
16. Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2012. CA Cancer J 
Clin, 2012. 62(1): p. 10-29.  
 
17. Hanson, E.D. and B.F. Hurley, Intervening on the side effects of hormone-
dependent cancer treatment: the role of strength training. J Aging Res 
[Internet], 2011. Available from: http: //www.ncbi.nlm.nih.gov/pmc/articles/ 
PMC3034975/pdf/JAR2011-903291.pdf: p. doi: 10.4061/2011/903291. 
 
18. Smith, M.R., F. Saad, B. Egerdie, P.R. Sieber, T.L. Tammela, C. Ke, B.Z. 
Leder, and C. Goessl, Sarcopenia during androgen-deprivation therapy for 
prostate cancer. J Clin Oncol, 2012. 30(26): p. 3271-6. 
 
19. Galvao, D.A., N.A. Spry, D.R. Taaffe, R.U. Newton, J. Stanley, T. Shannon, C. 
Rowling, and R. Prince, Changesin muscle, fat and bone mass after 36 weeks 
of maximal androgen blockade for prostate cancer. BJU Int, 2008. 102(1): p. 
44-7. 
 
20. Basaria, S., J. Lieb, A.M. Tang, T. DeWeese, M. Carducci, M. Eisenberger, and 
A.S. Dobs, Long-term effects of androgen deprivation therapy in prostate 
cancer patients. Clin Endocrinol (Oxf), 2002. 56(6): p. 779-786. 
 
21. de Bono, J.S., C.J. Logothetis, A. Molina, K. Fizazi, S. North, L. Chu, K.N. 
Chi, R.J. Jones, O.B. Goodman, Jr., F.Saad, J.N. Staffurth, P. Mainwaring, S. 
Harland, T.W. Flaig, T.E. Hutson, T. Cheng, H. Patterson, J.D. Hainsworth, 
C.J. Ryan, C.N. Sternberg, S.L. Ellard, A. Flechon, M. Saleh, M. Scholz, E. 
Efstathiou, A. Zivi, D. Bianchini, Y. Loriot, N. Chieffo, T. Kheoh, C.M. Haqq, 
H.I. Scher, and C.-A.-. Investigators, Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med, 2011. 364(21): p. 1995-2005. 
 
22. Smith, M.R., H. Lee, and D.M. Nathan, Insulin sensitivity during combined 
androgen blockade for prostate cancer. J Clin Endocrinol Metab, 2006. 91(4): 
p. 1305-8. 
 
23. Kantoff, P.W., C.S. Higano, N.D. Shore, E.R. Berger, E.J. Small, D.F. Penson, 
C.H. Redfern, A.C. Ferrari, R. Dreicer, R.B. Sims, Y. Xu, M.W. Frohlich, P.F. 
Schellhammer, and I.S. Investigators, Sipuleucel-T immunotherapy for 
castration-resistant prostate cancer. N Engl J Med, 2010. 363(5): p. 411-22. 
 

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24. Lassi, K. and N.A. Dawson, Emerging therapies in castrate-resistant prostate 
cancer. Curr Opin Oncol, 2009. 21(3): p. 260-5. 
 
27. Amaral, T.M., D. Macedo, I. Fernandes, and L. Costa, Castration-resistant 
prostate cancer: mechanisms, targets, and treatment. Prostate Cancer, 2012. 
2012: p. 327253. 
 
25. de Bono, J.S., S. Oudard, M. Ozguroglu, S. Hansen, J.P. Machiels, I. Kocak, G. 
Gravis, I. Bodrogi, M.J. Mackenzie, L. Shen, M. Roessner, S. Gupta, A.O. 
Sartor, and T. Investigators, Prednisone plus cabazitaxel or mitoxantrone for 
metastatic castration-resistant prostate cancer progressing after docetaxel 
treatment: a randomised open-label trial. Lancet, 2010. 376(9747): p. 1147-54. 
 
26. Kantoff, P.W., T.J. Schuetz, B.A. Blumenstein, L.M. Glode, D.L. Bilhartz, M. 
Wyand, K. Manson, D.L. Panicali, R. Laus, J. Schlom, W.L. Dahut, P.M. Arlen, 
J.L. Gulley, and W.R. Godfrey, Overall survival analysis of a phase II 
randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy 
in metastatic castration-resistant prostate cancer. J Clin Oncol, 2010. 28(7): p. 
1099-105. 
 
27. Kucuk, O., E. Fisher, C.M. Moinpour, D. Coleman, M.H. Hussain, A.O. Sartor, 
G.S. Chatta, B.A. Lowe, M.A. Eisenberger, and E.D. Crawford, Phase II trial 
of bicalutamide in patients with advanced prostate cancer in whom 
conventional hormonal therapy failed: a Southwest Oncology Group study 
(SWOG 9235). Urology, 2001. 58(1): p. 53-8. 
 
28. Tannock, I.F., R. de Wit, W.R. Berry, J. Horti, A. Pluzanska, K.N. Chi, S. 
Oudard, C. Theodore, N.D. James, I. Turesson, M.A. Rosenthal, M.A. 
Eisenberger, and T.A.X. Investigators, Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 
2004. 351(15): p. 1502-12. 
 
29. Smith, M.R., Changes in fat and lean body mass during androgen-deprivation 
therapy for prostate cancer. Urology, 2004. 63(4): p. 742-745.  
 
30. Smith, M.R., J.S. Finkelstein, F.J. McGovern, A.L. Zietman, M.A. Fallon, D.A. 
Schoenfeld, and P.W. Kantoff, Changes in body composition during androgen 
deprivation therapy for prostate cancer. J Clin Endocrinol Metab, 2002. 87(2): 
p. 599-603. 
 
31. van Londen, G.J., M.E. Levy, S. Perera, J.B. Nelson, and S.L. Greenspan, Body 
composition changes during androgen deprivation therapy for prostate cancer: 
a 2-year prospective study. Crit Rev Oncol Hematol, 2008. 68(2): p. 172-7. 
 
32. Levy, M.E., S. Perera, G.J. van Londen, J.B. Nelson, C.A. Clay, and S.L. 
Greenspan, Physical function changes in prostate cancer patients on androgen 

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deprivation therapy: a 2-year prospective study. Urology, 2008. 71(4): p.735-
9. 
 
33. Mauras, N., V. Hayes, S. Welch, A. Rini, K. Helgeson, M. Dokler, J.D. 
Veldhuis, and R.J. Urban, Testosterone deficiency in young men: marked 
alterations in whole body protein kinetics, strength, and adiposity. J Clin 
Endocrinol Metab, 1998. 83(6): p. 1886-1892. 
 
34. Saigal, C.S., J.L. Gore, T.L. Krupski, J. Hanley, M. Schonlau, and M.S. Litwin, 
Androgen deprivation therapy increases cardiovascular morbidity in men with 
prostate cancer. Cancer, 2007. 110(7): p. 1493-500.  
 
35. Tsai, H.K., A.V. D'Amico, N. Sadetsky, M.H. Chen, and P.R. Carroll, 
Androgen deprivation therapy for localized prostate cancer and the risk of 
cardiovascular mortality. J Natl Cancer Inst, 2007. 99(20): p. 1516-24.  
 
36. Basaria, S., D.C. Muller, M.A. Carducci, J. Egan, and A.S. Dobs, 
Hyperglycemia and insulin resistance in men with prostate carcinoma who 
receive androgen-deprivation therapy. Cancer, 2006. 106(3): p. 581-8. 
 
37. Basaria, S., Androgen deprivation therapy, insulin resistance, and 
cardiovascular mortality: an inconvenient truth. J Androl, 2008. 29(5): p. 534-
9. 
 
38. Smith, M.R., Osteoporosis and other adverse body composition changes during 
androgen deprivation therapy for prostate cancer. Cancer Metastasis Rev., 
2002. 21(2): p. 159-166. 
 
39. Smith, M.R., W.C. Lee, J. Brandman, Q. Wang, M. Botteman, and C.L. Pashos, 
Gonadotropin-releasing hormone agonists and fracture risk: a claims-based 
cohort study of men with nonmetastatic prostate cancer. J Clin Oncol, 2005. 
23(31): p. 7897-903. 
 
40. Serpa Neto, A., M. Tobias-Machado, M.A. Esteves, M.D. Senra, M.L. 
Wroclawski, F.L. Fonseca, R.B. dos Reis, A.C. Pompeo, and A. Del Giglio, A 
systematic review and meta-analysis of bone metabolism in prostate 
adenocarcinoma. BMC Urol, 2010. 10: p. 9. 
 
41. Martinez-Reig, M., L. Ahmad, and G. Duque, The Orthogeriatrics Model of 
Care: Systematic Review of Predictors of Institutionalization and Mortality in 
Post-Hip Fracture Patients and Evidence for Interventions. J Am Med Dir 
Assoc, 2012. 
 
42. Galvao, D.A., D.R. Taaffe, N. Spry, D. Joseph, D. Turner, and R.U. Newton, 
Reduced muscle strength and functional performance in men with prostate 

LCCC 1613 
 
CONFIDENTIAL 
PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
22 
cancer undergoing androgen suppression: a comprehensive crosssectional 
investigation. Prostate Cancer Prostatic Dis, 2009. 12(2): p. 198-203. 
 
43. Glover, E.I. and S.M. Phillips, Resistance exercise and appropriate nutrition to 
counteract muscle wasting and promote muscle hypertrophy. Curr Opin Clin 
Nutr Metab Care, 2010. 13(6): p. 630-4. 
 
44. Hurley, B.F., E.D. Hanson, and A.K. Sheaff, Strength training as a 
countermeasure to aging muscle and chronic disease. Sports Med, 2011. 41(4): 
p. 289-306. 
 
45. Segal, R.J., R.D. Reid, K.S. Courneya, R.J. Sigal, G.P. Kenny, D.G. 
Prud'Homme, S.C. Malone, G.A. Wells, C.G. Scott, and M.E. Slovinec 
D'Angelo, Randomized controlled trial of resistance or aerobic exercise in men 
receiving radiation therapy for prostate cancer. J Clin Oncol, 2009. 27(3): p. 
344-51. 
 
46. Hydock, D.S., C.Y. Lien, C.M. Schneider, and R. Hayward, Effects of voluntary 
wheel running on cardiac function and myosin heavy chain in chemically 
gonadectomized rats. Am J Physiol Heart Circ Physiol, 2007. 293(6): p. H3254-
64. 
 
47. Kyrdalen, A.E., A.A. Dahl, E. Hernes, E. Hem, and S.D. Fossa, Fatigue in 
prostate cancer survivors treated with definitive radiotherapy and LHRH 
analogs. Prostate, 2010. 70(13): p. 1480-9. 
 
48. Petersen, A.M. and B.K. Pedersen, The anti-inflammatory effect of exercise. J 
Appl Physiol, 2005. 98(4): p. 1154- 62. 
 
49. Vingren, J.L., W.J. Kraemer, N.A. Ratamess, J.M. Anderson, J.S. Volek, and 
C.M. Maresh, Testosterone physiology in resistance exercise and training: the 
up-stream regulatory elements. Sports Med, 2010. 40(12): p. 1037-53. 
 
50. Winters-Stone, K.M., J. Dobek, L. Nail, J.A. Bennett, M.C. Leo, A. Naik, and 
A. Schwartz, Strength training stopsbone loss and builds muscle in 
postmenopausal breast cancer survivors: a randomized, controlled trial. Breast 
Cancer Res Treat, 2011. 127(2): p. 447-56. 
 
51. Argiles, J.M., S. Busquets, and F.J. Lopez-Soriano, The pivotal role of cytokines 
in muscle wasting during cancer. Int J Biochem Cell Biol, 2005. 37(10): p. 
2036-46. 
 
52. Lira, F.S., A.S. Yamashita, J.C. Rosa, F.L. Tavares, E. Caperuto, L.C. 
Carnevali, Jr., G.D. Pimentel, R.V. Santos, M.L. Batista, Jr., A. Laviano, F. 
Rossi-Fanelli, and M. Seelaender, Hypothalamic inflammation is reversed 

LCCC 1613 
 
CONFIDENTIAL 
PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
February 15, 2017 
 
23 
byendurance training in anorectic-cachectic rats. Nutr Metab (Lond), 2011. 
8(1): p. 60. 
 
53. Irwin, M.L., ACSM's Guide to Exercise and Cancer Survivorship. American 
College of Sports Medicine. 2012: Human Kinetics Publishing. 
 
54. Hackney, A.C. and J. Dobridge, Exercise and male hypogonadism: testerone, 
the hypothalamic-pituitary axis and physica exercise, in Male Hypogondal 
Disorders: Contemporary Endocrinology Series, S. Winter, Editor. 2003, 
Humana Publishing. p. 314-333. 
 
55. Urban, R.J., Y.H. Bodenburg, C. Gilkison, J. Foxworth, A.R. Coggan, R.R. 
Wolfe, and A. Ferrando, Testosterone administration to elderly men increases 
skeletal muscle strength and protein synthesis. Am J Physiol, 1995. 269(5Pt 1): 
p. E820-E826. 
 
56. Harris, W.P., E.A. Mostaghel, P.S. Nelson, and B. Montgomery, Androgen 
deprivation therapy: progress in understanding mechanisms of resistance and 
optimizing androgen depletion. Nat Clin Pract Urol, 2009. 6(2): p. 76-85. 
 
57. Galvao, D.A., D.R. Taaffe, N. Spry, D. Joseph, and R.U. Newton, Acute versus 
chronic exposure to androgen suppression for prostate cancer: impact on the 
exercise response. J Urol, 2011. 186(4): p. 1291-7. 
 
58. Cuoco, A., D.M. Callahan, S. Sayers, W.R. Frontera, J. Bean, and R.A. 
Fielding, Impact of muscle power and force on gait speed in disabled older men 
and women. J Gerontol A Biol Sci Med Sci, 2004. 59(11): p. 1200-1206. 
 
59. Newton, R.U., D.R. Taaffe, N. Spry, R.A. Gardiner, G. Levin, B. Wall, D. 
Joseph, S.K. Chambers, and D.A. Galvao, A phase III clinical trial of exercise 
modalities on treatment side-effects in men receiving therapy for prostate 
cancer. BMC Cancer, 2009. 9: p. 210. 
 
60. Vincent, K.R. and R.W. Braith, Resistance exercise and bone turnover in 
elderly men and women. Med Sci Sports Exerc, 2002. 34(1): p. 17-23. 
 
61. Galvao, D.A. and D.R. Taaffe, Resistance exercise dosage in older adults: 
single- versus multiset effects on physical performance and body composition. 
J Am Geriatr Soc, 2005. 53(12): p. 2090-2097. 
 
62. Mangione, K.K., R.L. Craik, A.A. McCormick, H.L. Blevins, M.B. White, 
E.M. Sullivan-Marx, and J.D. Tomlinson, Detectable changes in physical 
performance measures in elderly African Americans. Phys Ther, 2010. 90(6): 
p. 921-7. 
 

LCCC 1613 
 
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PI: Hanson 
 
UNIVERSITY OF NORTH CAROLINA 
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24 
63. Temel, J.S., J.A. Greer, A. Muzikansky, E.R. Gallagher, S. Admane, V.A. 
Jackson, C.M. Dahlin, C.D. Blinderman, J. Jacobsen, W.F. Pirl, J.A. Billings, 
and T.J. Lynch, Early palliative care for patients with metastatic non-small-
celllung cancer. N Engl J Med, 2010. 363(8): p. 733-42. 
 
64. Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and Physical 
Activity Guidelines for Cancer Survivors. CA Cancer J Clin 2012. 62:242-274. 
 
65. Cormie P, Newton RU Spry N et al. Safety and efficacy of resistance exercise 
in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis. 
2013;16(4):328-335. 
 
66. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue 
severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer. 
1999;85:1186-1196. 
 
67. Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related 
adverse effects for patients with prostate cancer receiving androgen-
deprivation therapy: a systematic review. J Clin Oncol. 2014. 32(4):335-46. 
 
68. Spector D, Deal AM, Amos KD, Yang H, Battaglini CL. A pilot study of a 
home-based motivational exercise program for African American breast 
cancer survivors: clinical and quality-of-life outcomes. Integr Cancer Ther. 
2014. Mar;13(2):121-32.