Exercise Intensity Trial (EXCITE): A Randomized Trial Comparing the Effects of Linear Versus Nonlinear Aerobic Training in Women With Operable Breast Cancer
Phase: NA
Conditions: Breast Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Page 1 of 39 
 
 
Approval date: 07-Nov-2017 
Exercise Intensity Trial (EXCITE): A Randomized Trial Comp 
Versus Nonlinear Aerobic Training in Women with Ope 
PROTOCOL FACEPAGE FOR MSK THERAPEUTIC /D I 
Principal Investigator/Department: 
Jessica Scott, PhD 
aring the Effects of Linear 
rable Breast Cancer 
AGNOSTIC PROTOCOL 
Medicine — Exercise Oncology 
Co-Principal 
Chau Dang, MD 
Investigator(s)/Department: 
Medicine — Breast 
Investigator(s)/Department: 
José Baselga, MD, PhD 
Victoria S. Blinder, MD 
Jacqueline Bromberg, MD, PhD 
Sarat Chandarlapaty, MD, PhD 
Elizabeth Comen, MD 
Gabriella M. D‘Andrea, MD 
Maura N. Dickler, MD 
Monica N. Fornier, MD 
Devika Gajria, MD, MPH 
Teresa A. Gilewski, MD 
Shari B. Goldfarb, MD 
Ayca Gucalp, MD 
Neil M. Iyengar, MD 
Komal Jhaveri, MD 
Diana E. Lake, MD 
Shanu Modi, MD 
Mary Ellen Moynahan, MD 
Larry Norton, MD 
Mark E. Robson, MD 
Pedram Razavi, MD, PhD 
Andrew D. Seidman, MD 
Lillian Smyth, MD 
Nancy T. Sklarin, MD 
Tiffany A. Traina, MD 
Lee Jones, PhD 
Michael Baum, MD 
Carol Chen, MD 
Dipti Gupta, MD 
Michelle Johnson, MD 
Jennifer Liu, MD 
Eileen McAleer, MD 
Nancy Roistacher, MD 
Wendy Schaffer, MD 
Richard Steingart, MD 
Howard Weinstein, MD 
Anthony Yu, MD 
Catherine Capaci, MS 
Richard Happel, MS 
Kereshmeh Collins, BS 
Daniel Townend, BS 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Exercise Oncology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Cardiology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
 

Page 2 of 39 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
Meghan Michalski, MS 
Kylie Rowed, MKin 
Scott Adams, PhD 
Chaya Moskowitz, PhD 
Emily Zabor, MS 
Jonathan Landa, DO 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Biostatistics 
Biostatistics 
Radiology 
Consenting 
Professional(s)/Department: 
Jessica Scott, PhD 
Lee Jones, PhD 
José Baselga, MD, PhD 
Victoria S. Blinder, MD 
Jacqueline Bromberg, MD, PhD 
Sarat Chandarlapaty, MD, PhD 
Elizabeth Comen, MD 
Gabriella M. D‘Andrea, MD 
Chau Dang, MD 
Maura N. Dickler, MD 
Monica N. Fornier, MD 
Devika Gajria, MD, MPH 
Teresa A. Gilewski, MD 
Shari B. Goldfarb, MD 
Ayca Gucalp, MD 
Neil M. Iyengar, MD 
Komal Jhaveri, MD 
Diana E. Lake, MD 
Shanu Modi, MD 
Mary Ellen Moynahan, MD 
Larry Norton, MD 
Mark E. Robson, MD 
Andrew D. Seidman, MD 
Nancy T. Sklarin, MD 
Tiffany A. Traina, MD 
Kathleen Keenan, NP 
Rebecca Steed, NP 
Anthony Yu, MD 
Catherine Capaci, MS 
Richard Happel, MS 
Kereshmeh Collins, BS 
Daniel Townend, BS 
Meghan Michalski, MS 
Kylie Rowed, MKin 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Breast 
Medicine — Cardiology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Medicine — Exercise Oncology 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
Memorial Sloan Kettering Cancer Center 
 
 
 
1275 York Avenue 
New York, New York 10065 
Participating Institutions – If multicenter 
study coordinated by MSK: 
PI's Name 
Site's Role 
Duke University 
Pamela S. Douglas, MD 
Data Analysis 

Page 3 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .........................................................................4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................................6 
3.0 
BACKGROUND AND RATIONALE .......................................................................................5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................... 7 
4.1 
Design ................................................................................................................................... 7 
4.2 
Intervention ............................................................................................................................. 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ...............................................................................8 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................... 8 
6.1 
Subject Inclusion Criteria ........................................................................................................ 8 
6.2 
Subject Exclusion Criteria ...................................................................................................... 9 
7.0 
RECRUITMENT PLAN ......................................................................................................................... 10 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 13 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 16 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 20 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 22 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 22 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 25 
14.0 
BIOSTATISTICS .................................................................................................................. 26 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES28 
15.1 Research Participant Registration ............................................................................................. 28 
15.2 
Randomization ........................................................................................................................ 28 
16.0 
DAT A M ANAGEMENT ISSUES .......................................................................................... 28 
16.1 
Quality Assurance .............................................................................................................. 31 
16.2 
Data and Safety Monitoring .................................................................................................. 31 
17.0 
PROTECTION OF HUMAN SUBJECTS .............................................................................. 32 
17.1 
Privacy ................................................................................................................................ 34 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................. 34 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 36 
19.0 
REFERENCES ........................................................................................................................... 36 
20.0 
APPENDICES ...................................................................................................................... 39 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Primary Objective: To compare the efficacy of linear aerobic training versus nonlinear 
aerobic training, relative to progressive stretching (attention-control group), on exercise 
capacity (VO2peak) in women with operable breast cancer following the completion of primary 
adjuvant therapy. 
Design: A total of 174 women with histologically confirmed operable breast cancer, meeting 
the eligibility criteria defined in Section 6.0, will be randomized to one of the following three 
arms in a 1:1:1 ratio (n=59/group): Arm A: supervised linear aerobic training, Arm B: 
supervised nonlinear aerobic training, or Arm C: progressive stretching (attention-control 
group) (see Figure 1). 
 
This randomized controlled trial (RCT) is a continuation of a clinical trial initiated and 
conducted at Duke University Medical Center (DUMC) in Durham, NC by the principal 
investigator, Lee Jones, PhD. The trial was suspended at DUMC (protocol-independent) due 
to change of the PI‘s institution. At the time of trial suspension, a total of 115 participants had 
been randomly allocated to three study groups: n=38 in Arm A, n=39 in Arm B, and n=38 in 
Arm C. Of these 115 participants, 109 successfully completed all study procedures, and 6 
participants were lost to follow-up. 
 
At MSK, 59 participants will be enrolled and randomized until the target enrollment of n=174 
is met. Twenty participants will be randomized to Arm A; 19 to Arm B; and 20 to Arm C. At 
the end of the trial, data will be analyzed for the pre-planned target sample size (n=174). 
 
Figure 1: Study Schema 
 
 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
2 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Primary Objective 
 
To compare the effects of supervised linear aerobic training versus supervised nonlinear 
aerobic training, relative to progressive stretching (attention-control group), on VO2peak in 
women with operable breast cancer following the completion of primary adjuvant therapy. 
2.2 
Secondary Objectives 
 
• 
To compare the effects on resting and exercise cardiac function; 
• 
To compare the effects on pulmonary function; 
• 
To compare the effects on arterial stiffness; 
• 
To compare the effects on endothelial function; 
• 
To compare the effects on body composition; 
• 
To compare the effects on patient-reported outcomes (e.g., quality of life, fatigue) ; 
• 
To collect and bank blood samples for future correlative studies; and 
• 
To assess and compare the safety of supervised aerobic training. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Indication 
 
The intended indication for supervised linear or nonlinear aerobic training is the treatment of 
impaired exercise capacity (i.e., global cardiovascular function) in patients with operable 
breast cancer following the completion of primary adjuvant therapy. 
3.2 
Background and Rationale 
 
Exercise capacity is one of the most important indicators of health and longevity in 
humans.
1,2 The capacity of mammals to transport oxygen (O ) from the atmosphere to the 
muscle mitochondria determines an individual‘s exercise capacity.3  Maximal or peak oxygen 
consumption (VO2peak) provides the gold standard measurement of exercise capacity and is 
strongly and inversely related to risk of death.4 -8 
The importance of exercise capacity following a breast cancer diagnosis has received limited 
attention.9  However, over the past decade, there has been increased recognition and 
acceptance of the importance of therapy late effects (e.g., cardiovascular disease, type 2 
diabetes, fatigue, deconditioning) as a major but underappreciated area in breast cancer 
management.10  Poor exercise capacity may be of central importance for certain adverse late 
effects — including impaired left ventricular ejection fraction, elevated cardiovascular disease 
(CVD) risk profile, poor quality of life, and fatigue — following the completion of adjuvant 
therapy for operable breast cancer.
11-13  Further, recent landmark observational studies report 
that regular self-reported physical activity (e.g., brisk walking, ≥30 minutes/day, 5  
days/week), a major determinant of exercise capacity, is associated with 30% to 50% 
reductions in breast cancer-specific mortality and all-cause mortality following the completion 
of adjuvant therapy.14,15 

Page 6 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
Despite its importance, women with breast cancer have markedly reduced exercise capacity. 
In a series of studies by our group, we observed that VO2peak  was approximately 30% below 
that of age-matched sedentary healthy women up to three years following the completion of 
adjuvant therapy.11,12,16  The precise causes of the significant and marked impairments in 
VO2peak  are not known but likely are a consequence of direct cytotoxic therapy-associated 
injury to the cardiovascular system (e.g., impairments in the organ components that govern 
VO2peak) together with lifestyle perturbations (e.g., deconditioning and weight gain) that we 
have termed the ‗multiple hit‘ hypothesis.9 
A growing number of research groups have investigated the efficacy of supervised exercise 
training interventions (aerobic, resistance, or combination training) to counteract therapy- 
induced poor exercise capacity both during and following the completion of adjuvant therapy. 
Overall, the current literature base indicates that supervised exercise training is a safe and 
feasible adjunctive therapy associated with significant improvements in objective measures 
of exercise capacity (including VO2peak as measured by a symptom-limited cardiopulmonary 
exercise test (CPET)) as well as a broad range of PROs.17  Preliminary data also indicate that 
exercise training, particularly aerobic training, may cause favorable improvements in 
circulating metabolic hormone concentrations in women with operable breast cancer 
following the completion of adjuvant therapy.18,19 
Although much progress has been made over the past 20 years, the format and intensity of 
exercise training required to induce optimal improvements in VO2pe ak  and other pertinent 
outcomes in women with breast cancer have not been investigated. The American College of 
Sports Medicine (ACSM) convened a panel of experts to review the available evidence 
supporting exercise prescription guidelines for cancer survivors.20  The panel concluded that 
cancer patients follow the 2008 Physical Activity Guidelines for Americans (≥ 150 
minutes/week of moderate-intensity, or ≥ 75 minutes/week vigorous-intensity aerobic 
exercise or an equivalent combination of moderate- and vigorous intensity aerobic exercise), 
yet few studies have tested this empiric prescription in a formal randomized controlled trial. 
 
Moreover, the most important methodological consideration when conducting any exercise 
training trial is that the exercise prescription closely adheres to the fundamental principles of 
training (i.e., individualization, specificity, progressive overload, and rest/recovery). 
Alarmingly, two recent systematic reviews found that the vast majority of exercise training 
trials in the oncology setting did not comply with these fundamental principles.21,22  Rather, the 
vast majority of trials investigate the effects of exercise training prescriptions in which the 
majority of training sessions are performed at the same intensity and duration; thus, training 
volume remains constant across the entire intervention — this is known as a linear exercise 
training prescription. This is problematic because as VO2peak  improves, the adaptation from  
an identical exercise stimulus diminishes; therefore, there is an insufficient stimulus to induce 
further physiologic adaptation. 
In contrast, in nonlinear exercise training prescriptions, the intensity, duration, and 
occasionally, the frequency, of training sessions are sequenced in such a fashion that 
training volume is continually increased across the entire program (i.e., the principle of 
progressive overload). This approach also adds important variety to the presc ription that not 
only continually alters the exercise ‗stress‘ (to optimize adaptation), but can also stimulate 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
participant interest and motivation. In addition, training intensity is sequenced such that 
higher intensity or higher volume training is followed by lower intensity (recovery) training and 
rest days to optimize adaptation (i.e., the principle of rest and recovery). Our group has 
previously demonstrated the safety, feasibility, and potential efficacy of a nonlinear exercise 
training approach in several cancer populations.23-26  However, no study to date has  
compared whether a nonlinear exercise training approach is superior to the traditional, linear 
training approach in patients with cancer. 
 
Against this background, we designed the EXCITE trial, a randomized controlled trial 
comparing the effects of supervised linear aerobic training versus nonlinear aerobic training 
in women with operable breast cancer following the completion of primary adjuvant therapy. 
3.3 
Effects of Aerobic Training on Exposure to Other Conventional/Novel 
Anticancer Therapies 
 
There is no clinical data on the effect of aerobic training (or progressive stretching) on the 
therapeutic index of anticancer agents used in the management of breast cancer. Eligible 
subjects in this trial will not be receiving any primary adjuvant therapy, but they may 
potentially be receiving endocrine therapy. All clinical studies to date have focused on the 
effects of exercise training interventions to prevent and/or mitigate the psychosocial and/or 
physiological side-effects of cancer therapy; whether exercise training influences the 
pharmacodynamics (PD) or pharmacokinetics (PK) of anticancer therapy has not been 
investigated. 
3.4 
Effects of Conventional/Novel Anticancer Therapies on Aerobic Training 
 
Our group, as well as others, have demonstrated that different forms of anticancer therapy 
cause unique and varying degrees of damage to various components of the cardiopulmonary 
system (heart-lung-blood-muscle axis). Collectively, these effects lead to significant and 
marked declines in global cardiopulmonary function, manifest as poor exercise tolerance 
(decreased VO2peak). A major rationale for this trial is to determine the optimal aerobic training 
prescription approach to reverse this phenotype in women with operable breast cancer. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This open-label, three-arm randomized controlled trial will compare the effects of supervised 
linear aerobic training versus supervised nonlinear aerobic training, relative to progressive 
stretching (attention-control group), in women with operable breast cancer following the 
completion of primary adjuvant therapy. The primary endpoint is VO2peak, as measured by a 
symptom-limited cardiopulmonary exercise test (CPET). 
 
The study periods will include screening, study intervention, and follow-up assessments. 
 
 
 
4.3 
Intervention 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
Following eligibility confirmation participants will be randomized to one of three study arms. 
All participants will undergo their first aerobic or stretching training session at MSK within a 
maximum of 14 days following randomization. 
 
Participants will perform structured supervised aerobic training as part of clinical trial 
participation. Exercise performed outside the structured sessions (i.e., contamination) will be 
assessed via self-report of exercise behavior.  For ethical reasons, we will not instruct 
participants not to exercise outside the structured sessions, but we will encourage 
participants to maintain their level of exercise behavior prior to the initiation of the trial. 
 
At Weeks 4, 8, and 12, all participants will perform a fasting research blood draw. 
Participants assigned to the nonlinear aerobic training (Arm B) will also perform a CPET at 
midpoint. The purpose of this test is to re-assess exercise capacity to re-prescribe aerobic 
training to ensure progressive cardiovascular adaptation across the  entire  intervention 
period. 
 
4.4 
Future Use of Samples 
 
Following the completion of the trial, banked samples will be used for future correlative 
studies to evaluate the effects of different aerobic training prescriptions, relative to control, on 
blood-based biomarkers. Specific biomarkers of interest include metabolites and cytokine  
and angiogenic factors. A material transfer agreement (MTA) will be instituted before any 
samples are transferred. 
 
Any projects outside of the scope of this protocol will need to be approved by the IRB/PB. A 
biospecimen correlative protocol detailing the proposed project will need to be approved by 
the IRB/PB prior to the start of the project. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
There are no therapeutic agents in this trial. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Aged  45–80 years 
• 
Female 
• 
Has been diagnosed with early-stage breast cancer 
• 
Post-menopausal, defined as: 
o Age ≥ 45 with no menses for at least 2 years 
o Chemically induced menopause through ovarian suppression, as determined 
by the primary oncologist 
• 
An interval of at least one year, but no more than five years, following the full 
completion of primary therapy for malignant disease. Primary therapy is defined as: 
o Surgery plus radiation 
o Surgery plus chemotherapy 
o Surgery plus trastuzumab 
o Surgery plus hormone therapy 

Page 9 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
Note: For patients who receive hormone therapy following surgery, the definition of 
one-year post-completion of therapy is defined by the surgery date. Patients who are 
currently receiving hormone therapy are eligible for enrollment. 
• 
Weight of <205 kgs 
• 
ECOG status of 0 or 1 
• 
Life expectancy ≥ 6 months 
• 
Performing less than 150 minutes of structured moderate-intensity or strenuous 
intensity exercise per week. 
• 
Exercise intolerance, defined by a VO2peak  below that predicted for active age- and 
sex-matched individuals (see Appendix H). 
• 
Willing to be randomized to one of the study arms 
• 
Able to complete an acceptable baseline CPET, in the absence of high risk ECG 
findings or other inappropriate response to exercise as determined by the 
investigator. 
• 
Able to achieve an acceptable peak baseline CPET, as defined by any of the 
following criteria: 
o Achieving a plateau in oxygen consumption, concurrent with an increase in 
power output; 
o A respiratory exchange ratio ≥ 1.10; 
o Attainment of maximal predicted heart rate (HRmax) (i.e., within 10 bpm of age- 
predicted HRmax  [HRmax  = 220-Age[years]); 
o Volitional exhaustion, as measured by a rating of perceived exertion (RPE) ≥ 
18 on the BORG scale (see Appendix E) 
 
6.3 
Subject Exclusion Criteria 
 
• 
Any of the following absolute contraindications to cardiopulmonary exercise testing: 
o Acute myocardial infarction within 3–5 days of any planned study procedures 
o Unstable angina 
o Uncontrolled arrhythmia causing symptoms or hemodynamic compromise 
o Recurrent syncope 
o Active endocarditis 
o Acute myocarditis or pericarditis 
o Symptomatic severe aortic stenosis 
o Uncontrolled heart failure 
o Acute pulmonary embolus or pulmonary infarction within 3 months of any 
planned study procedures 
o Thrombosis of lower extremities 
o Suspected dissecting aneurysm 
o Uncontrolled asthma 
o Pulmonary edema 
o Respiratory failure 
o Acute non-cardiopulmonary disorders that may affect exercise performance or 
be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis) 
• 
Presence of any other concurrent, actively treated malignancy 
• 
History of  any  other  malignancy treated within the past 3  years  (other  than  non- 
melanoma skin cancer) 

Page 10 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
 
 
• 
Presence of metastatic disease 
• 
Room air desaturation at rest ≤ 85% 
• 
Mental impairment leading to inability to cooperate. 
• 
Any other condition or intercurrent illness that, in the opinion of the investigator, 
makes the participant a poor candidate for the trial 
 
 
7.1 
RECRUITMENT PLAN 
 
Potential participants will be identified by a member of the patient‘s treatment team, the 
protocol investigator, or members of the Exercise-Oncology Research Program (Ex-Onc) at 
Memorial Sloan Kettering Cancer Center (MSK). If the investigator is a member of the 
treatment team, s/he will screen their patients‘ medical records for suitable research study 
participants and discuss the study and their potential for enrolling in the research study. 
Potential participants contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
The principal investigator and Ex-Onc research staff may also screen the medical records of 
patients with whom they do not have a treatment relationship for the limited purpose of 
identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these patients regarding the possibility of enrolling in 
the study. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review portions 
of their medical records at MSK in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is  
eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information 
that must be maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective participant will be conducted either by 
the treatment team, investigator, or the Ex-Onc research staff working in consultation with the 
treatment team. The recruitment process outlined presents no more than minimal risk to the 
privacy of the patients who are screened and minimal PHI will be maintained as part of a 
screening log. For these reasons, we seek a (partial) limited waiver of authorization for the 
purposes of (1) reviewing medical records to identify potential research subjects and obtain 
information relevant to the enrollment process; (2) conversing with patients regarding 
possible enrollment; (3) handling of PHI contained within those records and provided by the 
potential participants; and (4) maintaining information in a screening log of patients 
approached (if applicable). 
 
Two strategies will be employed for participant recruitment: 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
1. Mail-Based Recruitment: Ex-Onc research staff will obtain from DataLine a list of 
potential participants meeting basic eligibility criteria. 
 
Ex-Onc research staff will contact the potentially eligible patient‘s primary attending 
physician to confirm the patient‘s current status and to seek approval to send the 
patient a mail-based letter of introduction (see Appendix B) and a copy of the 
consent form. The letter of introduction will be signed by the protocol PI. Patients 
interested in trial participation will be directed to call the Ex-Onc office to ask any 
questions they may have, receive further instructions, and discuss next steps. To 
further assess eligibility of potentially eligible patients, the GLTEQ will be 
administered by phone. Patients meeting all study requirements will be scheduled for 
a baseline protocol appointment. Patients will have the opportunity to review the 
written consent form prior to completing any tests or procedures during the baseline 
protocol appointment. The patient will sign the consent form at this visit. 
 
Patients not responding to the mailed letter of introduction within two weeks will be 
sent a second mailing. Patients still not responding a few weeks after the second 
mailing will be contacted by telephone by Ex-Onc personnel to gauge patient interest 
in trial participation. One additional phone call may be made to the patient, if needed. 
The study team will not make more than four total attempts (mailings and phone calls) 
to contact a patient. 
 
2. Clinic-Based Recruitment: Potentially eligible patients attending a scheduled clinic  
visit with their primary attending oncologist at the Breast and Imaging Center (BAIC) 
will be approached at that visit. Patients may also be given a brochure at this visit  
with their oncologist as an introduction to the program. Ex-Onc research staff will 
obtain primary attending oncologist approval prior to or in conjunction with 
approaching any patient about trial participation. This initial encounter will include a 
discussion of the proposed trial, proposed treatments, and the rationale for use. 
Interested patients will answer questions from the GLTEQ to assess eligibility. Eligible 
patients interested in trial participation will have the opportunity to review and sign an 
informed consent during this clinic visit. 
 
Following the initial consultation, interested participants will be contacted by telephone by Ex- 
Onc research staff to schedule the baseline assessment visit. Minorities and women are well- 
represented in the Breast Medicine clinics, and we anticipate appropriate representation in 
the trial accrual. 
7.1 
Blinding 
 
This study is open label. Due to the nature of aerobic training interventions, participants, 
exercise physiologists, investigators and Ex-Onc research staff cannot be blinded to arm 
allocation. 
7.2 
Study Duration 
 
The  total  duration  of  the  study  for  each  participant  will  be  a  maximum  of  17  weeks. 
Participants  may  receive  study  interventions  for  a  maximum  of  16  weeks,  unless  study 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
treatment is  discontinued. Patients  will  be followed for up  to one year following  the  last 
patient visit. 
 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1 
Screening Period 
 
The screening period consists of initial patient review, informed consent and GLTEQ. The 
GLTEQ is used to measure a persons current level of physical activity in terms of the 
duration and type of exercise. Ex-Onc research staff will maintain a screening log for all 
potential study participants. Each consented participant will be assigned a screening 
identification (Study ID) number in consecutive numerical order, beginning with 001. 
 
Patients consented who do not subsequently meet eligibility criteria will be registered as 
ineligible. If research samples have been collected on those patients they will be discarded in 
accordance with regulations. 
 
A new Study ID number will be assigned to a participant who is rescreened after originally 
failing to meet study eligibility. 
 
8.2 
Baseline Study Assessments 
 
Participants will complete a symptom-limited CPET before undergoing all other baseline 
assessments. The baseline study assessment period will take place within 30 days of 
registration, except where otherwise noted. 
 
Within 30 days of registration all participants will undergo the following baseline 
assessments: 
1. Fasting research blood draw; 
2. Fasting, non-invasive measurement of regional arterial stiffness (AS) and flow- 
mediated dilatation (FMD); 
3. Resting assessment of left ventricular function using echocardiography; 
4. Symptom-limited CPET with 12-lead ECG and pulmonary function testing; 
5. Post-VO2peak   echocardiography; 
6. Lifestyle questionnaire (see Appendix A); and 
7. A dual-energy X-ray absorptiometry (DEXA) scan to assess body composition. 
 
The completion of these assessments will take approximately 3 to 4 hours and will be 
conducted in the Ex-Onc Integrative Physiology Laboratories at Memorial Hospital (in 
Cardiology), the Rockefeller Outpatient Pavilion at 53rd  Street (in Cardiology), or the Sidney 
Kimmel Center for Prostate and Urologic Cancers. Participants will be given an opportunity to 
eat a light snack following their fasted assessments. Participants will be encouraged to bring 
their own snack; however, the Ex-Onc team will also have extra snacks, such as granola 
bars, available in case participants do not bring their own. 
At the baseline visit, participants will also receive a welcome packet (Appendices C, D, F), 
which contains information about the program and an easy-to-use study calendar. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
The DEXA scan will be performed at either the BAIC or the Rockefeller Outpatient Pavilion. 
 
To  maximize internal validity, we will try to schedule study endpoint assessments in the 
same order as they were completed at baseline, midpoint and followup. 
All baseline study assessments are described in Table 1. 
 
Table 1. Baseline Study Assessments 
 
REQUIRED  ASSESMENT 
DESCRIPTION 
Resting left ventricular function by 3- 
dimensional echocardiography (3DE) 
Three-dimensional transthoracic echocardiograms will be 
performed by experienced sonographers and acquired with 
commercially available equipment (Vivid 7 or E9, GE 
Healthcare, Milwaukee, WI). 
Following completion of the 2DE, a full volume dataset will be 
acquired using a matrix array transducer with gated 4 beat 
acquisitions for assessments of left ventricular (LV) volumes by 
3DE.  A 3DE acquisition of the entire LV will be generally 
performed in <10 seconds. All assessments will be stored 
digitally for offline analyses performed using EchoPAC PC 
workstation (version BT11, GE Medical, Milwaukee, WI). 
Conventional 2D measurements of LV dimensions, Doppler, and 
diastolic function parameters will be performed and averaged 
over 3 cardiac cycles according to American Society of 
Echocardiography  guidelines.29-31 
Left vent ricular volumes and left ventricular ejection fraction 
(LVEF) by 3DE will be determined by manipulating the full 
volume dataset to derive conventional apical 4-, 3-, and 2- 
chamber vi ews using Tom Tec offline analysis software (4D LV- 
Function, Unterschleisheim, Germany). After selection of 
reference points, a 3D endocardial contour will be automatically 
generated and manual adjustment will be performed as 
necessary.   The resultant end-diastolic (EDV) and end-systolic 
volumes (ESV) will be used to calculate LVEF.32 
Symptom-limited CPET to assess peak 
oxygen consumption  (VO2peak) 
VO2peak  will be evaluated using an electronic motorized treadmill 
test with 12-lead ECG monitoring (Mac® 5000, GE Healthcare) 
performed by certified exercise physiologists. 
CPET provi des assessment of peak oxygen consumption 
(VO2peak). Expired gases will be analyzed continuously by a 
metabolic measurement system (Parvo Medics TrueOne 2400). 
During the test, participants will begin walking on a treadmill at a 
participant-specific designated speed and grade for 
approximately 2 minutes. The speed and/or grade will then be 
increased every 1–2 minutes until exhaustion or a symptom- 
limitation is reached. 
During exercise, oxyhemoglobin saturation will be monitored 
using finger pulse oximetry, while blood pressure will be 
measured manually by auscultatory sphygmomanometer every 
two minutes (± 1 minute). 

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IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
 
The CPET may be terminated at the discretion of the exercise 
physiologist if abnormal ECG findings or abnormal response to 
exercise is observed, or if acceptable test criteria are not met. 
Post VO2peak  left ventricular function by 
2-dimensional  echocardiography (2DE) 
As soon as possible following completion of the CPET, 
participants will be placed in the supine position and 2DE 
grayscale images will be obtained in the apical 4 -, 3-, and 2- 
chamber vi ews. Wall motion scoring index (WMSI) will be 
calculated at rest and post-exercise using the 17 segment model 
by adding the indi vi dual segment scores (1 = normal; 2 = 
hypokinesia; 3 = akinesia; 4 = dyskinesia) and dividing by 
number of segments scored.29 2D LV vol umes and LVEF will be 
calculated offline using the modified Simpson‘s biplane method. 
Cardiac output will be calculated as the product of LV stroke 
volume and heart rate, indexed to body surface area (BSA). 
Pulmonary function testing 
Pulmonary function will be determined using standard 
spirometry. All measures will be performed in a sitting position 
according to the American Thoracic Society guidelines.36 
Regional arterial stiffness 
Conduit regional artery stiffness of the entire aorta will be 
assessed non-invasively by measuring carotid-femoral pulse 
wave velocity (PWV) using 2 hand-held tonometers (SPT-301 
Millar Instruments, Houston,  TX). 
Carotid and femoral artery waveforms will be recorded 
simultaneously with the mechanotransducers directly applied to 
the skin over the greatest area of pulsation.  Twenty consecutive 
reproducible beats will be collected simultaneously at both sites, 
with a concurrent electrocardiograph to obtain R-R intervals. 
Pulse transit time will be determined as the difference in time 
from R interval to systolic upstroke at each location. Systolic 
upstroke will be determined by identifying the foot or ―notch‖ of 
the blood pressure waveform. This will be done by applying a 
band pass filter between 5-30 Hz, selecting the minimum value 
of the filtered signal. 
Pulse distance will be determined using anthropometric 
measuring tape subtracting the distance from carotid 
measurement to sternal notch from the distance from sternal 
notch to femoral pulse measurement. This method has been 
shown to be the optimal non-invasi ve measurement compared 
to invasi ve measure. PWV will then be determined by taking the 
pulse transit time/distance. 
Flow-mediated dilatation (FMD) to 
assess endothelial function 
Peripheral artery flow-mediated dilatation (FMD) will be 
performed on one arm with the subject in a supine position with 
the forearm extended and slightly supinated. 
A rapid inflator blood pressure cuff will be placed on the forearm 
just distal to the antecubital crease and the brachial artery will be 
imaged using high-resolution B-mode ultrasound and a 7.5MHz 
linear array transducer (Terason, t3200). Ten-second r-wave 
triggered digital clips (artery diastole) will be captured at 
baseline (following 10min of supine rest), during five minutes of 
forearm occlusion, and a 120 sec r-wave triggered digital clip will 

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Approval date: 07-Nov-2017 
 
 
 
 
 
be captured beginning at cuff deflation (hyperemia) as 
previously  described.
37
 
Offline analysis using specialized software (Brachial Tools, 
Medical Imaging Applications, Illinois) will permit for identification 
of peak dilation and dilation at specific pre-specified time points 
(60, 120 sec).
37
 
Dual  energy x-ray absorptiometry 
(DEXA) to assess body composition 
Body fat percentage, and lean and fat body mass will be 
assessed by dual energy x-ray abs orpti ometry using a Lunar 
Prodigy multiple detector fan-beam densitometer (GE Medical 
Systems, Madison, WI). After calibration with an 
anthropomorphic phantom, single-beam, whole-body scanning 
will be employed on supine-positioned subjects. Data will be 
obtained from each scan for fat and lean body mass expressed 
to the nearest tenth of a gram (and percent) for the total body 
region, as well as in defined body zones (e.g., legs, trunk and 
arms). 
In the two hours prior to the DE XA scan, participants will be 
asked to avoid a large meal, avoid caffeine, avoid alcohol, and 
avoid tobacco. Participants will also be instructed to avoid 
strenuous acti vity for at least twelve hours before the scan. 
Efforts will be made for baseline and follow up DE XA 
assessments to be performed on the same machine. 
Patient-reported outcomes (via  Lifestyle 
Questionnaire, Appendix A) 
Patient-reported outcomes will be assessed using a patient- 
administered questionnaire to assess quality of li fe, fatigue, pain, 
and sleep quality. 
• 
Quality of Life (QOL) will be assessed by the Functional 
Assessment of Cancer Therapy–Breast (FACT-B) scale 
developed for the assessment of patient symptoms and 
QOL in breast cancer patients.38 
• 
Fatigue will be assessed using the 13-item FACIT- 
Fatigue scale for the assessment of fatigue in cancer 
patients.39 
• 
Pain will be assessed using the 10-item Brief Pain 
Inventory (BPI) which was designed to measure multiple 
clinically relevant aspects of pain such as pain intensity 
and interference from pain in cancer populations.40 
• 
Sleep Quality will be assessed by the Pittsburgh Sleep 
Quality Index (PSQI).41 
• 
Medical Outcomes Trust Short Form Health Survey (SF- 
36): The SF-36 is a psychometrically robust self-report 
questionnaire that measures general health-related 
quality of li fe in 8 domains of health: physical functioning 
(SF-36 PF), role limitations caused by physical health 
(role-physical), bodily pain, general health perceptions, 
vitality, social functioning, role limitation due to  
emotional problems (role-emotional) and mental 

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Approval date: 07-Nov-2017 
 
 
 
 
 
health.42 
Complete Blood Count (CBC), Glucose 
and Lipid Panel 
Blood will be drawn per clinical practice and analyzed by MSK 
Clinical Chemistry. 
Fasting research blood draw 
Blood collection should take place prior to the initiation of any - 
study related interventions, whenever possible. 
 
 
Following the completion of all baseline assessments and final confirmation of eligibility, 
participants will be randomized to one of the three study arms. 
 
Participants who do not meet eligibility criteria will be informed of their status and considered 
a screen failure. 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 
Study Assessments Visit Windows 
 
Testing slots and procedure availability must be taken into consideration when scheduling 
study follow-up visits. Visits may be split across the window to permit for completion of all 
study-related assessments. 
9.3 
Evaluation Prior to Initiation of Intervention 
 
Prior to the initiation of each intervention session participant resting vital signs will  be 
assessed as per Appendix H to ensure the participant can safely proceed with the session. 
The planned session will not be initiated if the exercise physiologist observes any concerns 
that may compromise participant safety and/or the integrity of the planned session. 
 
9.4 
Study Interventions 
 
The study interventions are supervised linear aerobic training (Arm A), supervised nonlinear 
aerobic training (Arm B), or progressive stretching (attention control) (Arm C). All sessions 
will be performed in a supervised setting  by a Ex-Onc exercise physiologist. Sessions will 
take place at the Sidney Kimmel Center for Prostate and Urologic Cancers or Sillerman 
Center for Rehabilitation. 
 
All aerobic training sessions will be prescribed by an exercise physiologist under the direction 
of the Program Director. All exercise physiologists are trained in either Basic or Advanced 
Cardiovascular Life Support (BLS/ACLS). 
 
Participants will be instructed to adhere to fasting guidelines for food, caffeine, tobacco, 
alcohol and exercise as outlined in Appendix H. 
 
All sessions, regardless of randomization arm, will include a warm-up. The aerobic arms, A 
and B, will also include a cool-down. Heart rate, oxygen saturation and blood pressure will be 

Page 17 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
assessed prior to and following each intervention session. All adjustments to the intervention 
sessions will be implemented according to the standard care procedures of the exercise 
physiologists and will be source documented. 
9.3.1 Arm A — Linear Aerobic Training 
 
The ultimate goal is for participants to complete approximately 130–180 minutes/week of 
aerobic training, at 60% to 75% of the individually determined exercise capacity (VO2peak), for 
16 weeks. VO2peak  will be determined by the second CPET performed at baseline. The 
weekly exercise will be achieved via either 3 to 4 individual aerobic training sessions (see 
Appendix H). All sessions are required to be supervised. Intensity and duration of aerobic 
training is prescribed and is implemented in accordance with standard exercise training 
principles. This approach will be applied to guide each participant‘s prescription, with dose 
and scheduling modifications made by exercise physiologists, as required. 
9.3.2 Arm B — Nonlinear Aerobic Training 
 
The ultimate goal is for participants to complete approximately 130–180 minutes/week of 
aerobic training at 55% to 100% of the individually determined exercise capacity (VO2peak), for 
16 weeks. VO2peak  will be determined by the second CPET performed at Baseline, as well as 
the CPET performed at midpoint. The weekly exercise will be achieved via 3 to 4 individual 
aerobic training sessions (see Appendix H). All sessions are required to be supervised. 
Intensity and duration of aerobic training is prescribed and is implemented in accordance 
with standard exercise training principles (e.g., in a progressive manner with planned 
recovery between high-intensity sessions). This approach will be applied to guide each 
participant‘s prescription, with dose and scheduling modifications made by exercise 
physiologists, as required. 
 
9.3.3 Arm C — Progressive Stretching Group (Attention control) 
 
The ultimate goal for the progressive stretching program is 3 to 4  individual  stretching 
sessions (see Appendix H). All sessions are required to be supervised. Duration of the 
stretching sessions is prescribed and implemented in accordance with standard stretching 
and flexibility training principles. This approach will be applied to guide each participant‘s 
prescribed stretching plan, with dose and scheduling modifications made by exercise 
physiologists, as required. 
 
9.4 
Early Termination of Intervention Sessions (Aerobic and Stretching) 
 
All intervention sessions will be immediately terminated if, at any time during a session, any 
adverse clinical signs and symptoms that will not allow the intervention to proceed safely are 
observed by the exercise physiologist. Determination of whether it is safe for the intervention 
to resume in the same session — for example, if the signs and symptoms are sufficiently 
subsided by a rest period — will be determined by the exercise physiologist. 
 
In the event of a session termination, the appropriate medical follow-up and clearance will be 
performed as per post-training clearance criteria specified in the ―Training Session Criteria‖ 
section of Appendix H. All signs and symptoms that result in session termination will be 

Page 18 of 39 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
source documented and reported as an adverse event to the study intervention. Future 
planned training sessions will continue at the discretion of the PI. 
9.5 
Intervention Session Dose Modification (Aerobic and Stretching) 
 
Vital signs will be monitored during intervention sessions to ensure participant safety. Vital 
sign changes that are outside the expected range of the intervention will be monitored by the 
exercise physiologist. The exercise physiologist will use clinical discretion to determine if a 
modification to the prescription or termination of the session is required. 
All modifications will be source documented and recorded in the study database, including 
the modification reason, how the session was modified, and clearance obtained, as 
appropriate. 
 
Participants requiring consistent modification of the planned prescription will be reviewed by 
the study PI and exercise physiologists to determine appropriate action (e.g., early study 
withdrawal, physiological re-evaluation). 
 
Final determination of the intensity and duration of the session against the planned session 
goals will be conducted by the supervising exercise physiologist following the session and 
will be source documented. 
 
9.6 
Study Intervention Continuation/Interruption 
 
If a session is missed or interrupted for an adverse event (AE), the participant will be treated 
for the AE as per the discretion of the attending oncologist and/or PI, as appropriate. The 
participant will resume the intervention only after clearance from the PI. 
 
Participants with treatment interruptions lasting longer than 4 consecutive weeks will be 
discontinued from the trial. In addition, any participant who misses a cumulative total of 8 
weeks of the study intervention will be discontinued from trial participation. When 
appropriate, study follow-up assessments will still be performed. 
 
When intervention sessions are resumed, the dosing will be progressively increased until the 
planned prescription can be safely resumed, according to the Ex-Onc Exercise Physiology 
standards of care and/or at the discretion of the Program Director. 
Participants will be allowed to ‗make up‘ missed sessions within the 16-week study window. 
Participants are not allowed to a priori ‗bank‘ aerobic training sessions. 
 
Participants experiencing disease recurrence will be removed from study. 
 
9.7 
Study Intervention Attendance and Compliance 
 
Attendance is calculated as the number of intervention sessions attended divided by the total 
number of planned sessions (i.e., 4 times/week x 16 weeks = 64). Compliance is calculated 
as the number of intervention sessions attended, as well as whether the training session 
dose was successfully completed (i.e., participant completed the intervention session at the 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
 
 
planned duration and intensity) divided by the total number of planned sessions. Non- 
compliance is defined as any intervention session requiring dose modification of either the 
planned intervention duration and/or intensity. 
9.8 
Concomitant Medications 
 
All concomitant medications at the time of study entry will be identified through a medical 
chart review and recorded in REDCap. Participation in the study intervention must not impact 
use of concomitant medications at any stage of the study period. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
All evaluations being conducted during the study intervention, including the window of time in 
which conduct of these tests is required, are described in the schedule of activities (Table 2). 
Further details are provided within this section. Assessments which are initially completed at 
baseline, midpoint and follow up may be repeated at the investigators discression. 
10.1 
Cardiopulmonary Exercise Testing (CPET) 
 
The midpoint CPET will take the place of one aerobic training session during Week 8 for 
participants in Arm B. This test is repeated at this time point to re-assess VO2peak under the 
expectation that VO2pe ak  is likely to have changed in the first 8 weeks of the aerobic training 
program. Thus, information from midpoint testing is used to re-prescribe the aerobic training 
prescription to ensure continual physiological adaptations across the entire study period. 
 
This test will not be repeated in the linear aerobic training prescription group (Arm A) or the 
progressive stretching group (Arm C) at Week 8. 
10.2 
Fasting Blood Draws 
At Weeks 4, 8, and 12, participants will undergo a fasting blood draw to obtain peripheral 
blood to assess complete blood count (CBC) and secondary endpoints. At Baseline and 
Study Follow-Up, participants will also undergo fasting blood draws for complete blood count 
(CBC), lipid panel, fasting glucose, as well as secondary endpoints. The CBC, fasting 
glucose, and lipid panel will be resulted by MSK clinical labs. Blood for secondary endpoints 
will be collected under protocol #06-107. Plasma from these research draws will be 
processed and stored per the Lab Manual, before shipment to a biorepository facility, 
KryoCal (d/b/a Kryosphere), for long-term banking. 
10.3 
Exercise Contamination 
We will monitor the amount of exercise performed outside of the study in all study arms using 
subjective methods. Participants in all arms will be asked to complete the GLTEQ  at  
midpoint and at study follow-up to report all exercise behavior performed outside the context 
of the exercise prescribed in the trial. This questionnaire is important to assess the degree of 
exercise being performed outside of the structured sessions in all arms, which may  
potentially contaminate study results. At the midpoint assessment, participants will be asked 
to report the average weekly exercise performed outside of study aerobic training sessions 
since study enrollment. At the follow-up visit, participants will be asked to report the average 
weekly exercise performed outside of study aerobic training sessions over the past 8 weeks 
since the midpoint assessment. 

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Approval date: 07-Nov-2017 
 
 
 
 
At the investigators discretion, patients may be required to repeat any of the above 
assessments. 

 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-147 A(9) 
Approval date: 07-Nov-2017 
 
 
Table 2. Schedule of Activities 
Training begins 
at Week 1 
 
Treatment Period (16 weeks) 
Training ends at 
Week 17 
 
Study Period or Visit 
Study Week 
Window (Weeks) 
Screening 
Baseline 
Pre- 
Treatment 
Monthly 
Follow-up 
Midpoint 
Assessment 
Monthly Follow- 
up 
Study FU 
NA 
-30 days7 
-2 to -1 
4 
8 
12 
17 
NA 
NA 
±1 
±1 
±1 
±1 
±2 
General Activities1 
Informed Consent 
X 
Medical History 
X 
Height, Weight, BMI 
X 
X 
X 
Vital Signs 
X 
X 
Performance Status (ECOG)2 
X 
Concomitant Medications 
X 
Randomization3 
X 
Study-Related End Points 
Cardiopulmonary exercise test (CPET)4 
X 
X5 
X 
Resting 3D Echocardiogram 
X 
X 
Post-exercise 2D Echocardiogram 
X 
X 
Pulmonary function 
X 
X 
Body composition (DEXA) 
X 
X 
Regional arterial stiffness 
X 
X 
Flow-mediated dilatation (FMD) 
X 
X 
Godin Leisure-Time Exercise Questionnaire (GLTEQ) 
X 
X 
X 
Patient-reported outcomes (Lifestyle Questionnaire) 
X 
X 
Complete Blood Count (CBC) 
X 
X 
X 
X 
X 
Lipid Panel & Fasting Glucose 
X 
X 
Aerobic Training6 
X 
X 
X 
Research Blood draw 
X 
X 
X 
X 
X 
 
[1] 
Testing slots/procedures availability must be taken into consideration when scheduling study follow -up visits. Visits may be split across the window to permit for 
completion of all study-related assessments. 
[2] 
Performance status by Eastern Cooperative Oncology Group (ECOG) scoring. 
[3] 
Randomization should be performed on or up to 2 weeks prior to Day 1, but only after eligibility is confirmed. 
[4] 
All potential participants will perform a second CPET at baseline within 30 days of registration to account for the presence of significant, and potentially clinically 
important, variability in CPET procedures (VO2peak measurement). 
[5] 
CPET at Week 8 is only for those randomized to Arm B. 
[6] 
Arms A and B only[7] 
Baseline assessments to be completed within 30 days of registration. 
 
 
 
 
Page 21 of 39 

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Page 22 of 39 
 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicity grading will be performed in accordance with NCI CTCAE, v 4.03. Adverse clinical 
symptoms that occur during or immediately following intervention sessions — with the 
exception of the expected heart rate, blood pressure, and SpO2 changes that are related to 
exercise — will be reported as adverse events. Adverse events will be reviewed by the 
exercise physiologist, and graded and attributed accordingly at the end of each session. 
Adverse events that are not resolved at the end of a session will be reviewed with the patient 
during the next scheduled session to assess whether or not the event is still ongoing. During 
the intervention phase, adverse events requiring adjustments to the two study aerobic 
training prescription approaches will be made according to the Ex-Onc Exercise Physiology 
standards of care and/or at the discretion of the Program Director. 
11.1 Side Effects 
 
Anticipated (expected) side-effects associated with a symptom-limited CPET, the two aerobic 
training doses, or progressive stretching include: 
• 
Fatigue 
• 
Myalgia 
• 
Arthralgia 
• 
Back pain 
• 
Shortness of breath (dyspnea) 
 
Unanticipated but possible side-effects that are rare, but serious include: 
• 
Cardiovascular: angina, hypotension, palpitations, rebound hypertension, syncope 
• 
Arrhythmias 
• 
Heart attack 
• 
Stroke 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 
Primary Study End Point 
 
Exercise Capacity (VO2peak): As described in Table 1, VO2pe ak  will be evaluated using an 
electronic motorized treadmill CPET test with 12-lead ECG monitoring (Mac ® 5000, GE 
Healthcare). 
 
Due to the presence of significant, and potentially clinically important, variability in CPET 
procedures (VO2peak measurement), all potential participants will perform a second CPET at 
baseline to account for potential learning effects and variability.35  If both the first and second 
CPET achieve acceptable test criteria, results of the second test will be used in all protocol 
procedures and statistical analyses. 
 
12.2 
Secondary Study End Points 
• 
Resting left ventricular function by 3-dimensional echocardiography (3DE): Three- 
dimensional transthoracic echocardiograms will be performed by experienced 
sonographers and acquired as outlined in Section 8, Table 1. 

Memorial Sloan Kettering Cancer Center 
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Page 23 of 39 
 
 
 
 
 
 
 
• 
Pulmonary Function will be determined using standard spirometry. All measures will be 
performed in a sitting position according to the American Thoracic Society guidelines.36 
 
• 
Post-exercise VO2peak: Post-exercise VO2peak  and left ventricular ejection fraction (LVEF) 
will be assessed via 2-D echocardiography. Images will be obtained as described in 
Section 8, Table 1. 
 
• 
Regional Arterial Stiffness: Assessment of arterial stiffness will be completed as 
described in Section 8, Table 1. 
 
• 
Flow-mediated dilatation (FMD): Endothelial function will be evaluated by peripheral 
artery flow-mediated dilatation. FMD will be performed on the left arm, as described in 
Section 8, Table 1. 
 
• 
Body Composition: Body composition, including body fat percentage, fat mass, and lean 
body mass, will be assessed by DEXA using the methods described in Section 8, Table 
1. 
 
• 
Patient-Reported Outcomes: Patient-reported outcomes will be assessed using a patient- 
administered Lifestyle Questionnaire (see Appendix A) to assess quality of life, fatigue, 
pain, and sleep quality. 
 
o Quality of Life (QOL) will be assessed by the Functional Assessment of Cancer 
Therapy–Breast (FACT-B) (version 4) scale. The FACT-B contains 37-items, 
divided into four primary subscales for physical well-being (7 items), functional 
well-being (7 items), emotional well-being (6 items), and social/family well-being  
(7 items) that comprise the FACT–General (FACT-G) scale, in addition to a breast 
cancer subscale (10 items). The five subscales will be summed to obtain the 
FACT-B score (for a total score of 148).38 We will also compute the FACT-G score 
(27 items, excluding the breast cancer subscale; total score of 108). All items are 
rated on a 0 to 4 Likert scale, using the following response format: 0 = not at all; 1 
= a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much. Respondents are asked 
to respond to each question as it applies to the past 7 days. Higher scores on the 
FACT-B indicate higher QOL. Internal consistency for the FACT-G and FACT-B is 
well established. 
 
o Fatigue will be assessed using the 13-item FACIT-Fatigue scale for the 
assessment of fatigue in cancer patients.
39  Items are scored on a 0 to 4 Likert 
scale, as follows: 0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = 
very much. Respondents are asked to respond to each question as it applies to 
the past 7 days. Higher scores on the FACT-fatigue indicate better quality of life. 
Internal consistency for the FACIT-Fatigue is well established.39 

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Page 24 of 39 
 
 
 
 
o Pain will be assessed using the 10-item Brief Pain Inventory (BPI) which was 
designed to measure multiple clinically relevant aspects of pain such as pain 
intensity and interference from pain in cancer populations.40  The BPI assesses for 
the presence of pain, pain intensity (i.e., worse, least, average, current) and 
functional interference from pain (i.e., activity, mood, walking ability, normal work, 
relations with others, sleep, and life enjoyment). It also catalogues the types of 
pain medications being used, and the percentage of pain relief obtained from 
medications. 
 
The BPI uses a mixture of item types. Items 1-3 querying about the presence of 
pain is a dichotomous ―yes‖, ―no‖. Items 4-7 (intensity items) utilize a 0 (no pain)  
to 10 (pain as bad as you can imagine) 11-point rating scale. Item 8 (percentage 
of pain relief) ranges from 0% (no relief) to 100% (complete relief). Item 9 inquires 
about the effectiveness of pain medication (as appropriate). Item 10 (a-g) inquires 
about interference using an 11-point numeric rating scale. Each item ranges 
between 0 (does not interfere) to 10 (completely interferes). Respondents are 
asked to respond to each question as it applies to the past 7 days. While some of 
the items represent single item values, pain intensity, indexed by the ―Pain 
Severity Score‖ is calculated by obtaining the mean of the 4 pain intensity items. 
The Pain Interference Score is obtained by calculating the mean of the 7 
interference items. The ―Pain Severity Score‖ has a maximum value of 10 (i.e., 
―pain as bad as you can imagine‖ and a minimum value of 0 (i.e., ―No pain‖). The 
Pain Interference Scale similarly has a maximum value of 10 (i.e., ―Completely 
Interferes‖) to 0 (i.e., ―Does not Interfere‖). Internal consistency for the Pain 
Severity Score and for the Interference scale has been reported as being 0.85 
and 0.88 respectively.40 
 
o Sleep Quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI).41  
The PSQI assesses sleep disturbance over the past month. The PSQI is a 9-item 
self-report questionnaire. The PSQI uses a mixture of item types. Items 1-4 are 
open-ended questions that query about sleep habits. All remaining items are 
scored on a 4-point Likert scale which range from 0 (not during the past month) to 
3 (3 or more times a week). The items produce seven component scores: sleep 
duration, sleep disturbance, sleep latency, daytime disturbance, habitual sleep 
efficiency, sleep quality, and use of sleep medications. The sum of these 
component scores yields a measure of global sleep quality which ranges from 0 to 
21. Reliability measures indicate that the PSQI generally has acceptable internal 
consistency (α = .80 to .85) and test-retest reliability (r = .85 to .87).41 
 
o Physical Functioning will be assessed using the physical functioning subscale 
(PF) of the Short-Form (SF) 36.42 The physical functioning subscale is a 6-item 
self-report questionnaire.  The PF uses a mixture of item types. Item 1 queries 
about overall health, scored on a 5-point scale ranging from excellent to poor. 
Item 2 queries about limitations to normal activities of daily living including 
participation in vigorous and moderate activities. All items are rated on a 3-point 

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Approval date: 07-Nov-2017 
Page 25 of 39 
 
 
 
 
Likert scale from ―yes, limited a lot‖ to ―no, not limited at all‖. Item 3 queries about 
limitations relating to work over the past 4 weeks using a dichotomized response 
(yes vs. no). Item 4 queries about bodily pain over the past 4 weeks ranging from 
―none‖ to ―extremely‖. Item 5 queries about pain during the normal work week 
ranging from ―not at all‖ to ―extremely‖. Finally, item 6 asks four statements about 
general health perceptions scored on 5-point Likert scale ranging from ―definitely 
true‖ to ―definitely false‖. The sum of item 2 yields a measure of physical 
functioning ranging from 0 to 20. Other items will be considered and summed as 
single items. Higher scores indicate higher physical functioning. The SF-36 has 
well established internal consistency and test-retest reliability.42 
 
Safety will be evaluated by the type and prevalence of adverse events during study- 
related assessments as well as aerobic training and progressive stretching sessions. The 
type and nature of SAEs considered in this trial include unanticipated but possible 
adverse events associated with exercise testing or aerobic training . 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
The primary reasons for permanent intervention discontinuation are listed in Table 3. 
 
Table 3. Primary Reasons for Permanent Intervention Discontinuation 
 
Reason 
Description 
Self-withdrawal  (withdrawal of consent) 
Participants may permanently discontinue study intervention and 
withdraw from the study at any time for any reason. Following 
study intervention discontinuation, participants should have 
protocol-required follow-up assessments unless the participant 
specifically declines  further follow-up. 
Adverse event or intercurrent illness 
Any intolerable adverse event (associated or not associated with 
the study intervention) that cannot be ameliorated by 
the use of adequate medical intervention or that, in the 
opinion of the principal investigator, would lead to 
undue risk if study intervention were continued. 
Gross non-compliance with protocol 
(viol ation) 
The investigator may request permanent discontinuation of the 
study intervention in the event of lack of cooperation or complete 
noncompliance. 
Disease progression 
Study intervention will be discontinued upon histologically- 
confirmed diagnosis of invasi ve breast cancer or DCIS found 
during standard of care screening. 
Lost-to-foll ow-up 
Reasonable effort should be made to contact any pa rticipant lost 
to follow-up during the course of the study in order to complete 
study-related assessments and record outstanding data. 
Death 
N/A 

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14.1 
BIOSTATISTICS 
 
14.2 
Sample Size Calculation and Justification 
 
The power of both an overall F-test comparison for the study‘s primary outcome variable, 
exercise capacity (VO2peak), among study arms is considered as part of power calculations, 
as well as two primary pairwise comparisons (i.e., Arm A versus Arm B; Arm B versus Arm 
C). The power of pairwise comparisons is computed with adjustment for multiple 
comparisons using a Bonferroni correction factor (=0.05/2 = 0.025). The comparison of Arm 
A vs. Arm C is also of interest but is not a primary pairwise comparison. 
The power estimates were calculated using the following observed/expected change in 
VO2peak  from baseline to Week 17: 
• 
Arm A: +1.5 mL.kg.-1min-1 
• 
Arm B: +4.0 mL.kg.-1min-1 
• 
Arm C: 0.0 mL.kg.-1min-1 
 
Power estimates assume the SD for the change in VO2peak  to be equal for all these groups 
(4.0 mL.kg.-1min-1) obtained from our prior work among post therapy breast cancer 
patients.11,12  In accordance to the principles of intention-to-treat, 174 patients will have 
evaluable post-intervention follow-up providing >99% power to detect the noted difference 
among the three experimental groups with an F-test conducted with two degree of freedom. 
With 58 patients per group having evaluable post-intervention follow-up, there is 86% power 
to detect a 2.5 mL.kg.
-1min
-1 difference in VO 2peak between Arms A and B; and >99% power to 
detect a 4.0 mL.kg.-1min-1 difference in VO2pe ak  between Arm B and Arm C  using a two-sided 
alpha of 0.025. 
 
A final important consideration when conducting exercise RCTs is extent of exercise ‗drop-in‘ 
or contamination in Arm C. In other words, the concern is that patients assigned to attention- 
control may independently initiate an exercise training program which, in turn, potentially 
dilutes the efficacy of aerobic training on the outcomes of interest. However, we feel this is 
less of a concern in the present study because patients in the aerobic training arms (Arm A 
and B) will be provided with a personalized exercise prescription. which will be difficult to 
replicate without sophisticated prescription algorithms and expertise. In addition, attention 
control participants are also provided with a supervised attention intervention. 
Nevertheless, we will carefully monitor the amount of exercise performed outside of the study 
in both aerobic training arms as well as the attention control group using subjective methods 
described in other sections of this protocol. 
14.3 
Primary and Secondary End Point Analyses 
 
14.3.1 Primary End Point Analysis: The primary objective will be to compare the 
effects of supervised linear aerobic training (Arm A) versus supervised nonlinear 
aerobic training (Arm B), relative to progressive stretching (attention-control group) 
(Arm C), on VO2peak  in women with operable breast cancer following the completion of 
primary adjuvant therapy. 

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An intent-to-treat statistical analysis will be conducted. Baseline characteristics will be 
compared using the Fisher exact test for categorical variables or a Wilcoxon rank sum 
test for continuous variables. The primary end point comparison will be analyzed 
using a multiple regression model to test for differences among and between the  
study arms in VO2peak  from baseline to the follow-up assessment (Week 17). The 
regression model will include the stratification factors [i.e., treatment with 
chemotherapy (yes vs. no) and current treatment with endocrine therapy (yes vs. no)]. 
 
In the absence of evidence to the contrary, multiple imputation strategies for missing 
Week 17 VO2peak  data will be performed assuming data were missing at random using 
logistic regression. Results will be aggregated over 20 imputed sets using the 
variance formula by Rubin. In addition, a per-protocol analysis will be performed  
using a multiple regression model to test for differences among and between the  
study arms in VO2peak  from baseline to the follow-up assessment (Week 17) on the 
basis of exercise adherence to the supervised aerobic training sessions (<80% 
versus ≥80%). In the event that groups are unbalanced on medical or demographic 
characteristics at baseline, we will also perform a sensitivity analysis that includes 
these factors in the model. 
14.3.2 Secondary End Point Analyses: As for the primary end point, the intention- 
to-treat principle will be employed for analysis of all secondary end points. Multiple 
regression models will be used to test for differences among and between the study 
arms in secondary end points from baseline to the follow-up assessment (Week 17). 
The regression model will include the baseline value of the end point, as well as any 
other baseline characteristics that are not balanced between groups. All secondary 
end points are continuous. 
In the absence of evidence to the contrary, multiple imputation strategies for missing 
Week 17 end point data will be performed assuming data were missing at random 
using logistic regression, as described above. Again, a per-protocol analysis will be 
performed using a multiple regression model to test for differences among and 
between the study arms in secondary end points from baseline to the follow-up 
assessment (Week 17) on the basis of exercise adherence to the supervised aerobic 
training sessions (<80% versus ≥80%). Finally, we will also perform a sensitivity 
analysis in the event that groups are unbalanced on medical or demographic 
characteristics at baseline. 

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15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming that the participant is eligible to enroll in the study. Study staff are responsible 
for ensuring that all institutional requirements necessary to enroll a participant to the study 
have been completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 
15.3 
Randomization 
 
Participants  will be randomly allocated, on an  individual basis, to one of  the three study 
groups. 
Randomly allocated participants will remain in the same group for the entire duration of the 
intervention (i.e., no cross-over). To ensure randomized groups are  similar  at  baseline, 
patient randomization will be stratified based on prior treatment with chemotherapy (yes vs. 
no) and current treatment with endocrine therapy (yes vs. no). Chemotherapy causes greater 
reductions in VO2peak relative to other types of cancer therapy (e.g., radiotherapy); thus, it is 
important for groups to be balanced on this factor. Similarly, current treatment with endocrine 
therapy is also expected to influence the effect of aerobic  training on VO 2peak and other 
endpoints; thus it is important to ensure that groups are also balanced on this variable. 
 
A permuted block design with allocation weight of 1:1:1 is used to generate the treatment 
assignments. Following the successful completion of all baseline assessments, Ex-Onc staff 
will enter randomization criteria into REDCap. Upon confirmation of stratification factors 
(chemotherapy treatment and/or endocrine treatment), REDCap will electronically randomize 
the patient. 
 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study, and will be under the close 
supervision of the Clinical Research Manager and Principal Investigator in Ex-Onc. The 
responsibilities of the RSA include project compliance; data collection, abstraction and entry; 
data reporting; regulatory monitoring; problem resolution and prioritization; and coordinating 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database (REDCap and 
CRDB). Source documentation will be available to support the computerized patient record. 
The principal investigator (Dr. Jones) will maintain ultimate responsibility for the clinical trial. 

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The study will be reported in accordance with the CONSORT (Consolidated Standards of 
Reporting Trials) statement for behavioral randomized trials; http://www.consort-  
statement.org/.50 
16.2 
Role of Duke University Medical Center (DUMC) 
The current trial is a single-site, phase II trial comparing the effects of a standard aerobic 
training prescription approach versus a novel aerobic training prescription approach in 
women with operable breast cancer following the completion of primary adjuvant therapy. 
However, this trial represents a continuing effort that was first initiated at DUMC 
approximately 5 years ago by the principal investigator, Dr. Jones. Prior to his appointment at 
MSK in February 2014, Dr. Jones was a principal investigator at DUMC. During his tenure 
there, Dr. Jones secured a 5-year R01 grant from the National Cancer Institute to conduct  
the present study. During trial conduct, Dr. Jones accepted a position at MSK and hence the 
protocol was closed to accrual. Participants ‗on trial‘ completed all study-related procedures 
but the study was closed to new patient enrollment. 
IRB correspondence: All local IRB correspondence for DUMC that is initiated after the MSK 
protocol is open to accrual should be submitted to MSK. This includes but is not limited to 
approvals for amendments and continuing reviews as noted below. All other correspondence 
should be submitted to the local IRB according to local guidelines. 
 
Amendments: Each change to the protocol document must be organized and documented 
by MSK and first approved by the MSK IRB/PB. Upon receipt of MSK IRB/PB approval, Ex- 
Onc research staff will immediately distribute all non-expedited amendments to DUMC for 
submission to the local IRB. 
 
DUMC must obtain approval for all non-expedited amendments from their IRB within 90 
calendar days of MSK IRB/PB approval. 
Continuing Review Approval: The Continuing Review Approval letter from the DUMC IRB 
and the most current, approved version of the informed consent form should be submitted to 
MSK within 7 days of expiration. 
 
Document maintenance: The MSK PI and the DUMC PI will maintain adequate and 
accurate records to enable the implementation of the protocol to be fully documented and the 
data to be subsequently verified. 
 
 
 
16.3 
Current Status 
As of September 2013, the trial status is as follows: The grant was released on 10/09/2009 
and the protocol received Institutional Review Board (IRB) approval from DUMC on 
03/25/2010. As of September 2013, a total of 115 patients (of a planned 174 participants; 
66%) had been recruited and randomized. Of these, 106 patients (92%) successfully 
completed study procedures, with 9 patients lost-to-follow-up (8%). The mean adherence 
rate was 77% across Arms A and B, with minimal adverse events, suggesting that all 
intervention sessions were well-tolerated. 

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Additional details are available. Overall, we were pleased with the study progress at the time 
of trial suspension and patient self-reports of the benefits of the trial. 
 
16.4 
Proposed Plan at MSK 
Following successful transition of the PI from DUMC to MSK (and establishment of a close 
collaborative relationship with the Breast Medicine Service under the  leadership  of  Dr. 
Clifford Hudis), the goal of this continuation trial is to complete study accural as planned (i.e., 
accrual of the remaining 59 patients). Based on the recruitment rate prior to trial suspension 
at DUMC (~3.4 patients/month) and the number of patients who would potentially be eligible 
for the study at MSK, we estimate that study accrual will complete within ~17 months. 
 
16.5 
Data Management 
All prior data collected on this protocol is securely stored and managed in a REDCap 
database system at DUMC under the stewardship of Pamela Douglas, MD and James E. 
Herndon, II, PhD. Although the trial has been closed to enrollment at DUMC, it remains open 
in the DUMC IRB to permit future medical chart data abstraction; Dr. Pamela Douglas is the 
acting PI at DUMC. 
 
Given that this trial was developed and initiated at DUMC, we propose that DUMC remains 
the data management and statistical center for this trial under the direction of James E. 
Herndon, II, PhD (trial biostatistician). Specifically, all study-related procedures and data 
collected here at MSK will be entered into two systems: (1) a REDCap database on the MSK 
server, and (2) REDCap software at DUMC. 
 
REDCap software is a tool that does not require client local software and can be accessed 
from anywhere on the Internet. The program is secured on a Duke Health Technology 
Services (DHTS) server. This database will be developed, and maintenance performed, with 
support of the School of Medicine (SOM) Duke Office of Clinical Research (DOCR). SOM‘s 
DOCR has partnered with the School of Medicine (SOM) to implement REDCap (developed 
by Vanderbilt‘s CTSA and currently used and supported by more than 1000 consortium 
partners). REDCap provides: 1) a stream-lined process for rapidly building a database; 2) an 
intuitive interface for collecting data (with data validation and audit trail); 3) automated export 
procedures for seamless data downloads to common statistical packages (SAS, SPSS, etc.); 
4) branching logic, file uploading, and calculated fields; and 5) a quick and easy protocol set- 
up. 
 
REDCap accounts are stored within the DTMI LDAP server hosted by the Duke Office of 
Information Technology (O IT). Authentication occurs via the OIT implementation of Kerberos. 
All connections to the system, both external and internal, occur over encrypted channels. 
Access to components of the system is role-based and can only be granted by administrators 
of the system. All collected information is stored on a standalone database server hosted by 
Duke Health Technology Services (DHTS). The database server resides behind the DHTS 
internal firewall and access to the server is controlled via firewall rules. 

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All collected data is backed up daily, both on the local server and by the DHTS enterprise 
backup system. Cory Ennis (919-668-8284) is responsible for managing the server for 
REDCap. Ceci Chamorro, in the Duke Office of Clinical Research (919-668-9262), is 
responsible for managing the database platform for REDCap. At the time of this submission, 
REDCap is on version 5.0.20. 
 
Server location: Fitz-East Data Center (Fitzpatrick); the directory is: /var/lib/mysql_backup/ 
Server support: Cory Ennis, DOCR – DHTS hosts servers (919-668-8284;  
cory.ennis@duke.edu) 
 
Operational support: Ceci Chamorro, DOCR (919-668-9262; ceci.chamorro@duke.edu) 
 
Of importance, staff entering MSK participant-related data from the Ex-Onc at MSK will not 
be able to view or manipulate data pertaining to DUMC participants already entered into the 
REDCap database. Similarly, only James E. Herndon, II, PhD and Samantha Thomas, MS 
(trial statisticians) will have access to MSK patient data. 
 
The consent form contains language explaining that basic MSK participant information can 
only be accessed by specific individuals at DUMC. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness  
of registration data. Routine data quality reports will be generated to assess missing data  
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, or more frequently, as appropriate. 
16.2 
Data and Safety Monitoring 
 
This protocol describes a trial which is currently registered on ClinicalTrials.gov. 
 
The Data and Safety Monitoring (DSM) Plans at MSK were approved by the National Cancer 
Institute in September 2001. The plans address the new policies set forth by the NCI in the 
document entitled ―Policy of the National Cancer Institute for Data and Safety Monitoring of 
Clinical Trials‖ which can be found at: http://www.cancer.gov/clinicaltrials/patientsafety/dsm -  
guidelines/page1. 
 
The DSM Plans at MSK were established and are monitored by the Office of Clinical 
Research. The MSK Data and Safety Monitoring Plans can be found on the MSK Intranet at:  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%   
20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 

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education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center‘s Research Council and Institutional Review Board. During 
the protocol development and review process, each protocol will be assessed for its level or 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each participant, the risks, benefits and objectives of the study will 
be reviewed with the participant, including a discussion of the possible toxicities and side 
effects. Alternative, non-protocol, treatment options will be discussed with the participant. It 
will be reviewed that participation in this clinical trial is voluntary and that the participant may 
withdraw consent at any time. The study is designed with careful safety monitoring for 
toxicity, including physician visits and serial cardiac monitoring. Specific guidelines for 
symptom management are in place to protect the study participant. 
 
This protocol establishes operational guidance based on current ethical and legal standards 
for the procurement and banking of human biologic specimens for use in future biomedical 
research. The protocol includes an informed consent document and research authorization 
that meets statutory guidelines. They inform participants of the purpose of the bank, their 
rights in relation to it, and the safeguards in place to protect the confidentiality of their health 
information. 
 
Consent process: All patients at MSK who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All participants will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. The informed consent procedure is 
described in Section 18.0. 
 
Potential Risks: Our eligibility criteria and screening procedures are established to exclude 
individuals for whom graded exercise testing, blood collection, and supervised moderate- 
intensity aerobic training are not appropriate. Our screening procedures begin with medical 
chart review to identify individuals with any condition or reasons that may prohibit study 
entry, followed by oncologist approval to screen/identify patients who may not be eligible for 
any additional reasons. Finally, in-person assessments will be performed to screen/identify 
patients for cardiovascular or ECG contraindications on a symptom-limited graded exercise 
test (CPET). This multi-gated comprehensive approach should systematically identify and 
screen out any individual for whom this study is contraindicated. The risks associated with 
trial participation are described in detail in Section 11. 
 
Cardiopulmonary Exercise Testing (CPET) — Graded exercise testing carries a finite risk of 
adverse cardiovascular event with <1/100,000 in well individuals and 1/10,000 in clinical 
populations. 

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Blood Collection  — There  are some minor risks  associated with a  blood draw,  such as 
bruising and/or discomfort; however, this procedure is considered to be of minimal risk. 
 
Supervised Aerobic Training — Similar to graded exercise testing, aerobic training carries a 
finite risk of an adverse cardiovascular event. Under our laboratory conditions, we have not 
experienced any serious adverse events in five years of aerobic training across literally 
hundreds of cancer patients and 1,000+ hours of training. Further, all participants would have 
undergone a full ECG, graded exercise test prior to aerobic training, and all sessions will be 
supervised by a exercise physiologist. 
 
Dual Energy X-ray Absorptiometry (DEXA) — A DEXA carries the risk of radiation exposure; 
the average full-body dose of radiation is 1 to 3 mrad per DEXA scan. In this study, two 
DEXA scans will be completed for each patient enrolled, and the total average full-body dose 
of radiation per patient is 3 to 9 mrad over the course of the study. Although very rare, a 
potential health risk associated with DEXA is subsequent induction of cancer. 
 
There are no known risks to undergoing the other study-related assessments in this trial. 
 
Risks of research participation: The greatest risk is release of information from health or 
research records in a way that violates privacy rights. MSK will protect records so that name, 
address, phone number, and any other information that identifies the participant will be kept 
private. It will be stated to the participant that the chance that this information will be given to 
an unauthorized individual without the participant‘s permission is very small. 
 
Benefits: A behavioral treatment strategy, such as aerobic training in women with operable 
breast cancer who have exercise intolerance due to the direct and secondary effects of 
adjuvant therapy, may improve these outcomes. 
 
It is unlikely that the research using collected biospecimens will be of any medical benefit to 
participants. Neither the patient nor the treating physician will be told the specific results of 
any research tests on the samples; except in the case of an uncovered incidental finding 
which may be critical to the preventive care of the participant or their family. Research using 
blood or tissues in this study could lead to medical and scientific products that could improve 
prevention, diagnosis and treatment of disease. 
 
Costs/compensation: Participants will be charged for physician visits, routine laboratory 
tests, and radiologic studies required to monitor their condition. Participants will not be billed 
for any study-related procedures. The participant will be informed that there are no plans to 
provide financial compensation for use of their human biologic specimens, nor are there 
plans for the participant to receive money for any new products, tests, and discoveries that 
might come from this research. Nevertheless, all participants will be reimbursed (in the form 
of two $50 gift certificates) for completion of study procedures. The total amount participants 
may receive is $50 for the completion of the baseline assessment and $50 for completion of 
follow-up assessments (Week 17). A research study receipt will be used to document 

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participant reimbursement at each time point. A copy of the receipt will be kept in the 
participant‘s study file. 
 
Alternatives: The alternative to this trial would be not to participate in the study and receive 
routine standard of care. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patients‘ names and any other identifying information will 
not be used in reports or publications resulting from this study. Other authorized agencies 
and appropriate internal personnel (e.g., qualified monitors from MSK) and external 
personnel, its authorized agents, the FDA, and/or other governmental agencies may review 
patient records as required. 
 
Patient safety: Participants are monitored by physicians, oncology nurses, and exercise 
physiologists who are very familiar with clinical trials. In the case of an adverse reaction, 
immediate medical attention is available. In the evenings and on weekends, we have a 24- 
hour urgent care facility for outpatients. 
Voluntariness of research participation: It is stated that taking part in this study is 
voluntary and patients have the right to withdraw at any time. Participation in the study will 
not impact the clinical care patients receive. 
 
Withdrawal: Participants may decide at a later date that they do not want identified blood 
and/or tissue samples to be stored for future research. If participants decide to withdraw from 
the study, specimens will not be used in new studies and any remaining portions of samples 
that have not been used for research will be used only for clinical purposes or, if requested  
by the participant, destroyed. When a participant withdraws from protocol, OCR/PPR should 
be notified immediately. The withdrawal request will be documented in CRDB and the system 
updated accordingly. In addition, a note documenting the participant‘s withdrawal must be 
filed in his/her EMR. 
 
 
 
17.2 
Privacy 
 
MSK‘s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 

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• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required 
for 30-days after the participant‘s last investigational treatment or intervention. Any events 
that occur after the 30-day period and that are at least possibly related to protocol treatment 
must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‗Reporting of Serious 
Adverse Events‘, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org.  All other 
reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‘s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 

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o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‘s signature and the date it was signed are required on the completed report. 
 
 
 
17.2.1 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study, including available standard and investigational 
therapies. Additionally, participants will be offered an option of supportive care for 
therapeutic studies. 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all participants must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Balady GJ. Survival of the fittest--more evidence. N Engl J Med. Mar 14 2002;346(11):852- 
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20.0 
APPENDICES 
 
1. Appendix A: Lifestyle Questionnaire 
2. Appendix B: Introduction Letter 
3. Appendix C: Welcome Letter 
4. Appendix D: Study Timeline 
5. Appendix E: Borg Rating Scales for Perceived Exertion, Dyspnea, and Leg Fatigue 
6. Appendix F: Exercise Session Information 
7. Appendix H: Exercise Physiology Guidelines