Lung Cancer Exercise Training Study: A Randomized Trial of Aerobic Training, Resistance Training, or Both in Lung Cancer Patients
Phase: NA
Conditions: Lung Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 1 of 48
 
 
 
Lung Cancer Exercise Training Study: A Randomized Trial of Aerobic Training, Resistance 
Training, or Both in Lung Cancer Patients 
 
PROTOCOL FACE PAGE FOR 
MSK THE RAPEUTIC/D !AGNOSTIC PROTOCOL 
I 
Principal Investigator/Department:
Lee Jones, PhD
Medicine/Exercise Oncology
Co-Principal
Investigator( s)/Department: 
Valerie Rusch, MD
James Huang, MD 
Jamie E. Chatt, MD 
Surgery/Thoracic
Surgery/Thoracic 
Medicine/Thoracic Oncology
Investigator( s)/Department:
Charles M. Rudin, MD, PhD
Alexander Drilon, MD 
Mark G. Kris, MD 
Piro Lito, MD, PhD 
Paul K. Paik, MD 
Gregory J. Riely, MD, PhD 
Stephen R. Veach, MD 
Helena A. Yu, MD 
Matthew Hellmann, MD 
Bob Li, MD 
Marjorie G. Zauderer, MD 
Medicine/Thoracic Oncology
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology
 
Prasad S. Adusumilli, MD 
Manjit S. Bains, MD 
Robert J. Downey, MD 
David R. Jones, MD 
Bernard J. Park, MD 
Nabil Pierre Rizk, MD 
Matthew Bott, MD 
James Isbell, MD 
Daniela Molena, MD 
Smita Sihag, MD 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
Surgery/Thoracic 
 
Alison Berkowitz-Hergianto, NP 
Dyana Katherine Sumner, NP 
Stacie Corcoran, NP 
Elizabeth Panora, NP 
Leslie Tyson, NP 
Amy Devigne, NP 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
 
Nicholas VanderEls, MD 
Mohit Chawla, MD 
Medicine/Pulmonary 
Medicine/Pulmonary 
 
Annemarie Shepherd, MD 
Andreas Rimner, MD 
Abraham Wu, MD 
John Cuaron, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 2 of 48
 
 
 
 
 
Richard M. Steingart, MD 
Carol L. Chen, MD 
Michael S. Baum, MD 
Dipti Gupta, MD, MPH 
Michelle N. Johnson, MD, MPH 
Jennifer Liu, MD 
Eileen P. McAleer, MD 
Nancy Roistacher, MD 
Wendy Schaffer, MD, PhD 
Howard Weinstein, MD 
Anthony Yu, MD 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Medicine/Cardiology 
Jessica Scott, PhD 
Meghan Michalski 
Daniel Townend, BS 
Catherine Capaci, MS 
Kereshmeh Collins, BS 
Richard Happel, MS 
Kylie Rowed, MKin 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology
Jonathan Landa, DO 
Radiology 
Consenting Professional(s)/Department:
Lee Jones, PhD
Jessica Scott, PhD 
Jamie E. Chaft, MD 
Charles M. Rudin, MD, PhD 
Alexander Drilon, MD 
Mark G. Kris, MD 
Medicine/Exercise Oncology
Medicine/Exercise Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology
 
Piro Lita, MD, PhD 
Paul K. Paik, MD 
Gregory J. Riely, MD, PhD 
Stephen R. Veach, MD 
Helena A. Yu, MD 
Marjorie G. Zauderer, MD 
Matthew Hellmann, MD 
Bob Li, MD 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology 
Medicine/Thoracic Oncology
 
Annemarie Shepherd, MD 
Andreas Rimner, MD 
Abraham Wu, MD 
John Cuaron, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
Meghan Michalski, MS 
Daniel Townend, BS 
Catherine Capaci, MS 
Kereshmeh Collins, BS 
Richard Happel, MS 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology 
Medicine/Exercise Oncology
Medicine/Exercise Oncology

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 3 of 48
 
 
Medicine/Exercise OncologIy 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
Participating Institutions - If multicenter
study coordinated by MSK: 
Pl's Name
Site's Role
Duke University
Pamela S. Douglas, MD
Data Analysis
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Kylie Rowed, MKin
 
 
 
 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 4 of 48
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 6 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 9 
4.1 
Design ............................................................................................................................. 9 
4.2 
Intervention ...................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 10 
6.1 
Subject Inclusion Criteria ................................................................................................ 10 
6.2 
Subject Exclusion Criteria .............................................................................................. 11 
7.0 
RECRUITMENT PLAN ...................................................................................................... 11 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 17 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 22 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................... 28 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 29 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 26 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 33 
14.0 
BIOSTATISTICS ............................................................................................................... 35 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 36 
15.1 Research Participant Registration .................................................................................. 36 
15.2 Randomization ............................................................................................................... 36 
16.0 
DATA MANAGEMENT ISSUES ....................................................................................... 37 
16.1 Quality Assurance .......................................................................................................... 40 
16.2 Data and Safety Monitoring ............................................................................................ 40 
17.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................... 41 
17.1 Privacy ........................................................................................................................... 43 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................ 43 
18.0 INFORMED CONSENT PROCEDURES ........................................................................... 44 
19.0 
REFERENCES .................................................................................................................. 45 
20.0 
APPENDICES ................................................................................................................... 48 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 5 of 48
 
 
 
Primary Objective: To compare the efficacy of different types of exercise training 
modalities, relative to progressive stretching (attention control group), on exercise capacity 
(V02peak) in patients with lung cancer. 
Design: Patients with Memorial Sloan Kettering Cancer Center (MSK) histologically- 
confirmed lung cancer will be randomized to one of the following four arms: Arm A: 
supervised aerobic training; Arm B: supervised resistance training; Arm C: supervised 
combined aerobic and resistance training; and Arm D: stretching (attention control group). 
The goal of this RCT is to recruit a total of 160 patients with histologically-confirmed lung 
cancer at any stage or receiving any type of therapy. A total of 40 per arm patients will be 
randomized in a 1:1:1:1 ratio to the four study arms. 
This RCT was initially initiated and conducted at Duke University Medical Center (DUMC) 
by the principal investigator (Lee Jones, PhD). The trial was suspended at DUMC 
(protocol-independent) due to change of the Pl's institution (Dr. Jones is now at MSK). At 
the time of trial suspension, a total of 93 participants had been randomly allocated to the 
four study arms: Arm A supervised aerobic training (n=24), Arm B: supervised resistance 
training (n=23), Arm C: supervised combined aerobic and resistance training (n=24), and 
Arm D: progressive stretching (attention control group) (n=22) 
At MSK, patients will be enrolled and randomized until target enrollment is met (67 
patients in total at MSK): Arm A: supervised aerobic training (n=16), Arm B: supervised 
resistance training (n=17), Arm C: supervised combined aerobic and resistance training 
(n=16), and Arm D: progressive stretching (attention control group) (n=18); At the end of 
the trial, data will be analyzed for the pre-planned sample size (n=160). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Page 6 of 48
 
Approv  date: 31-0ct-2017 
 
 
Figure 1. Study Schematic for MSK Recruitment 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary Objective 
To compare the efficacy of different types of exercise training modalities, relative to progressive 
stretching (attention control group), on VO2peak in patients with advanced lung cancer or a history 
of operable lung cancer. 
2.2 
Secondary Objectives 
 
• 
To compare the effects on one-repetition maximum 
• 
To compare the effects on resting and exercise cardiac function 
• 
To compare the effects on pulmonary function 
• 
To compare the effects on arterial stiffness 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
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-
 
 
• 
To compare the effects on endothelial function (Flow Mediated Dilation) 
• 
To compare the effects on body compasition 
• 
To compare the effects on functional measures of performance 
• 
To compare the effects on patient-reported outcomes (e.g., quality of life, fatigue), and 
• 
To collect and bank blood samples for future correlative studies. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Indication 
The intended indication for supervised exercise training is the treatment of impaired exercise 
capacity (i.e., global cardiovascular function) in patients with lung cancer. 
3.2 
Background and Rationale 
Improvements in surgical techniques, together with more effective cytotoxic therapies have led to 
improvements in overall survival (in patients with early-stage disease) and progression-free 
survival (in patients with advanced disease) . With improving prognosis, acute and longer-term 
disease- and treatment-related morbidity (symptom control) are now recognized as issues of 
major clinical importance in the multidisciplinary management of lung cancer.1 6 A parameter of 
central importance that may mediate acute and late-occurring disease and treatment-related 
toxicity in lung cancer is exercise capacity. Exercise capacity, as measured by an objective 
cardiopulmonary exercise test (CPET), reflects the integrative capacity of components in the 
oxygen (02) cascade to supply adequate 02 for adenosine triphosphate (ATP) resynthesis. Peak 
oxygen consumption (V02peak) provides the gold standard (direct) assessment of exercise 
capacity. Direct or estimated measurement of V02peak is a well-established independent predictor 
of mortality in a broad range of non-cancer, adult populations.7•8 
 
Not surprisingly, lung cancer patients have significant and marked reductions in V02peak• Lung 
cancer patients are subject to the effects of normal aging, age-related and/or disease-related 
comorbid conditions and deconditioning that adversely impact components of the 02 cascade. 
However, these 'normal' consequences are profoundly accelerated by disease pathophysiology 
and the use of conventional adjuvant therapy to create a 'perfect deconditioning storm', reducing 
either the body's ability to deliver and/or utilize 02 and substrate leading to poor V02peak·9 Such 
effects have important implications across the entire lung cancer continuum.10 
First, preoperative V02peak is a well-established risk stratification tool to determine perioperative 
and postoperative complication risk.11-14 Second, following resection, V02peak - 
as well as self- 
reported exercise behavior (a major determinant of V02peak) - are strong predictors of patient- 
reported outcomes (PR0s), such as overall Q0L, fatigue, and other Q0L domains.15 Finally, our 
group found that pre-operative V02peak is a strong independent predictor of overall survival in lung 
cancer surgical candidates, even when controlling for performance status, gender, and age.16 In 
totality, these data provide strong evidence that V02peak is an attractive modifiable therapeutic 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 8 of 48
 
•
 
 
target to improve surgical risk and/or recovery, symptom control and, possibly, disease outcome 
in lung cancer. 
Chronic, repeated aerobic training (i.e., continuous activity involving large muscle groups) is 
widely established as the most effective method to improve V02peak in healthy humans, although a 
paucity of studies have investigated the role of exercise in lung cancer.10 Given the preliminary 
nature of this field, we recently completed two uncontrolled pilot studies investigating the 
feasibility and preliminary efficacy of supervised aerobic training in the pre-operative and post- 
operative setting in lung cancer. Results of these pilot studies provided 'proof of principle' that 
aerobic training is a safe and feasible intervention for lung cancer patients; however, the 
improvements in V02peak were modest (<15%), particularly in the post-operative setting (~10%), 
despite good exercise attendance rates ( 70% of planned sessions).17 18 
The reasons for the relatively modest improvement in V02peak in lung cancer relative to other 
clinical populations (i.e., ~15%-20% improvement in V02peak following traditional aerobic training 
recommendations) remain to be elucidated. An obvious potential explanation is a ventilatory 
limitation or inadequate gas exchange following removal of a substantial portion of lung 
parenchyma. However, several elegant studies have demonstrated that V02peak is not limited by 
ventilation or diffusion capacity19-22, suggesting that exercise-induced adaptations (or lack thereof) 
in the other organ components of the 02 cascade are responsible. V02peak in lung cancer patients 
is likely principally governed by poor cardiovascular 02 delivery and oxidative capacity as 'vt€// as 
unfavorable fiber type distribution and muscle atrophy/weakness similar to the limitations to 
exercise described in patients with chronic obstructive pulmonary disease (COPD). Major 
contributors to skeletal muscle dysfunction in lung cancer likely include direct skeletal myopathy 
(from the use of oral corticosteroids), deconditioning (from physical inactivity), and high levels of 
systemic inflammation (from underlying disease and therapy).23 
Importantly, aerobic training will cause favorable adaptations in most 02 transport components but 
will not reverse skeletal muscle atrophy/weakness, and will only partially reverse a more glycolytic 
fiber type distribution. Thus, aerobic training alone may be insufficient to ameliorate skeletal 
muscle dysfunction likely to manifest in lung cancer. Standard resistance training (i.e., activity 
involving the acute exertion of force) performed according to standard guidelines (i.e., 2-5 
times/week, 50%-80% of one repetition maximum for 12-24 weeks) is unequivocally 
acknowledged as the most effective method to improve skeletal muscle function in human 
subjects.24-28 tvbreover, in severely deconditioned adults, resistance training causes 
improvements in V02peak29-
34
, although the mechanisms underlying this effect are not clearly 
understood. In theory, while aerobic and resistance training might independently improve V02peak 
in lung cancer, such improvements are likely to be modest (~10%). Instead, the combination of 
aerobic and resistance training may be the most effective form of exercise training to optimally 
augment V02peak• The complementary physiologic adaptations from the combination approach will 
result in higher cardiovascular 02 delivery, skeletal muscle oxidative phosphoryation, muscle 
strength, and optimal fiber type composition, leading to higher muscle endurance, reduced 
fatigability, a higher threshold to the metabolic waste products of exercise, and reduced 
ventilatory requirements during exercise. This approach is hypothesized to maximize physiologic 

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IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 9 of 48
 
 
 
adaptations in the principal factors underlying poor VO2peak in lung cancer patients more 
effectively than either exercise modality alone. 
Against this background, we designed the Lung Cancer gxerclse Iraining Study (LUNGEVITY), a 
randomized trial to investigate the efficacy of different types of exercise training in post-operative 
NSCLC patients. The protocol was amended in July 2017 to include patients with advanced 
(inoperable) lung cancer. The fundamental rationale for this multi-center trial is to identify the 
optimal type of exercise training to improve VO2peak in lung cancer patients and understand the 
physiologimechanisms underlying this effect. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is an open-label, multi-center, four-arm randomized controlled trial (RCT) to compare 
the effects of different exercise training modalities, relative to progressive stretching 
(attention control group), in patients with lung cancer. The primary endpoint is VO2peak, as 
measured by a symptom-limited CPET assessed at baseline and follow up (Week 17). 
Secondary outcome assessments include muscle strength, cardiac function, pulmonary 
function, arterial/ vascular function, body composition, functional capacity, and patient- 
reported outcomes. All study outcomes will be assessed at baseline and follow up. 
4.2 
Intervention 
As part of clinical trial participation, participants will undergo one of three training 
interventions - supervised aerobic training, supervised resistance training, or the 
combination. Exercise performed outside of the structured sessions (i.e., contamination) 
will be assessed via self-report of exercise behavior. We will encourage participants to 
maintain their level of exercise behavior prior to the initiation of the trial. 
Following the successful completion of baseline assessments, eligible participants will be 
randomly assigned to one of four study arms - 
patients will be enrolled until 40 patients 
have been assigned to each study arm. The exercise training conditions (Arms A, B, and 
C) will include three supervised exercise sessions per week at an intensity between 50% 
to 100% of the individually determined VO2peakfor aerobic training, and an intensity 
between 30% to 100% of one-repetition maximum for resistance training. 
At midpoint, some participants will perform a CPET as well as a 1RM test, in order to re- 
assess exercise capacity to re-prescribe aerobic training to ensure progressive 
cardiovascular adaptation across the entire intervention period. 
Participants assigned to the attention-control group will be provided with a progressive 
stretching program matched to the exercise interventions in terms of program length (16 
weeks), social interaction (all sessions will be one-on-one), sessions per week (3x/wk) and 
session duration (30-60 mins/session). 
4.3 
Future Use of Samples 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Page 10 of 48
 
Approv  date: 31-0ct-2017 
 
 
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 
attention-control, on blood-based biomarkers. Specific biomarkers of interest include 
metabolites and cytokine and angiogenic factors. Fasting plasma will be processed and 
banked at -80°C and stored at MSK. On a periodic basis, samples will be shipped to a 
biorepository facility, Kryosphere (dba KryoCal), for long-term banking. A material transfer 
agreement (MT A) 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. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
• 
Signed informed consent prior to initiation of study-related procedures 
• 
Age 21-80 
• 
Weight <205 kgs 
• 
ECOG 
1 
• 
Diagnosed with histologically confirmed lung cancer, regardless of disease stage 
and receiving any prior line of any therapy in the context of metastatic disease 
• 
An interval of at least three months following the completion of primary resection, if 
appropriate 
• 
An interval of no longer than ten years following completion of primary therapy, if 
appropriate 
• 
Life expectancy 4 months 
• 
Performing less than 150 minutes of structured moderate-intensity or strenuous- 
intensity exercise per week. 
• 
Exercise intolerance (i.e., patients must have a VO2reak below that predicted for 
active age and sex-matched individuals) 
• 
Willing to be randomized to one of the study arms 
• 
Willing to commit to the study program and comply with all related protocol 
procedures 
• 
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 
1.1O; 
o 
attainment of maximal predicted heart rate (HRmax) (i.e., within 10 bpm of 
age-predicted HRmax [HRmax = 220-Age[years]); 

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Approval date: 31-0ct-2017 
 
 
o 
volitional exhaustion, as measured by a rating of perceived exertion (RPE) 
18 on the BORG scale. 
• 
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 Pl. 
• 
Ability to achieve and complete an acceptable baseline one-repetition maximum 
muscular strength test as defined by the effective execution of protocol-specific 
joint and muscle ranges of motion without remarkable signs or symptoms of pain, 
discomfort or distress. 
6.2 
Subject Exclusion Criteria 
• 
Presence of a concurrent, actively treated other malignancy, or history of other 
malignancy treated within the past 3 years (other than non-melanoma skin cancer); 
• 
Room air desaturation at rest :5 85%; 
• 
Mental impairment leading to inability to cooperate. 
• 
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 (within 3 months) pulmonary embolus or pulmonary infarction; 
o Thrombosis of lower extremities; 
o 
Suspected dissecting aneurysm; 
o 
Uncontrolled asthma; 
o Pulmonary edema;Respiratory failure; 
o Acute non-cardiopulmonary disorders that may affect exercise performance 
or be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis) 
 
7.0 
RECRUITMENT PLAN 
Potential participants will be identified by a member of the patient's treatment team, the protocol 
investigator, or Exercise Oncology (ExOnc) personnel at 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 the potential for enrolling in the research study with eligible 
patients. Potential participants contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
Investigators and ExOnc 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 

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date: 31-0ct-2017 
Page 12 of 48
 
 
 
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 is found to be ineligible for the 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 subject will be conducted by the treatment 
team, investigator or the ExOnc 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 subjects; and (4) maintaining information in a 
screening log of patients approached (if applicable).. 
 
Three strategies will be employed for participant recruitment: 
 
Mail-Based Recruitment: ExOnc research staff will obtain a list of potential eligible patients 
from dataline that meet basic eligibility criteria. ExOnc research staff will contact the 
potentially eligible patient's primary attending physician to confirm the patient's current 
status, if they are an appropriate candidate, and seek approval to send the patient a mail- 
based introductory letter (see Appendix I and a copy of the consent form. The letter of 
introduction will be signed by both the protocol Pl and the patient's primary attending. 
Patients interested in trial participation will be directed to call or email the ExOnc office to 
ask any questions they may have, receive further instructions, and discuss next steps. 
Patients meeting all study requirements will be scheduled for a baseline protocol 
appointment where a consenting professional will obtain written informed consent. 
 
 
Patients not responding to the mailed letter of introduction will be sent a second mailing. 
Patients still not responding a few weeks after the second mailing will be contacted by 
telephone by ExOnc personnel (see Appendix G) 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. 
 
Clinic-Based Recruitment: Potentially eligible patients attending a scheduled clinical visit 
will be approached following the clinical visit with their primary attending. ExOnc research 
personnel will obtain primary attending approval prior to approaching any patient about 

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date: 31-0ct-2017 
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trial participation. This initial encounter will include a discussion of the proposed trial, 
proposed treatments and the rationale for its use. Patients may also be given a brochure at 
this visit with their oncologist as an introduction to the program. Interested participants will 
answer questions from the exercise behavior questionnaire to assess eligibility. Eligible 
patients interested in trial participation will have the opportunity to review and sign an 
informed consent during their clinic visit. 
 
Web-Based Recruitment: Potentially eligible patients attending a scheduled clinic visit with 
their primary attending oncologist may be approached via email following their visit. Ex 
One research staff will obtain primary attending oncologist approval prior or in conjunction 
with approaching any patient about trial participation. Potentially eligible patients will 
receive a recruitment email asking if they would be interested in participation (see 
Appendix F). Patients are able to contact Ex One staff via phone or email. Ex One 
research staff will be able to follow up from an initial email with a phone call to see if a 
patient would like to participate 
 
 
Following the initial consultation, interested participants will be contacted by telephone by 
members of the ExOnc team to schedule the baseline assessment visit. Patients will also receive 
a welcome packet (see Appendices C-E). 
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 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). 
Minorities and women are well-represented in the Thoracic DMT clinics, and we expect that they 
will be well represented in the trial accrual. 
Enrollment and study procedures are summarized in the following subsections. The timing of all 
study procedures is provided in the schedule of activities. 

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7.1 
Screening Period 
The screening period will take place within 4 weeks of Day 1, except where otherwise noted. 
Assessments not completed within the specified interval must be repeated. 
7.2 
Screening Identification Numbers 
Study site personnel will maintain a screening log for all potential study participants, and will 
assign a screening identification ( ID) number in consecutive order as listed on the screening log. 
The screening ID number will be used on all study forms and laboratory specimens throughout 
the study. 
A new screening ID number will be assigned to a patient who is rescreened after originally failing 
to meet study eligibility. 
For patients who provide informed consent and subsequently do not meet eligibility criteria, or 
withdraw consent, study site personnel will ensure that the source record includes appropriate 
documentation, such as eligibility criteria reviewed, protocol procedures performed, and reason 
for screen failure. 

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Approv  date: 31-0ct-2017 
 
 
7.3 
Study Procedures 
Table 1. Schedule of Activities 
 
 
 
Treatment Period (16 weeks\ 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] 
Testing slo1s/procedures availability must be taken into consideration when scheduling study follow-up visi1s. Visi1s may be split across the window to permit for 
Study Period or Visit
Screening
 
 
 
 
Study FU
Treatment
Traning
Window (Weeks) I
Study Week I
NA
NA
 
 
General Activities
1 
Informed Consent 
Medica History 
Height, Weight 
Vita Signs 
Performance Status (ECOG)' 
Concomitant Medications 
Randomization" 
Study-Related End Points 
Cardiopulmonary exercise test 
(CPET)4'5 
One repetition maximum 
(1RM)6 
Function performance 
measures 
Resting eft ventricu ar ejection 
fraction 
Pulmonary Function Test 
Post-exercise eft ventricu ar 
ejection fraction 
DEXA (body composition) 
Regional arterial stiffness 
Flow Mediated Dilation 
Patient-reported outcomes 
(lifestyle questionnaire) 
Training 
Complete Blood Count (CBC) 
 
X
I
I
Midpoint 
Assessmen 
t 
I 
8 
X
X
X
X
X
X
I
X
X
I
X
X
u
X
X
ri
Arms A and I
X
X
I Arms Band I  
X 
 
X
X
X
X
X 
X
]
X 
X
X 
X
X 
X
[
]
X 
X
X 
X
I
] 
X
I
I 
I
X 
X
I
I
...
I
I 
... 
X 
X
T

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Approval date: 31-0ct-2017 
 
 
completion of all study-related assessmen1s. 
[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] 
Must be assessed within 4 weeks of randomization to confirm eligibility. All potential participan1s will perform a second CPET at baseline to account for potential 
learning effec1s and variability to account for the presence of significant, and potentially clinically important, variability in CPET procedures (VO 2peakmeasurement), 
[5] 
CPET at midpoint is for patients randomized to Arms A and Conly. 
[6] 
One repetition maximum at midpoint is for patients randomized to Arms Band Conly. 

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7.4 
Blinding 
This study is open label. All patients and study exercise physiologists monitoring exercise training 
sessions will be unblinded to treatment allocation (due to the nature of aerobic training interventions, 
neither patients nor study personnel can be blinded to treatment allocation). Nevertheless, all study 
investigators will be blinded to intervention allocation. Only the trial statistician and the data 
monitoring committee will have access to unblinded data. 
7.5 
Study Duration 
The study should be accruing patients for around 24 months from the start of accrual. Patients will 
be followed for up to one year following the last patients last follow up appointment. 
 
8.0 
PRETREATMENT EVALUATION 
After obtaining written consent and GLTEQ, all participants will be scheduled for a baseline study 
assessment visit by a member of the ExOnc research team. Following appropriate scheduling 
procedures, at the study visit, the participant will complete the following assessments prior to 
randomization: 
1. Fasting blood draw 
2. Fasting, non-invasive measurement of regional arterial stiffness and flow mediated dilation 
3. Resting assessment of left ventricular function using echocardiography 
4. Symptom-limited cardiopulmonary exercise test with 12-lead electrocardiography (including 
pulmonary function testing) and post-exercise echocardiography 
5. Functional measures 
6. Body composition 
7. Patient-reported outcomes 
8. One repetition maximum 
 
The completion of these assessments will take approximately 3 to 4 hours and will be conducted in 
the ExOnc Integrative Physiology Laboratories at either: l\t1ain Campus (in Cardiology), the 
Rockefeller Outpatient Pavilion at 53rd Street, or the Sidney Kimmel Center for Prostate and Urologic 
Cancers. 
 
The DEXA scan will be performed at either the Breast and Imaging Center (BAIC) or the Rockefeller 
Outpatient Pavilion. 
 
In order to maximize internal validity of study endpoint accessments efforts will be made to ensure 
assessments at baseline, midpoint and follow-up are in the same order. 
 
 
All baseline study assessments are described in Table 2. 
Table 2. Pretreatment Evaluations (including Baseline Study Measures) 
 
Activity/ Assessment/ Timing
Comment

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Symptom-limited cardiopulmonary
exercise test (CPET) to assess peak 
oxygen consumption (V02peak) 
VO2peak will be evaluated using a magnetically-braked cycle 
ergometer test with 12-lead ECG monitoring (Mac® 5000, GE 
Healthcare) performed by certified exercise physiologists. 
 
Cardiopulmonary exercise testing is considered the gold 
standard assessment of exercise capacity and provides 
assessment of peak oxygen consumption (VO2peak)- Expired 
gases will be analyzed continuously by a metabolic 
measurement system (Parvo Medics TrueOne 2400). After 
stable resting metabolic values have been achieved (including 
blood pressure and heart rate), participants will begin cycling at 
a participant-specific designated power output for 1 minute and 
the power output will be increased every 1 minute until 
exhaustion or a symptom-Ii mited peak is achieved measured by 
peak oxygen consumption (VO2peak) (mL·kg·-1min-1) 
This protocol has been previously demonstrated to be 
appropriate for measuring VO2peak in our prior studies among 
cancer patients.36 37 
' 
 
Acceptable test criteria for this assessment include any of the 
following: (1) a plateau or decrease in oxygen consumption 
concurrent with increased workload, 2) heartrate 220-age 
(±10 beats) (3) a respiratory exchange ratio =1.1, (4) volitional 
exhaustion, a rating of perceived exertion 
18. This protocol 
has been previously demonstrated to be appropriate for 
measuring VO2peak in our prior studies of early-stage and 
advanced cancer patients. 36•
37
 
 
The test will be terminated if any ECG abnormalities are 
observed. 
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.38 If both the first and second CPET achieve 
acceptable test criteria, the best test will be used. 
One repetition maximum (1RM)
Participants will perform a cardiovascular warm-up on a treadmill
or bicycle ergomete r prior to testing for 5 minutes. After an 
appropriate rest period, participants will be familiarized with each 
of the resistance machines by performing 8-10 repetitions of a 
light load (~30-40% of predicted 1RM). After ~3 min of rest, 
participants will complete a priming load at 60-80% of estimated 
1RM for 3-8 repetitions. Following 5 min of rest the participant 
will attempt a lift of ~90-100% of estimated 1RM through the full 
range of motion. After each successful performance, the weight 
will be increased until a failed attempt occurs. The highest 
weight moved once through the particular range of motion with 
maximal exertion will be defined as the 1RM. In order to allow 
for appropriate recovery and reduce the influence of fatigue, 
exercises will be alternated between the upper and lower body. 
Three to five minute rests will be given between each attempt 
and the 1RM will ideally be attained within 5 attempts. 
Resting left ventricular function by 3-
Three-dimensional transthoracic echocardiograms will be

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dimensional echocardiography (3DE)
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 accordin to American Society of 
Echocardiography guidelines. 9 1 
-4 
 
Left l.€nt ricular volumes and left 1.€ ntricula r ejection fraction 
(LVEF) by 3DE will be determined by manipulating the full 
volume dataset to derive conventional apical 4-, 3-, and 2- 
chamber views using TomTec 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.42 
Post VO2peEJ<left ventricular function by
2-dimensional echocardiography (2DE) 
Upon completion of the cardiopulmonary exercise test, subjects
will be placed in the supine position and 2DE grayscale images 
will be obtained in the apical 4-, 3-, and 2-chamber views. Wall 
motion scoring index (WMSI) will be calculated at rest and post- 
exercise using the 17 segment model by adding the individual 
segment scores (1 = normal; 2 = hypokinesia; 3 = akinesia; 4 = 
dyskinesia) and dividing by number of segments scored.39 2D 
LV v0lumes 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). 
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 
independently, as long as the heart rate and rhythm are 
consistent throughout, with the mechanotransducers directly 
applied to the skin over the greatest area of pulsation. Twenty 
consecutil.€ reproducible beats will be collected 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. 

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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\€ measurement compared 
to invasive measure. PWV will then be determined by taking the 
pulse transit time/distance. 
Flow Mediated Dilation
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 brachia! 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 
be captured beginnin at cuff deflation (hyperemia) as 
previously described. 7 
 
Offline analysis using specialized software (Brachia! 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 ebergy 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 absorptiometry 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). 
 
Each participant's Baseline and Follow Up DEXA assessments 
will be performed on the same machine as best possible. 
Patient-reported outcomes (via
questionnaire) 
Patient-reported outcomes will be assessed using a patient-
administered questionnaire to assess quality of life, fatigue, pain, 
and sleep quality. 
Quality of Life (QOL) will be assessed by the Functional 
Assessment of Cancer Therapy (FACT) 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-ite m Brief Pain 
Inventory (BPI) which was designed to measure multi e 
clinically relevant aspects of pain such as pain intensity 

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and interference from pain in cancer populations.4u 
 
Sleep Quality will be assessed by the Pittsburgh Sleep 
Quality Index (PSQl).41 
Medical Outcomes Trust Short Form Health Survey (SF- 
36): The SF-36 is a psychometrically robust self-report 
questionnaire that measures generaI health-related 
quality of life 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 
health.42 
Fasting research blood draw
Blood collection should take place prior to the initiation
of any study related interventions, whenever possible. 
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.53 
Functional performance measures
Assessment of functional measures will include the performance
of the following tests: 
 
• 
Short Physical Performance Battery (SPPB): The SPPB 
is a brief performance-based functional mobility 
measure that includes measures of standing balance, 
usual pace walking speed, and ability and time to rise 
from a chair 5 times. 
 
• 
Six-Minute Walk Test (6MWT): The 6MWT is a valid 
responsive, interpretable self-paced test that quantifies 
functional exercise capacity in terms of the distance 
walked in six minutes. 
 
• 
Chair-stand test: Chair-stand test (number of sit to 
stands a subject can complete in 30 seconds) will be 
used as a measure of functional lower body strength. 
 
• 
Timed Up and Go (TUG): TUG is a timed measure of 
balance and functional mobility. The test requires the 
patient to rise from a standard armchair, walk 3 meters 
at a comfortable pace, walk back to the chair, and sit 
down. 
 
Following the completion of all baseline assessments, patients will be randomly assigned to one of 
the four study arms. 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9. 1 
Evaluation Prior to Initiation of Intervention 

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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. 
 
9.2 
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 an 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 
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. 
Aerobic Training Interventions (Arms A-C) (General Considerations) 
 
The overall goal for all the exercise training groups will be 3 supervised exercise sessions per week 
an intensity between 50 to 100% of the individually determined V02peak for aerobic training and an 
intensity between 50% to 85% of 1-RM for resistance training. All the exercise interventions are 
designed such that participants begin exercising at a low intensity (~50%-60% V02peak / 1RM) that is 
subsequently increased to more moderate to vigorous intensity(~70%-100% V02peak / ~70-85% 
1RM) when appropriate. All interventions will be individually tailored to each patient following the 
principles of aerobic or resistance training prescription guidelines for adults. 
9.2.1 Arm A -Aerobic Training 
 
All aerobic training sessions will be performed on a cycle ergometers, targeting delivery of 
three cycling sessions/week at 55%-100% of V02peak• In the introductory phase of the 
program (Weeks 1-4), the frequency, duration, and intensity of aerobic training will be 
progressively increased from an initial prescription of 3 session/wk for ~30-60 mins/session at 
~60-70% of V02peak to the overall goal of this prescription 60%-100% V02peak) at the end of 
Week 4. In Weeks 5 to 8 (intermediate phase), the goal will be to introduce higher intensity 
aerobic training. Specifically, exercise intensity will range between ~60%-70% V02peak for 
two sessions per week; in the remaining session, exercise intensity will be set at ventilatory 

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threshold (~75% V02peak). In Weeks 9 to 16 (optimization phase), similar to the intermediate 
phase, participants will be asked to perform 3 aerobic sessions per week; 2 sessions will be 
performed at ~60%-80% V02peak, and one interval workout. Interval workouts will consist of 
1-2 min at the workload associated with V02peak (100% of V02peak) followed by 2-4 min of 
active recovery for 8-12 or 4-6 intervals, depending on the length of the interval. At midpoint 
participants will undergo a CPET to re-assess V02peak· On the basis of these results, the 
exercise prescription will be adjusted to ensure progressive improvements in V02peak across 
the entire intervention. 
9.2.2 Arm B - Resistance Training 
Resistance training will be prescribed with the aim of increasing V02peak· The ultimate goal for 
resistance training alone is 3 resistance training sessions/week at an intensity above 50% to 
85% of 1-RM for 30-60 minutes/session. Resistance training will be performed on stationary 
weight machines, modification in equipment may be made by Exercise Physiologist. Patients 
will be progressively trained to perform two to three sets of 75-85% of maximal strength. 
9.2.3 Arm C - Combined Aerobic and Resistance Training 
Combined aerobic and resistance training will be prescribed with the and aim of increasing 
V02peak• The ultimate goal will be three combined exercise sessions per week at an intensity 
above 50% V02peak and above 50% 1-RM for aerobic and resistance training, respectively for 
30-90 minutes/session. In this arm, the duration of aerobic training and resistance training 
will not be added together but rather the exercise prescription is designed to exploit the 
complementary properties of aerobic and resistance training to optimally improve V02peak· 
The prescription will be balanced to ensure that on days when aerobic training is prescribed 
at a high-intensity, resistance training (on the same day) will be conducted at a lower (easy) 
intensity and vice versa. This approach will optimize the desired adaptations without causing 
excessive fatigue and will help avoid potential interference effects between aerobic and 
resistance training. 
9.2.4 Arm D - Progressive Stretching Group (Attention-Control) 
 
The ultimate goal for the progressive stretching program is 3 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. 
 
9.3 
Intervention Attendance and Adherence 
 
Attendance is calculated as the number of intervention sessions attended divided by the total 
number of planned sessions (i.e., 3 times/wk x 16 weeks= 48). Adherence is defined as the number 
of scheduled training sessions attended, as well as whether the training session dose was 

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successfully completed (i.e., participant completed the intervention session at the planned duration 
and intensity) divided by the total number of planned sessions (i.e., 48). 
9.4 
Aerobic and Resistance Training Dose Modification 
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 Pl 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. 
 
9.5 
Aerobic Training /Resistance Training/ Progressive Stretching Discontinuation 
Permanent treatment discontinuation is defined as cessation of aerobic training, resistance training 
or progressive stretching administration. When appropriate, follow up assessments will still be 
performed. 
Temporary treatment interruption due to an adverse event is not considered permanent 
discontinuation. Patients whose treatment is interrupted due to an adverse event and then restarted 
will continue to have regularly scheduled study visits. In both experimental groups, the intensity and 
duration of the next scheduled session will be reviewed and discussed by ExOnc exercise 
personnel. However, if a participant misses more than 6 weeks of continuous sessions, the 
participant will begin the intervention from the starting prescription, due to the anticipated impact of 
deconditioning during the 6 weeks of intervention interruption. 
 
9.6 
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. 
 
 
9.7 
Effects of Aerobic Training or Resistance Training on Exposure to Other 
Conventional/ Novel Anticancer Therapies 

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There is no clinical data on the effect of aerobic training and/or resistance training (or progressive 
stretching) on the therapeutic index of anticancer agents used in the management of lung cancer.. 
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. 
9.8 
Effects of Conventional/Novel Anticancer Therapies on Aerobic Training or 
Resistance Training 
Our group, as well as others, have demonstrated that different forms of anticancer therapy causes 
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 V02peak)- A major 
rationale for this trial is to determine the optimal exercise training modality to mitigate and/or reverse 
this phenotype in patients with lung cancer. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
All evaluations being conducted during the treatment intervention, including the window of time in 
which conduct of these tests is required, are described in the schedule of activities (Table 1). Further 
details are provided herein. Assessments which are initially completed at baseline, midpoint and 
follow up may be repeated at the investigators discretion. 
10.1 
CPET 
At the end of week 8, participants in the aerobic training arm (Arm A) and the combined aerobic and 
resistance training arm (Arm C) will repeat the cardiopulmonary exercise test. This test is repeated 
at this period to re-assess V02peak under the expectation that V02peak is likely to have improved in the 
first 8 weeks of the program. Thus, information from the second test is used to re-prescribe exercise 
training prescription to ensure continual cardiovascular adaptations across the entire study period. 
This test will not be repeated in the resistance training group (Arm B) or the progressive stretching 
group (Arm D). 
10.2 
1-RM Testing 
At the end of Week 8, participants in the resistance training arm (Arm B) and the combined aerobic 
and resistance training arm (Arm C) will repeat the one repetition maximum strength test. This test is 
repeated at this period to re-assess lower and upper body strength under the expectation that these 
parameters would have improved in the first 8 weeks of the program. Thus, information from the 
second test is used to re-prescribe exercise training prescription to ensure continual strength 
adaptations across the entire study period. This test will not be repeated in the aerobic training 
group (Arm A) or the progressive stretching group (Arm D). 
10.2 
Fasting Blood Draws 
At baseline and study follow-up, participants will undergo a fasting blood draw to obtain peripheral 
blood for complete blood count (CBC), and secondary endpoints. The CBC will be resulted by MSK 
clinical labs. In addition, data will be collected on any CBC tests that are performed as part of 
standard of care while the patient is on study. 

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Research blood samples will be collected, processed and stored per the Lab Manual. 
 
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 SpO2changes 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 ExOnc 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 
• 
Arthralg ia 
• 
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 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Primary Study End Point 
Exercise Capacity (VO2peak): VO2peak will be evaluated using an magnetically breaked cycle 
ergometer test with 12-lead ECG monitoring (Mac® 5000, GE Healthcare) performed by trained 
exercise physiologists. 
 
Cardiopulmonary exercise testing is considered the gold standard assessment of exercise capacity 
and provides assessment of peak oxygen consumption (VO2peak)- Expired gases will be analyzed 
continuously by a metabolic measurement system (Parvo Medics TrueOne 2400). After stable 
resting metabolic values have been achieved (including blood pressure and heart rate), participants 
will begin cycling at a participant-specific designated power output for 1 minute and the power output 

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will be increased every minute until exhaustion or a symptom-limited peak is achieved measured by 
peak oxygen consumption (VO2peak) (mL·kg·-1min-1). 
 
Acceptable test criteria for this assessment include any of the following: (1) a plateau or decrease in oxygen 
consumption concurrent with increased workload, 2) heartrate 220-age (±10 beats) (3) a respiratory 
exchange ratio =1.1, (4) volitional exhaustion, a rating of perceived exertion 18. This protocol has been 
previously demonstrated to be appropriate for measuring VO2peak in our prior studies of early-stage and 
advanced cancer patients. 36•37 
 
All participants will be monitored continuously with 12-lead ECG during exercise and five minutes of 
recovery. During exercise, oxyhemoglobin saturation will be monitored continuously using finger 
pulse oximetery while blood pressure will be measured manually by auscultatory 
sphygmomanometer every two minutes. 
 
Exercise testing-related events were operationalized as any event occurring during this procedure. 
SAEs will be defined as the occurrence of any of the following: (1) significant angina, (2) sustained 
ventricular tachycardia, (3) myocardial infarction, (4) external defibrillation or implantable 
cardioverter-defibrillator discharge, (5) syncope, (6) provision of cardiac life support medications, (7) 
direct admission to emergency room, or (8) death. A positive test was defined as identification of any 
of the following ECG changes: (1) significant ischemic changes in ECG during exercise or recovery 
or (2) development of exercise induced bundle branch block. Criteria for ischemic changes in ECG 
included 0·1 mV deviation of the ST segment horizontal to or away from the baseline isoelectric line 
at O·OB seconds after the J-point in the absence of significant resting ST-T abnormalities or left 
bundle branch block. ST segment changes toward the isoelectric line will not be considered positive, 
regardless of the magnitude of change. If the baseline ECG reveals a J-ST segment depression 
>0-05 mV, a "double criteria" (an additional 0·2 mV) of ST depression will be required with the 
appropriate horizontal or downsloping morphology to qualify as a positive test. 
 
Clinical exercise physiologists within the ExOnc at MSK will perform all cardiopulmonary exercise 
tests. All personnel are trained to read (but not interpret) exercise ECG's and are trained in 
Advanced Cardiovascular Life Support (ACLS). All tests will only be conducted when physician 
coverage on the clinical floor is available. 
 
All cardiopulmonary exercise testing will be conducted in Cardiology Service space either at Main 
Campus or in the Outpatient Facility on 53rd Street, or at the Sidney Kimmel Center for Prostate and 
Urologic Cancers, on designated ExOnc equipment specifically designated for research purposes. 
 
If any ECG abnormalities are observed either prior to, during, or after the exercise test, all 
procedures will be immediately stopped. At this point, a cardiologist will be asked to review the ECG 
to determine the appropriate course of action. The participant will not be allowed to leave the facility 
until such an examination has been performed by the physician. All events will be recorded in the 
participants REDCAP. The participants attending oncologist will be informed of this event (by email) 
within 12 hours of the event. 

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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.30 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 
 
• 
Lol/1.er and Upper Body Maximal Muscular Strength will be assessed as a voluntary one- 
repetition maximum (1-RM) using the following exercises: (1) leg press, (2) chest press, and 
(3) seated row. These tests will be repeated twice and the heaviest weight lifted while 
adhering to strict technique and form will be used as the score. 
 
• 
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 1\/ledical, Milwaukee, WI). 
 
Conventional 20 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. 39-41 
 
Left ventricular 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 views using TomTec 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.42 
 
All resting echocardiography assessments will be conducted in Cardiology either at the 
Sidney Kimmel Center for Prostate and Urologic Centers or at the Main Campus or at the 
Rockefeller Outpatient Pavilion on 53rd Street, by a select group of sonographers in the 
Cardiology Service, using commercially-available GE Medical systems. 
 
If any cardiac abnormalities are observed either prior to, during, or after the exercise test, all 
procedures will be immediately stopped. At this point, the physician on the floor will be asked 
to review the echocardiographic images to determine the appropriate course of action. The 
participant will not be allowed to leave the facility until such an examination has been 

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performed by the physician. All events will be recorded in the participant's REDCAP. The 
participant's attending oncologist will be informed of this event by email within 12 hours of 
occurrence. 
 
• 
Post VO2peak Left Ventricular Function by 3-Dimensional Echocardiography (3DE):Within 30 
seconds of completion of the cardiopulmonary exercise test, subjects will be placed in the 
supine position and 2DE grayscale images will be obtained in the apical 4-, 3-, and 2- 
chamber views. Wall motion scoring index (WMSI) will be calculated at rest and post- 
exercise using the 17 segment model by adding the individual segment scores (1 = normal; 2 
= hypokinesia; 3 = akinesia; 4 = dyskinesia) and dividing by number of segments scored.39 
 
30 LV volumes 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). 
 
All post-exercise echocardiography assessments will be conducted in Cardiology either at 
the Sidney Kimmel Center for Prostate and Urologic Centers or at the rv1ain Campus or at the 
Rockefeller Outpatient Pavilion on 53rd Street, by a select group of sonographers in the 
Cardiology Service, using commercially-available GE Medical systems. 
 
If any cardiac abnormalities are observed after the exercise test, all procedures will be 
immediately stopped. At this point, the physician on the floor will be asked to review the 
echocardiographic images to determine the appropriate course of action. The participant will 
not be allowed to leave the facility until such an examination has been performed by the 
physician. This event will be recorded in the participant's REDCAP. The participant's 
attending oncologist will be informed of this event by email within 12 hours of occurrence. 
 
• 
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 fr001 sternal notch to 
femoral pulse measurement. This method has been shown to be the optimal non-invasive 

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measurement compared to invasive measure. PWV will then be determined by taking the 
pulse transit time/distance. 
 
All arterial stiffness measurements will be conducted in Cardiology Service space either at 
the Sidney Kimmel Center for Prostate and Urologic Centers or at the rvlain Campus or at the 
Rockefeller Outpatient Pavilion on 53rd Street, or at the Sidney Kimmel Center for Prostate 
and Urologic Cancers, on ExOnc equipment specifically designated for research purposes. 
All tests will be conducted by ExOnc exercise physiologists . 
 
• 
Flow Mediated Dilation: Peripheral artery flow-mediated dilatation will be performed on the 
left arm with the subject in a supine position with the forearm extended and slightly 
supinated. A rapid inflater blood pressure cuff will be placed on the forearm just distal to the 
antecubital crease and the brachiaI 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 
be captured beginning at cuff deflation (hyperemia) as previously described.43 Offline 
analysis using specialized software (Brachia! Tools, Medical Imaging Applications, Illinois) 
will permit for identification of peak dilation and dilation at specific pre-specified time points 
(60, 120 sec).44 Due to the potential confounding effects, patients will be asked to withhold 
vasodilatory substances (e.g., caffeine, exercise) 24 hours prior to assessment. 
 
• 
Body Composition: Body composition will include percent body fat, fat mass (FM), and lean 
body mass (LBM) evaluated by dual-energy x-ray absorptiometry (DEXA) using a GE Lunar 
Prodigy multiple detector fan-beam densitometer. 
 
• 
Pulmonary Function will be determined using standard spirometry. All measures will be 
performed in a sitting position according to the American Thoracic Society guidelines. 53 
 
• 
Functional Performance Measures: Assessment of functional measures will include the 
performance on the following tests: 
 
o Short Physical Performance Battery (SPPB): The SPPB is a brief performance-based 
functional mobility measure that includes measures of standing balance, usual pace 
walking speed, and ability and time to rise from a chair 5 times. 
 
o Six-Minute Walk Test (6MWT): The 6MWT is a valid responsive, interpretable self- 
paced test that quantifies functional exercise capacity in terms of the distance walked 
in six minutes. 
 
o Chair-stand test: Chair-stand test (number of sit to stands a subject can complete in 
30 seconds) will be used as a measure of functional lower body strength. 

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o 
Timed Up and Go (TUG): TUG is a timed measure of balance and functional mobility. 
The test requires the patient to rise from a standard armchair, walk 3 meters at a 
comfortable pace, walk back to the chair, and sit down. 
 
All functional performance measurements will be conducted by ExOnc exercise physiologist 
at the Sidney Kimmel Center for Prostate and Urologic Cancers or Sillerman Center for 
Rehabilitation. 
 
 
 
• 
Patient-Reported Outcomes: Patient-reported outcomes will be assessed using a patient- 
administered questionnaire 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-Lung (FACT-L) scale. The FACT-L contains subscales for physical (7 
items), functional (7 items), emotional (6 items), and social or family well-being (7 
items) that comprise the FACT-General (FACT-G) scale, plus a lung cancer subscale 
(7 items). The five subscales will be summed to obtain the FACT-L score (all 34 
items; total score of 136). We will also compute the FACT-G score (27 items, 
excluding the breast cancer subscale; total score of 108).45 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. We will also calculate the Trial Outcome 
Index (TOI). The TOI is the sum of the Physical Well-Being (PWB), Functional Well- 
Being (FWB), and Lung Cancer subscales. Respondents are asked to respond to 
each question as it applies to the past 7 days. Higher scores on the FACT-L indicate 
higher QOL. Internal consistency for the FACT-G and FACT-Lis established. 
 
o Fatigue will be assessed using the 13-item FACT-fatigue scale for the assessment of 
fatigue in cancer patients.46 the 13 items will be summed to obtain the total fatigue 
score (total score of 52). All items are rated on a Oto 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-fatigue indicate higher fatigue. Internal 
consistency for the FACT-fatigue is well established.46 
 
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.47 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 

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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 pa in 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 respectively47 
 
o Sleep Quality will be assessed by the Pittsburgh Sleep Quality Index (PSQl).48 The 
PSQI assesses sleep disturbance over the past month. The PSQI is an 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 Oto 21. Reliability measures 
indicate that the PSQI generally has acceptable internal consistency (a = .80 to .85) 
and test-retest reliability (r = .85 to .87).48 
 
o Exercise behavior will be assessed by the leisure score index (LSI) of the Godin 
Leisure-Time Exercise Questionnaire (GLTEQ) which is used to measure the minutes 
and type of exercise per week.49•
50 The LSI contains three questions that assess the 
average frequency of mild, moderate, and strenuous intensity exercise during free 
time in a typical week over the past month. In this protocol, participants will be asked 
to report their average weekly exercise over the past month. We will also ask for 
average duration within each exercise intensity. An independent evaluation of this 
measure found its reliability and validity to compare favorably to nine other self-report 
measures of exercise based on various criteria including test-retest scores, objective 
activity monitors, and fitness indices (Jacobs et al. 1993). The LSI demonstrated a 
one-month test-retest reliability of .62 and concurrent validity coefficients of .32 with 
an objective activity indicator (CALTRAC accelerometer), .56 with VO2max (as 
measured by expired gases), and -.43 with% body fat (as measured by hydrostatic 
weighing). 

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o Physical Functioning will be assessed using the physical functioning subscale (PF) of 
the Short-Form (SF) 36.51 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 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 
4 statements asking 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 Oto 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.51 
 
• 
Safety will be evaluated by the type and prevalence of adverse events during study-related 
assessments as well as exercise training sessions. The type and nature of SAEs considered 
in this trial include those DLTs listed in Section 9.3 as well as those events listed in Section 
11.1 (the unanticipated but possible adverse events associated with CPET, 1RM, aerobic 
training or resistance training). 
 
Tracking and monitoring of exercise-related adverse events will be assessed using the 
following methods: 
 
1. Stringent monitoring and recording (in the patient REDCAP) of physiologic outcomes and 
vital signs (e.g., heart rate, blood pressure, etc.) prior to, during, and following every 
intervention session. 
2. At the beginning of each week, the exercise specialist will spend the first 10 minutes of every 
session discussing any potential negative side-effects of the intervention assignment and any 
injuries that may have occurred. All events will be recorded in the patient REDCAP. 
3. Early stopping rules in response to a differential higher frequency of adverse events in a 
particular study group as identified in planned interim analyses (see Section 14.0). 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
The primary reasons for permanent treatment discontinuation are listed in Table 4. 
 
 
Table 4. Primary Reasons for Permanent Treatment Discontinuation 
I Reason 
I Comment 
I Self-withdrawal (withdrawal of consent) I Patients may permanently discontinue study treatment and 
 

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withdraw from the study at any time for any reason. Following
study intervention discontinuation, patients should have 
protocol-required safety follow-up and long-term follow-up 
assessments unless the patient specifically declines further 
follow-up. 
Ad\terse event or intercurrent illness or
disease recurrence 
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 treatment were continued. 
Gross noncompliance with protocol
(violation) 
The investigator may request permanent discontinuation of
study treatment in the event of a major protocol deviation, lack of 
cooperation, or complete noncompliance. 
Lost-to-follow-up
Reasonable effort should be made to contact any patient 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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14.0 
BIOSTATISTICS 
14.1 
Sample Size Calculation and Justification 
 
This randomized phase trial will accrue 67 subjects with lung cancer over an accrual period of ~36 
months. The primary analysis will compare the efficacy of different types of exercise training 
modalities, relative to progressive stretching (attention control group), on V02peak. Three separate t- 
tests will be used to compare each exercise training arm to the attention-control arm in mean 
change across time for V02peak• The overall alpha level will be controlled at a two-sided 0.05 by 
using Holm's procedure.56 That is, Holm's procedure first ranks the three p-values from lowest to 
highest. The first (lowest) p-value has to be less than 0.05/3 (0.0167) to be significant and permit 
continuation to the other t-tests. The Holm's procedure continues sequentially in this fashion using 
alpha levels of 0.05/2 (0.025) and 0.05/1 (0.05) for the remaining two t-tests, respectively. Power for 
this study is defined as the probability that at least one of the three t-tests of the arm effect on 
V02peak is significant; in other words, power is the probability that the first of the 3 ordered t-tests are 
significant. We assume that change in V02peak will have a standard deviation of 3.0 mL·kg-·1min-1. 
Statistical power depends upon the configuration of mean change in V02peak across the 4 arms. 
Thus, for example, 80% power is obtained when the mean change in V02peak across Arms A, B, C, 
and Dis 0.60, 0.60, 2.10, and 0.0 (mL·kg-·1min-1), respectively. 
A final important consideration when conducting exercise RCTs, is extent of exercise 'drop-in' or 
contamination in Arm D. In other words, the concern is that patients assigned to attention control 
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 exercise training arms) will be provided with supervised, 
individualized training prescriptions (which will be difficult to replicate without sophisticated 
prescription algorithms and expertise) and 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 all 
study arms using subjective (i.e., self-report exercise logs) methods. 
14.2 
Primary and Secondary End Point Analyses 
14.2.1 Primary End Point Analysis: The primary analysis will compare the efficacy of 
different types of exercise training modalities, relative to progressive stretching (attention 
control group), on V02peak in lung cancer. 
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 
linear regression model to test for differences among and between the study arms in V02peak 
from baseline to follow up. The multiple linear regression model will include the baseline 
value of V02peak, the stratification variables (i.e., chemotherapy treatment and sex), and study 
site. 

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In the absence of evidence to the contrary, multiple imputation strategies for missing Week 
17 V02peak data will be performed assuming data were missing at random using linear 
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 linear regression 
model to test for differences among and between the study arms in V02peak from baseline to 
the post-intervention assessment (Week 17) on the basis of exercise attendance and 
adherence to the supervised exercise training in Arms A to C (<80% versus 80%). 
14.2.2 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 linear regression 
models will be used to test for differences among and between the study arms in secondary 
end points from baseline to the postintervention assessment (Week 17). The multiple linear 
regression model will include the baseline value of V02peak, the stratification variables (i.e., 
chemotherapy treatment and sex), and study site. 
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 linear 
regression, as described above. Again, a per-protocol analysis will be performed using a 
multiple linear regression model to test for differences among and between the study arms in 
secondary end points from baseline to the post-intervention assessment (Week 17) on the 
basis of exercise attendance and adherence to the supervised exercise training sessions in 
Arms A to C (<80% versus 80%). 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
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 whether or not 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). 
 
 
15.2 
Randomization 
Participants will be randomly allocated, on an individual basis, to one of the four study arms. 
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 whether their lung cancer was operable or 
inoperable, prior treatment with chemotherapy (yes vs. no) and sex (male vs. female). 
Chemotherapy causes significant reductions in V02peak, thus it is important for groups to be 
balanced on this factor. Similarly, male participants have higher V02peak than female 

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participants and therefore is also expected to influence the effect of exercise training on 
VO2peak 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: 1:1 is used to generate the treatment 
assignments. Following the successful completion of all baseline assessments, ExOnc 
research team personnel will enter randomization criteria into REDCap. Upon confirmation of 
stratification factors (chemotherapy treatment and/or sex) REDCap will electronically 
randomized the patient. Written confirmation of group allocation will be provided by email, a 
copy of which will be placed in the patient's case report form. The primary study RSA will 
then inform the participant of their group allocation. 
16.0 
DATA MANAGEMENT ISSUES 
 
A Clinical Research Supervisor (CRS) and Research Study Assistant (RSA) will be assigned to the 
study, and will be under the close supervision of the Clinical Research Manager in the ExOnc. The 
responsibilities of the CRS and/or 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 the Clinical Research Database (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. 
16.01 Role of Duke University Medical Center 
 
This trial is a multi-site, randomized controlled trial comparing the effects of different exercise 
training interventions, relative to attention control, in patients with lung cancer following the 
completion of definitive adjuvant therapy. However, this trial represents a continuing effort 
that was first initiated at DUMC approximately 4 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 all trial recruitment and study-related procedures 
were closed (all 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. Protocol amendments that affect MSK only (e.g. change in 
MSK Co-Investigator, MSK translation, etc.) do not require IRB review at the participating 

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site(s). All other protocol amendments will be immediately distributed to each participating 
site upon receipt of MSK IRB/PB approval. 
Duke must obtain IRB approval for all amendments 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 Pl and the DUMC Pl will maintain adequate and accurate records to enable the 
implementation of the protocol to be fully documented and the data to be subsequently 
verified. 
16.02 Current Status 
 
As of September, 2013, the trial status is as follows: A total of 78 operable participants had 
been randomly allocated to four study arms: Arm A supervised aerobic training (n=20), Arm 
B: supervised resistance training (n=20), Arm C: supervised combined aerobic and 
resistance training (n=19), and Arm D: progressive stretching (attention control group) 
(n=19). Of these, 70 (88%) participants successfully completed all study procedures, with 8 
(12%) participants lost-to-follow-up. The mean adherence rate was 77% across Arms A to C, 
with minimal adverse events, suggesting that all intervention sessions are well-tolerated. 
A total of 15 inoperable patients had been randomly allocated to four study arms: Arm A: 
supervised aerobic training (n=4), Arm B: supervised resistance training (n=4), Arm C: 
supervised combined aerobic and resistance training (n=4), and Arm D: progressive 
stretching (attention control group) (n=3). 
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. 
16.03 Proposed Plan at MSK 
 
Following successful transition of the PI to MSK (and establishment of a close collaborative 
relationship with the Thoracic DMT under the leadership of Ors. Jones and Rudin), the goal 
of this continuation trial is to complete study accrual as planned (i.e., accrual of the remaining 
67 patients). Based on the potential subject availability at MSK, we anticipate that subject 
accrual will take 24 months from the first accrual at MSK. 
16.04 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 Pl at DUMC. 

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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, 11, PhD (trial biostatistician). Specifically, all study-related procedures and data 
collected here at MSK will be entered into two systems: (1) the CRDB here at MSK, and (2) 
REDCap software at DUMC. 
In terms of the latter, 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 (OIT). 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. 
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 ExOnc 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, 11, PhD and Samantha Thomas, MS 
(trial statisticians) will have access to MSK PHI-related information. 
The consent form contains language explaining that basic MSK participant information can 
only be accessed by specific individuals at DUMC. 

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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, more frequently, as appropriate. 
16.2 
Data and Safety Monitoring 
 
This protocol describes a trial which is currently registered on ClinicalTrials.gov (it is currently 
registered to DUMC but will be switched to MSK upon IRB approval). 
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 
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 Ill 
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. 
Trial Type/Level of Review: Phase II Behavioral Trial - This study does not involve the 
testing of pharmacologic agents or any therapeutic treatments. It is a randomized behavioral 
trial designed to compare the efficacy of different exercise training modalities relative to 
progressive stretching (attention control group), on VO2peak in patients with lung cancer 
following the completion of definitive adjuvant therapy. Thus, it is classified as a Type 2 
Study (Non-Therapeutic Intervention Study), a minimal risk level study. 

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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, 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 patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient 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 storage 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 patients 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 patients 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 any 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. This multi-gated comprehensive 
approach should systematically identify and screen out any individual for whom this pilot 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. 
Blood Collection - There are some minor risks associated with a blood draw, i.e., bruising and/or 
discomfort; however this procedure is considered to be of minimal risk and will be performed by 
trained nurses/PA's either at the Sidney Kimmel Center for Prostate and Urologic Centers or at the 
Main Campus or the Rockefeller Outpatient Pavilion on 53rd Street. 
Supervised Exercise Training - Similar to graded exercise testing, exercise 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 exercise training across literally hundreds of cancer 
patients and 1,000+ hours of exercise training. Further, all participants would have undergone a full 
ECG, graded exercise test prior to exercise training, and all sessions will be supervised by a 
exercise specialist. 
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, three DEXA scans 

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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. 
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 exercise training among patients with lung 
cancer who have exercise intolerance due to the direct and effects 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 of 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: Patients will be charged for physician visits, routine laboratory tests and 
radiologic studies required for monitoring their condition. The patients will not be billed for any study- 
related procedures. The participant is 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 the second assessment at the end of the 
study (Week 17). 
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: Patients 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 weekends, we have a 24-hour urgent care facility for 
outpatients. The Pl will also be available at all times to organize any necessary intervention. 
Monitoring of data to ensure safety: This study is to be monitored by the institutional IRB. This 
incorporates an independent data and safety monitoring board established by arrangement with the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-215 A(4) 
Approval date: 31-0ct-2017 
Page 43 of 48
 
 
 
National Cancer Institute. The analysis of safety will include all patients. Adverse events, including 
all toxic effects of treatment, will be tabulated individually, and summarized by severity and causality. 
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 on the 
clinical care patients receive. 
 
Withdrawal: Participants may also 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 patient, 
destroyed. When a patient withdraws from protocol, OCR-PPR should be notified immediately. The 
withdrawal request will be documented in CRDBi and the system updated accordingly. In addition, a 
note-to-file documenting the patient's withdraw must be filed in his/her EMR. 
 
17.1 
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). 
17.2 
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 
• 
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. 

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Approv  date: 31-0ct-2017 
 
 
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 
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 Pl's signature and the date it was signed are required on the completed report. 
 
 
18.0 
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 IRS/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. 

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Page 45 of 48
 
 
 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients 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 patients 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 
 
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20.0 
APPENDICES 
1. Appendix A 
2. Appendix B: 
3. Appendix C: 
4. Appendix D: 
5. Appendix E: 
6. Appendix F: 
7. Appendix G: 
8. Appendix H: 
9. Appendix I: 
 
 
Lifestyle Questionnaire 
Borg Rating Scales for Perceived Exertion, Dyspnea, and Leg Fatigue 
Study Timeline 
Welcome Letter 
Training Exercise Session Information 
Mail Based Recruitment 
Introduction Call 
Exercise Physiology Guidelines 
Introduction Email