Effects of Physical Activity Plus Short Course of Dexamethasone for Cancer-Related Fatigue in Advanced Cancer
Phase: PHASE2
Conditions: Advanced Malignant Neoplasm, Fatigue, Metastatic Malignant Neoplasm, Recurrent Malignant Neoplasm, Refractory Malignant Neoplasm
Sponsor: M.D. Anderson Cancer Center

Protocol 2014-0436
Rev. August 17, 2016
1
Protocol Title: Effects of Physical Activity Plus Short Course of Dexamethasone for Cancer-Related Fatigue in 
Advanced Cancer 
Study PI: Sriram Yennu 
Study Co-PI: Eduardo Bruera 
Study Collaborators: Karen Basen-Engquist, Naifa Lamki Busaidy, Kenneth Hess, James Reuben
A. OBJECTIVES:  
Primary Objectives:  
1. To determine the feasibility, adherence, and satisfaction with Physical Activity (PA) plus Dexamethasone 
(PA+ DEX).  
1.1. PA+ DEX will be feasible as evidenced by adherence rate to daily use of PA+ DEX 
 
1.2. More than 75% of patients will indicate satisfaction with the PA+ DEX as somewhat satisfied or completely 
satisfied.  
Secondary Objectives: 
2. To explore the preliminary efficacy of PA+ Hi Dex group (PA for 4 weeks plus high dose dexamethasone for 
1 week) and PA+ Lo Dex groups (PA for 4 weeks plus low dose dexamethasone for 1 week) on CRF as 
measured by FACIT-F at the end of one week  
2.1. PA+ Hi Dex will result in robust reduction in FACIT-
improvement in 60%of 
patients)  
3. To explore the effects of PA+ Hi Dex  on the various dimensions of CRF [PROMIS-F], i.e., 
affective/emotional (Hospital Anxiety Depression Scale[HADS]); physical/behavioral (The Multidimensional 
Fatigue Symptom Inventory-Short Form[MFSI-SF], Pittsburg Sleep Quality Index), physical activity and 
function (30 second sit-to stand test, Six minute walk test) before and after treatment.  
3.1. By targeting the various associated factors of CRF including subjective measures (such as anxiety, 
depression, and sleep disturbance) and objective measures, PA+ Hi Dex improves CRF. 
B. BACKGROUND / RATIONALE:  
Cancer-related fatigue (CRF) is the most frequently reported symptom associated with cancer and its 
treatment. CRF is more severe and debilitating in patients with advanced cancer than in those with early 
cancer or in cancer survivors.1-4 Its frequency ranges from 60% to 90% in patients who are receiving palliative 
care.4,5 As a result of improved therapy, patients with advanced cancer are living longer, and due to advances 
in treatment for pain and nausea, clinicians are more frequently recognizing CRF as an important symptom 
that negatively affects quality of life (QOL), interferes with daily activity, has potentially devastating social and 
economic consequences, and affects the ability to receive palliative cancer therapy.6 However, only a few 
studies have been conducted to determine whether established therapies for CRF such as physical activity are 
effective in palliative care patients.3,7,8 In addition, prior pharmacological studies for CRF in palliative care have 
shown mixed results.1,7,9 Given the high frequency and adverse effects of CRF and the limited treatment 
options in advanced cancer patients, further research on new treatment strategies is greatly needed. 
Preliminary data from our group10 and others7,10-15 have shown that corticosteroids are able to improve CRF and 
related symptoms in patients with advanced cancer. In a recent study of 84 evaluable patients, oral 
dexamethasone (Dex) at a standard dose of 8 mg daily was associated with significant improvement in CRF.16
There were no significant differences in the adverse effects between patients who received Dex and placebo 
(41/62 vs. 44/58; p=0.14). However, despite improvement, patients still had persistent CRF (56% responded to 
Dex with significant improvement in CRF, whereas 44% had minimal or no improvement). In cancer patients 
receiving treatment and in cancer survivors, physical activity has been shown to improve CRF.16-19 Randomized 
clinical trials among cancer patients who participated in an physical activity program showed significant 
increases in cardiovascular capacity, improved overall health-related QOL, less fatigue, fewer sleeping 

Protocol 2014-0436
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2
problems, and increased self-reported physical functioning, general well-being, self-esteem, and energy.17,18 A 
recent Cochrane meta-analysis18 of 28 clinical trials that included more than 2000 cancer patients confirmed 
these findings. However, the evidence suggests that physical activity has a very modest benefit (effect size 
0.23) in improving CRF.19 
Cancer Illness Therapy-Fatigue (FACIT-F) subscale)20 to these treatments may be due to a lack of effect on the 
multidimensional and multifactorial nature of CRF.21 Hence there is a need to test combined therapies for CRF 
such as higher doses of Dex with physical activity intervention, since these treatments individually target the 
multidimensional causative factors contributing to CRF in advanced cancer. Our long-term goal is to reduce 
CRF and thereby improve QOL in patients with advanced cancer. The objective of the proposed study is to 
evaluate the effects of PA+ Hi Dex for the treatment of CRF in patients with advanced cancer.  
Rationale to conduct this study: 
Cancer-related fatigue (CRF) is more severe and debilitating in patients with advanced cancer than in those 
with early cancer or in survivors. In advanced cancer patients receiving palliative care, moderate to severe 
fatigue is associated with poor quality of life outcomes, performance status scores, frailty and poor overall 
survival. Only a few studies have been conducted to determine whether established therapies for CRF such as 
physical activity (PA) are effective in palliative care patients. Even in early cancer and survivors patients the 
overall clinical effectiveness of PA is low to moderate (Effect size ~0.28). In advanced cancer patients another 
barrier to PA is adherence to the initiation and adherence. In addition, prior pharmacological studies for CRF in 
palliative care have shown mixed results.  
 
Prior study using low dose dexamethasone 4mg orally twice daily was associated with significant 
improvement of fatigue at Day 8 in dexamethasone arm [8.01 (7.81)] compared to placebo arm 
[3.06(7.28)], p=0.005 but the numbers of adverse effects did not significantly differ between the 
groups at 2 weeks and at the end of open label phase (17/62 vs. 11/58, P=0.14; and 20/42 vs 18/47, 
P=0.37). Despite improvement, patients still had persistent CRF (56% responded to Dexamethasone 
with significant improvement in CRF, whereas 44% had minimal or no improvement). The low dose 
dexamethasone 4mg orally twice a day used in our previous study will be our control group and will 
be used to compare dexamethasone 8mg orally twice along with physical activity to evaluate from the 
perspective of feasibility, efficacy, and toxicity it will be also help us to define the effect size for a large 
randomized controlled study. 
The overall hypothesis of this project is that the use of the combination of dexamethasone plus PA is feasible 
and high dose dexamethasone with PA would provide more robust improvement of cancer related fatigue in 
60% of patients due to the anti-inflammatory effect, improvement in symptoms distress improvement overall 
well-being and this would enable the patient in initiation and adherence to the PA intervention and thereby 
engage and sustain PA over the period of 4 weeks. We also anticipate the study will be safe and feasible and 
this based on the data from previous studies in which 341 advanced cancer patients received similar dose of 
dexamethasone or equivalent as will be used in this study of dexamethasone. In addition, measures such as 
excluding patients with history of falls, infections, monitoring the blood glucose and performing the sit and 
stand test will ensure safety in terms of hyperglycemia and myopathy.  
Significance: The proposed research is significant because it will be the first to test the effects of the 
combined interventions of Dexamethasone and physical activity in advanced cancer patients, a group that is 
living longer as more treatments are available yet experience the most severe levels of CRF among cancer 
patients because of the lack of effective treatment options.10,11 As preliminary studies12-15 indicate, we 
anticipate that this combination therapy, if effective, will provide more robust and clinically effective 
improvement of CRF,16 which would facilitate patients continuing cancer therapy since it would be tolerated 
and effective in controlling disease. This study will provide important evidence to show the joint effects of 
Dexamethasone and physical activity in improving CRF. Other important benefits of this study are that it will 
provide important data on the role of combination intervention in other QOL measures such as anxiety, 

Protocol 2014-0436
Rev. August 17, 2016
3
depression, and the role of combination interventions on objective measures of physical activity, strength, and 
pro-inflammatory cytokines. 
C. Preliminary Studies: 
Pharmacologic Treatment of Fatigue: 
establish the high frequency, severity and multidimensional nature of fatigue.12,14,15,17-24 We conducted studies 
of various assessment methods for fatigue and were able characterize fatigue in this patient population.24-28 In 
a preliminary study of 31 advanced cancer patients, we found that methylprednisolone (MP) 32mg/day 
significantly improved CRF (p<0.01) compared with placebo with no significant differences in side-effects 
between groups.14  As shown in Table 1, this study was unable to detect sustained responses to Day 33 
perhaps due to low doses, type of the steroid, and lack of validated tools. In a recently published15 RCT study
of 84 patients with advanced cancer, oral Dexamethasone at 8 mg/day for 14 days was found to be effective in 
alleviating CRF compared with placebo. The mean improvement in the FACIT-F subscale was significantly 
higher in the Dexamethasone group than in the placebo at Day 8 in dexamethasone arm [8.01 (7.81)] 
compared to placebo arm [3.06(7.28)], p=0.005 as well as Day 15(9 [10.3] vs. 3.1 [9.59], P=0.008).15 When 
both the groups received Dexamethasone for 14 more days on an open-label basis (Day15-29), the effect of 
Dexamethasone was not sustained in the Dexamethasone compared with the placebo group (0.67 [9.4] vs. 
6.86 [13]; P=0.044) [fig. 2]. However, the numbers of adverse effects did not significantly differ between the 
groups at Day 15 (primary end point) and at the end of open label phase (17/62 vs. 11/58, P=0.14; and 20/42 
vs 18/47, P=0.37). Based on the preliminary data, we conclude that 8 mg/d of Dexamethasone is safe if 
administered for 7 days as proposed in this study; however, the improvement of CRF was not robust enough 
for sustained clinical benefit. Hence, we hypothesize that the joint effects of a PA+ Hi Dex would result in a 
robust response (defined as 
 points on FACIT-F scores16).  
  

Protocol 2014-0436
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4
Table 2. Corticosteroids (dosage and duration) in the management of cancer 
related symptoms 
Author
Number of 
patients 
Treatment 
Duration 
(days) 
Study 
Drug* 
Equivalent 
Dexamethas
one 
daily dose 
(mg) 
Primary Outcome for the 
study 
Moertal et al. 197415
116
14
Dex
0.75-1.5
Cancer related symptoms 
including low appetite, 
strength, and overall 
survival 
Willox et al. 198426
41
14
PS
2.25
Poor appetite
Bruera et al 198543**
40
14
MP
6
Combination of pain, 
tiredness, anorexia and 
depression 
Della Cuna 198914**
40
56
MP
23
Quality of life
Popiela et al 198913**
173
56
MP
23
Quality of life
Loprinzi et al 199912**
455
30
Dex
3
Low appetite
Hardy et al 200125
160
22
Dex
12
Anorexia, nausea, low 
mood, pain and vomiting. 
Mercadante et al 200111
376
26
Dex, MP
4-16
Cancer related symptoms 
including anorexia, fatigue, 
dyspnea, headache and 
drowsiness 
Bruera et al 200437** 
51 
7 
Dex 
20 
Chronic nausea 
Yennurajalingam et al 
201316** 
84 
14  
Dex 
8 
fatigue 
Paulsen et al 201470** 
50 
7 
MP 
8 
pain 
*MP= Methylprednisolone, Dex=Dexamethasone, PS=Prednisolone 
** Randomized, double blind placebo controlled studies 
 
Prior studies conducted in palliative patients by our team and others used various doses of steriods (Table 2). 
In the 341 patients who received more than 16 mg /day or equivalent dose of dexamethasone for 7 days there 
was no report of significant toxicity due to hyperglycemia and myopathy. 
Physical activity: Prior studies led by Dr. Basen-Engquist (Co-I) tested intervention in patients with highly 
symptomatic prostate cancer (TPRB-98-103-01-PBP)29 and in breast cancer (CA89519).30 The breast cancer 
study improved 6-minute walk performance and QOL.30 In an R01-funded study of physical activity in
endometrial cancer survivors,31 the intervention completed a high percentage and was well received among 
the participants. The same methods will be used in the proposed study.  

Protocol 2014-0436
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An ongoing study in highly symptomatic prostate cancer patients, NCT01410942, conducted by the same team 
as that in the proposed study (PI: Yennu), uses the same standardized physical activity regimen in combination 
with study drug. Table 3 shows the completion rates adherence and safety data of the first 12 patients enrolled 
(blinded). The enrolled patients in this ongoing study had no difficulty in completing all the assessments. Based 
on the preliminary data presented, we conclude that this proposed physical activity would be feasible and safe.  
Inflammatory cytokine studies: Prior studies32-35 by our group showed wide variability in serum cytokine 
levels in patients with advanced cancer and hence the need to assess cytokines levels in LPS activated 
monocytes. Physical activity results in modulation of TNF- , IL-1b, and IL-6,36 interleukin-1 receptor antagonist 
(IL-1RA), TNF-receptors (TNF-R), and IL-10 levels.37 Figure 4 shows the synthesis of TNF-a by LPS-activated 
monocytes isolated from patients at baseline (D0) and at weeks 1- 5 after treatment with Dexamethasone 
(Dex). In patients treated with 8 mg Dex daily (dark histograms), the percentage of LPS-activated monocytes 
that synthesized TNF-
decreased, whereas in patients receiving placebo (light histograms) for the first 2 
weeks there was no change in the percentage of LPS-activated monocytes that synthesized TNF-
from D0 
until week 2. Thereafter, when placebo patients (light histograms) switched to open-label Dex, there was a 
decrease in the percentage of LPS-activated monocytes that synthesized TNF-a. We will be collecting optional 
blood for future research which may include this cytokine analysis. 

Protocol 2014-0436
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6
 
Fig. 3. Change in TNF-
 LPS-activated monocytes from dexamethasone-treated patients and 
placebo-treated patients in double-blind phase (Days 8 and 15) and in dexamethasone-only open-label phase 
(Days 29 and 35). 
 
Figure 4. Monocyte Phenotype and LPS-induced cytokine synthesis.  (A) Monocytes are enumerated in whole 
blood as CD14+SSCmid cells.  (B)  After a 4 hour incubation with LPS, the percentage of cell synthesizing 
cytokines can be enumerated.  C) TNF-
dexamethasone daily.  

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D. RESEARCH DESIGN AND METHODS 
D1.  
Eligibility Criteria:  
Inclusion criteria:  
(A)   A diagnosis of advanced cancer (defined as metastatic or recurrent) 
-
10 scale) on the Edmonton Symptom Assessment Scale (ESAS) 
(B)   The presence of fatigue for at least 2 weeks;  
(C)   Normal cognition;  
(D)   Hemoglobin >8 
months.  
(E)   No evidence of significant anxiety or depression as determined by a total HADS scores of 
<21;  
(F)   Definition of advanced cancer includes those patients who have metastatic or refractory 
disease according to their treating oncologist 
(G) Patients must be able to understand, read, write, and speak English or Spanish.
Exclusion criteria:  
a) Patients with history of hypersensitivity to dexamethasone or having any 
contraindication to physical activity as determined by the treating physician;  
b) Reports a fall in the past 30 days; 
c) Uncontrolled diabetes mellitus as defined by a random blood sugar of >200mg/dl not 
being monitored by their primary care physician  
d) Sepsis and/or acute, chronic, or ongoing infections that are currently being treated with 
systemic antimicrobials 
e) We will exclude patients with current, active Peptic ulcer disease,  
f) Neutropenia as defined by an absolute neutrophil count (ANC) of < 1000 cells/mm 
g) Regular participation in moderate- or vigorous-intensity physical activity 
 
h) Severe cardiac disease (New York Heart Association functional class III or IV) or 
coronary artery disease. 
Rationale for Various Tumor Types:  
(1) CRF is a syndrome that results from increased production of inflammatory cytokines and tumor by-
products. This pathophysiology is more related to the interaction between cancer and the host rather than to 
any specific histology, as demonstrated by similar rates of frequency and severity of fatigue across various 
tumor types in patients with advanced cancer.22,24  
(2) The frequency, severity, and mechanisms of CRF in patients with advanced cancer who have various 
tumor types are largely the same, on the basis of clinical trials of methylphenidate,42 donepezil,14 and fish oil40 
in the treatment of CRF by our group and according to studies by other groups.  
(3) By including patients with various tumor types, we will obtain a more representative distribution in terms of 
age, sex, and behavior than we would in a study of patients with a single tumor type.  
(4) Despite the type of cancer that patients have, those with advanced cancer who are undergoing treatment 
for CRF, rate CRF as the most significant of all symptoms that affect their QOL. Our ultimate goal is to reduce 

Protocol 2014-0436
Rev. August 17, 2016
8
these symptoms in this distressed cohort/population. Eligible patients with complete the study assessments (as 
detailed in Table 2).  
Patient Recruitment: 70 patients will be recruited from outpatient centers of palliative care, pain, and 
oncology at the MD Anderson Cancer Center, Houston, Texas.  
For this study, we will use a randomized double-blind design. Seventy patients will be randomized equally 
between the 2 treatment arms. The randomized assignment will be obtained via the Department of 
Biostatistics, Clinical Trial Conduct Website. 
 
D2. Treatment Plan:  
Potential study subjects will be asked for verbal consent prior to completing the HADS to determine eligibility.
Patients who are eligible and interested in participating will be asked to give written consent and then 
randomized into 1 of the 2 arms of the study. The length of dexamethasone treatment is 7 days. Patients will 
complete the assessments as shown in Table 4. 
 in all 
cases prior to study enrollment. 
Figure 5 
 
The research nurse/coordinator will conduct all baseline assessments and follow-up as shown Table 2. The 
pharmacological treatment assigned to individual patients will be known to only the statistician and the 
investigational pharmacy. The research nurse will then provide instructions and prescriptions for the study 
medication.  The research nurse/coordinator will then perform scheduled assessment as per Table 2. 
Rationale for use of one week of dexamethasone and four weeks of physical activity intervention.
In cancer patients receiving treatment, physical activity (PA) has been shown to improve CRF (Cramp F 2012). 
Randomized clinical trials among cancer patients who participated in an PA showed significant increases in 
cardiovascular capacity; improved overall health-related QOL; less fatigue; fewer sleeping problems; and 
increased self-reported physical functioning, general well-being, self-esteem, and energy 41,42. A recent 
Cochrane meta-analysis (Cramp F 2012) of 28 clinical trials that included more than 2,000 cancer patients 
confirmed these findings. However, the evidence suggests that physical activity has a very modest benefit 
(effect size 0.23) in improving CRF 13. Also PA is a universal prescription given to patients at our supportive 
care center. The low effect size regards to benefit of physical activity is due to low adherence. 
We therefore hypothesize that the use of high dose dexamethasone for 7 days would provide more robust 
improvement of cancer related fatigue in 60% of patients due to the anti-inflammatory effect, improvement in 
symptoms distress improvement overall well-being and this would enable the patient in initiation and 
adherence to the PA intervention and thereby engage and sustain PA over the period of 4 weeks. 
Objective #1: To determine the feasibility, adherence, and satisfaction with PA+ Dexamethasone.

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Rev. August 17, 2016
9
Since no study to date has determined the feasibility of using the combined intervention of Dexamethasone
and physical activity in fatigued patients with advanced cancer, the primary objective in this study is to obtain 
preliminary data for feasibility, adherence, and satisfaction with use of PA+ Dexamethasone. Variables to be 
evaluated include rates of participant recruitment and retention, frequency of use of the physical activity 
prescription and % of completion, the proportion of pills taken, acceptability of the physical activity and study 
drug to patients, and barriers to participation. Adherence will be calculated as the mean (across all patients) 
percentage of total prescribed endurance physical activity/walking minutes.  Our experienced team is confident 
that we can successfully accrue the necessary number of study patients, based on the prior successful accrual 
of more than 500 patients in other fatigue treatment trials including studies involving combined therapies 
(NCT01410942) for CRF39 that had eligibility criteria similar to those in our proposed study.12,18-21,40
Objective #2: To explore the preliminary efficacy of EX+ Hi Dex group and EX+ Lo Dex groups on CRF as 
measured by FACIT-F at the end of one week: To test this hypothesis, we will use a randomized controlled 
design. The primary outcome would be a change in FACIT-F subscale scores from baseline to Day 8.
FACIT-F is a well-validated QOL instrument.43 This FACIT-F fatigue subscale was chosen as the primary 
outcome measure since it has been widely used in CRF treatment trials by our team and by others.12,18,19,21,45
The 13-item fatigue subscale is a patient-rated assessment of intensity of fatigue and its related symptoms on 
0.95), sensitivity of 
0.92, and specificity of 0.6923. 
Drug Intervention: Eligible patients randomized to receive a high-dose regimen [8 mg of 
dexamethasone orally, twice a day for 7 days] or low-dose regimen [4 mg of dexamethasone, twice a 
day for 7 days]. All patients will be given a proton pump inhibitor during the course of their treatment.
During the study blood glucose will be monitored and hyperglycemia will be managed at the Supportive 
Care Center by the PI (Dr Sriram Yennu MD, MS) under the supervision of our Endocrine collaborator 
(Dr Busaidy) who will be consulted as necessary. We will collect blood samples at baseline and day 29 
and patients will perform fasting finger sticks (after instruction) using the glucometer on day 3 (+/-1), 
day 8 (+/-1), and day 15 (+/-1) to monitor the blood glucose levels. 
Physical Activity or Exercise Intervention: For this study, we plan to use a standardized physical activity 
intervention supervised by the Research Staff. We will use a combination of a supervised and home physical 
activity regimen. The weekly regimen will include a graded resistance physical activity program and a walking 
regimen. The graded resistance physical activity program has been designed to strengthen the major muscles 
of the lower body, including the quadriceps, hamstrings, gluteus maximus, and hip flexor group. These 
exercises will include (but will not be limited to) squats, lunges, leg extensions, leg curls, and hip extensions. 
position independently. We plan to use resistance tubes as our mode of resistance. These tubes are color-
coded to indicate their specific resistance level: light, moderate, or hard. The resistance exercise sessions are 
to be completed 3 days a week, allowing at least 48 hours between each session. This allows the muscles 
adequate time for rest and prevents overtraining. The graded resistance program will be designed so that the 
individual begins with a lighter resistance and progresses to heavier resistance once a level has been 
mastered. The participant will begin with 2 sets of 12 repetitions at the established intensity level. If the 
participant is not able to complete 2 sets of 12 repetitions for any one of the exercises assigned, we will ask 
them to do what they are able to with or without bands and document in the records. The individual will engage 
in a walking program. Since the level of aerobic fitness will vary among participants, the intensity and duration 
of the walking program will be established based on t
-minute walk test). The walking 
recommendation may vary in frequency and duration, but the intensity will be moderate. This intervention may 
include a 10-min walk 1-3 times a day at a moderate intensity level or up to a 30-min walk once a day at a 
relatively hard intensity level. To encourage and monitor adherence to the walking program, we will provide 
participants with a pedometer and an exercise log to record the number of steps they take each day. The 
participants will be asked to walk a minimum of 5 days a week at the duration established by the Research 

Protocol 2014-0436
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Staff.  At the first study visit, the research staff will meet with each participant to evaluate his or her current 
strength and aerobic fitness level and to teach the assigned exercises. Participants will be given an exercise 
log to record their resistance exercise sessions as well as their walking sessions. Participants will also receive 
a pedometer to be used during the entire intervention, which provides a tool to help them monitor their physical 
activity. They can set goals for the number of steps per day and record the steps on the pedometer to monitor 
their progress. They will receive weekly phone calls from the research staff after the initial in-person 
instructional meeting to assess their progress and to help them identify and overcome any barriers to 
completing the exercise program as a part of a formal behavioral support program (i.e., self-monitoring, goal 
setting, problem-solving overcoming barriers, cognitive restructuring, and rewarding oneself). The frequency, 
intensity, and duration of the assigned exercises will also be evaluated and adjusted as necessary. 
D3. Measures: We will use the 30 second chair stand test, six-minute walk test, and an accelerometer. A self-
report physical activity questionnaire, the Godin leisure-time physical activity questionnaire, will be used to 
complement the objective measures. A Myopathy questionnaire will be administered to assess patient-reported 
weakness due to myopathy (Appendix O) at baseline, Days 8, 15, 29, and one month after the last visit.  
Respironics Actiwatch 2 accelerometers will be used to objectively measure physical activity for patients who 
agree to this optional procedure. These accelerometers complement the self-report for estimating physical 
activity and can record physical activity in 2 minute increments for 30 days. Patients will wear the 
accelerometer for the four weeks they are on study. Physical activity data will be downloaded to a personal 
The 
Satisfaction Scale (Appendix J) and Satisfaction Questionnaire (Appendix P) will be used to assess patient 
satisfaction. These questionnaires will be administered and physical performance measures performed on the 
last day the research nurse/ coordinator sees the patient. One month after the last visit, the questionnaires will 
be administered (in person or by telephone) and physical performance measures will be performed if the 
patient is in clinic. 
Objective #3: To explore the effects of PA+ Dexamethasone on the various dimensions of fatigue (PROMIS), 
i.e., affective/emotional (HADS); physical/behavioral (MFSI-SF, ESAS, PSQI), physical activity and function (30 
second sit-to-stand test, six minute walk). 
A. PROMIS measures key symptoms and health concepts applicable to advanced cancer, enabling efficient 
and interpretable clinical trial research and clinical practice application of patient-reported outcomes 
(PROs).45,46 The PROMIS fatigue measure used in the study was found to be highly correlated with the legacy 
measures.9  
B. MFSI-SF consists of 30 items designed to assess the multidimensional nature of fatigue.47 Ratings are 
summed to obtain scores for 5 subscales (general fatigue, physical fatigue, emotional fatigue, mental fatigue, 
and vigor).  
C. HADS: This 14-item questionnaire has been validated in a number of clinical situations and has been widely 
used in medically ill patients.48  
D. PSQI: This instrument provides a brief, clinically useful assessment of a variety of sleep disturbances that 
might affect sleep quality. 49  
E. 30 second sit-to-stand test: The 30 second sit-to-stand test will be administered at baseline, Day 29, and 
one month follow up visit if the patient is in clinic. The 30 second sit-to-stand test will assess lower body 
strength.51  A standard chair without arms with an approximate height of 17 inches will be used.  After a 
demonstration, a practice trial of one repetition will be done to check for proper form.  On the start signal, the 
participant rises to a full stand and then returns to a fully seated position.  The patient completes as many full 
stands as possible within a 30 second period. We will also assess the sit-to-stand test to monitor for myopathy. 
Previous studies also have suggested that physical activity would reduce the risk of myopathy due to steroids.

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F. Six minute walk Test: The 6 minute walk test will be administered at baseline, Day 29, and one month 
follow up visit if the patient is in clinic. This will be used to assess physical function and has been 
recommended by the American Thoracic Society (ATS) as an objective measure of functional capacity.  This
test has been found to be an objective measure of functional capacity in patients with chronic respiratory 
conditions, fibromyalgia, stroke, and cancer. Our group has used this methodology in the assessment of 
fatigue and dyspnea. In the six-minute walk test, participants are asked to walk as fast and as far as they can 
for six minutes, and the distance walked is measured.  The test will be conducted in an area with a 250 foot 
hallway and minimal traffic.  The six-minute walk test has high test-retest and inter-tester reliability, and its 
validity is supported by correlations with self-report measures of fatigue and functional status 71. The patient 
will be strongly encouraged to give a maximum effort.  
G. Cytokine assessments/chemistries:  Optional blood will be collected and stored for future cytokine 
research.   
Chemistries to be collected include chloride, sodium, potassium, carbon dioxide, calcium, and glucose will be 
analyzed in the diagnostic center as standard of care.  
During the study blood glucose will be monitored (Table 4). We will have our Endocrine collaborator (Dr 
Busaidy) who will work with us for patients that become hyperglycemic and will be consulted as necessary. We 
will collect blood samples at baseline and day 29 and patients will perform fasting finger sticks (after 
instruction) using the glucometer on day 3 (+/-1), day 8 (+/-1), and day 15 (+/-1) to monitor blood glucose 
levels.  
Table 4. Study Assessments 
ASSESSMENTS 
BASELINE 
 
DAY 
8 
(± 3) 
DAY 
15 
(± 3) 
DAY 
21 
(± 3) 
DAY 
29 
(± 3) 
 
1 month 
post 
study   
History/Physical Exam 
X 
 
 
 
X 
 
Zubrod score 
X 
 
 
 
 
 
Medication review 
X 
X 
X 
X 
X 
X 
FACIT-F, ESAS , MFSI-SF, HADS, 
PSQI 
 
X 
 
 
X 
 
 
X 
 
X 
PROMIS 
X 
X 
X 
 
X 
X 
Myopathy Questionnaire 
X 
X 
X 
 
X 
X 
Physical Performance tests (30 
second chair stand test and 6 
minute walk test) 
X 
 
 
 
X 
X 
Physical activity (pedometer, 
accelerometer, Godin leisure-time 
physical activity questionnaire) 
X 
X 
 
 
X 
X 
Hematology/chemistry/optional 
blood 
X 
X©
X© 
 
X 
 
Toxicity evaluation 
X 
X 
X 
X 
X 
Satisfaction Scale and Satisfaction 
Questionnaire 
 
 
 
X 
X 
 The purpose of 1 month post-study is to assess the long-term effects of study  treatment 
 
© During the study, blood glucose will be monitored. We will have our Endocrine collaborator (Dr. Busaidy) who will work with us for 
patients that become hypoglycemic and will be consulted as necessary. We will collect blood samples at baseline and day 29 and 
patients will perform fasting finger sticks (after instruction) using the glucometer on day 3 (+/- 1), day 8 (+/-1) and day 15 (+/-1). 

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E. STATISTICAL CONSIDERATIONS: 
The primary study objective is to assess the feasibility, adherence, and satisfaction with Dexamethasone
combined with physical activity. If the patient states that they did participate in the study by taking at least a dose 
of drug or participated in any exercise intervention they are evaluable. To be considered adherent the patient 
needs to meet the adherence parameters of study drug, walking exercise and resistance exercise. For this study 
we will use only the available data provided by the patient to calculate feasibility. If no data is provided by the 
patient, then they will be considered non-compliant (if evaluable). If only one type of data (study drug or walking 
exercise or resistance exercise) is available, we will use the available data to consider adherence. If a patient 
provides two types of data then that patient would have to satisfy the adherence thresholds for both types of 
.  Adherence to study drug is defined as having taken at least 10 pills. Adherence 
to walking exercise is defined as at least 90 min every week. Adherence to resistance exercise is defined as at 
least 1.8 sets of exercises every week. The study will be considered feasible if > 75% of patients demonstrate 
adherence. Satisfaction is defined as any patient who choose options somewhat satisfied or completely satisfied. 
We will use either phone or exercise dairies to document compliance. With 35 patients in each arm, a 95% 
confidence interval for 0.75 would have a half width of 0.15. The key secondary end point of the study is the 
difference between the FACIT-F subscale score at baseline and at 8 days. We will estimate the mean difference 
in FACIT-F scores with 95% confidence intervals.  
Sample Size Justification: Our prior data16 [Fig.2], showed that 4mg twice a day of dexamethasone resulted in 
-F score) in 33% of patients. In this feasibility 
study, a change in FACIT-F subscale scores will be evaluated in the HiDex group (8mg orally of dexamethasone
twice a day for 7days) and LoDex group (4mg orally twice a day of dexamethasone for 7days), both groups also 
will also undergo 4 weeks of physical activity intervention [See Treatment Schema Fig 5 below].  In order to 
obtain a reliable estimate of clinically relevant or robust improvement at Day 8, physical activity plus HiDex group 
in Physical Activity plus LoDex group, we need 35 in each group with a total sample size of 70. If the robust 
response proportions are 0.33 or 0.60, the half-widths of 95% confidence intervals will be 0.16. As this study is 
designed to be a non-comparative trial to assess feasibility, adherence and satisfaction, a sample size of 70 
patients would be sufficient to evaluate the primary objective of this preliminary study and therefore no additional 
patients to account for dropouts are added. 
To address issues related to missing data, we will perform multiple imputation analyses.72 We recognize the 
potential need for steroids while receiving other therapies and we will collect the information and include as 
covariates in the secondary analysis.  Since FACIT-F scores will be obtained at 0, 8, 15, 29, and 60 days, we 
will also analyze the data by using linear mixed effects longitudinal models. We will perform exploratory data 
analyses to assess treatment effects for other continuous outcome variables including MFSI-SF, PROMIS, 
HADS, and cytokine levels by using the same statistical methods described above. Before performing inferential 
procedures, we will conduct extensive descriptive statistical analyses of the outcome and predictor variables. 
Standard descriptive statistics, including means, standard deviations, ranges, and frequencies, will be computed 
where appropriate. Distributional characteristics of relevant variables will also be closely examined with use of 
box plots and histograms. If the data do not appear to be approximately normally distributed, transformations will 
be made to the data, or appropriate nonparametric methods will be used. 
F. PROTECTION OF HUMAN SUBJECTS 
We will obtain authorization for use and disclosure of Protected Health Information (PHI) from patients. This 
will be included in the written informed consent. We will follow The Health Insurance Portability and 
Accountability Act (HIPAA) guidelines during the study based on the following 3 criteria: 1) All research staff 
have completed research training concerning confidentiality of protected health information. Patient's name, 
social security number and other patient identifiers will not be used for data collection. Only protocol accession 
numbers will be used in data collection. The principal investigator will keep the collected data in a locked file 
cabinet; 2) Data collected for this study will be retained for 2 years after publication of the research and then it 
will be destroyed by a mechanic shredder; 3) The data will be used for this study only. Only the PI, the project 

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13
manager, the research nurse and the data manager will have access to the data. The data will not be disclosed 
to any other parties. 
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