Time-Restricted Eating and Cancer: Clinical Outcomes, Mechanisms, and Moderators
Phase: NA
Conditions: Colorectal Cancer, Breast Cancer
Sponsor: Cedars-Sinai Medical Center

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Time-Restricted Eating and Cancer:  
Clinical Outcomes, Mechanisms, and Moderators 
NCT04722341 
 
 
January 8, 2023 
 
Jane C. Figueiredo, Ph.D. 
Cedars-Sinai Cancer 
 
Sarah-Jeanne Salvy, Ph.D. 
Cedars-Sinai Cancer 
 
Courtney Peterson, Ph.D. 
University of Alabama at Birmingham  
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY .............................................................................................................. 4 
GENERAL INFORMATION ........................................................................................................ 5 
1.0 BACKGROUND, RATIONALE .............................................................................................. 5 
2.0 STUDY OBJECTIVES ............................................................................................................ 5 
3.0 Study Population ...................................................................................................................... 6 
3.1 Selection of the Study Population ...................................................................................... 6 
3.2 Inclusion Criteria ................................................................................................................ 6 
3.3 Exclusion Criteria ............................................................................................................... 6 
3.4 Subject Screening and Enrollment .................................................................................... 7 
3.5 Subject recruitment............................................................................................................. 7 
4.0 STUDY DESIGN AND METHODS ....................................................................................... 7 
5.0 DATA COLLECTION and MANAGEMENT ...................................................................... 15 
5.1 Data Procurement ............................................................................................................. 15 
5.2 Time Period of Data Under Review ................................................................................. 15 
5.3 Variables Collected ........................................................................................................... 15 
5.4 Source Documents ............................................................................................................. 15 
5.5 Data Collection and Storage ............................................................................................. 15 
5.6 Confidentiality and Security of Data ............................................................................... 16 
6.0 Data and Safety Monitoring .................................................................................................. 16 
6.1 Data and Safety Monitoring Plan .................................................................................... 16 
6.2 Data Monitoring and Quality Assurance ........................................................................ 17 
6.3 Safety Monitoring .............................................................................................................. 17 
6.4 Multicenter Monitoring Plan ........................................................................................... 18 
6.5 Record Retention ............................................................................................................... 18 
6.6 Adherence to Protocol ....................................................................................................... 19 
6.7 Emergency Modifications ................................................................................................. 19 
6.8 Protocol Exceptions and Eligibility Waivers .................................................................. 19 
6.9 Other Protocol Deviations ................................................................................................ 20 
6.10 Amendments to the Protocol .......................................................................................... 20 
6.11 Obligations of Investigators ........................................................................................... 20 

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7.0 DATA MANAGEMENT & STATISTICS ............................................................................ 21 
8.0 STUDY MANAGEMENT ...................................................................................................... 23 
8.1 Conflict of Interest ............................................................................................................ 23 
8.2 Institutional Review Board (IRB) Approval and Consent ............................................ 23 
8.3 Registration Procedures ................................................................................................... 23 
8.5 Data Management and Quality Control and Reporting ................................................ 25 
9.0 REFERENCES ...................................................................................................................... 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY  
Purpose and Knowledge to be 
Gained 
 
• The purpose of this study is to test whether the timing 
of meals can improve treatment-related adverse 
events, influence tumor biology, and alter a person’s 
mood and behaviors. 
• This work has the potential to understand the role of 
meal timing and alignment of circadian rhythm on 
toxicity burden, tumor regression, and ultimately 
provide evidence-based knowledge to influence the 
standard of care for cancer patients.  Importantly, 
these findings may have broad oncologic 
implications, likely extending to other cancer disease 
sites and treatment paradigms. 
 
Research Procedures 
 
The primary research procedures are: 
• Randomization into one of two arms (TRE or 
control) 
• Medical chart abstraction  
• Blood draws 
• Continuous glucose monitoring (CGM) 
• Stool collection 
• Weight, height, heart rate, and blood pressure 
• Short weekly surveys (a few minutes per week) 
• Portable accelerometry sensor to measure physical 
activity 
• Questionnaires about pain, fatigue, sleep, mood, 
physical activity, food intake, quality of life, and 
social life   
• Exit interview (end of intervention) 
Subject Population 
• Any sex/gender of any ethnic/racial background  
• Age ≥ 18 years 
• Histologically confirmed rectal cancer stage II, III, or 
IV (only if definitive intent) per AJCC criteria 
• BMI ≥ 18.5 kg/m2 
• Plan to receive total neoadjuvant therapy (TNT) with 
5-FU based regimen 
• Willing and able to adhere to the assessments, visit 
schedules, prohibitions, and restrictions 
Duration 
• The study includes three required study visits 
between enrollment and surgery (or the equivalent 
time frame).  
• The total study duration is up to 5 years.  

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GENERAL INFORMATION 
CSMC Co-Investigators  
Jun Gong, MD 
Katelyn M. Atkins, MD, PhD 
Karen Zaghiyan, MD 
Gillian Gresham, PhD 
Márcio Augusto Diniz, PhD 
Alix Sleight, PhD 
Sponsor/Funder 
National Institutes of Health/ National Cancer Institute   
Collaborating Institutions 
Involved in the Research 
University of Alabama at Birmingham:  
Courtney Peterson, PhD 
Drew Gunnells, MD 
Robert Hollis, MD 
1.0 BACKGROUND, RATIONALE 
Combining fasting with chemotherapy is known to cause complete tumor regression and long-
term survival in animal models. According to the Differential Stress Sensitization (DSS) theory, 
acute fasting sensitizes tumor cells to the cytotoxic effects of chemotherapy and radiation, while 
protecting healthy cells by increasing stress resistance. These effects are believed to be largely 
mediated via the Insulin-like Growth Factor (IGF-1) pathway. However, extended fasting can be 
challenging for patients and poses undue health risks. A number of alternative intermittent 
fasting regimens have been proposed to overcome the challenges of prolonged caloric restriction. 
One promising approach is time-restricted eating (TRE), which involves eating within a period 
of 10 hours or less, followed by fasting for at least 14 hours daily. TRE does not involve 
extended caloric restriction, and because of its simplicity, it may be more sustainable than other 
fasting regimens. TRE improves several cardiometabolic endpoints independent of calorie 
restriction in both animals and humans, including insulin sensitivity, blood pressure, fat 
oxidation, and hunger. Our team’s pilot and feasibility trials suggest that TRE may also have 
anti-cancer effects: it decreases IGF-1 levels, reduces oxidative stress, upregulates antioxidant 
defenses, and enhances autophagy. Moreover, our data suggest TRE is sustainable, as 
participants were adherent 6.0 ± 0.8 days/week over a 14-week period. These findings lead to the 
following provocative question: Can TRE reduce treatment-related toxicity, induce tumor 
regression, and improve both patient-reported and clinical outcomes? We propose to conduct the 
largest randomized controlled trial of any form of intermittent fasting in patients undergoing 
cancer treatment. We focus on patients with localized rectal cancer because it is one of the few 
treatment paradigms in which tumor characteristics can be measured before and after 
chemoradiation therapy.  
2.0 STUDY OBJECTIVES 
This research will answer three key questions:  
(1) Can TRE improve clinical outcomes, including treatment toxicity, patient-reported outcomes, 
and increase the chances of tumor regression (i.e., help shrink the tumor)?  

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(2) Do the underlying molecular mechanisms support the Differential Stress Sensitization 
theory?  
(3) How does TRE affect mood, social functioning and lifestyle behaviors to moderate patient 
outcomes?  
As the largest randomized controlled trial of TRE in cancer patients, we expect this trial will 
greatly influence clinical practice 
3.0 STUDY POPULATION  
 
3.1 SELECTION OF THE STUDY POPULATION 
The study population includes adults diagnosed with localized rectal cancer (ICD-10 
C20, stage II, III, or IV [if definitive intent]) who receive neoadjuvant treatment as part of 
their clinical care. All patients are treated at Cedars-Sinai Medical Center, UAB or 
referring sites.  
 
3.2 INCLUSION CRITERIA 
• Any sex/gender of any ethnic/racial background  
• Age ≥ 18 years 
• Histologically confirmed rectal cancer stage II, III, or IV (if curative) per AJCC 
criteria 
• BMI ≥ 18.5 kg/m2 
• Will receive total neoadjuvant therapy (TNT) with 5-FU based regimen 
• Willing and able to adhere to the assessments, visit schedules, prohibitions, and 
restrictions 
 
3.3 EXCLUSION CRITERIA  
Applicants will not be eligible to participate if they meet any of the following criteria: 
• History of cytotoxic chemotherapy ≤12 months prior to rectal cancer diagnosis  
• Allergic reaction to any of the treatment agents 
• Any prior pelvic radiotherapy 
• Currently active second malignancy other than non-melanoma skin cancers or 
cervical carcinoma in situ 
• History of GI perforation ≤12 months prior to enrollment 
• History of predisposing colonic or small bowel disorders with severe or rapidly 
worsening symptoms (not related to current cancer symptoms) 
• Receiving any parenteral nutrition or enteral (tube) feeding or using similar 
nutritional supplement during the study period 
• History of uncontrolled CHF defined as NYHA Class III or greater 
• Pre-existing grade ≥3 neuropathy 

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• Currently participating in or has participated in a study of an investigational agent 
or investigational device ≤4 weeks of the first dose of treatment 
• Pregnant or breastfeeding  
• Currently perform overnight shift work more than one day/week on average  
• Strictly adhering to a <10-hour eating window on most days  
• Known psychiatric or substance abuse disorders that would interfere with 
adhering to the requirements of the trial 
 
3.4 SUBJECT SCREENING AND ENROLLMENT 
All screening and identification work will be done via study staff using approved 
methods for patient contact and recruitment including EHR, Deep6, electronic 
communications and/or telephone. 
3.5 SUBJECT RECRUITMENT 
Participants will be recruited from Cedars-Sinai Medical Center (CSMC), University of 
Alabama’s O'Neal Comprehensive Cancer Center (UAB), and from referring sites using 
two different approaches: 
Clinic. At CSMC, UAB or referring sites, the study oncologists (co-Is) or referring 
physicians/surgeons will introduce the study to their patients and connect interested 
patients with study staff. If the patient expresses interest in participating, staff will 
carefully review the full consent form with the patient in person, via phone, or via  IRB-
approved electronic communication platforms (such as Zoom) and answer the patient’s 
questions about the study. Participants will be allowed to electronically sign consent 
forms online using DocuSign, REDCap’s e-consent tool, or printed forms in-person. 
Medical Records. At CSMC and UAB, research staff will review medical records of 
potential participants in order to identify patients who may be eligible. Deep6 (or the 
equivalent) will also be used for rapid searches of electronic medical records to identify 
patients with specified criteria to recruit into studies. In other instances, patients will be 
contacted by the research team only after the treating physician/surgeon has broached the 
topic of participation in a research study and received confirmation that the patient is 
interested in learning more about the trial. The treating physician/surgeon will be 
provided with the study consent form and any other information summarizing study 
participation that has been approved for use with potential participants. After the initial 
recruitment process, a follow-up phone call will be made by a trained recruiter to answer 
questions and solicit participation if study consent was not received by treating physician 
or study coordinator at in-person visit.  
4.0 STUDY DESIGN AND METHODS 
This study is a prospective, single-blinded, two-parallel-arm, randomized controlled superiority 
trial comparing time- restricted eating (TRE) to a control eating schedule (Control). We will 
enroll 300 economically, ethnically, and racially diverse women and men newly diagnosed with 

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rectal cancer (stage II, III, or IV [if definitive intent]) and who are undergoing TNT. Patients will 
be enrolled from Cedars-Sinai Medical Center (Los Angeles, CA), UAB's O'Neal 
Comprehensive Cancer Center (Birmingham, AL) or referring sites. Randomization will be 
blocked in permuted blocks of random size and stratified by radiation sequence (before vs. after 
chemo), T stage (T4 vs. T3 or less), sex (male vs. female), and site (CSMC vs. UAB). The 
randomization list will be completed by the biostatistician and uploaded in REDCap. Behavioral 
counselors will randomize eligible participants using the REDCap randomization tool. 
Providers and outcome assessors will be blinded, except for S.J.S., counselors, and dietitians 
who cannot be blinded as they are providing counseling/safety monitoring for the intervention. 
Participants will also not be blinded to the intervention but will not be aware of which arm is 
expected to have a better outcome. 
 
Intervention Arms. All participants will receive the standard of cancer care from their 
respective healthcare providers. We will aim to enroll most participants shortly before or at the 
time of starting treatment, though patients may enroll after starting treatment as long as they have 
not complete a majority of their planned oncologic treatment. Participants will be randomized to 
one of two groups:  
(1) Time-restricted eating (TRE): a consistent daily ≤8-hour eating period, starting within 2.5 
hours after waking up, or  
(2) Control group: ≥12-hour eating period each day.  
Participants will be instructed to follow their assigned meal-timing schedule ≥6 days/week 
every week. To account for inter-individual differences in sleep and circadian rhythms, we timed 
the TRE schedules relative to sleep time (not clock time), which is a reasonable proxy for 
circadian time. The control group was designed to mimic typical eating habits in the U.S., as data 
from NHANES suggest that the median American eats over a ~12-hour period each day.1 Aside 
from these general prescriptions, no set number of snacks, meals, or calories will be prescribed. 
Instead, we measure how TRE affects self-reported meal-times, meal frequency, and food intake 
through a combination of daily adherence surveys and 3-day food records.  
 
Standard of Care. All participants will receive the standard of care at CSMC, UAB and 
referring sites. Standard of care is provided by registered dietitians with master's degrees and 
Sample schedules for participants who wake up at 7:00 AM for each intervention arm   

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board-certification in oncology nutrition. Every new patient starting chemotherapy in the 
infusion center will meet with a dietitian for a nutrition consultation. Patients can also be referred 
to a dietitian by a physician if warranted by the malnutrition screening tool (MST) and the 
Wellbeing Screening Tool. Nutrition consults include a nutrition assessment, development of 
individualized nutrition care plans, and nutrition counseling and/or education. Dietary 
recommendations and goal setting are based on cancer diagnosis, medical history, treatment 
plan, laboratory values, nutrition-focused physical exams, and the patient's personal dietary 
preferences. Follow-up appointments are scheduled based on clinical need and nutrition risk 
(high, moderate, low) as determined by the dietitian, as well as patient preference. If there are 
any differences in standard of care practices as described here at the referring sites, then local 
site practices will be followed. For this trial, all participants will be evaluated by a dietitian at 
enrollment (45 minutes of one-on-one diet counseling) and re-evaluated monthly to monitor 
participants' weight, blood pressure, and adverse events. Participants may receive more frequent 
dietary counseling, if recommended by the MPIs and/or physicians. 
Intervention Dosage and Fidelity. Intervention fidelity encompasses integrity (interventions are 
implemented according to established procedures) and differentiation (interventions are distinct 
from one another).37 We will implement the following strategies and safeguards to preserve 
intervention integrity and differentiation: (1) Comprehensive assessment of the standard of 
care avoids content overlap between intervention arms, (2) asking participants to record the time 
they started and finished eating every day, and (3) frequent contacts with participants to review 
adherence to meal timing and to problem-solve issues and challenges encountered. In our 
experience, participants feel comfortable reporting whether they followed the assigned meal 
schedule and report challenges precluding them from adhering to meal timing. If a participant 
adheres to meal timing protocol <4 days/week, a follow-up call or videoconference will be 
scheduled to address challenges and to counsel participants. Each participant will meet monthly 
with the clinical dietitian to review his or her dietary intake and to address concerns. 
Behavioral Counseling. All participants will meet with a behavioral counselor who is also a 
dietitian (trained and supervised by S.J.S.) on a frequent basis to promote adherence. During the 
first one-hour counseling session, the dietitian will explain their assigned study arm and answer 
questions. Thereafter, participants will meet with their counselor weekly for the first month, and 
monthly therafter, unless additional support is needed. Follow-up counseling sessions will 
typically be short (~15-30 minutes). 
Adherence. Participants in both groups will be instructed to follow their assigned eating 
schedule at least 6 days/week every week. Participants will be asked to self-report their 
adherence using a weekly survey, which asks participants to record the time they start and finish 
eating each day and to document any reasons for non-adherence. Participants may complete the 
survey via REDCap, by text message, or on paper, as preferred. Days with missing data will be 
counted as non-adherent. If a participant adheres to their assigned meal timing protocol <4 
days/week, a follow-up call or videoconference will be scheduled to address challenges and to 
help problem solve barriers to adherence.   

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Reducing Attrition. We will use strategies that we have found effective for retention, such as: 
(1) providing all participants with a $50 gift card at 3 data collection timepoints, with all 
incentives paid after assessments have been completed; (2) ensuring regular contacts (texts or 
calls) with all participants to maintain engagement and foster open communication; (3) 
acknowledging birthdays and milestones; (4) providing reminder phone calls before assessments; 
and (5) seeking contact information of relatives or friends to be able to reach participants. In 
addition, Internet-based data collection will allow us to monitor patient compliance in real-time 
and provide phone, text, and email reminders for timely completion as needed 
 
Clinical and Outcomes Assessment: 
 
Medical Chart Abstraction. Several clinical variables will be extracted from medical records, 
including demographics, anthropometrics, medical history, vital signs, tumor markers (e.g., 
CEA) the date of diagnosis, disease stage (TNM staging), MSI status, surgical treatment (e.g., 
dates and type), chemotherapy (e.g., agents, dose, dates and number of infusions), and radiation 
therapy (e.g., dates, number of treatments, and dose). Treatment-related toxicities will be also 
extracted from medical records. We will use the standard approach to AE reporting in cancer 
trials, which is the Common Terminology Criteria for Adverse Events (CTCAE), maintained by 
the US National Cancer Institute (NCI). 
 
Testing Visits. Testing visits will be used primarily to collect blood samples, anthropometrics, 
and vital signs and to administer questionnaires, continuous glucose monitors, and 
accelerometers. In-person testing visits will be conducted at three timepoints: baseline, in the 
middle of the intervention, and post-intervention. The baseline visit will be conducted as soon as 
possible after consenting each patient. The post-intervention visit will be conducted in the couple 
weeks prior to surgery or when surgery would have been scheduled. Each testing visit will be 
conducted after a 8-hour or longer fast. To reduce participant burden, participants may choose to 
complete their questionnaires at home, rather than during the in-person testing visit.  
 
Co-Primary Endpoints. The co-primary endpoints will be the pathological Complete Response 
(pCR) rate and treatment-related toxicity. pCR will be defined as an absence of residual invasive 
cancer on hematoxylin and eosin evaluation of the complete resected rectal specimen and all 
sampled regional lymph nodes. It will be treated as a binary variable. The Patient Reported 
Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE v.5) measurement 
system will be used to measure treatment-related toxicities. We will administer the PRO-CTCAE 
on a weekly basis throughout the intervention and calculate the average over all items for each 
time point. Surveys will be timed relative to the start of each oncologic treatment segment.  
 
Secondary Endpoints. Secondary endpoints include the Clinical Complete Response (cCR), 
tumor volume, objective response rate (ORR), neoadjuvant rectal (NAR) score, provider-
reported adverse events, health-related quality of life, and other clinical outcomes. Descriptions 
of the secondary endpoints are provided below. 
 

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• Clinical Complete Response (cCR). A cCR will be defined as the clinical absence of 
residual disease on physical examination, endoscopic examination, and/or repeat MRI 
imaging following completion of total neoadjuvant treatment.  
• Tumor Volume. Standard of care CT and MRI images will be obtained at the time of 
diagnosis for staging. A repeat standard of care MRI imaging may be obtained prior to 
surgery to assess response to neoadjuvant therapy and to guide clinical and surgical 
management. We will obtain routine clinical restaging scans from participants and use 
them to estimate changes in tumor volume between the two time points. We may also use 
the scans to explore changes in body composition. 
• Objective Response Rate (ORR). We will also assess the ORR, which is defined as the 
percentage of people who have a partial response (defined as a decrease in tumor volume) 
or a complete response to treatment between enrollment and surgery. 
• Neoadjuvant Rectal (NAR) Score. The NAR score is a validated surrogate endpoint for 
oncologic outcomes used in rectal cancer clinical trials. It takes as input the pathologic 
nodal status and the clinical and pathologic T-stage.  
• Secondary Measures of Toxicity. As secondary measures of toxicity, we will collect 
provider-reported adverse event data. We will analyze the incidence of grade 3-4 
toxicities and calculate the aggregated Toxicity Index (TI). The TI accounts for the 
frequency and cumulative burden of all toxicities during the treatment period.  
• Health-Related Quality of Life. We will use the widely-used and validated European 
Organization for Research and Treatment of Cancer Quality of Life (QOL) core 
questionnaire C30 (EORTC QLQ-C30) and the colorectal-cancer specific questionnaire 
(EORTC CR29). For this study, we focus on highly prevalent rectal cancer treatment-
related symptoms, including fatigue, insomnia, pain and bowel-related items (stool 
frequency, flatulence, and fecal incontinence).  
• Other Clinical Outcomes. We will also attempt to collect follow-up data on 
progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS).  
 
Additional Endpoints. Several additional endpoints are described below. 
 
Questionnaires. Participants will be asked to complete standard/validated questionnaires using 
web-based or paper-based forms. Questionnaires and recalls will be administered by experienced 
study coordinators (bilingual: English/Spanish). Specific questionnaires will include the General 
Physical Activity Questionnaire (GPAQ), Munich Chronotype Questionnaire (MCTQ), the 
Pittsburgh Sleep Quality Index (PSQI), the Appetite Questionnaire (AQ; includes a couple extra 
visual analogue scale questionnaires), the Dutch Eating Behaviors Questionnaire (DEBQ), 
Satisfaction with Participation in Discretionary Social Activities Questionnaires, UCLA 
Loneliness Scale (short version), two cancer-related quality of life questionnaires (EORTC 
QLQCR29 and EORTC QLQ30), the Patient Health Questionnaire-8 (PHQ-8), and NIH 
PROMIS scales relating to physical function, fatigue, and emotional distress/anxiety. 
Anthropometrics. Participants’ height will be measured at baseline or extracted from the 
medical record (if measurement by research staff is not possible). Weight will be measured using 
an electronic scale according to standard procedures during clinical care. Blood pressure and 

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heart rate will also be measured at each testing visit according to standard procedures during 
clinical care.  
Biospecimen Collection and Analyses. Blood specimens will be collected at three time points: 
baseline, 3 months, and pre-surgery, with an optional fourth collection in between treatment 
segments (radiation vs. long-course chemo). Participants must fast at least 8 hours prior to 
collection. Blood specimens will be used to measure IGF-1 and its binding proteins—IGFBP-1 
and IGFBP-3. Samples will be measured in duplicate using ELISAs from American Laboratory 
Products Company (ALPCO; Salem, NH, USA). We will also measure fasting glucose, insulin, 
and lipid levels, as well as complete blood counts (CBCs). Glucose will be measured on a 
DXC600 instrument (Beckman Coulter; Brea, CA, USA) using standard reagents, while insulin 
will be measured using chemiluminescent immunoassays on an Immulite 2000 instrument 
(Siemens Corporation; Washington, DC). We will also collect peripheral blood mononuclear 
cells (PBMCs) to represent healthy cells. PBMCs will be obtained as follows. In brief, PBMCs 
will be obtained by collecting whole blood and transferring it into Leucosep tubes containing 
Lymphoprep reagent (StemCell Technologies Inc.; Cambridge, MA), following the 
manufacturer’s instructions. The resultant solution will be centrifuged at 1000-1200 g for 12 
minutes with the brake on. The mononucleocyte layer will be transferred into a new Leucosep 
tube and centrifuged at 400 g for 6 minutes. Most of the supernatant will be discarded, and the 
white pellet will be resuspended in the remaining 1-2 mL of supernatant. After determining cell 
density, the solution will be centrifuged again at 400 for six minutes, and the remaining 
supernatant will be discarded. The pellet will then be resuspended using Invitrogen™ 
RNAlater™ (Life Technologies Corporation; Carlsbad, CA) and frozen at -80ºC for future 
analyses. PBMCs will be used to measure indicators of stress resistance, such as total antioxidant 
capacity (catalog #ab65329; Abcam plc; Cambridge, MA). Lastly, FFPE slides with 
normal/rectal tumor tissue will be obtained as part of the standard of care and will be obtained by 
request from each site’s Department of Pathology. We will obtain slides of FFPE normal/tumor 
tissue from the diagnostic biopsy and at resection, whenever possible.  
 
Protein Expression. To test the differential stress resistance (DSR) theory, we will measure 
markers representing cell growth and death dynamics and stress resistance, including Ki67 (cell 
proliferation), caspase 3 (apoptosis), LC3-I/LC3-II (autophagy), and γ-H2AX (DNA damage). 
Protein expression will be measured in FFPE tumor and adjacent normal tissue using 
Nanostring’s GeoMx technology (Nanostring Technologies, Inc.; Seattle, WA). Nanostring’s 
technology involves multiplex antibody cocktails that have been barcoded with unique synthetic 
DNA oligonucleotides that are recognized by a unique reporter probe conjugated to a fluorescent 
barcode. We will use monoclonal, knockout-validated antibodies from Abcam (Abcam plc; 
Cambridge, MA). Samples will undergo cycles of incubation and hybridization with the 
fluorescent tags and then will be loaded an nCounter instrument to quantify expression levels. 
We will use NanoString’s nSolver software to quantify expression levels, using the geometric 
mean of selected housekeeping proteins. 
 
Continuous glucose monitors (CGMs). Abbott FreeStyle Libre Pro CGMs will be used at baseline 
and around the time of surgery (post-intervention) to measure blood sugar levels. Continuous 
glucose monitoring tracks glucose levels in interstitial fluid at regular and frequent intervals to 
generate dynamic information on mean 24-hour levels and glycemic excursions/variability. 
 

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Stool Collection (Optional). At baseline and before surgery, patients will be asked if they would 
be willing to take home a stool collection kit. If they are willing and able, the patients will then 
be asked to provide a stool sample from home prior to surgery date. If we cannot collect stools 
using these methods, we will try to collect remnant stool leftover from clinical procedures. All 
materials for the stool sample collections (including gloves, stool collection containers, written 
instructions, a return mailer, and a short questionnaire) will be provided by mail or at the initial 
office visit. Stool samples can also be collected via a digital rectal exam. Stool samples collected 
at home will be placed in the provided mailing containers and frozen overnight at 0◦C. Then the 
frozen sample will be shipped to Cedars in the pre-paid self-addressed mailer that we will 
provide. Upon arrival at Cedars, the stool sample will be frozen at -80◦C until processing. 
 
Dietary Intake. Dietary intake will be assessed using three-day food records at baseline, the 
intermediate time point, and prior to surgery. To analyze participants’ food intake, we will use 
the Nutrition Data System for Research software (NDSR; Nutrition Coordinating Center, 
University of Minnesota). We will assess changes in total energy intake, macronutrient 
composition, and the Healthy Eating Index (HEI 2015), as well as changes in added sugar, fruits, 
and vegetables, solid fats, alcoholic beverages, and sodium between groups.  
 
Physical Activity. Wrist actigraphy is a non-intrusive, objective measure of sleep and physical 
activity. Each participant will be instructed to continuously wear an Actigraph (Pensacola, FL) 
on the non-dominant wrist for a week at baseline and around the time of surgery. The actigraph 
uses a piezoelectric accelerometer to measure the degree and intensity of motion, sampling every 
second. Physical activity will be operationalized as the mean metabolic equivalent units (METs) 
per hour and percent of time spent in sedentary, light, moderate, and vigorous activity, as 
assessed by the Friedson (2011) algorithms. To objectively measure sleep, we will use an open-
source and validated set of algorithms to assess sleep and activity outcomes (GGIR package, R-
software). 
 
Exit Interview. A study team member with expertise in qualitative methodology will conduct 
semi-structured qualitative interviews with each participant at the conclusion of the intervention. 
The goal of these interviews will be to present open-ended questions about how participants 
experienced their assigned eating schedules in the context of cancer treatment, symptoms, and 
side effects, and in the context of their roles, values, and routines. Participants will also be asked 
to discuss challenges they faced (if any) with habit changes needed to adhere to a new eating 
schedule, as well as any positive or negative outcomes that they felt stemmed from this new 
eating schedule. Interviews will be audio-recorded and transcribed verbatim. Dedoose™ 
software will be used for analysis of qualitative data. Data analysis will be informed by a social 
constructivist, interpretive framework consistent with grounded theory and 
interpretive.  Independent coding of transcripts will be completed by two researchers trained in 
qualitative methodology, and a codebook will be developed using in vivo codes that emerged 
during interviews as well as a priori codes originating from background concepts that inform the 
overall research problem (e.g., “social components of eating”). Discrepancies in coding will be 
resolved by a third member of the study team with qualitative expertise. Themes uncovered by 
this qualitative investigation may inform the interpretation of acceptability and feasibility data. 
 
.

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Schedule of Procedures 
 
METHODOLOGY 
 
Init
ial 
Visi
t  
Transi
tion 
Visit 
(Optio
nal) 
3-
mont
h 
Visit 
Befor
e 
Surg
ery 
Visit 
Adherence to meal 
schedule  
• Eating schedule daily log completed by all 
participants (TRE and control) 
• Weekly/monthly contact with staff to problem-
solve challenges with mela schedule adherence  
 
 
 
 
Demographic and 
medical history 
• Baseline questionnaires and medical chart 
reviews 
 
 
 
 
Blood draws  
• Hospital phlebotomist/RN at clinical sites 
 
 
 
 
Weight, Height, Heart 
Rate, Blood Pressure 
and Waist 
circumference 
• Hospital phlebotomist/RN at clinical sites; 
trained study staff 
 
 
 
 
Exit interview 
• Semi-structured interview  
 
 
 
 
Treatment 
tolerability/toxicity 
Assessed adverse events 
CTCAE v. 5.0 
 
 
 
 
 
Patient-reported adverse 
events 
PRO-CTCAE  
 
 
 
 
Patient-reported HR 
QOL 
Health related Quality of 
Life 
EORTC QLQ30 and 
EORTC QLQCR 29 
 
 
 
 
Continuous glucose 
monitoring 
Abbott FreeStyle Libre Pro 
 
 
 
 
Stool collection 
(optional) 
• In-home or clinic collection kit 
 
 
 
 
Psychosocial 
functioning 
• Questionnaires 
 
 
 
 
Mood 
• NIH Patient-Reported Outcomes Measurements 
Information System (PROMIS©) anxiety and 
depression short forms 
 
 
 
 
Sleep 
• Questionnaires: MCTQ, PSQI 
• Objective accelerometry using wrist-worn 
actigraphy 
 
 
 
 
Dietary intake 
• 3-day food records 
 
 
 
 
Daily physical 
activity/movement 
• Objective accelerometry using wrist-worn 
actigraphy 
 
 
 
 
Tissue collection 
• Biopsy and surgeries as part of standard of care 
 
 
 
 
 

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5.0 DATA COLLECTION AND MANAGEMENT 
 
5.1 DATA PROCUREMENT 
• Data will be collected by the investigators and study staff from the EHR, with 
manual procurement from each participant’s electronic chart as needed, from 
the questionnaires, and from assay and clinical laboratories. 
 
 
5.2 TIME PERIOD OF DATA UNDER REVIEW  
• Data will be reviewed from 02/01/2021 to 12/31/2026. Data will be collected 
prospectively as well as retrospectively using EHR records where available. 
• Data will be reviewed from the start of data collected to the end of the study 
(up to 10 years from enrollment of the last study subject). 
• All research data and related information will be retained in a secure access-
controlled location for at least 2 years and up to 7 years (as required by certain 
sponsors) after completion of the study. 
5.3 VARIABLES COLLECTED  
• The following data points/variables will be collected: all variables captured by 
the medial chart review, questionnaires, CT/PET/MRI images and derived 
outcomes, accelerometry data, CGM, vital signs, anthropometrics, 
accelerometers, and biomarker assays. 
5.4 SOURCE DOCUMENTS 
• Study participant medical records, questionnaire, and outcomes data generated 
from the study will comprise the source documents. 
5.5 DATA COLLECTION AND STORAGE  
• Secure storage: Data will be collected via EHR or REDCap based 
questionnaires. All captured data will be housed in a HIPAA-compliant secure 
storage system, such as REDCap or Box, within the Cedars-Sinai network with 
access restricted to only approved members of the research team.  
• Limited Access: Private identifiable information, will be accessible only to IRB 
approved study team members with current IRB training. 
• Unique ID Numbers: Each patient will be assigned a unique ID number, as 
needed, for data merging.  
• Removal of Identifiers: Direct identifiers (e.g., name or MRN) will be removed 
from any research records and destroyed as soon as scientifically possible and 
maintained only as long as necessary to abstract, analyze and verify data. Only 
de-identified coded data will be available for approved data analysts to perform 
statistical analyses. 
• Storage of Physical Records: Any physical records for this study will be 
maintained at a secure location where access is limited to approved personnel. 
The records will not be removed from Cedars-Sinai premises. 
• Storage of Specimens: Specimens will be maintained for this study at a secure 
location where access is limited to approved personnel.  
 

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5.6 CONFIDENTIALITY AND SECURITY OF DATA 
To protect privacy, electronically stored data will be protected through stringent security 
measures and through the use of coded ID numbers and electronic security systems 
required by HIPAA. Paper documents will be scanned and saved on a secure network and 
also stored in locked cabinets in locked offices. Biological specimens will be stored and 
analyzed in locked areas with restricted access. Access to participants’ data and 
biological specimens will be limited only to the study’s investigators, clinical support 
staff for this study, the overseers of clinical facilities, and the study sponsor—all on a 
need-to-know basis.  
 
6.0 DATA AND SAFETY MONITORING  
 
6.1 DATA AND SAFETY MONITORING PLAN 
The MPIs (Figueiredo, Peterson, and Salvy), study oncologists/surgeons, and the study 
dietitians will review the safety and progress of this study on an ongoing basis every 2-4 
weeks throughout the duration of enrollment. The IRB will review this protocol on an 
annual basis for subject safety, and we will include results of the review in the annual 
progress reports submitted to NIH. The annual reports will include a list of adverse 
events and will address: (1) whether adverse event rates are consistent with pre-study 
assumptions; (2) reasons for dropouts from the study; (3) whether all participants met 
entry criteria; and (4) whether continuation of the study is justified on the basis that 
additional data are needed to accomplish the stated aims of the study.  
 
Each participant will be evaluated for adverse events using the PRO-CTCAE (self-report) 
and via extraction of adverse events from the medical record (clinical report). Any severe 
unanticipated adverse event will be immediately reported to the IRBs (within 48 hours of 
occurrence or recognition) and the NIH. All adverse events will be summarized annually 
and submitted to the IRBs and NIH. Any action resulting in a temporary or permanent 
suspension of this study (e.g., IRB actions) will be reported to the NIH. In the unlikely 
case of a pattern of unexpected adverse events, this change will be brought to the 
attention of the IRB for review, current and future participants will be notified of this 
change and stopping rules will be considered.  
 
Quarterly safety reports will begin with a brief statement of the purpose of the study and 
a summary of the study design, including an organizational chart of all study personnel, 
as well as the projected timetable and targeted numbers for participant recruitment, 
intervention, and assessment. The study progress will be summarized, including 
enrollment, status, and retention of each cohort. In addition, a cumulative summary of the 
demographic breakdown of the sample will be summarized. Interim analyses will then be 
summarized. We will provide a detailed summary of any SAEs that have occurred since 
the previous Safety Report, including the participant name, nature of the event, date 
reported, action taken, resolution or ongoing complication(s) from the serious event, and 
whether the serious event was likely or unlikely related to participation in the study. 
There will also be a brief summary of SAEs that have taken place across the duration of 
the study. In addition, any major issues or problems encountered, and steps taken to 
correct or address them will be summarized. Finally, in the latter stages of the study when 

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it becomes relevant, the Safety Reports will also include a study summary, including a 
summary of the main findings, and procedures for preparing a report of study findings. 
Interim analyses of change in weight will be conducted, and the results summarized in 
the Safety Report. 
 
The study’s data safety and monitoring plan further includes the following components, 
overseen by the MPIs:  
 
All Cedars-Sinai IRB policies and continuous reporting requirements will be followed in 
conducting the study. Any actions taken by the IRB as part of its continuing review will 
be immediately reported to NIH.   
 
The MPIs will implement procedures to ensure that each participant provides informed 
consent and that all data remain confidential. In the case of a breach of confidentiality or 
other adverse event, the MPIs will report the event to the IRB and the appropriate NIH 
officials, and appropriate procedural changes will be implemented to prevent future 
breaches or adverse events.  
 
 
6.2 DATA MONITORING AND QUALITY ASSURANCE 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the contact PI during the course of the study through routine Disease 
Research Group (DRG) meetings (or equivalent). In addition, the SOCCI Cancer Clinical 
Trials Office (CCTO) Quality Management Core (QMC) will conduct focused internal 
monitoring visits and audits for data quality and protocol adherence. QMC reports will be 
forwarded to the SOCCI Data and Safety Monitoring Committee (DSMC). Refer to the 
DSMC Charter for more details. For any protocol, QMC has the authority to request more 
frequent reviews or focused safety monitoring if it is deemed appropriate for any reason.  
 
 
6.3 SAFETY MONITORING 
Oversight of the progress and safety of the study will be provided by the PI. The PI will 
maintain continuous safety monitoring for the duration of the study by reviewing 
subject/study data. Adverse events and unanticipated problems are not expected, but if 
they occur, they will be documented and reported according to CS-IRB policies and 
procedures. If the PI becomes aware of any new safety information that may place 
subjects at increased risk than what was previously known, the IRB will be promptly 
notified and if warranted, enrollment may be held until the PI determines whether a 
modification to the study is necessary and/or the informed consent documents are 
updated accordingly. It is the responsibility of the principal investigator to adhere to the 
Data Safety Monitoring Plan throughout the life of the study. 
In addition, this protocol will utilize the SOCCI Data and Safety Monitoring Committee 
will provide another layer of data and safety oversight. DSMC membership and 
responsibilities are governed by the committee charter. The annual DSMC findings and 

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recommendations will be reported in writing to the Principal Investigator as a summary 
letter which will be forwarded by the Principal Investigator or designee to the CS-IRB. 
The DSMC may increase or decrease the frequency of study review, at their discretion. 
Refer to the DSMC Charter for details of the DSMC review.  
6.4 MULTICENTER MONITORING PLAN 
This trial will comply with the current requirements of the SOCCI Data and Safety 
Monitoring Committee.  The SOCCI CCTO will be the Coordinating Center for this 
multicenter phase trial.  
In accordance with the Data and Safety Monitoring Committee, investigators will 
conduct continuous review of data and patient safety.  In addition, conference calls 
facilitated by the Study Lead at the Coordinating Center with investigators and staff at all 
participating sites will be scheduled at least monthly (and more often as needed) to 
discuss study progress. If there are no patients on treatment or in follow-up, email 
communication may be used in lieu of a teleconference, or in the circumstance where a 
scheduling conflict does not permit phone attendance. Meeting summaries will be 
included and document review of data and patient safety; meeting minutes will be 
submitted and reviewed by the DSMC.   
All multicenter investigator-initiated trials conducted at the SOCCI are subject to data 
monitoring by the CCTO Quality Monitoring Committee (QMC).  QMC has the 
responsibility for study monitoring for protocol compliance, data accuracy, performance 
of audits and monitoring of accrual (details found in the SOCCI Data Safety Monitoring 
Plan).  All open trials are reviewed at a minimum once a year by the QMC (or more often 
depending on risk).  This annual review includes the following: evaluation of the current 
accrual relative to the planned total accrual; examination of all reported violations; 
review of past monitoring visits and correspondence with the PI; review of previous 
correspondence between the PI and the QMC/DSMC.  External sites will be notified of 
upcoming monitoring visits and will be expected to provide de-identified source 
documents for remote monitoring of patients, and/or access to the site EMR.  Queries will 
be issued in the EDC and a detailed monitoring report will be provided to the 
participating site.  The SOCCI CCTO will also forward any monitoring and/or auditing 
reports to the DSMC.  
6.5 RECORD RETENTION 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. Government agency regulations and directives require that the 
study investigator must retain all study documentation pertaining to the conduct of a 
clinical trial. Study documents should be kept on file in accordance with all applicable 

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federal guidelines and local guidelines. 
Investigators will make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request. 
Following closure of the study, each participating site will maintain a copy of all site 
study records in a safe and secure location. The Coordinating Center will inform the 
investigator at each site at such time that the records may be destroyed. 
6.6 ADHERENCE TO PROTOCOL 
The Investigator-sponsor will ensure that patient recruitment and enrollment, treatment, 
follow-up for toxicities and response, and documentation and reporting at SOCCI are all 
performed as specified in the protocol. At the UAB site, the Principal Investigator will 
assume the responsibilities for the day-to-day monitoring of the trial.  Except for an 
emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, or a protocol exception request approved by 
the SOCCI Medical Director and IRB of record, the study shall be conducted exactly as 
described in the approved protocol. 
6.7 EMERGENCY MODIFICATIONS 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, the IRB must be notified as soon as possible, but 
no more than 10 days from the investigator’s awareness of the event. 
6.8 PROTOCOL EXCEPTIONS AND ELIGIBILITY WAIVERS  
A protocol exception is an anticipated or planned deviation from the IRB-approved 
research protocol, as described in the CSMC IRB Policy, Reporting Possible 
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) Policy: 
Institutional Review Board/Research Compliance and Quality Improvement.. A protocol 
exception most often involves a single subject and is not a permanent revision to the 
research protocol. Protocol exceptions that extend beyond a single subject should result 
in a protocol amendment to avoid serial violations.  
Planned exceptions to the protocol that are more than logistical in nature and/or impact an 
eligibility criterion, affect timing of study drug administration, or the investigator 
assesses the event may impact subject safety and/or study integrity, may not be 
implemented without prior IRB approval. The PI or her/his designee is responsible for 
submitting a protocol exception request and its supporting documents to the CSMC IRB 
if it meets the CS-IRB UPIRSO policy guidelines of a reportable exception/waiver. Study 
team should also refer to the IRB Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement guidelines to determine which deviations and 

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exception requests require IRB reporting. UAB will adhere to the policy of the IRB of 
record. Once IRB approved, the deviation or exception can be implemented. 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. 
In the rare event that it is appropriate for subject inclusion, the rationale/justification and 
subject case history should be submitted to the IRB for approval. Such requests for 
minimal risk studies do not require prior review by the CCTO Medical Director.  
6.9 OTHER PROTOCOL DEVIATIONS 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an 
individual subject) do not require prior IRB approval unless the deviation has the 
potential to affect the subject’s safety or study integrity. Such planned deviations that do 
meet this definition and do not affect the subject’s safety or study integrity should be 
noted in the subject’s research record or deviation log as described in the SOCCI CCTO’s 
Standard Operating Procedure 12: Deviation and Noncompliance Reporting. For multi-
site studies, follow local policy. 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB within 10 days from when the investigator 
becomes aware that such a deviation has occurred, as outlined in the SOCCI CCTO’s 
Standard Operating Procedure 12: Deviation and Noncompliance Reporting (or local 
policy, for multi-site studies). In this case, a Protocol Deviation report must be submitted 
in CS-IRB, per CSMC IRB policy, Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement. UAB will follow the policy of the IRB of record. 
All submissions should include a description of the plan to avoid similar deviations or 
exceptions in the future.   
6.10 AMENDMENTS TO THE PROTOCOL  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
6.11 OBLIGATIONS OF INVESTIGATORS 
The Principal Investigators are responsible for the conduct of the clinical trial at each site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigators are responsible for personally overseeing the 
treatment of all study patients. The Principal Investigators must assure that all study site 

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personnel, including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both 
during and after study completion. 
The Principal Investigators will be responsible for assuring that all the required data will 
be collected and entered onto the Case Report Forms and/or into a HIPAA-compliant 
study database. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all case report forms will be reviewed by 
the Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 
6.12 PUBLICATIONS 
The publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
7.0 DATA MANAGEMENT & STATISTICS 
 
7.1 BLINDING 
All research staff and study investigators will be blinded, with the exception of S.J.S., the 
intervention counselors, and the study dietitian who will remain unblinded because of 
their required roles in delivering intervention counseling. Analyses of blood analytes will 
be performed by technicians who are blinded and not associated with the trial. 
 
7.2 POWER CALCULATION  
We powered the study using the two primary endpoints of the pCR rate and the average 
PRO-CTCAE score. Based on preliminary data, we estimated the pCR rate for the control 
arm to be 30%. For the average PRO-CTCAE score, we assumed asymptotic normality 
and calculated the minimum detectable difference/effect size (MDD/ES) at 80% power 
and using type 1 error rate of α=0.05 without correction for multiple endpoints. For a 
sample size of 135 completers per arm (n=270), the MDD in pCR is 17%  (increase from 
30% to 47%)  using an exact binomial test and the MDES for the PRO-CTCAE score is 
0.32 using a two-sided independent samples t-test with equal variance, which is a small-
to-medium effect size. We expected to detect even smaller effect sizes when considering 
repeated measures of PRO-CTCAE. Assuming a 10% dropout rate, we will therefore enroll 
N=150 patients per arm in order to have N=135 completers.  
We also performed a power calculation for one of the secondary outcomes: health-
related quality of life (EORTC QLQ-C30). Assuming a within-group standard deviation 
of 23.92 and a sample size of 135 participants per arm, we calculated MDDs of 10.3, 9.0, 
7.3, and 5.2 for ICCs of 0.2, 0.4, 0.6, and 0.8, respectively, using a two-sided independent 
samples t-test with equal variance at a power of 80% and a type 1 error rate of α=0.05.  
 
7.3 STATISTICAL ANALYSES 

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All analyses will be performed blinded using two-sided tests and α=0.05 in the software 
program R. The primary analyses of clinical outcomes will be intention-to-treat. We will 
also perform a secondary per-protocol analysis using marginal structural models with 
inverse-probability-of-treatment weighted (IPTW) estimators to describe treatment effect 
as a function of levels of adherence.   
Descriptive statistics will be presented for both quantitative and qualitative variables. 
Contingency tables for treatment and toxicity data aggregated by grade, system, or term 
will be summarized with correspondence analysis.  
In the primary analysis, we will test differences in pCR using a Fisher’s Exact test. 
We will calculate the PRO-CTCAE average over items at specific time points as the 
response variable of a multivariable linear mixed model using baseline average PRO-
CTCAE, group, time, and interaction between group and time as covariates. Furthermore, 
we will consider include additional potentially relevant covariates, such as sex, age, race, 
stage, surgical status, and treatment modality. Random effects will describe the 
correlation within repeated measures and sites. We will also test the interaction of group 
with sex, age, surgical status, and treatment modality. In the presence of interaction 
effects, we will perform subgroup analyses with Holm correction for multiple groups.  
As a secondary analysis of toxicity, we will calculate the Toxicity Index (TI) using 
CTCAE data, using on methods proposed in Rogatko et al.3. Following Gresham et al.4, 
we will fit a multivariable probabilistic index model, which is a generalization of the 
Mann-Whitney test, where the toxicity index is the response variable and we will 
consider adjusting by sex, age, race, stage, surgical status, and/or treatment modality. 
Furthermore, we will calculate the toxicity index for subcategories of treatment-emergent 
adverse events (e.g., gastrointestinal).  
For other outcomes, Multivariable Generalized Additive Models for Location, Scale 
and Shape (GAMLSS) will be fitted. In particular, GAMLSS will be fitted to total quality 
of life scores and subscores as response variables and group, time, and interaction 
between groups and TRE will be  covariates. We will also adjust for any relevant and 
impactful covariates, such as sex, age, race, stage, surgical status, and treatment modality 
as fixed effects. Random effects will be added to consider the correlation from repeated 
measures and different sites. Adequate probability distribution for the response variable 
will be defined based on diagnostic plots and the AIC. These methods will also be 
applied to analysis of IGF-1 and the ratios of IGF-1 to its two binding proteins as the 
response variables. Furthermore, the molecular outcomes (γ-H2AX, Ki67, caspase-3, 
LC3-I/II, and total antioxidant capacity) will be analyzed with adjustment for multiple 
endpoints using the Hochberg correction, assuming the markers are positively correlated.  
To test the hypothesis that IGF-1 mediates changes in molecular endpoints, 
mediation analysis will be performed based on linear regression models with normal 
errors: (1) the outcome model will be defined with the change in blood analytes as the 
response variable and group and the change in IGF-1 as covariates; and (2) the mediator 
model will be defined with the change in IGF-1 as the response variable and the group as 
a covariate. Average mediation and direct effects will be calculated with the control arm 
as the reference, following methods in Imai et al.5, assuming no interaction between 
group and the mediator and assuming sequential ignorability. Baseline covariates (e.g., 
sex, age, race, stage, surgical status, and treatment modality) will be considered in the 

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model to strengthen the validity of sequential ignorability, and sensitivity analyses will be 
performed for both assumptions.  
We will also adopt the same modelling strategy based on GAMLSS for mood (e.g., 
NIH PROMIS t-scores), psychosocial functioning, sleep (accelerometry and PSQI), daily 
activity counts and intensity (accelerometry), and dietary intake (calorie intake, 
macronutrient composition, Healthy Eating Index, added sugar, fruits and vegetables, 
solid fats, alcoholic beverages, sodium, and fat). To test how mood, psychosocial 
functioning, sleep, activity, and dietary intake moderate the relationship between the 
intervention arms and clinical outcomes, we will add interaction terms to the model, as 
described above. If the interaction effects are statistically significant, then we 
will interpret the data using a graphical approach. To draw the graphs, we will use the 
“pick-a-point’ approach6. This approach involves selecting representative high and low 
values (mean ± 1 SD) of the moderator variable and then estimating the effect of the focal 
predictor at those values.  
Finally, patterns of missing data will be analyzed, and missing values for covariates 
will by imputed using multivariate imputation by chained equations under the assumption 
of missing data at random (MAR). The plausibility of imputed values will be checked by 
corresponding diagnostics. The outlined statistical analysis will be performed for each 
imputed dataset and results will be pooled according to Rubin’s Rule. In addition, we 
expect that patients who decrease well-being might dropout over time. Therefore, a 
sensitivity analysis will be performed to evaluate the robustness of the MAR assumption 
and departures towards Missing Not at Random (MNAR) assumption considering 
scenarios to assess the robustness of the results.  
8.0 STUDY MANAGEMENT 
8.1 CONFLICT OF INTEREST 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined 
in the Informed Consent Form. 
8.2 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. A reliance agreement will be utilized to permit 
Cedars-Sinai to be the IRB of record (reviewing IRB) and the University of Alabama at 
Birmingham will be the relying institution. In accordance with the reliance agreement, all 
pertinent study documents (i.e., protocol, ICF) will be reviewed and approved by the 
Cedars-Sinai IRB prior to study initiation. The investigators will comply with the 
applicable regulatory requirement(s) and adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
8.3 REGISTRATION PROCEDURES 
Eligibility Verification 
Prior to registration, all subjects must undergo an eligibility verification by the study-
specific research staff. Minimal risk studies are exempt from SOCCI Quality 
Management Core (QMC) central eligibility checklist review and eligibility verification. 

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QMC central eligibility checklist review and eligibility verification for all subjects 
enrolled is performed only if requested by the PI at any time during the life of the study. 
Registration 
After eligibility is verified, each site will assign the subject a study number and site staff 
will then register the patient in OnCore® and/or REDCap 
All subjects that sign informed consent will be assigned a subject number sequentially by 
their date of consent.  Those subjects who are consented to participate in the clinical trial 
but do not meet one or more criteria required for participation during the screening phase 
will be listed as screen failures on the master list of consented subjects.  Eligible subjects, 
as determined by screening procedures and verified by a treating investigator, will be 
registered on study at Cedars Sinai Medical Center by the Study Coordinator.   
Issues that would cause treatment delays after registration will be discussed with the 
Principal Investigator (PI). If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study will be canceled.   
Assignment of Subject ID: The study teams will track all subjects who sign consent using 
OnCore and/or REDCap. Subjects found to be ineligible will be recorded as screen 
failures. Subjects found to be eligible will be registered using a lead-in number of 01, 
followed by a three-digit numeric ID that follows the standard SOCCI format (001, 002, 
etc.).  Subjects found to be eligible at the University of Alabama at Birmingham (UAB) 
site will be registered using lead-in number of 02, followed by a three-digit numeric ID 
that follows the standard SOCCI format (001, 002, etc.). At UAB, only limited patient 
information will be entered into OnCore (i.e. updating status to enrolled).  
Subject ID’s will follow the format below: 
Cedars-Sinai Medical Center 
Screening 11, 12, 13, 14, 
Enrolling CSMC-001, CSMC-002 
The University of Alabama at Birmingham 
Screening 610-1, 610-2, 610-3 
 
 
Enrolling UAB-001, UAB-002 
 
Registration is completed as follows: 
Assignment of a patient study number 
Assignment to the patient a dose/treatment arm as determined through communication with 
Biostatistics and the principal investigator, if applicable  
Enter the patient in OnCore 
 

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8.5 DATA MANAGEMENT AND QUALITY CONTROL AND 
REPORTING 
 
REDCap is the Cedars-Sinai Cancer institutional choice for the electronic data capture of 
case report forms for SOCCI Investigator Initiated Trials. REDCap, a HIPAA-compliant 
database, will be used for electronic case report forms in accordance with institutional 
requirements, as appropriate for the project. The Study Staff will be responsible for data 
processing, in accordance with procedural documentation. Database lock will occur once 
quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials.   
 
 

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9.0 REFERENCES 
 
1. 
Marinac CR, Nelson SH, Breen CI, et al. Prolonged Nightly Fasting and Breast Cancer 
Prognosis. JAMA Oncol 2016;2:1049-55. 
2. 
Han CJ, Gigic B, Schneider M, et al. Risk factors for cancer-related distress in colorectal 
cancer survivors: one year post surgery. J Cancer Surviv 2020. 
3. 
Rogatko A, Babb JS, Wang H, et al. Patient characteristics compete with dose as 
predictors of acute treatment toxicity in early phase clinical trials. Clin Cancer Res 
2004;10:4645-51. 
4. 
Gresham G, Diniz MA, Razaee ZS, et al. Evaluating Treatment Tolerability in Cancer 
Clinical Trials using the Toxicity Index. J Natl Cancer Inst 2020. 
5. 
Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. 
Psychological methods 2010;15:309. 
6. 
Rogosa D. Comparing nonparallel regression lines. Psychological Bulletin 1980;88:307-
321. 
7.  
Hays RD, Gresham G, Ganz PA, Tighiouart M. Comparison of Simple-Summated 
Scoring and Toxicity Index Scoring of Symptom Bother in the NSABP B-30 Clinical 
Trial. Applied Research in Quality of Life. 2022 Sep 9:1-1