Neoadjuvant FOLFOX Therapy With Short Course Radiation and Active Surveillance in Locally Advanced Rectal Cancer: A Phase II Study
Phase: PHASE2
Conditions: Advanced Rectal Cancer
Sponsor: University of Rochester

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Neoadjuvant FOLFOX therapy with Short Course Radiation and active surveillance in locally advanced 
Rectal Cancer: A Phase II Study
Principal Investigator: Richard Dunne, MD
Statistician: Andrea Baran
Site: University of Rochester
James P. Wilmot Cancer Institute
601 Elmwood Ave. Box 704
Rochester, NY 14642
Figure 1. Schema
NCT03781323
Version Date: 12/9/2019

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Table of Contents
6 cycles of mFOLFOX
(5-Fluorouracil, Leucovorin, Oxaliplatin)
Stable or Progressive Disease 
(<20% tumor reduction)
Partial or Near/Complete 
Response
4-6 cycles of mFOLFOX: 
(5-Fluorouracil, Leucovorin, Oxaliplatin)
Subjects will be removed from 
study and proceed with treatment 
per the treating investigator. 
Complete or Near 
Complete Response
Partial Response (≥30% 
tumor reduction) or Stable 
disease
Progressive Disease (<20% 
tumor reduction)
Watch and wait 
surveillance
Proceed to 
Surgery
Subjects will be removed from 
study and proceed with treatment 
per the treating investigator 

Total number of patients enrolled to 
start chemotherapy, N=30

All patients included in evaluation of 
complete clinical response, safety, 
toxicity, quality of life, and overall 
survival
Short Course          
Radiation
Short Course          
Radiation
Complete or Near 
Complete Response
Complete or Near 
Complete 
Response
Partial Response or 
Stable Disease
INTERVAL 
ASSESSMENT
RESTAGING
ASSESSMENT
POST RADIATION 
ASSESSMENT

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1.0 
Purpose of Study and Rationale
1.1 
Purpose of Study
1.2 
Rationale
2.0 
Study Objectives
2.1 
Primary Objective
2.2 
Secondary Objectives
3.0 
Study Design
4.0 
Selection Criteria
4.1 
Inclusion Criteria
4.2 
Exclusion Criteria
5.0 
Methods and Study Procedures
5.1 
Subject Recruitment and Consent
5.2 
Pretreatment Evaluation
5.3 
Administration Schedule
5.4 
Disease Progression
5.5 
Posttreatment evaluation
5.6 
Discontinuation of Study
6.0 
Schedule of Events
7.0 
Treatment Dosing Modifications
8.0 
Study Treatment Toxicities
8.1 
Oxaliplatin
8.2 
Leucovorin
8.3 
5-Flurouracil
9.0 
Adverse Events Monitoring and Reporting
9.1 
Definition of Adverse Event
9.2 
Definition of Serious Adverse Event
9.3 
Reporting of Adverse Events
9.4 
Severity of Adverse Events
10.0 Objectives and Data Analysis 
10.1 Primary Endpoint
10.2 Secondary Endpoints
10.3 Data Analysis
11.0 Data Safety and Monitoring
12.0 Data Confidentiality and Storage
13.0 Data and Specimen Banking for Future Use
14.0 References
1.0Purpose of Study and Rationale

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1.1Purpose of Study
The purpose of this study is to evaluate the treatment of patients with locally advanced rectal 
cancer for complete response to neoadjuvant chemotherapy followed by short course radiation. 
without surgery.  These patients will be evaluated for complete clinical response (cCR) after 
completing up to 12 cycles of modified FOLFOX (mFOLFOX) (fluorouracil, leucovorin, oxaliplatin) 
chemotherapy, plus the use of short course radiation.  Patients who have stable or progressive 
disease will be removed from study and treated per discretion of the treating physician.  Those 
determined to have a near complete or complete response will complete full neoadjuvant 
treatment (chemotherapy and short course radiation) and undergo close surveillance with 
watchful waiting for local recurrence without immediate surgery. The primary endpoint of this 
study will be the rate of cCR, which is to include complete and near complete clinical response 
with induction chemotherapy and short course radiation, with secondary endpoints of disease-
free survival (DFS), overall survival (OS), quality of life (QOL), as well as evaluation of safety and 
toxicity.  
1.2Rationale
Colorectal cancer has been well studied as it is the second leading cause of cancer death in the 
United States, with over 39,000 estimated newly diagnosed cases of rectal cancer each year. 
Due to ongoing improvements in treatment, there has been a decline in the overall incidence 
and mortality in the past two decades though annual deaths still total approximately 49,000 
from combined colorectal cancer[1]. The current standard of care for locally advanced rectal 
adenocarcinoma is chemoradiation therapy (CRT) before or following surgical intervention, 
which has yielded a significant decrease in local recurrence at the expense of acute or extended 
toxicity from treatment.  Disease free survival for neoadjuvant or adjuvant treatment for locally 
advanced rectal cancer has been shown to be 68% and 65% at five years, respectively[2]. 
However, this multi-modality treatment of CRT followed by surgery is associated with a high 
potential for creating substantial morbidity including diarrhea, hematologic toxicity, 
dermatologic toxicity, sexual dysfunction, bowel and bladder dysfunction, small bowel 
obstruction, and strictures at the site of anastomosis[2-4].  Additionally, patients undergoing 
surgery have higher rates of wound dehiscence following CRT[4].  Though sphincter-sparing 
surgery is preferable for improved quality of life, it is not always possible to obtain negative 
margins.  When sphincter-sparing surgery is not an option, such patients require an 
abdominoperineal resection (APR), resulting in a permanent colostomy.  
In review of earlier studies employing CRT, much of the current evidence supporting 
neoadjuvant therapy is derived from the randomized controlled trial by the German Rectal 
Cancer Study Group in 2004 comparing preoperative CRT with postoperative treatment.  Though 
rates in overall survival remained unchanged, local recurrence rates were decreased, and more 
patients completed preoperative treatment.  We note that 8% of those patients in the 
preoperative CRT arm were found to have a complete pathologic response (pCR) based on 
histopathology at the time of surgery[2]. 
Due to treatment related morbidity, and a growing trend of rectal cancer in patients younger 
than 50 years old, it has come in to question if rectal cancer has been over-treated in select 

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individuals[1]. At our own institution, following patient enrollment evaluating total neoadjuvant 
therapy (TNT) with 6 cycles of FOLFOX therapy followed by surgery in a collaborative study, it 
was noted that several individuals had a clinical complete or near complete response, or 
complete pathologic response.  We now seek to evaluate if total neoadjuvant therapy with 
chemotherapy alone may produce such a response in some individuals, utilizing chemotherapy 
with short course radiation therapy.  Those with a complete or near complete response may be 
spared surgical intervention.
Neoadjuvant therapy with watch and wait surveillance  
 In a 2014 study, 90 of 183 (49%) patients in a single institution study achieved a complete 
clinical response (cCR) after receiving CRT for 8 weeks alone.  Following a close surveillance 
schedule of visits, 28 (31%) of initial responders experienced local recurrence, with 17 of these 
patients within the first year.  Salvage therapy with surgery was feasible in 26 (93%) of these 
patients, and R0 resection in 25 (89%).  The results of this study suggest that there is a 
population of patients not requiring CRT with surgery for their locally advanced disease.  With a 
median follow up of 60 months, 62 (34%) of the 183 patients remained disease free and could 
safely avoid surgery.  The 5-year overall survival for all patients was 91% and disease-free 
survival 68%.  This study included tumors cT2-T4 and node-positive disease[4].
Evaluation of pathologic complete response rate after chemotherapy, chemoradiation
Several more recently published studies evaluated tumor response to neoadjuvant 
chemotherapy alone followed by surgery.  Schrag et al. in 2014 conducted a phase II, single 
institution study of 32 patients with T2N+, T3N0, or T3N+ rectal tumors, excluding T4 staged 
disease.  Patients underwent six cycles of FOLFOX plus bevacizumab, followed by total 
mesorectal excision (TME).  Following completion of neoadjuvant therapy, 8 patients (25%) 
were found to have pCR at surgery.  Four-year DFS and OS were 84% and 91%, respectively[5].  
One may hypothesize the increased rates of DFS and OS may be improved from earlier trials 
with the exclusion of T4 tumors as part of the study. In a similar pilot study of 45 patients who 
had undergone six cycles of neoadjuvant FOLFOX without bevacizumab, only 2 patients (4.4%) 
were found to have cCR, with 29 (64.4%) in partial response, however, pCR following TME was 
observed in 8 (17.8%) patients.  This study had included T4a disease (T2-T4a, N0-N2) and three-
year DFS 67.9% and OS 80.8% [3]. 
Initial results of the Chinese FOWARC study, a multicenter trial of 495 patients comparing 
neoadjuvant fluorouracil-radiotherapy, FOLFOX-radiotherapy, and FOLFOX alone, achieved pCR 
in 14.0%, 27.5%, and 6.6% of patients, respectively.  However, study protocol allowed for a 
minimum of only four cycles of FOLFOX therapy preoperatively, and inclusion criteria allowed 
for stage II (T3-4, N0) or stage III (T1-4, N1-2)[6].   The above study found lower rates of pCR with 
chemotherapy alone, especially when cycles became increasingly limited.
Complete response rates following neoadjuvant therapy with combined chemotherapy and 
chemoradiation.

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There are a number of studies that has specifically evaluated pathologic or clinical complete 
response following the combination of CRT followed by further consolidative chemotherapy. 
Habr-Gama et al. evaluated 34 patients with CRT followed by 3 additional cycles of 5-FU and 
leucovorin, no oxaliplatin, followed by surveillance if there was complete response.  CCR was 
maintained for at least 12 months in 48% of patients, with 5 additional patients demonstrating 
pCR after surgery, with portal combined complete response rate of 65%.  This study did evaluate 
for long-term durability of results. A multicenter phase II study by Garcia-Aguilar et al. involving 
292 patients compared pCR in patients receiving standard neoadjuvant CRT, or followed by 2, 4, 
or 6 cycles of FOLFOX.  The study included patients with stage II-III locally advanced rectal 
cancer.  The standard neoadjuvant group obtained a pCR rate of 18%, with pCR rates of 25%, 
30%, and 30% with increasing cycles of FOLFOX therapy, respectively.
Recently, a retrospective cohort has been published by Memorial Sloan Kettering Cancer Center 
evaluating 628 patients with locally advanced T3-4, or N1-2 rectal cancer evaluating patients 
who had either received TNT or chemoradiation followed by adjuvant therapy after surgery. 
Participants in TNT cohort received 8 cycles of FOLFOX or 5 cycles CAPOX, followed by 
chemoradiation with 5-FU or capecitabine plus long course radiotherapy.  The possibility of pCR 
was explained to patients who were found to have cCR at completion of TNT and given the 
choice if to proceed to surgery or undergo watchful waiting. CCR was recorded only at the 12-
month mark, as most local recurrences occurred within that period.  Of 308 patients with stage 
II or III disease, 18.3% of patients had a sustained cCR, and 21.8% with pCR with those who had 
proceeded immediately to surgery.  A total of 36% of patients had either pCR or cCR with TNT at 
one year, compared to 21% of patients with pCR who received neoadjuvant CRT followed by 
adjuvant therapy. [7]
Short Course radiation in treatment of rectal cancer
In the above studies, we see that total neoadjuvant therapy has not been studied with 
chemotherapy and radiation and watch and wait surveillance, and with chemotherapy alone 
preceding surgery.  The addition of radiation to locally advanced rectal tumors may provide 
additional local control and downstaging tumors prior to surgery.  As there is growing evidence 
of it’s not inferiorly to long course radiation in reducing patient time of treatment, our trial will 
add short course radiation to neoadjuvant chemotherapy. 
Short course radiation therapy (RT) 5 to a radiation therapy inferior fractions, typically within 
one week compared to 5-6 weeks with long course RT. Short course RT has been studied in 
phase II and subsequently phase III trials by Bujko et al. in which it was compared with long 
course RT. Results of a phase III study demonstrated T3 and T4 tumor undergoing short course 
RT have  significantly lower overall toxicity (p=0.006), overall survival of 73% versus 65% at 3 
years (0.046) and trended towards improved pathologic response (0.07). The Stockholm III that 
he compared long course RT with a delay prior to surgery, short course RT with delay, and short 
course RT without delay.  Short course RT with delay demonstrated similar outcomes for 
recurrence free survival and multivitamin analysis compared to the 2 other cohort, but 
demonstrated significantly lower postoperative complications and short course RT without 
delay. 

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Since completion of these studies, short course RT has been included in TNT trials.  In a recently 
published abstract of a retrospective cohort study, 388 patients received either a long course RT 
(n=236) or short course RT (n=152) as part of TNT prior to surgery.  Though the short course 
cohort had a higher number participants with more advanced stage disease, pCR and recurrence 
rates were found to be not severely different from the long course cohort, further support that 
short course RT is not inferior to long course therapy.  Prospective trials are currently underway; 
the RAPIDO trial, early active but no longer enrolling patients, is evaluating the use of short 
course RT with chemotherapy prior to surgery (TNT) compared to conventional long course 
chemoradiation  followed by adjuvant therapy postoperatively.
To our knowledge, there are no studies currently evaluating a complete response to full, upfront 
neoadjuvant chemotherapy with mFOLFOX plus short course CT  in locally advanced rectal 
adenocarcinoma followed by surveillance. From review of available literature, we conclude that 
there is the potential for an identifiable population of patients that may benefit from treatment 
with systemic therapy and short course RT with a complete or near complete response, while 
sparing these patients the toxicity of a total mesorectal excision.  Earlier phase II studies 
demonstrate a range of complete response from 25% to 65% for total neoadjuvant therapy, but 
we conclude from these studies that the complete response rate is likely in the range of 30-40%. 
In conclusion, we hypothesize that some patients with locally advanced rectal cancer with stage 
I (T2N)-IIIB disease (excluding clinical T4 or N2b staging) will benefit from our proposed protocol 
of total neoadjuvant therapy, with proposed reduction in surgical related toxicities.     
2.0Study Objectives
2.1Primary Objective
The primary objective of this study will be to assess the rate of clinical complete or near 
complete response to total neoadjuvant therapy with up to 12 cycles of mFOLFOX and 
short course radiation.
2.2Secondary Objectives
 
The secondary objectives of this study will be to evaluate rate of clinical complete 
response to induction chemotherapy, 1-year disease free survival, 5-year disease free 
survival, overall survival, quality of life assessment, as well as safety and toxicity of 
treatment.  Patients proceeding to surgery after stable or progressive disease during 
total neoadjuvant treatment and patients with recurrence within 5 years will be 
evaluated for rate of R0 resection.
3.0  Study Design

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This is a multi-center, phase II study investigating the efficacy of total neoadjuvant therapy with 
mFOLFOX and short course radiation and selective non-operative management in patients with 
locally advanced rectal cancer.  
Participants with Stage IIA, IIIA, IIIB rectal adenocarcinomas, except for any T4 or N2b disease, 
who would otherwise undergo long course concurrent chemotherapy and radiation therapy 
followed by TME may be enrolled for treatment with mFOLFOX therapy.  Participants with lower 
sphincter rectal cancer deemed not eligible for sphincter sparing surgery are not eligible for 
participation. Participants would be treated with up to 12 cycles of mFOLFOX therapy. (One 
cycle of mFOLFOX= 14 days) and short course radiation.
All patients will be evaluated once following six cycles of chemotherapy via endoscopy and CT 
plus MRI. 
Patients with a partial, near or complete response will receive an additional 4-6 cycles of 
chemotherapy followed by reassessment. 
Patients with stable or progressive disease defined as less than 20% reduction will be removed 
from study.
Following completion of all chemotherapy (10-12 cycles) patients will be re-assessed via 
endoscopy and CT plus MRI. Patients will then receive short course radiation followed by repeat 
assessment with endoscopy and CT/MRI.  Those patients with evidence of complete or near 
complete clinical response following completion of all chemotherapy and radiation will be 
treated non-operatively and undergo close surveillance. 
Patients with a partial response or stable disease will undergoTME.
Those with <20% response will be removed from study and undergo treatment per the treating 
investigator.  These patients will be followed for survival at six month intervals for up to 5 years.   
All patients will be followed for 5 years following last date of treatment:
For patients in the study not requiring surgery following chemotherapy, the last day of 
treatment will be considered the last day of mFOLFOX therapy.
For patients who receive short course radiation, the last day of treatment will be 
considered the last day of radiation.
For patients in the TME group, the last day of treatment will be considered the day of 
surgery.
4.0Selection Criteria
4.1Inclusion Criteria
1. Participants must be >18 years old at time of diagnosis

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2. Histologically confirmed adenocarcinoma of the rectum from biopsy, excluding 
lower rectal cancer, (defined as patients requiring an abdominoperineal 
resection)
3. Clinical staging including T2N0, T3N0 tumors, or T1-3 with N1-2a disease
4. Rectal tumors must be determined as likely requiring total mesorectal excision 
(TME)
5. Participant must be treatment naïve for rectal cancer, with no prior radiation 
chemotherapy, radiation, or surgery specific for rectal cancer
6. No history of prior pelvic radiation 
7. No active infections requiring intravenous antibiotics within 14 days of initiating 
treatment
8. Baseline lab work must meet the following parameters:
a. Absolute neutrophil count (ANC) ≥1500/mm3
b. Platelet count ≥100,000/mm3
c. Hemoglobin ≥8.0 g/dL
d. Total bilirubin ≤ 1.5x upper limit of normal (ULN)
e. Total creatinine ≤ 1.5x upper limit of normal (ULN)
f. AST and ALT ≤ 2.5 x ULN
9. Women of childbearing potential (WCBP) will be defined as those biologically 
capable of becoming pregnant. WCBP must be negative for pregnancy testing 
(urine or blood) and agree to use effective contraception starting after negative 
pregnancy testing and extending to one year after end of treatment as defined 
in Section 3.0. Viable contraception should be used after trial screening, before 
initiation of chemotherapy, and throughout the duration of active treatment in 
the study. 
10.Participants must be explained the purposes of the study and sign a statement 
of informed consent prior to participation.  Those who do not read or 
understand English are eligible and may be consented according to institutional 
and federal regulations.
4.2Exclusion Criteria
1. Recurrent or refractory rectal adenocarcinoma
2. T1N0, T4a, T4b, or N2b tumors 
3. Patients with lower rectal cancer requiring abdominoperioneal resection are 
excluded
4. Any evidence of metastatic disease
5. Primary unresectable rectal cancer.  A tumor will be considered 
unresectable when invading adjacent organs such that an en bloc resection 
cannot achieve negative margins 
6. Patients unable to undergo MRI imaging
7. Patient with a history of any arterial thrombotic event within the past 6 
months.  This includes angina, myocardial infarction, transient ischemic 
attack, or cerebral vascular accident. 

10
8. Patients with history of venous thrombotic episodes such as deep vein 
thrombosis, pulmonary embolus occurring more than 6 months prior to 
enrollment may be considered for protocol participation, provided they are 
on stable doses of anticoagulant therapy.  Patients who are anticoagulated 
for atrial fibrillation or other conditions may participate only if on stable 
doses of anticoagulant therapy.
9. Patients with cardiovascular, hepatic, or renal systemic diseases that would 
preclude use of chemotherapy per the treating investigator. 
10.Peripheral neuropathy >grade 1 by Common Terminology Criteria for 
Adverse Events, or CTCAE
11.The patient must not be on any clinical trials involving other experimental 
therapies before or during study treatment 
12.Women who are currently pregnant or breast-feeding
13.Men and women who are actively trying to father/conceive children 
14.Patients with any other concurrent medical or psychiatric condition which 
were deemed inappropriate for entry into the study per the investigator.
15.History of other invasive malignancy within the past 3 years, except for 
adequately treated non-melanoma skin cancer, ductal carcinoma in situ of 
the breast, bladder carcinoma in situ or carcinoma in situ of the cervix.
aCTCAE version 5.0 from Department of Health and Human Services
5.0 
Treatment Plan
5.1Subject Recruitment and Consent
Patients will be recruited by GI oncology treatment teams, the research team, and by 
the principal and sub-investigators in the study.  Potential patients will have their 
medical records screened to identify them as eligible for study.  Eligible patients will be 
counseled on the rationale of the study, potential benefits and risks, and presented with 
a consent.  Consent may be obtained by an investigator of the study.
5.2Pre-treatment Evaluation
Patients eligible for treatment and have been consented will be registered in RED CAP 
by the Study Coordinator.  Those patients who have been consented and become 
participants in the trial must complete pretreatment evaluation within 45 days (+/- 15 
days) days of starting neoadjuvant therapy administration (Cycle 1, Day 1).  
All patients will undergo pre-treatment staging via physical examination, labs, 
proctoscopy/sigmoidoscopy, baseline imaging, and pathologic assessment of the tumor 
within 45 days from the start of treatment (+/-15 days).  Colorectal surgery must 
document if the participant has a lower rectal adenocarcinoma, generally tumors in the 
lower third of the rectum, not eligible for sphincter sparing surgery. 

11
Pelvic MRI will also be performed to obtain baseline evaluation of the tumor.   
Endorectal ultrasound may be used if MRI is not conclusive in lymph node evaluation. 
Each patient will be evaluated by the treating physician to determine 
their eligibility for mFOLFOX therapy. If a patient is unable to obtain a CT due to contrast 
allergy or other contraindication, MRI imaging will be acceptable for evaluation. 
Patients will complete an evaluation prior to treatment regarding their quality of life 
(QOL).  This will also be completed during the interval assessment, restaging 
assessment, post radiation assessment, 6 months follow up, and annually for 5 years. 
Validated QOL forms EORTC QLQ-30, and EORTC QLQ-CR29 will be used for 
assessment[8, 9]. These two surveys can be completed on the phone or at clinic visits, 
and consist of four pages of questions pertaining to daily activities, symptoms, and 
overall health before, during, and after treatment.  These would take an estimated 10 
minutes to complete. 
Rescreening may be allowed one time within 30 days of a screen failure. The patient will 
retain the same screening number.  
Optional blood work will also be collected for correlative biomarkers at baseline, at 
cycle 6 day 1 and at the time of the post radiation assessment. 
5.3Administration Schedule
Patients treated on protocol will be treated with modified FOLFOX.  Patients will receive 
up to 12 cycles of mFOLFOX, administered every other week.  mFOLFOX will be given on 
day 1 of each 14 day cycle. 
Patients will receive oxaliplatin 85 mg/m² IV over 120 minutes, leucovorin 400 mg/m² IV 
over 120 minutes, 5-FU 400 mg/m² IVP followed by 5-FU 2400 mg/m² infuse over 46 
hours.
In an attempt to prevent adverse events, all patients will be treated with anti-emetics 
and supportive care agents per institutional guidelines.  It is recommended that all 
patients receive dexamethasone, prochlorperazine maleate, and palonosetron. The use 
of growth factor support will be determined by the treating investigator.       
Prior to radiation patients will undergo CT simulation (with IV and/or oral contrast if 
needed). The radiation prescription will be 20 Gy in 5 fractions to lymph node regions 
including mesorectum, internal iliac, and pre-sacral with simultaneous boost to 25 Gy in 
5 fractions to the grossly involved rectal tumor plus adjacent mesorectum and grossly 
involved adenopathy. Treatment will be delivered over 5 days. 

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Table 1. Treatment Dosing
5.4Disease Progression
Patients with stable disease (<20% response) or disease progression at the interval 
assessment will be removed from study and follow treatment per the treating 
investigator.   
   
Progression after completion of total neoadjuvant therapy or while on observation will 
also be at the discretion of the primary oncology provider. 
5.5Post-treatment Evaluation
All patients will be subject to surveillance for 5 years to monitor for progression of 
disease. Patients on watch and wait surveillance will undergo history and physical 
examination, imaging, laboratory testing, and surgical oncology evaluation as outlined in 
Table 4. Those patients who received surgery after partial response will be followed per 
NCCN guidelines regarding history and physical exam, CEA, imaging, and evaluation by 
colonoscopy.
5.6Discontinuation of Study
Participants may be discontinued from treatment for any of the following reasons:
1. The participant wishes to no longer participate in treatment
2. The provider in charge of the patient’s treatment withdraws the participant
Treatment Agent
Dose
Administration 
Day in Cycle
Oxaliplatin
85 mg/m2
IV infusion over 120 
minutes
1
Leucovorin
400 mg/m2
IV infusion over 120 
minutes
1
5-Fluorouracil
(bolus)
400 mg/m2
IV bolus infusion after 
oxaliplatin and 
leucovorin
1
5-Fluorouracil
(infusion)
2400 mg/m2
IV infusion over 46 
hours following 5-FU 
bolus
1 

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3. The participant is determined to have unacceptable or intolerable toxicity
4. A participant becomes pregnant
5. A participant is diagnosed with another malignancy requiring treatment
6. The participant is lost to follow up
7.If treatment is held for greater than 28 days 
All participants who are discharged from treatment and the study will continue to be 
followed for severe adverse events, disease free and overall survival whenever possible. 

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6.0    Schedule of Events
  
Table 2. Study Initiation to Interval Assessment
Prior To 
Treatment
mFOLFOX
(1 cycle =14 days)
Interval Assessment
e
Study Day
Within 30 
days of C1D1 
(+/- 15 days)
C1D1
(+/-3days)
C2D1
(+/-3days)
C3D1
(+/-3days)
C4D1
(+/-3days)
C5D1
(+/-3days)
C6D1
(+/-3days)
Within 14 days of C6D1
(+/-7days)
History/Physical Exam
H&P
X
X
X
X
Heighta and Weight
X
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Colorectal Surgical Oncologist 
Evaluation
X
X
EKG
X
QOL
X
X
Review medications & adverse events
X
X
X
X
X
X
X
X
Imaging
MRI pelvis
X
X
CT chest/abdomen/pelvis
X
X
Procedural
Proctoscopy or Sigmoidoscopy, and DRE X
X
Laboratory
b,f
CBC
X
X
X
X
X
X
X
X
CMP
X
X
X
X
X
X
X
X
CEA
X
X
X
X
BHCG in WCBPc
X
Correlative Biomarkerd
X
X
aHeight needs to be obtained only at time of screening
bLaboratory work can be obtained up to 48 hours prior to any treatment or assessment
cWomen of child-bearing potential (urine or blood testing)

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d1 vial of extra blood will be collected and stored for biomarker research. Correlative biomarker for screening can also be collected at C1D1 prior 
to treatment
ePatients who have stable disease or progression will be removed from study and followed for survival. 
F Pre-study labs can be used for C1D1 if performed within 7 days

16
Table 3.  Partial or Complete Response after Interval Assessment to Restaging Assessment
aQOL will be assessed on all patients, including those that did not continue mFOLFOX after cycle 6 due to stable or progressive disease
bLaboratory work can be obtained up to 48 hours prior to any treatment or assessment
mFOLFOX
Restaging 
Assessment
Short course
Radiation
Post Radiation 
Asssesment
Study Day
C7D1
(+/-3 
days)
C8D1
(+/-3 
days)
C9D1
(+/-3 
days)
C10D1
(+/-3 
days)
C11D1
(+/-3 days 
if 
applicable)
C12D1
(+/-3 days 
if 
applicable)
Within 4-12 
weeks of last 
chemo
(+/-7 days)
Days 1-5
(if applicable)
Within 6-12 weeks 
following RT
History/Physical Exam
H&P
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Colorectal Surgical 
Evaluation
X
QOLa
X
X
Review medications & 
adverse events
X
X
X
X
X
X
X
X
X
Imaging
MRI pelvis 
X
X
CT chest/abdomen/pelvis
X
Procedural
Proctoscopy or 
Sigmoidoscopy, and DRE
X
X
Laboratory
b
CBC
X
X
X
X
X
X
X
X
X
CMP
X
X
X
X
X
X
X
X
X
CEA
X
X
X
X
Correlative Biomarker
X

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Table 4. Surveillance following completion of total neoadjuvant therapy without surgery             
aQOL will be assess on all patients, including those that did not continue watch and wait surveillance as the proceeded to surgery
Year 1
Year 2
Year 3
Year 4
Year 5
Months from completion of study
3-6
9-12
15-18
21-24
30 36
42
48 54 60
History/Physical Exam
H&P
X
X
X
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
X
X
X
QOLa
X
X
X
X
X
X
X
X
Imaging
MRI pelvis
X
X
X
X
X
X
CT chest/abdomen/pelvis
X    
X
X
X
X
X
Procedural
Proctoscopy or Sigmoidoscopy, and DRE
X
X
X
X
X
X
X
X
X
X
Laboratory
CBC
X
X
X
X
X
X
X
X
X
X
CMP
X
X
X
X
X
X
X
X
X
X
CEA
X
X
X
X
X
X
X
X
X
X

18
7.0Treatment Dose Modifications
Treatment dose may be modified or held by the primary treating oncologist at their 
discretion.  Treatment may be held a total of 4 weeks to account for toxicity.  We 
recommend the following dose modifications in the event of ≥Grade 2 toxicity. If treatment 
has been held for greater than 4 weeks the patient will be discontinued from study. If dose 
modifications require more than 2 dose level reductions, the patient will be discontinued 
from the study.
Patients with grade 2 or greater neuropathy attributed to Oxaliplatin can discontinue 
oxaliplatin provided that they have received at least 6 cycles and be treated with single 
agent 5-Fluorouracil. 
Growth factor support, such as pegfilgrastim, may be used at provider discretion.
Table 5. Dose Modifications Guide
Treatment
Dose Level 0
Dose Level -1
Dose Level -2
Oxaliplatin
85 mg/m2
65 mg/m2
50 mg/m2
Leucovorin
400 mg/m2
320 mg/m2
260 mg/m2
5-Fluorouracil (bolus)
400 mg/m2
320 mg/m2
260 mg/m2
5-Fluorouracil (infusion) 2400 mg/m2
1920 mg/m2
1540 mg/m2
8.0Study Treatment Toxicities
8.1Oxaliplatin
Common Toxicities:
Peripheral neuropathy (may be dose limiting)
Nausea
Vomiting
Diarrhea
Fatigue
Abdominal pain
Constipation
Increased liver transaminases AST and ALT
Anemia 
Thrombocytopenia
Less Common Toxicities: 
Leukopenia
Anorexia
Cough

19
Back or myalgias (muscle aches)
Arthralgias (joint aches)
Edema
Flushing
Skin Rash
Alopecia
Dyspepsia
Dysgeusia
Hypersensitivity 
Local site reaction with redness or swelling
Increase serum creatinine
Rare but serious: 
Anaphylaxis
Chest pain
Shortness of breath
Palmar-plantar erythrodysesthesia (hand-foot syndrome, with redness 
and/or pain)
Sepsis
Death
8.2Leucovorin
Toxicities:
Thrombocytopenia
Pruritus
Hypersensitivity
Urticaria
Wheezing
Skin rash 
Erythema (redness)
Toxicities of 5-fluorouracil are enhanced
Rare but Serious: 
Anaphylaxis
Seizures
Death
8.35-Fluorouracil
Common Toxicities:
Anemia
Thrombocytopenia

20
Leukopenia
Nausea
Vomiting
Anorexia
Diarrhea
Nail changes, brittle nails
Less Common Toxicities 
Chest pain
Alopecia
Headache
Palmar-plantar erythrodysesthesia (hand-foot syndrome, with redness, 
pain)
Venous hyperpigmentation
Dermatitis
Rare but Serious: 
Vasospasm
Myocardial Infarction
Death
8.4Short Course Radiation
Common Toxicities:
Fatigue
Diarrhea
Rectal pain/pressure
Perineal Skin irritation
Dysuria
Less Common Toxicities 
Change in bowel habit
Vomiting
Abdominal Pain 
Rare but Serious: 
Bowel Obstruction
Fecal Incontinence 
Secondary Malignancy

21
9.0  Adverse Events Monitoring and Reporting
9.1Definition of Adverse Event (AE)
Adverse events (AE) will be defined as any sign, symptom, illness, abnormal or 
adverse laboratory value, or experience that was not present at the start of 
treatment and occurs or worsens during the course of the therapy proposed 
regardless if related to that therapy. 
9.2Serious Adverse Event (SAE)
A serious adverse event (SAE) will be those signs, symptoms, illnesses, abnormal or 
adverse laboratory values, or experiences that were not present at the start of 
treatment and occurs, or worsens during the course of therapy and has one of the 
following outcomes: 
Death
Is life-threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
A congenital anomaly/birth defect
Requires medical or surgical intervention to prevent permanent impairment 
or damage
9.3Reporting of Adverse Events
With each visit, the patient provider will assess the patient for AE since prior visits.  
Providers will directly ask about adverse events and record their occurrence, as well 
as those that are offered voluntarily by the participant. 
Events will be documented to include:
The participant’s identification, disease and stage, cycle and day of 
treatment when AE occurred (if applicable)
Time of onset
Duration
Severity by grade (per CTCAE Version 5.0), 
A brief description of the event
Drug, device, or intervention suspected of causing the event
Contributing factors, if applicable
Action taken to intervene 
Time of resolution, or
If the AE is ongoing at the conclusion of participation in the study
Laboratory values will be included as adverse events if clinically significant 
and included in reporting.

22
9.4Severity of Adverse Events
Numerical grading of adverse events will follow the Common Terminology for 
Criteria for Adverse Events version 5.0 from the U.S. Department of Health and 
Human Services: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic implications 
only; intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living. 
Grade 4: Life-threatening consequences with urgent intervention indicated. 
Grade 5: Death from AE. 
10.0 
Objectives and Data Analysis
10.1 
Primary Endpoint
The primary outcome will be the rate of a complete clinical response. Response 
rates will be determined by the following:
A complete response will consist of a digital rectal exam with normal 
appearing mucosa and sigmoidoscopy/proctoscopy with scarring but no 
nodularity or ulcerations.  
A near complete response will consist of digital rectal exam with smooth or 
minor mucosal abnormalities, and sigmoidoscopy/proctoscopy with small 
mucosal abnormalities, or superficial ulceration or erythematous scarring.  
No palpable lymph nodes but some induration/mucosal abnormalities
Partial response, in our study, will be those tumors read with a ≥20% 
decrease in size without obtaining near or complete response, or remaining 
palpable lymph nodes with partial response

23
Stable disease, in our study, will be those tumors read with a <20% 
decrease in size without obtaining near or complete response, or palpable 
lymph nodes, no change in size on proctoscopy/sigmoidoscopy
Progressive disease will be those tumors with >20% increase in size, new 
lesions or palpable lymph nodes. 
10.2 
Secondary Endpoints
Secondary outcomes of our study will include the analysis of safety and toxicity, 
disease free survival, and overall survival from data included up to five years after 
enrollment in the study.  Date will be stored in the RedCap database. 
10.3 
Data Analysis
We aim to accrue 40 participants over approximately a 5-year period.  Though we 
hypothesize that this study will be of clinical benefit to those who may avoid surgical 
intervention, we have no knowledge that a similar study has been conducted. Thus, 
we aim to gain a preliminary estimate of the rate of locally advanced rectal cancer 
patients that can be spared surgical intervention through the use of neoadjuvant 
chemotherapy plus short course radiation.  We anticipate a 30% rate of complete or 
near complete clinical response to neoadjuvant chemotherapy plus short course 
radiation at the post-radiation assessment. This rate will include subjects 
discontinuing mFOLFOX due to stable or progressive disease at the interval 
assessment or re-staging assessment in the denominator.
With an anticipated response rate of 30%, a sample size of 40 subjects produces a 
one-sided 95% lower-limit exact binomial confidence interval with a width of 13.4%  
(lower limit of 16.6%). The maximum width of a one-sided 95% lower-limit 
confidence interval with 40 subjects would be 16.1% when the response rate is 50%. 
We target the lower limit of the confidence interval to determine if this regimen 
demonstrates sufficient evidence of efficacy to be considered worthy of future 
study. 
The complete or near complete response rate and associated 95% one-sided exact 
binomial confidence interval will be presented. Disease-free and overall survival will 
be described using the Kaplan-Meier method. Types and grades of adverse events 
will be tabulated. Changes in QOL (from baseline) will be described using means and 
standard deviations at each time point assessed. We will calculate these summary 
measures separately in those who obtain a complete or near complete response to 
up to 12 cycles of mFOLFOX and short course radiation and are entering watch and 
wait surveillance, and those who required surgery with or without radiation therapy 
prior to completion of mFOLFOX therapy.  QOL will be measured using validated 

24
QOL forms EORTC QLQ-30, and EORTC QLQ-CR29 as mentioned in Section 5.2, with 
paper-based surveys and scored according to the EORTC scoring manual [10].
11.0 
Data and Safety Monitoring
11.1
 Assessments and documentation of adverse events:  
Adverse events and grade will be recorded at each follow-up visit. Serious adverse 
events will be collected and reported from the time patient signs informed consent 
until the first surveillance safety follow-up visit. Non-serious adverse events will be 
collected from the time of first study drug dosing until the first surveillance safety 
follow-up visit.  
11.2 
Reporting of serious adverse events: 
The definition of serious adverse events (SAEs) is given in Section 9.2.
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory 
abnormality that is assigned grade 4, according to CTC definition, is not reportable 
as an SAE; unless the investigator assesses that the event meets standard ICH 
criteria for an SAE. CTC grade 4 baseline laboratory abnormalities that are part of 
the disease profile should not be reported as an SAE, specifically when they are 
allowed or not excluded by the protocol inclusion/exclusion criteria. 
When required, and according to local law and regulations, serious adverse events 
must be reported to the Ethics Committee and Regulatory Authorities.  
Study Investigators will conduct continuous review of data and patient safety.  The 
Investigator will submit twice yearly progress reports of these data to the Data Safety 
Monitoring Committee for review.  The review will include:  the number of patients 
enrolled, withdrawals, significant toxicities as described in the protocol, serious 
adverse events both expected and unexpected, dose adjustments, and responses 
observed.  The PI maintains a database of all adverse events with toxicity grade and 
information regarding treatment required, complications, or sequelae.  The 
Investigator will submit a copy of the AE spreadsheet along with a Progress Report to 
the Data Safety Monitoring Committee (DSMC) for review. Actual review dates will be 
assigned when the 1st patient is accrued. 
The DSMC at the Wilmot Cancer Institute, University of Rochester provides oversight 
of study progress and safety by review of accrual and adverse events at twice yearly 
meetings or more often if concerns arise. Any adverse event requiting expedited 
review per protocol, including those occurring at participating sites, will be submitted 
to the Safety Coordinator of the DSMC at the University of Rochester for 

25
determination as to whether further action is required. When patient safety is of 
concern, an interim meeting may be called 
Any serious adverse event that is serious, related AND unexpected must be 
reported within 10 calendar days to both the DSMC Safety Coordinator and 
the RSRB (see RSRB guidelines).  The DSMC Chair will determine whether 
further action is required, and when patient safety is of concern, an interim 
meeting may be called. 
Serious adverse events that are related AND expected or unrelated AND 
unexpected will be reported to the DSMC for review at the quarterly 
meeting.  SAE reports are expected to include sufficient detail so that the 
DSMC can determine the severity, toxicity grade, expectedness, treatment 
required, and a follow up report documenting resolution or if there are 
sequelae.  Serious adverse events that require detailed reports (but not 
necessarily expedited) are expected, related, non-hematologic toxicities of 
grades 3, 4 or 5. 
The Safety Coordinator administratively coordinates reports and data collection and 
prepares documents for the DSMC Chair and committee review.  The Safety Coordinator 
will administratively monitor adverse event rates utilizing the report from the study 
database.  If any study has had two or more of the same SAE’s reported in a month or 
more than six of the same SAE’s 
in six months, the DSMC will review the summary of SAEs, 
discuss events with Study Chair, and conduct a more detailed review with the Study Chair. 
The Data Safety Monitoring Chair will determine if further action is required. 
  
 
12.0 
Data Confidentiality and Storage
During participation in the study, subject data including laboratory results, 
imaging, exams, treatments, and outcomes will be part of the patient’s chart.  
Data extracted from the chart for the purpose of the study will be stored in the 
RedCap database. 
Subjects will each have their own unique code in place of name, date of birth or 
other identifier that may be used in charting. The key will not be derived from 
patient data and will be available to the principle and/or sub-investigators. To 
avoid unauthorized disclosure of subject data with consent, the following 
safeguards will be in place:
• Not storing identifying information in the research database except unique 
subject code that will be used for subject identification
• Subject codes will be randomly assigned, and codes will be protected and 
treated as confidential as they link subject to data
• Security measures for physical and electronic data i.e.) locking up research 
files/logging out of electronic systems while they are unsupervised 
• Using screensavers 

26
• Shredding excess copies of paper documents 
13.0 
Data and Specimen Banking for Future Research Use 
Upon consenting for study enrollment, participants will be given the option also 
to consent for banking of their rectal tissue specimen(s) for future use related to 
the study. The purpose of banking is to have the option to evaluate for genetic, 
histologic, or molecular information retrospectively following the initial study.  
This may be used to continue further research or clinical questions that may 
arise from our proposed study. 
Consideration for access to these specimens will be determined by the principal 
investigator. Raw data from the study will be stored in the RedCap database, 
and participant specimens will be stored with pathology for 5 years.  Both data 
and specimen(s) will be identified by a unique assigned subject code not derived 
from patient data as to protect confidentiality, with the key remaining with the 
principle investigator and/or sub-investigators.  
Subjects will not be re-consented for use of their specimens if used in part of 
this study by the current principle and sub-investigators.  The subject may 
request for their data or specimen(s) to be removed from the study or storage 
at any at the initiation of study or thereafter. 
Optional Correlative Biomarker:
Patients will have the option to consent for additional correlative biomarker 
blood samples for future research use. Two 10.0 mL EDTA lavender tubes (total 
of 20.0 mL) will be collected at each time point – baseline, Cycle 6 Day 1 and 
time of post radiation assessment (if applicable). Both plasma and buffy coat 
samples will be collected. Within 1 hour of collection, centrifuge collection 
tubes for 10 minutes at 1600 x g. Transfer the supernatant into a conical tube. 
Remove the buffy coat (~1.0 mL) from the collection tubes and place in 1.5 mL 
cryotube. Centrifuge supernatant for an additional 10 minutes at 1600 x g. 
Divide the plasma into three cryotubes – two 3.0 mL tubes and one 1.5 mL tube. 
Freeze plasma and buffy coat samples in -80°C freezer. All samples should be 
labeled with subject ID number, study time point, collection date and sample 
type.

27
14.0 
References
1. NCCN, N.C.C.N., NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. 
2018(Version 4.2017).
2. Sauer, R., et al., Preoperative versus postoperative chemoradiotherapy for rectal cancer. 
N Engl J Med, 2004. 351(17): p. 1731-40.
3. AlGizawy, S.M., H.H. Essa, and B.M. Ahmed, Chemotherapy Alone for Patients With 
Stage II/III Rectal Cancer Undergoing Radical Surgery. Oncologist, 2015. 20(7): p. 752-7.
4. Habr-Gama, A., et al., Local recurrence after complete clinical response and watch and 
wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local 
disease control. Int J Radiat Oncol Biol Phys, 2014. 88(4): p. 822-8.
5. Schrag, D., et al., Neoadjuvant chemotherapy without routine use of radiation therapy 
for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol, 2014. 32(6): p. 513-
8.
6. Deng, Y., et al., Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and 
Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: 
Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm 
Phase III Trial. J Clin Oncol, 2016. 34(27): p. 3300-7.
7. Cercek, A., et al., Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal 
Cancer. JAMA Oncol, 2018.
8. Whistance, R.N., et al., Clinical and psychometric validation of the EORTC QLQ-CR29 
questionnaire module to assess health-related quality of life in patients with colorectal 
cancer. Eur J Cancer, 2009. 45(17): p. 3017-26.
9. Aaronson NK, A.S., Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F. , The European Organisation for Research and Treatment 
of Cancer QLQ-C30: A quality-of-life intrument for use in international clinical trials in 
oncology. . Journal of the National Cancer Institute, 1993. 85: p. 365-376.
10.Fayers, P., Aaronson NK, Bjrodal K, Groenvold M, Curran D, Bottomley A, The EORTC 
QLQ-C30 Scoring Manual (3rd Edition). European Organisation for Research and Treatment 
of Cancer, Brussels, 2001.