Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum (NORMAL-R)
Phase: PHASE2
Conditions: Cancer of Rectum, Cancer of the Rectum, Neoplasm, Rectum, Rectal Cancer, Rectum Cancer, Rectum Neoplasms, Adenocarcinoma of the Rectum
Sponsor: Washington University School of Medicine

Version 06/01/18- Amendment 4 
 
page 1 of 39 
 
 
Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum 
(NORMAL-R) 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 S. Euclid Ave., CB 8224 
St. Louis, MO 63110 
 
Protocol #: 201512140 
Version date: 06/01/2018 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
 
Hyun Kim, M.D. 
Phone:  (314) 362-8502 
E-mail:  kim.hyun@wustl.edu  
 
Medical Oncology Co-PI: 
Katrina Pedersen, M.D. 
Surgery Co-PI: 
 
 
Steven Hunt, M.D. 
 
Sub-Investigators  
 
 
Institution 
 
 
Modality 
Manik Amin, M.D.  
 
 
Washington University 
Medical Oncology 
Elisa Birnbaum, M.D. 
 
 
Washington University 
Colorectal Surgery 
Sekhar Dharmarajan, M.D. 
 
Washington University 
Colorectal Surgery 
Sean Glasgow, M.D. 
 
 
Washington University 
Colorectal Surgery 
Kian-Huat Lim, M.D., Ph.D. 
 
Washington University 
Medical Oncology 
Parag J. Parikh, M.D. 
 
 
Washington University 
Radiation Oncology 
Michael Roach, M.D. 
 
 
Washington University 
Radiation Oncology 
Matthew Mutch, M.D. 
 
 
Washington University 
Colorectal Surgery 
Matthew Silviera, M.D. 
 
 
Washington University 
Colorectal Surgery 
Rama Suresh, M.D. 
 
 
Washington University 
Medical Oncology 
Benjamin R. Tan, M.D. 
 
 
Washington University 
Medical Oncology 
Paul Wise, M.D. 
 
 
 
Washington University 
Colorectal Surgery 
Radhika Smith, M.D. 
 
 
Washington University 
Colorectal Surgery 
Andrea Wang-Gillam, M.D., Ph.D.  
Washington University 
Medical Oncology 
Haeseong Park, M.D. 
 
 
Washington University 
Medical Oncology 
Nikolaos Trikalinos, M.D.  
 
Washington University 
Medical Oncology 
 
Clinicaltrials.gov #: NCT02641691 
 
 
 

Version 06/01/18- Amendment 4 
 
page 2 of 39 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons 
to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them 
 

Version 06/01/18- Amendment 4 
 
page 3 of 39 
Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum 
(NORMAL-R) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
01/12/2016 
Amendment #1 Version 
 
 
 
 
 
 
04/18/2016 
Amendment #2 Version 
 
 
 
 
 
 
11/28/2016 
Amendment #3 Version 
 
 
 
 
 
 
11/14/2017 
Amendment #4 Version 
 
 
 
 
 
 
06/01/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version 06/01/18- Amendment 4 
 
page 4 of 39 
 
Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum 
(NORMAL-R) 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 
PI Signature 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States 
Code of Federal Regulations or local regulations governing the conduct 
of clinical studies. 
 
 

Version 06/01/18- Amendment 4 
 
page 5 of 39 
 
SCHEMA 
 
 
 
Primary Objective 
To determine the clinical response rate of patients with Stage I-IIIB (cT1-3, N0-1, M0) rectal 
cancer being treated with sequential short course radiotherapy followed by 8 cycles of multi-drug 
chemotherapy. 
 
Secondary Objectives: 
1. To obtain prospective patient reported outcomes from an organ preservation approach 
towards early stage rectal cancer 
2. To determine the incidence of any grade ≥ 3 toxicity during treatment 
3. To determine the incidence of post chemoradiotherapy grade ≥ 3 toxicity at 1 year 
4. Determine quality of anorectal function at 1 year using the FACT-C questionnaire 
 
 
 
Pelvic 
Radiotherapy 
(5 Gy x 5)  
Optional SIB 1-2 
Gy x 5 
FOLFOX x 8 
cycles 
Complete Clinical 
Response: Non-
Operative Management 
Persistent Disease: 
TME 

Version 06/01/18- Amendment 4 
 
page 6 of 39 
Table of Contents  
 
SCHEMA ........................................................................................................................................ 5 
1 
BACKGROUND ..................................................................................................................... 8 
2 
OBJECTIVES .......................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Secondary Objectives ....................................................................................................... 9 
3 
ELIGIBILITY CRITERIA .................................................................................................... 10 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 10 
3.3 
Inclusion of Women and Minorities............................................................................... 11 
4 
Patient Registration................................................................................................................ 11 
4.1 
Confirmation of Patient Eligibility ................................................................................. 11 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 11 
4.3 
Assignment of UPN ....................................................................................................... 12 
5 
EVALUATION STUDIES .................................................................................................... 12 
5.1 
Pre-treatment .................................................................................................................. 12 
5.2 
During Radiotherapy and Chemotherapy ....................................................................... 12 
5.3 
Completion of Chemotherapy/Post-Treatment Evaluation ............................................ 13 
5.4 
Follow-up ....................................................................................................................... 13 
6 
RADIATION THERAPY GUIDELINES ............................................................................. 13 
6.1 
Dose, Fractionation ........................................................................................................ 13 
6.2 
Treatment Planning Procedures ..................................................................................... 14 
6.3 
Simulation Procedures/Patient Positioning .................................................................... 14 
6.4 
Clinical Target Volume (CTV) and Planning Target Volume (PTV) Definitions ......... 14 
6.5 
Normal Tissue Contours................................................................................................. 15 
7 
CHEMOTHERAPY GUIDELINES...................................................................................... 15 
7.1 
Chemotherapy Schedule and Doses ............................................................................... 15 
7.2 
Agent Administration ..................................................................................................... 15 
7.3 
Supportive Care Recommendations ............................................................................... 16 
8 
DOSE DELAYS/DOSE MODIFICATIONS ........................................................................ 16 
8.1 
Dose Levels .................................................................................................................... 17 
8.2 
Dose Modifications for Toxicity Related to FOLFOX-6 ............................................... 18 
8.3 
Dose Modifications for Neurologic Toxicity (Paresthesia or Dysesthesia) Related to 
Oxaliplatin................................................................................................................................. 19 
9 
ADVERSE EVENT REPORTING ....................................................................................... 19 
9.1 
Definitions ...................................................................................................................... 19 
9.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
21 
9.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ............................................................................................................. 22 
9.4 
Reporting Requirements for Secondary Sites ................................................................ 22 
9.5 
Reporting to Secondary Sites ......................................................................................... 22 
9.6 
Timeframe for Reporting Required Events .................................................................... 22 
10 
PHARMACEUTICAL INFORMATION .......................................................................... 23 
10.1 Leucovorin ..................................................................................................................... 23 

Version 06/01/18- Amendment 4 
 
page 7 of 39 
10.2 5-Fluorouracil (5-FU) ..................................................................................................... 24 
10.3 Oxaliplatin ...................................................................................................................... 25 
11 
STUDY CALENDAR ....................................................................................................... 28 
12 
DATA SUBMISSION SCHEDULE ................................................................................. 30 
13 
MEASUREMENT OF EFFECT........................................................................................ 30 
14 
DATA AND SAFETY MONITORING PLAN ................................................................ 30 
15 
AUDITING ........................................................................................................................ 31 
16 
STATISTICAL CONSIDERATIONS............................................................................... 32 
16.1 Study Objectives and Endpoints .................................................................................... 32 
16.2 Study Design and Sample Size Justification .................................................................. 32 
16.3 Interim Analyses and Stopping Rules ............................................................................ 33 
16.4 Definition of Evaluability............................................................................................... 33 
16.5 Data Analysis ................................................................................................................. 33 
16.6 Accrual ........................................................................................................................... 33 
17 
MULTICENTER REGULATORY REQUIREMENTS ................................................... 33 
18 
REFERENCES .................................................................................................................. 35 
Appendix A: FACT-C Questionnaire ........................................................................................... 37 
 
 
 

Version 06/01/18- Amendment 4 
 
page 8 of 39 
 
1 
BACKGROUND 
With the exception of a small group of favorable risk stage I disease, the standard of care for stage 
I-III rectal cancer usually includes a total mesorectal excision (TME). TME in the form of an 
abdominoperineal resection (APR) results in a permanent stoma, which may significantly impact 
the patient’s self-image and quality of life (QOL). TME in the form of a low anterior resection 
(LAR) obviates the need of an ostomy but is associated with poorer rectal function. 
 
There are increasing data supporting the use of chemotherapy and radiation therapy for non-
operative management of rectal cancer1–4. Habr-Gama et al. treated 70 distal rectal cancer (T2-4 
N0-2) patients with 54 Gy in 30 fractions and concurrent 5-fluorouracil (5FU)/leucovorin and 
demonstrated an initial complete clinical response (cCR) in 47 (68%) patients with 39 (57%) 
demonstrating a sustained cCR at 56 months4. Appelt et al. treated 55 patients (T2-3 N0-1) with 
60 Gy in 30 fractions with a 5 Gy brachytherapy boost plus oral tegafur-uracil5. Seventy-eight 
percent of patients demonstrated cCR with 16% local recurrence at 24 months5. Maas et al. found 
that patients with cCR after neoadjuvant chemoradiation therapy have similar oncologic outcomes 
to those with pathologic complete response (pCR)6. The radiation in these trials was delivered 
over 5-6 weeks of daily treatment. 
 
Short course radiation therapy delivered as 25 Gy in 5 fractions is routinely used as preoperative 
therapy in Europe and Australia7–9. The first Polish rectal study demonstrated that patients with 
T3-4 resectable rectal cancer treated with 25 Gy in 5 fractions followed by surgery versus 50.4 
Gy in 28 fractions with concurrent 5FU followed by surgery had similar local recurrence (9% vs 
14%), disease free survival (58% vs 56%) and overall survival (67% vs 66%)8. The second Polish 
rectal trial demonstrated that there was no difference in R0 resection and pCR rates in patients 
with T3-4 rectal cancer treated with 25 Gy in 5 fractions followed by FOLFOX then surgery 
compared to 50.4 in 28 fractions with FOLFOX followed by surgery9. There was even a 3 year 
overall survival advantage for short course radiation (73% versus 65%), but the reason for this 
survival advantage in light of a non-significant difference in disease free survival is unclear. 
Important to note is that the dose prescribed with pre-operative short course radiation (5 Gy x 5 
fractions) has a biologic effective dose (BED) of 37.5 Gy (α/β=10) in contrast to the BED of 63.7 
Gy when 54 Gy is given in 30 daily fractions. Increasing the radiation dose to the tumor may 
further increase the clinical complete response (cCR) rate and allow for non-operative 
management. 
 
There are increasing data to support increasing the interval from radiation to surgery. The pCR 
rate of standard short course radiation followed by surgery 1 week later is approximately 1%7,8. 
Increasing the interval to surgery from 2 to 6-8 weeks may increase the pCR rate without 
compromising oncologic outcomes10–12. The Lyon R90-01 trial demonstrated that patients with T2 
rectal adenocarcinoma treated with 39 Gy in 13 fractions had increased pCR if surgery is delayed 
to 6-8 weeks post-radiation versus 2 weeks post-radiation (26% vs 10%)10. In the non-inferiority 
Stockholm III, which evaluated short course radiation followed by surgery at 1 versus 4-8 weeks 
versus long course radiation therapy, there were no differences in long term cancer outcomes 
between the three treatment groups13. Thus increasing the interval from radiation completion to 
surgery may improve treatment outcomes. 
 

Version 06/01/18- Amendment 4 
 
page 9 of 39 
 
In a phase II trial for patients with cT3-4, any N, any M rectal cancer recently completed at 
Washington University (HRPO# 09-0696) evaluating short-course radiotherapy followed by 4 
cycles of FOLFOX chemotherapy (5FU, oxaliplatin, and leucovorin), a complete tumor response 
was seen in 28% of patients, with a complete pathologic response rate of 42% and downstaging 
rate of 87% for patients with lower risk tumors (3).  QOL data was prospectively evaluated using 
the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire. Mean FACT-
C scores for all five categories were not significantly different for pre-treatment (20.6 +/- 5.6), pre-
surgery (20.2 +/- 5.4), or post-surgery time points (20.0 +/- 5.4) (p = 0.8), confirming clinically 
observed absence of treatment related toxicity.  Improved patient-reported functional outcomes 
were observed for patients undergoing sphincter sparing surgery, compared to those requiring an 
abdominoperineal resection with ostomy,  In patients with an ostomy, FACT-C scores for 
functional well-being 1-year post-surgery were significantly reduced (lower QOL) compared to 
patients without ostomy (13.2 vs 19.2, p = 0.01) (2).  Given the negative quality of life impact of 
abdominoperineal resection with ostomy, it is plausible that the side effect profile of radiation 
therapy and chemotherapy may allow improved overall quality of life in the context of an organ 
preservation strategy. 
 
To date, short course radiation therapy has not been evaluated in the setting of non-operative 
management. Given the highly favorable response rates reported in higher risk stage II-III patients 
and patient-reported outcomes data which confirm a benefit to sphincter sparing approaches, we 
propose a pilot study of organ preservation treatment for rectal cancer which would otherwise 
require total mesorectal excision (TME).  
 
 
2 
OBJECTIVES 
 
Our principal objectives in this trial will be to determine if short course radiotherapy followed by 
8 cycles of chemotherapy results in cCR , to permit an organ preservation strategy for patients with 
stage I-IIIB (cT1-3, N0-2, M0) rectal cancer. We do not anticipate being able to prove this in the 
present single arm pilot study; that would be the principal objective of a successor, multi-institution 
phase II/III protocol. 
 
2.1 
Primary Objective 
 
To determine the cCR response rate of patients with stage I-IIIB (cT1-3, N0-2, M0) rectal 
cancer being treated with sequential short course radiotherapy followed by 8 cycles of 
multi-drug chemotherapy. 
 
2.2 
Secondary Objectives 
 
1. To obtain prospective patient reported outcomes from an organ preservation approach 
for early stage rectal cancer. 
2. To determine the incidence of any grade ≥ 3 toxicity during treatment. 
3. To determine the incidence of post chemoradiotherapy grade ≥ 3 toxicity at 1 year 
4. To determine quality of anorectal function at 1 year using the FACT-C questionnaire. 

Version 06/01/18- Amendment 4 
 
page 10 of 39 
 
 
3 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
1. Diagnosis of biopsy proven stage I-IIIB (cT1-3, N0-2, M0) adenocarcinoma of the 
rectum; staging must also be based on multidisciplinary evaluation including MRI 
and/or endorectal ultrasound 
2. Tumor ≤ 12 cm from anal verge as determined by MRI or endoscopy 
3. ECOG performance status 0-2 
4. At least 18 years of age 
5. Adequate bone marrow function defined as: 
a. ANC > 1,500 cells/mm3 
b. Hgb > 8 g/dl 
c. platelets >100,000 cells/mm3 
6. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
7. Able to understand and willing to sign an IRB-approved written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
1. No clinically detectable (MR, endoscopy or DRE) tumor present. 
2. Prior radiation therapy, chemotherapy or extirpative surgery for rectal cancer. 
3. Any evidence of disease from another malignancy or history of other malignancy ≤ 3 
years previous (with the exception of basal cell or squamous cell carcinoma of the skin 
which were treated with local resection only or carcinoma in situ of the cervix). Patients 
with history of prostate cancer treated without radiotherapy and no evidence of disease 
are eligible. 
4. Currently receiving any investigational agents. 
5. A history of allergic reaction attributed to compounds of similar chemical or biologic 
composition to 5FU, oxaliplatin, or leucovorin. 
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
7. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test within 14 days of study entry. 
8. Known HIV-positivity and on combination antiretroviral therapy because of the 
potential for pharmacokinetic interactions with the study drugs.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 

Version 06/01/18- Amendment 4 
 
page 11 of 39 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4 
Patient Registration 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 

Version 06/01/18- Amendment 4 
 
page 12 of 39 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5 
EVALUATION STUDIES 
 
5.1 
Pre-treatment 
 
Within 12 weeks of day of simulation for RT but no later than the first radiation treatment: 
 
• Staging study to evaluate extent of disease in the abdomen and pelvis: CT with IV 
contrast or MRI w/ IV contrast. 
• Staging study to evaluate the lungs: CT scan of the chest  
• CBC, CMP, CEA 
• Pregnancy test (for women of childbearing potential) – within 14 days of first 
treatment 
• Colonoscopy 
• Examination by treating surgeon, medical oncologist, and radiation oncologist 
 
If feasible it is strongly recommended that the following physical findings should 
be scored: 
- 
Tumor location (distance in cm from the anal verge to the distal tumor margin) 
- 
Circumferential lesion Y/N 
 
• Imaging study to assess the local extent of the primary tumor, including T stage.  A 
pelvic MRI is the preferred method for doing this; but depending on the lesion this 
could be endorectal ultrasound, or CT scan.   
• FACT-C quality of life questionnaire 
 
5.2 
During Radiotherapy and Chemotherapy 
 
Routine standard of care examinations and blood work will be done.  This consists of a 
CMP and a CBC with differential prior to each cycle of chemotherapy and examination by 
the radiation oncologist during the week of radiation therapy and by a medical oncology 
physician or nurse with each cycle of chemotherapy.  Please see Section 6 for radiation 
therapy guidelines and Section 7 for chemotherapy guidelines. 
 

Version 06/01/18- Amendment 4 
 
page 13 of 39 
5.3 
Completion of Chemotherapy/Post-Treatment Evaluation 
 
Two to four weeks after completion of chemotherapy, patients will have the following 
assessments: 
• FACT-C questionnaire. 
• Surgical assessment w/ endoscopy (sigmoidoscopy preferred, rigid proctoscopy 
acceptable) to evaluate the extent of residual tumor 
• MRI (when feasible) to evaluate ycT stage 
• DRE (when feasible) to evaluate ycT stage 
  
For patients with a cCR, non-operative management will be pursued. Patients will be 
assessed for sustained cCR by pelvic MR, endoscopy (sigmoidoscopy preferred, rigid 
proctoscopy accepted) and DRE every three months (not necessarily on the same day / 
appointment) for 1 year. Follow-up after 1 year will be left to the discretion of the treating 
physician, although DRE, pelvic MR and endoscopy every 3-4 months is recommended 
for the second year. CT chest/abdomen/pelvis every 6 months is recommended for at least 
the first 2 years. For patients with residual disease who do not meet criteria for cCR by 4 
weeks after completion of the 8th cycle of FOLFOX, further therapy is mandated and at the 
discretion of the treating physicians.  Patients whose disease is amenable to transanal 
endoscopic microexcision (TEM) or local excision (LE) may undergo TEM/LE to evaluate 
degree of residual disease.  For those with pT1 disease without LVSI present, non-operative 
management may continue with evaluation noted above.  For those with residual T2-3 
disease or T1 with LVSI, extirpative surgery including TME is recommended with 
treatment at investigators discretion proceeding off-study. 
 
Post-treatment lymph nodes are to be evaluated by imaging and reviewed in 
muldisciplinary tumor board with a radiologist and classified as progressive, persistent 
disease, indeterminate or benign. Patients with progressive or persistent lymph node 
disease will not be eligible for non-operative management and will undergo additional 
therapy. Patients with indeterminate or benign lymph nodes AND cCR of primary will 
undergo non-operative management. 
 
5.4 
Follow-up 
 
The FACT-C questionnaire and follow-up visit will be done 10-14 months from treatment 
(radiotherapy) start date.  Long-term follow-up will be done per routine policies of the 
treating physicians.  It is recommended that there be follow up visits every 6 months with 
clinical exam until 5 years from study enrollment.  
 
 
6 
RADIATION THERAPY GUIDELINES 
 
6.1 
Dose, Fractionation and Constraints 
 
When feasible it is strongly recommended that radiotherapy begin on a Monday. It is 
accepted that occasional logistical delays may occur during radiotherapy treatment due to 

Version 06/01/18- Amendment 4 
 
page 14 of 39 
machine downtime or other issues.  Radiotherapy as administered during this study may 
take up to 10 business days without being considered a protocol deviation. 
 
Radiotherapy will consist of five fractions, delivered once daily, to a total dose of 25 Gy at 
5 Gy per fraction (PTV2500). Daily imaging to verify accurate setup is mandatory.  It is 
required that at least 95% of the PTVs receive at least 95% of the prescription dose and 
that the maximum dose be < 115% of the prescription dose. Every effort should be made 
for 100% of the PTV to be covered by 95% of the prescription dose. The maximum allowed 
dose to small bowel is 25 Gy.   
 
An optional concomitant boost may be delivered to the primary tumor of 1-2 Gy per day 
(30-35 Gy to tumor total). If a boost is given then the maximum allowed dose to small 
bowel is 25 Gy.  Lymph nodes that are outside of the mesorectum may be boosted up to 35 
Gy in 5 fractions also, as long as this small bowel constraint is met. 
 
The following constraints are recommended when boosting lymph node or primary:  
Bladder V20Gy < 15 cc. Dmax < 38 Gy.  
Penile bulb V30Gy < 3 cc.  
Femoral heads V30Gy < 10 cc.  
Skin V36.5Gy < 10 cc. Dmax < 38.5 Gy. 
  
6.2 
Treatment Planning Procedures 
 
Image-based treatment planning and intensity modulated radiotherapy (IMRT) is 
permitted.  Proton therapy is not permitted. Dose volume histogram (DVH) information 
for the target volumes, small bowel, and uninvolved colon (defined to be large bowel 
outside the clinical target volumes) is mandatory.  This is to assist in interpreting outcome, 
including morbidity.   
 
6.3 
Simulation Procedures/Patient Positioning 
 
The prone position with a bowel displacement device incorporated into the immobilization 
cast is generally recommended as the best way to exclude small bowel from the pelvis. The 
exceptions would be patients unable to lay prone or morbidly obese patients whose 
diagnostic supine CT scans demonstrate little or no small bowel in the pelvis.   Those 
patients with good bladder control should be treated with a full bladder to further exclude 
small bowel.  All patients should be simulated with oral small bowel contrast.  
 
6.4 
Clinical Target Volume (CTV) and Planning Target Volume (PTV) 
Definitions 
 
CTV2500 should include rectum and associated mesentery extending caudad at least to 
two cm below the distal edge of palpable disease.  Superiorly it should include the rectum 
and its mesentery to the level of the rectosigmoid or two cm proximal to macroscopic 
disease, whichever is more cephalad.  In addition, the internal iliac, internal obturator, and 
pre-sacral lymph node regions should be included. Contouring should be as per the RTOG 

Version 06/01/18- Amendment 4 
 
page 15 of 39 
anorectal contouring atlas (www.rtog.org). 
 
If the concomitant boost is prescribed then the GTV3500 is defined by radiographic 
findings and clinical exam, as per treating physician judgment. Pelvic MRI is required for 
patients to receive boost. 
 
PTV2500 is generated by a uniform 0.7 cm expansion about CTV2500.  PTV expansion 
for boost is 1-1.5 cm expansion off of the GTV (including mesorectum at the axial level of 
the GTV is at physician’s discretion). In order for this tight PTV margin to be used, it is 
required that a physician review daily setup images for each of the five fractions. 
 
6.5 
Normal Tissue Contours 
 
Small bowel and uninvolved colon should be contoured tightly.  Uninvolved colon is 
defined to be large bowel that lies outside the CTV.  Colon that lies within the CTV (rectum 
and parts of the sigmoid) is a target structure, not an avoidance structure, hence its 
exclusion from “uninvolved colon.”  The CTV is NOT to be extracted from small bowel.  
If small bowel lies within a CTV, that WILL contribute to the small bowel dose.  Since 
absolute rather than relative bowel volumes are to be tracked, it is not necessary to contour 
the entire large and small bowel, only those loops caudal to 1 cm above the most cephalad 
extent of CTV2500.  
 
 
7 
CHEMOTHERAPY GUIDELINES 
 
7.1 
Chemotherapy Schedule and Doses 
 
Chemotherapy should begin 2 to 4 weeks after completion of radiotherapy and will consist 
of 5FU/leucovorin/oxaliplatin every other week for 8 courses (16 weeks). Alternatively, 
capecitabine/oxaliplatin (CAPE PO 1000 mg/m2 BID days 1-14  Q21 days, oxaliplatin IV 
130 mg/m2 IV Q21 days on day 1) x 5 cycles over 15 weeks may be administered instead 
of FOLFOX.  A maximum (total) delay of treatment of 4 weeks is allowed per protocol 
due to factors/AEs listed in this section.  Cumulative delays in excess of 4 weeks will need 
to be discussed with the Principal Investigator.  Such cases will need to be individualized 
depending on the clinical scenario.  
 
7.2 
Agent Administration 
 
Folfox 
Dose  
Route 
Schedule 
Oxaliplatin* 
85 mg/m2 
IV over 2 hours On Day 1, Q 14 days 
Leucovorin* 
400 mg/m2 
IV over 2 hours On Day 1, Q 14 days 
5-FU Bolus* 
400 mg/m2 
IV push  
On Day 1, Q 14 days 
5-FU Infusion*  
2400 mg/m2 
IV CIIV 
On Day 1, Q 14 days 
over 46 hours 
*Administer sequentially as written, except oxaliplatin and leucovorin may be administered concurrently 
 

Version 06/01/18- Amendment 4 
 
page 16 of 39 
CapeOx 
Dose  
Route 
Schedule 
Oxaliplatin 
130 mg/m2 
IV  
On Day 1, Q 21 days 
Capecitabine 
1000mg/m2 
PO BID 
On Days 1-14, Q 21 
days 
 
Dose calculations should be based on actual weight and not corrected for obesity. 
 
 
7.3 
Supportive Care Recommendations 
 
Veno-occlusive disease is a very rare AE associated with the administration of the 
combination of 5-FU and oxaliplatin. VOD disease is characterized by hepatomegaly, 
ascites, and jaundice. These signs and symptoms should prompt consideration of VOD. A 
Doppler ultrasound showing reversal of portal blood flow or other evidence of portal 
hypertension is suggestive of this diagnosis. In addition, standard clinical practice for 
evaluation of VOD should include observation of liver and spleen size, history of or 
gastrointestinal bleeding, development of esophageal varices, ascites, bleeding, or 
jaundice.  All patients on and off therapy who develop signs and symptoms suggestive of 
VOD should be thoroughly evaluated and closely monitored and supported as clinically 
dictated. 
 
Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, has been 
observed with oxaliplatin.  These allergic reactions, which can be fatal, can occur within 
minutes of administration, and can occur during any cycle.  There were similar in nature 
and severity to those reported with other platinum-containing compounds, such as rash, 
urticaria, erythema, pruritus, and rarely bronchospasm and hypotension.  These reactions 
are usually managed with standard epinephrine, corticosteroid, and antihistamine therapy, 
and require discontinuation of therapy. 
 
Ice should be avoided during the infusion of oxaliplatin because cold temperatures can 
exacerbate acute neurological symptoms. 
 
 
8 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Radiotherapy for this trial may take place over a maximum of 10 business days before it is 
considered a protocol deviation.  There are no dose adjustments (reductions, omissions) associated 
with radiotherapy. 
 
All toxicities should be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0.  Dose modifications are based upon dose level administered at last 
treatment day. If the dose level has been reduced due to toxicity, re-escalation is not permitted. If 
dose reduction is required after dose level -3, patient will discontinue protocol therapy. 
 
 

Version 06/01/18- Amendment 4 
 
page 17 of 39 
8.1 
Dose Levels 
 
Folfox 
Starting Dose 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
40 mg/m2 
Bolus 5-FU 
400 mg/m2 
300 mg/m2 
200 mg/m2 
100 mg/m2 
Infusion 5-FU 
2400 mg/m2 
1920 mg/m2 
1600 mg/m2 
1360 mg/m2 
Leucovorin 
400 mg/m2 
400 mg/m2 
400 mg/m2 
400 mg/m2 
 
CapeOx 
Starting Dose 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Capecitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
540 mg/m2 
Oxaliplatin 
130 mg/m2 
104 mg/m2 
78 mg/m2 
70 mg/m2 
*Rounding capecitabine to nearest full tablet dose is acceptable (i.e. Dose 1900 mg rounded to 
2000 mg (4x 500 mg tablets) daily). 
 

Version 06/01/18- Amendment 4 
 
page 18 of 39 
8.2 
Dose Modifications for Toxicity Related to FOLFOX and CapeOx 
 
The provided dose modifications are strongly recommended. However, out of consideration of 
unforeseen clinical scenarios, dose modifications during FOLFOX chemotherapy are ultimately at 
the discretion of the primary treating provider. The use of 5-FU bolus is at the discretion of the 
treating physician. Modifications should be reported to the research coordinator. Refer to table 8.2 
and 8.3 for guidance regarding suggested dose reductions and treatment delays, consistent with 
best oncologic practices.  
Toxicity NCI Grade (Value) 
Worst interval toxicity 
Day of treatment 
Neutropenia (ANC)  
Grade 1 
(ANC < LLN – 1500/mm³) 
Maintain dose level 
If ANC < 1000 on day of treatment, hold 
and check weekly until > 1000 mm3. Then 
treat based on interval toxicity. If ANC < 
1000 after 4 weeks, discontinue therapy. 
 
Grade 2 
(ANC <1499 – 1000/mm³) 
 
Grade 3 
(ANC <999 – 500/mm³) 
Reduce 1 dose level  
Grade 4 
(ANC < 500/mm³) 
Thrombocytopenia 
Grade 1 
(PLT < LLN – 75,000/mm3) 
Maintain dose level 
If PLT < 75,000 on day of treatment, hold 
and check weekly until > 75,000 mm3. 
Then treat based on interval toxicity. If 
PLT < 75,000 after 4 weeks, discontinue 
therapy. 
Grade 2 
(PLT 74,999 – 50,000/mm3) 
Grade 3 
(PLT 49,999 – 25,000/mm3) 
Reduce 1 dose level  
Grade 4 
(PLT< 25,000/mm3) 
Diarrhea 
Grade 1 
Maintain dose level 
Hold chemotherapy if any grade of 
diarrhea above grade 1 is present with the 
patient not taking antidiarrheal agents 
within 24 hours of treatment. Reduce 5-
FU and oxaliplatin 1 dose level upon 
resolution of diarrhea. If diarrhea has not 
resolved within 4 weeks of scheduled 
treatment day, discontinue therapy. 
Grade 2 
Reduce 
5-FU 
and 
oxaliplatin 1 dose level 
Grade 3 
Grade 4 
Other nonhematologic toxicities 
(except neurologic, alopecia, anorexia, nausea/vomiting if can be controlled by antiemetics) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Grade 3 
Reduce 1 dose level  
Hold until resolved to grade ≤1. 
Reduce 5-FU and oxaliplatin 1 
dose level 
Grade 4 
 
 
 

Version 06/01/18- Amendment 4 
 
page 19 of 39 
 
8.3 
Dose Modifications for Neurologic Toxicity (Paresthesia or Dysesthesia) 
Related to Oxaliplatin 
 
Grade 
 
Duration of Toxicity 
1 – 7 Days 
> 7 Days 
Persistent 
Between 
Doses 
Grade 1 
Short duration that resolves and 
does not interfere with function 
No change 
 
No change 
 
No change 
 
Grade 2 
Interfering with function, but not 
activities of daily living (ADL) 
No change 
 
No change 
 
Reduce 
oxaliplatin 1 
dose level 
Grade 3 
With pain or with functional 
impairment that also interferes with 
ADL 
 
1st time: reduce 
oxaliplatin 1 dose 
level 
 
2nd time: reduce 
oxaliplatin another 
dose level 
1st time: reduce 
oxaliplatin 1 dose 
level 
 
2nd time: reduce 
oxaliplatin another 
dose level 
Discontinue 
oxaliplatin 
 
Grade 4 
Persistent symptoms that are 
disabling or life-threatening 
Discontinue 
oxaliplatin 
 
Discontinue 
oxaliplatin 
 
Discontinue 
oxaliplatin 
 
 
 
9 
ADVERSE EVENT REPORTING 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 9.2. 
 
9.1 
Definitions 
 
9.1.1 Adverse Events (AEs) 
 
Definition:  any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading:  the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 

Version 06/01/18- Amendment 4 
 
page 20 of 39 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.html 
 
9.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
9.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
9.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
9.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 

Version 06/01/18- Amendment 4 
 
page 21 of 39 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
 
9.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
9.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
9.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the 
event.  For secondary sites, the Washington University PI will issue approval of the 
exception, but it must also be submitted to the local IRB with documentation of 
approval forwarded to Washington University.  Washington University IRB 
approval is not required for protocol exceptions occurring at secondary sites. 
 
9.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 

Version 06/01/18- Amendment 4 
 
page 22 of 39 
event or notification to the PI of the event. 
 
9.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
9.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 9.2) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required 
or an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death 
of a research participant that qualifies as a reportable event should be reported within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.   
 
9.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all reportable events that have occurred at other sites within 10 working days of the 
occurrence of the event or notification of the PI of the event.  This includes events that take 
place both at Washington University and at other secondary sites, if applicable. 
 
9.6 
Timeframe for Reporting Required Events 
 
All Grade 3 and above adverse events should be collected until 1 year post start of radiation 
therapy on case report forms and reported to the QASMC as part of the DSM Report as 
applicable.  
  
 
 

Version 06/01/18- Amendment 4 
 
page 23 of 39 
10 
PHARMACEUTICAL INFORMATION 
 
FOLFOX is a standard of care, FDA-approved regimen for the treatment of rectal cancer, and 
treatment will be provided and administered according to standard of care guidelines. More 
detailed information can be found in the products’ package inserts. 
 
10.1 
Leucovorin  
 
10.1.1 Mechanism of action 
 
Leucovorin is a tetrahydrofolate acid derivative that acts as a biochemical cofactor 
for carbon transfer reactions in the synthesis of purines and pyrimidines. 
Leucovorin does not require the enzyme dihydrofolate reductase for conversion to 
tetrahydrofolic acid. Leucovorin potentiates the effects of fluorinated pyrimidines 
like 5-FU. Leucovorin increases the folate pool, increasing the biding of folate 
cofactor and active metabolites of 5-FU.  
 
10.1.2 Pharmacodynamics 
 
Leucovorin is well absorbed after oral administration and is readily converted to 5-
methyltetrahydrofolate after administration. Peak serum concentrations occur 1.7 
to 2.5 hours after an oral dose. Leucovorin is excreted in the urine as metabolites 
and has a half-life of approximately 2-6 hours.  
 
10.1.3 Availability 
 
Leucovorin calcium is commercially available in: 50 mg, 100 mg, 350 mg vials for 
reconstitution. 
 
10.1.4 Supplier(s) 
 
Leucovorin is commercially available and will not be provided by this study. 
 
10.1.5 Storage and Stability 
 
Intact vials should be stored at room temperature and protected from light. 
Solutions reconstituted with Bacteriostatic Water for Injection (BWI) are stable for 
at least 7 days at room temperature. 
 
10.1.6 Administration 
 
Leucovorin may be reconstituted with BWI or with sterile water. Solutions should 
be further diluted in D5W, 0.9% NaCl or Ringers solution for infusion over two 
hours. 
 
Leucovorin will be administered as a 400 mg/m2 IV infusion over 2 hours. It may 

Version 06/01/18- Amendment 4 
 
page 24 of 39 
be given either concurrent with (via a separate infusion line) or following 
oxaliplatin and immediately before fluorouracil. 
 
10.2 
5-Fluorouracil (5-FU) 
 
10.2.1 Mechanism of Action 
 
Fluorouracil, C4H3FN2O2, a pyrimidine antagonist, is an antimetabolite 
antineoplastic agent. Although the precise mechanisms of action of fluorouracil 
have not been fully elucidated, the main mechanism is thought to be the binding of 
the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5-10-
methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently 
bound ternary complex, which inhibits the formation of thymidylate from uracil, 
thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into 
RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and 
interfering with RNA processing and protein synthesis. 
 
10.2.2 Pharmacodynamics/kinetics 
 
Absorption: Following IV administration of fluorouracil, no intact drug is detected 
in plasma after 3 hours. 
 
Distribution: Fluorouracil is distributed into tumors, intestinal mucosa, bone 
marrow, liver, and other tissues. Despite its limited lipid solubility, the drug readily 
crosses the blood-brain barrier and distributes into CSF and brain tissue. 
Distribution studies in humans and animals have usually shown a higher 
concentration of the drug or its metabolites in the tumor than in surrounding tissue 
or in corresponding normal tissue. It has also been shown that there is a longer 
persistence of fluorouracil in some tumors than in the normal tissues of the host, 
perhaps due to impaired uracil catabolism. From these data, it has been suggested 
that the drug may possibly have some specificity against certain tumors in 
comparison with normal tissues. 
 
Elimination: Following IV administration, the plasma elimination half-life 
averages about 16 minutes (range: 8-20 minutes) and is dose dependent. A small 
portion of fluorouracil is anabolized in the tissues to 5-fluoro-2-deoxyuridine and 
then to 5-fluoro-2-deoxyuridine-5-monophosphate, the active metabolite of the 
drug. The major portion of the drug is degraded in the liver. The metabolites are 
excreted as respiratory carbon dioxide and as urea, α-fluoro-β-alanine, α-fluoro-β-
guanidopropionic acid, and α-fluoro- β-ureidopropionic acid in urine. Following a 
single IV dose of fluorouracil, approximately 15% of the dose is excreted in urine 
as intact drug within 6 hours; over 90% of this is excreted in the first hour. 
 
 
 

Version 06/01/18- Amendment 4 
 
page 25 of 39 
10.2.3 Availability 
 
Fluorouracil is commercially available as a 50 mg/mL solution for injection in 10 
mL, 20 mL, 50 mL and 100 mL vials. 
 
10.2.4 Supplier(s) 
 
5-FU is commercially available and will not be provided by this study. 
 
10.2.5 Solution Preparation  
 
Inspect for precipitate; if found, agitate or gently heat in water bath. Bolus 
injections are prepared using undiluted drug. Continuous infusions of fluorouracil 
should be prepared for administration via ambulatory infusion pump according to 
the individual institution’s standards. These solutions may be prepared in D5W or 
0.9% NaCl.  
 
10.2.6 Storage and Stability 
 
Intact vials should be stored at room temperature and protected from light. Slight 
yellow discoloration does not usually indicate decomposition. 5-FU is stable in 
syringes for up to 72 hours. Stability in ambulatory pumps varies according to the 
pump, manufacturer of drug, concentration and dilution. Please refer to appropriate 
reference sources for additional information.  
 
10.2.7 Administration 
 
Fluorouracil will be given as a 400 mg/m2 IV bolus injection followed by 2400 
mg/m2 continuous IV infusion over 46 hours. 
 
10.3 
Oxaliplatin 
 
10.3.1 Mechanism of action 
 
Oxaliplatin is a new platinum derivative with an oxalo ligand group. Although the 
exact mechanism of oxaliplatin’s action remains unclear, the cytotoxicity of 
platinum compounds is thought to result from inhibition of DNA synthesis. 
Intrastrand platinum DNA adducts, the main cytotoxic lesions, are formed by cross-
linking activated platinum species and specific base sequences, notably 2 adjacent 
guanine residues or 2 adjacent guanine-adenine bases. 
 
10.3.2 Pharmacodynamics/kinetics 
 
Time to peak concentration with a single 2-hour infusion of oxaliplatin 85 
milligrams/square meter yielded a peak plasma concentration (Cmax) of 0.814 
micrograms/milliliter. The area under the curve for total plasma platinum was 207-

Version 06/01/18- Amendment 4 
 
page 26 of 39 
290 mg/L x hr; ultrafilterable plasma platinum was 11.9-13.6 mg/L x hr. Oxaliplatin 
has 70 to 95% platinum-protein binding while 37% represents total platinum taken 
up by red blood cells (addition of oxaliplatin to whole blood). The volume of 
distribution is 440 liters after a single 2-hour infusion of 85 milligrams/square meter 
oxaliplatin. Oxaliplatin undergoes rapid and extensive (30%) nonenzymatic 
biotransformation.  In vitro studies indicate no cytochrome P450-mediated 
metabolism. Oxaliplatin metabolites include approximately 17 different platinum 
containing derivatives with some being cytotoxic (monochloro DACH platinum, 
dichloro DACH platinum, and monoaquo and diaquo DACH platinum).  Breast 
milk – It is not known whether oxaliplatin is excreted into breast milk. Renal 
clearance is 9.3-17 liters/hour. Elimination half life: intravenous, total plasma 
platinum, alpha half-life (0.2-0.43 hours), beta half-life (15-16.8 hours), gamma 
half-life (252-391 hours). The decline of ultrafilterable platinum levels is 
triexponential with a relatively short alpha and beta half-life (0.43 hours and 16.8 
hours) and a long terminal gamma half-life (391 hours).  
 
10.3.3 Formulation  
 
Molecular formula: C8H14N2O4Pt with the chemical name of cis-[(1R, 2R)-1,2 
cyclohexanediamine-N, N’][oxaloto (2-)-o, o’] platinum. Molecular weight is 
397.3. 
 
10.3.4 Availability 
 
Oxaliplatin is formulated as a white freeze-dried powder in amber glass vials 
containing 50 mg and 100 mg of oxaliplatin in lactose monohydrate.  Each vial is 
sealed with a stopper with a crimped aluminum cap. Drug will be ordered from 
commercial supply. 
 
10.3.5 Supplier(s) 
 
Oxaliplatin is commercially available and will not be provided by this study. 
 
10.3.6 Solution Preparation  
 
The freeze-dried powder is reconstituted by adding 10 to 20 ml (for the 50-mg vial) 
or 20 to 40 ml (for the 100-mg vials) of sterile water for Injection or 5% dextrose 
solution and then by diluting in an infusion solution of 250 ml or 500 ml of 5% 
dextrose solution.  Avoid performing these manipulations with aluminum needles.  
The reconstitution or final dilution must never be performed with a sodium chloride 
solution. 
 
10.3.7 Storage and Stability 
 
Oxaliplatin freeze-dried powder may be stored at room temperature protected from 
light. Do not combine with alkaline medications or media, which cause oxaliplatin 

Version 06/01/18- Amendment 4 
 
page 27 of 39 
to degrade. Do not use needles or intravenous infusion sets containing aluminum 
items (risk of degradation of oxaliplatin upon contact with aluminum) for the 
preparation or administration of oxaliplatin. Do not mix oxaliplatin with sodium 
chloride or other chloride containing solutions. Freeze-dried powder: The 
compound may be stored for 3 years at room temperature protected from light. 
Reconstituted solution:  In 5% dextrose solution or sterile Water for Injection in the 
original vial, the solution may be stored for 24 to 48 hours at 2-80° C. Infusion 
solution:  after dilution in 5% dextrose solution, the shelf-life is 24 hours at room 
temperature.  
 
10.3.8 Administration 
 
Antiemetic premedication (5-HT3 blocker with or without dexamethasone) is 
recommended. Cold temperatures can precipitate/exacerbate neurological 
symptoms-avoid during the infusion of oxaliplatin. Never reconstitute/dilute with 
a chloride-containing solution; avoid aluminum parts when preparing/mixing 
oxaliplatin. Incompatible with alkaline media (i.e., solutions of 5-fluorouracil). 
Prepare oxaliplatin in 250-500 mL D5W. 

Version 06/01/18- Amendment 4 
 
page 28 of 39 
11 
STUDY CALENDAR 
 
 
Screening4 
 
During 
Radiotherapy 
Day 1 of Each 
Cycle of 
Chemotherapy8 
Completion of 
Chemotherapy10 
10 to 14 
Months after 
Radiotherapy 
Long-term 
Follow-up9 
Informed consent 
X 
 
 
 
 
 
H&P 
X 
X (once) 
X 
X 
X 
 
CBC diff, plts 
X 
X (once) 
X 
 
 
 
CMP 
X 
 
X 
 
 
 
Pregnancy test5 
X6 
 
 
 
 
 
Colonoscopy or barium enema or Hypaque 
enema 
X11 
 
 
 
 
 
Surgical assessment with proctoscopy or 
sigmoidoscopy 
 
 
 
X 
 
 
Digital rectal exam 
X 
 
 
X 
 
 
Staging study to evaluate disease in 
abdomen and pelvis1 
X 
 
 
 
 
 
Staging study to evaluate disease in lungs2 
X 
 
 
 
 
 
Imaging study to assess local extent of 
primary tumor3 
X 
 
 
X 
 
 
Radiotherapy 
 
X7 
 
 
 
 
FOLFOX / CAPEOX 
 
 
X 
 
 
 
FACT-C 
X 
 
 
X 
X 
 

Version 06/01/18- Amendment 4 
 
page 29 of 39 
AE assessment 
AEs should be collected through 1 year following the start of RT 
 
1. CT with contrast or MRI or PET/CT or PET/MRI 
2. Chest x-ray or CT of the chest or PET/CT 
3. Pelvic MRI (preferred), endorectal ultrasound, MRI, CT scan 
4. Within 8 weeks of day of simulation for RT but no later than the first radiation treatment 
5. Women of childbearing potential only 
6. No more than 14 days prior to the first day of treatment 
7. 5 fractions delivered over the course of 5 days (preferably starting on a Monday).  Optional concomitant boost may be delivered to the primary tumor of 1-2 
Gy per day (30-35 Gy to tumor total). If a boost is given then the maximum allowed dose to small bowel is 25 Gy.   
8. Chemotherapy should start 2 to 4 weeks after the end of RT.  Each cycle is 14 days; a total of 8 cycles of chemotherapy will be given 
9. Long-term follow-up will be done per routine policies of the treating physicians.  It is recommended that there be follow up visits every 6 months with clinical 
exam until 5 years from study enrollment.  Data will be collected from the medical record every 6 months on progression/recurrence and survival. 
10. 3-8 weeks after the end of chemotherapy 
11. Within 12 weeks of day of simulation for RT but no later than the first radiation treatment  
 
 
 

Version 06/01/18- Amendment 4 
 
page 30 of 39 
 
12 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Form 
Completion Schedule 
On-Study Form 
Time of registration 
Radiation Therapy Form 
Completion of RT 
Chemotherapy Form 
At the end of each cycle of chemotherapy 
RECIST Form 
Baseline 
Completion of chemoradiation 
Follow-Up Form 
1 year after the start of RT 
FACT-C 
Baseline 
Completion of chemoradiation 
10-14 months after chemoradiation 
Long-Term Follow-Up Form 
Every 6 months for 5 years after the start of RT 
Adverse Events Form 
Ongoing 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
13 
MEASUREMENT OF EFFECT 
 
Criteria for complete clinical response: 
• No residual gross tumor at procto/sigmoidoscopy, or only erythematous scar or ulcer 
• No palpable tumor on DRE 
• No radiographic evidence of tumor on MRI 
• No suspicious mesorectal lymph nodes on MRI 
• Negative biopsy from scar, ulcer, or former tumor site (if necessary according to surgeon’s 
judgment) 
 
Criteria for no significant clinical response: 
• Residual disease by DRE, endoscopy or MR. 
• Increase in primary tumor size upon clinical exam or imaging 
• Any new lesions 
 
 
14 
DATA AND SAFETY MONITORING PLAN 
 
Outcome, including response rates and patient morbidity, will be reviewed by the principal 
investigator with the medical oncology and surgery co-investigators (Drs. Singh and Hunt) every 
six months. 
 

Version 06/01/18- Amendment 4 
 
page 31 of 39 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
15 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 

Version 06/01/18- Amendment 4 
 
page 32 of 39 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Completeness of participant documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf 
 
 
16 
STATISTICAL CONSIDERATIONS 
 
16.1 
Study Objectives and Endpoints 
 
Primary Objective:  
Demonstrate that sequential short course radiotherapy followed by 8 cycles of multi-drug 
chemotherapy will elicit a rate of significant clinical response to allow an organ 
preservation approach for at least 30% (6/20) patients at 1 year. 
 
Secondary Objectives 
1. Obtain prospective patient reported outcomes from an organ preservation approach 
for early stage rectal cancer. 
2. Determine the incidence of any grade ≥ 3 toxicity during treatment. 
3. Determine the incidence of post chemoradiotherapy grade ≥ 3 toxicity at 1 year 
4. Determine quality of anorectal function at 1 year by FACT-C 
 
16.2 
Study Design and Sample Size Justification  
 
This pilot study is designed to demonstrate proof of concept for an organ preservation 
strategy applied to a low risk rectal cancer cohort.  As such, the sample size is not 
determined by traditional power calculations, but rather by clinical judgment – if organ 
preservation is not possible in 30% of this initial cohort (6/20 patients), then the strategy 
will be abandoned.  If at least 30% of patients at 1 year may be treated with organ 
preservation, then the concept may proceed to a separate phase II approach. 
 

Version 06/01/18- Amendment 4 
 
page 33 of 39 
16.3 
Interim Analyses and Stopping Rules 
 
An interim analysis will be performed on the primary endpoint once 10 subjects have been 
enrolled and have completed the evaluation after chemotherapy.  There will be possible 
early stopping if less than 2/10 of the initial patients enrolled who complete radiotherapy 
and chemotherapy remain potential candidates for organ preservation. 
 
16.4 
Definition of Evaluability 
 
Patients who have completed all radiotherapy and chemotherapy will be considered 
evaluable for analysis.  Patients who are inevaluable for the primary endpoint will be 
replaced. 
 
16.5 
Data Analysis 
 
Demographic and clinical characteristics of the sample, as well as response, toxicity by 
grade and loss to follow up will be summarized using descriptive statistics. Incidence of 
grade 3 or higher acute toxicities (overall and gastrointestinal), incidence of organ 
preservation will be calculated. Descriptive statistics from the FACT-C questionnaire will 
be generated for evaluation of anorectal function at 1 year.  The incidence of post 
radiotherapy grade 3 or higher toxicities at 1 year will also be provided.  
 
16.6 
Accrual  
 
Assuming 10% inevaluable cases, the overall accrual will be 22 patients. The rate of accrual 
for the study is expected to be about 8 patients per year.  It is expected that the accrual 
period of the study will be completed in about 3 years. 
 
17 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including 
the Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 

Version 06/01/18- Amendment 4 
 
page 34 of 39 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 
 
 

Version 06/01/18- Amendment 4 
 
page 35 of 39 
18 
REFERENCES 
 
1. 
Smith J, Chow O, Eaton A, Widmar M, Nash G, Temple L, editors. Organ preservation in 
patients with rectal cancer with clinical complete response after neoadjuvant therapy. ASCO 
Gastrointestinal Cancers Symposium; 2015. 
2. 
Khwaja S, Markovina S, Hunt S, Tan B, Myerson R, Parkih P, et al. Patient-Reported QOL 
Outcomes From a Prospective Phase 2 Trial of Short Course Radiation Therapy Followed by 
FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer. International journal of 
radiation oncology, biology, physics. 2014;1(90):S712-S3. 
3. 
Myerson RJ, Tan B, Hunt S, Olsen J, Birnbaum E, Fleshman J, et al. Five fractions of 
radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for 
rectal cancer. International journal of radiation oncology, biology, physics. 2014;88(4):829-36. 
Epub 2014/03/13. doi: 10.1016/j.ijrobp.2013.12.028. PubMed PMID: 24606849; PubMed Central 
PMCID: PMCPMC4028157. 
4. 
Garcia-Aguilar J, Shi Q, Thomas CR, Jr., Chan E, Cataldo P, Marcet J, et al. A phase II 
trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: preliminary results 
of the ACOSOG Z6041 trial. Annals of surgical oncology. 2012;19(2):384-91. Epub 2011/07/15. 
doi: 10.1245/s10434-011-1933-7. PubMed PMID: 21755378. 
5. 
Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, et al. Long-term outcome in 
patients with a pathological complete response after chemoradiation for rectal cancer: a pooled 
analysis of individual patient data. The lancet oncology. 2010;11(9):835-44. Epub 2010/08/10. 
doi: 10.1016/s1470-2045(10)70172-8. PubMed PMID: 20692872. 
6. 
Trial Evaluating 3-year Disease Free Survival in Patients With Locally Advanced Rectal 
Cancer Treated With Chemoradiation Plus Induction or Consolidation Chemotherapy and Total 
Mesorectal Excision or Non-operative Management ClinicalTrials.gov [Internet]. National Library 
of 
Medicine 
(US). 
2013 
[cited 
July 
8, 
2015]. 
Available 
from: 
https://clinicaltrials.gov/ct2/show/NCT02008656. 
7. 
Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized 
Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of 
Local Recurrence in Patients with T3 Rectal Cancer:  Trans-Tasman Radiation Oncology Group 
Trial 01.04.  Journal of clinical oncology.  2012;30:31, 3827-33. 
8. 
Bujko K, Nowack MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. 
Long-term results of a randomized trial comparing preoperative short-course radiotherapy with 
preoperative conventinally fractionated chemoradiation for rectal cancer.  British journal of 
surgery. 2006; 93(10):1215-23. 
9. 
Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, Partensky C, et al. Influence 
of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the 
Rate of Sphincter-Sparing Surgery for Rectal Cancer:  The Lyon R90-01 Randomized Trial. 
Journal of clinical oncology. 1999;17(8), 2396-02. 
10. 
Habr-Gama A, Perez RO, Proscurshim I, Nunes Dos Santos RM, Kiss D, Gama-Rodrigues 
J, et al. Interval Between Surgery and Neoadjuvant Chemoradiation Therapy for Distal Rectal 
Cancer: Does Delayed Surgery Have an Impact on Outcome? Internal journal of radiation 
oncology, biology, physics. 2008;71(4):1181-88. 
11.  
Kerr SF, Norton S, Glynne-Jones. Delaying surgery after neoadjuvant chemoradiotherapy 
for rectal cancer may reduce postoperative morbidity without compromising prognosis. British 
journal of surgery. 2008;95(10):1534-40. 

Version 06/01/18- Amendment 4 
 
page 36 of 39 
12. 
Erlandsson J, Torbjörn H, Pettersson D, Berglund Å, Cedermark B, Radu C, et al. Optimal 
fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): 
a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. The lancet oncology. 
2017;18(3):336-46. 
 
 

Version 06/01/18- Amendment 4 
 
page 37 of 39 
Appendix A: FACT-C Questionnaire 
 
Patient ID#:    
 
 
 
Date of Completion:    
 
 
 

Version 06/01/18- Amendment 4 
 
page 38 of 39 
Patient ID#:    
 
 
 
Date of Completion:    
 
 
 
 

Version 06/01/18- Amendment 4 
 
page 39 of 39 
Patient ID#:    
 
 
 
Date of Completion: