Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT) in the Reirradiation of Locoregionally Recurrent Rectal Cancer - IMPARC
Phase: NA
Conditions: Recurrent Rectal Cancer
Sponsor: Washington University School of Medicine

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Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT) in 
the Reirradiation of Locoregionally Recurrent Rectal Cancer - IMPARC 
 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, MSC 8224 
St. Louis, MO  63110 
 
Protocol #:  202103218 
Version date: 11 September 2025 
 
 
Principal Investigator:  
 
Michael Waters, MD 
 
 
 
 
 
Phone: (314) 747-7236  
 
 
 
 
 
E-mail: m.r.waters@wustl.edu  
 
 
 
 
 
  
 
 
 
 
 
Sub-Investigator 
 
 
Modality  
 
Carl DeSelm, M.D., Ph.D. 
 
Radiation Oncology 
  
 
 
 
Study Device: 
 
 
MEVION S250i Hyperscan and Adaptive Aperture Proton  
Therapy Machine 
NCT#: 
 
 
 
NCT04827732 
Funded by: 
 
 
 
Departmental 
 
 
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 
 
 

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Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT) in 
the Reirradiation of Locoregionally Recurrent Rectal Cancer 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
02 March 2021 
Amendment #1 Version 
 
 
 
 
 
 
09 June 2021 
Amendment #2 Version 
 
 
 
 
 
 
13 September 2021 
Amendment #3 Version 
 
 
 
 
 
 
23 November 2022 
Amendment #4 Version 
 
 
 
 
 
 
25 April 2023 
Amendment #5 Version 
 
 
 
 
 
 
26 July 2023 
Amendment #6 Version 
 
 
 
 
 
 
11 November 2024 
Amendment #7 Version                                                                                16 July 2025   
Amendment #8 Version                                                                                11 September 2025           

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following ethical guidelines and regulations:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 

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GLOSSARY OF ABBREVIATIONS  
 
AC 
 
Adenocarcinoma 
AE  
 
Adverse Event  
ALT 
 
Alanine Aminotransferase  
AST   
Aspartate Aminotransferase  
BED   
Biologically Effective Dose 
BUN  
Blood Urea Nitrogen  
CBC   
Complete Blood Count 
CBCT  
Cone Beam Computed Tomography  
CEA  
Carcinoembryonic Antigen 
CMP  
Comprehensive Metabolic Panel  
CRF 
 
Case Report Form 
CRP 
 
C-reactive Protein  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV1   
Clinical Target Volume 1 
DHHS  
Department of Health and Human Services  
DLT 
 
Dose Limiting Toxicity  
DRE   
Digital Rectal Exam  
ECOG  
Eastern Cooperative Oncology Group 
GTV   
Gross Tumor Volume 
IMPT  
Intensity Modulated Proton Therapy 
IRB  
 
Institutional Review Board  
LDH  
Lactate Dehydrogenase  
LRC   
Locoregional Control  
LRFS   
Local Relapse-free Survival  
MTD   
Maximum Tolerated Dose 
OAR   
Organs at Risk  
OHRP  
Office of Human Research Protections 
OS  
 
Overall Survival 
PFS  
 
Progression-free Survival  
PRO   
Patient Reported Outcomes 
PS 
 
Performance Status 
PTV 
 
Planning Target Volumes 
QOL   
Quality of Life 
RT 
 
Radiation Therapy  
RTOG  
Radiation Therapy Oncology Group  
SAE   
Severe Adverse Event  
SCCA   
Squamous Cell Carcinoma Antigen  
SBRT  
Stereotactic Radiation  
SF-12   
Short Form Survey-12  
TITE-CRM 
Time-to-Event Continual Reassessment Method 
SIB    
Simultaneous Integrated Boost 
UPN  
Unique Patient Number  
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ..........................................................................................................7 
SCHEMA ................................................................................................................................. 10 
SCHEDULE OF ACTIVITIES ................................................................................................. 11 
1 
BACKGROUND ............................................................................................................... 12 
1.1 
Recurrent Rectal Cancer .............................................................................................. 12 
1.2 
Reirradiation ............................................................................................................... 12 
1.3 
Hypofractionated Radiation Therapy ........................................................................... 13 
1.4 
Proton Therapy ........................................................................................................... 13 
1.5 
Patient-Reported Outcomes (PROs) ............................................................................ 14 
1.6 
Squamous cell carcinoma antigen and inflammatory markers ...................................... 15 
1.7 
Study Design............................................................................................................... 15 
2 
OBJECTIVES AND ENDPOINTS .................................................................................... 17 
3 
STUDY POPULATION .................................................................................................... 19 
3.1 
Inclusion Criteria ........................................................................................................ 19 
3.2 
Exclusion Criteria ....................................................................................................... 20 
3.3 
Inclusion of Women and Minorities ............................................................................ 20 
4 
REGISTRATION PROCEDURES .................................................................................... 20 
4.1 
Confirmation of Patient Eligibility .............................................................................. 21 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database........................... 21 
4.3 
Assignment of UPN ...................................................... Error! Bookmark not defined. 
4.4 
Screen Failures............................................................................................................ 22 
4.5 
Strategies for Recruitment and Retention .................................................................... 22 
5 
TREATMENT PLAN ........................................................................................................ 22 
5.1 
Hypofractionated IMPT .............................................................................................. 22 
5.2 
Dose Escalation Schema and MTD Definition ............................................................. 25 
5.3 
Study Procedures ........................................................................................................ 25 
5.4 
Definitions of Evaluability .......................................................................................... 27 
5.5 
Supportive Care Guidelines ......................................................................................... 28 
5.6 
Women of Childbearing Potential ............................................................................... 28 
5.7 
Duration of Therapy .................................................................................................... 28 
5.8 
Duration of Follow-up................................................................................................. 29 
5.9 
Lost to Follow-Up ....................................................................................................... 29 
6 
REGULATORY AND REPORTING REQUIREMENTS .................................................. 30 
6.1 
WU PI Reporting Requirements .................................................................................. 30 
6.2 
Exceptions to Expedited Reporting ............................................................................. 31 
7 
DATA SUBMISSION SCHEDULE .................................................................................. 31 
7.1 
Adverse Event Collection in the Case Report Forms ................................................... 31 
8 
MEASUREMENT OF EFFECT ........................................................................................ 32 
8.1 
Antitumor Effect – RECIST 1.1 .................................................................................. 32 
9 
DATA AND SAFETY MONITORING ............................................................................. 38 

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10 
STASTISTICAL CONSIDERATIONS .......................................................................... 39 
10.1 Phase I Methodology for Primary Endpoint ................................................................. 39 
10.2 Simulation and Sample Size Calculations .................................................................... 41 
11 
REFERENCES ............................................................................................................... 45 
APPENDIX A: ECOG Performance Status Scale ...................................................................... 53 
APPENDIX B: EORTC QLQ-C30 Quality of Life of Cancer Patients ....................................... 54 
APPENDIX C: EORTC QLQ-CR29 Colorectal QOL ............................................................... 56 
APPENDIX D: Definitions for Adverse Event Reporting .......................................................... 58 
APPENDIX E: Reporting Timelines ......................................................................................... 60 
APPENDIX F: Study-Specific DSM Tables .............................................................................. 62 
 
 

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PROTOCOL SUMMARY 
 
 
Title: 
Hypofractionated Pencil-Beam Scanning Intensity-modulated 
Proton Therapy (IMPT) in the Reirradiation of Locoregionally 
Recurrent Rectal Cancer - IMPARC 
Study Description: 
The purpose of this trial is to determine the maximum tolerated 
dose (MTD) of hypofractionated IMPT for the reirradiation of 
locoregionally recurrent rectal cancer.  
Objectives: 
Primary Objective: 
To determine the MTD of reirradiation using hypofractionated 
IMPT. 
 
Secondary Objectives: 
1. To determine the clinical complete response rate of patients 
with locoregionally recurrent rectal cancer who receive 
hypofractionated IMPT. 
2. To estimate median freedom from locoregional progression 
(FFLP) in patients with locoregionally recurrent rectal 
cancer who receive hypofractionated IMPT. 
3. To estimate median overall survival (OS) in patients with 
locoregionally recurrent rectal cancer who receive 
hypofractionated IMPT. 
4. To estimate median progression-free survival (PFS) in 
patients with locoregionally recurrent rectal cancer who 
receive hypofractionated IMPT. 
5. To evaluate patient reported outcomes (PRO) in patients 
with locoregionally recurrent rectal cancer who receive 
hypofractionated IMPT via QOL questionnaires. 
6. To evaluate the toxicity profile of hypofractionated IMPT 
in patients with locoregionally recurrent rectal cancer.  
 
Exploratory Objectives: 
1. To explore the prognostic value of serum SCCA in 
patients with locoregionally recurrent rectal cancer who 
receive hypofractionated IMPT. 
2. To evaluate the changes in serum inflammatory markers, 
CRP and LDH, in patients with locoregionally recurrent 
rectal cancer who receive hypofractionated IMPT. 
Endpoints: 
Primary Endpoint: 
The maximum tolerated dose (MTD) of reirradiation using 
hypofractionated IMPT for patients with locoregionally recurrent 
rectal cancer will be defined as the dose associated with a 35% 
probability of dose-limiting toxicity (DLT). Toxicity will be coded 
using CTCAE v5, and DLT will be defined as any toxicity listed 
below that occurs within 6 months from the start of treatment and 

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is considered possibly, probably or definitely related to proton 
reirradiation:  
 
• Any grade 5 toxicities 
• Any grade 4-5 GI toxicities 
• Bowel obstruction  
• Grade 3-5 
o Diarrhea 
o Anal, colonic, or bowel ulcers  
o Bladder perforation 
o Any fistula formations 
o Peripheral motor/sensatory neuropathy of the 
pelvis above baseline 
o Osteonecrosis/soft tissue necrosis  
o Radiation dermatitis 
o Hematuria 
o Hematochezia 
o Bowel/pelvic hemorrhage   
o Reproductive tract toxicity 
 
Secondary Endpoints: 
1. The clinical complete response rate as measured by DRE, 
endoscopy and cross-sectional imaging.   
2. Freedom from locoregional progression (FFLP), defined as 
time from end of RT to date of first instance of local or 
regional tumor progression at 12 months.      
3. Overall survival at 12 months. 
4. Progression-free survival, defined as time from end of RT 
to the earliest date of locoregional progression, distant 
progression, or death from any cause at 12 months. 
5. To determine patient reported quality of life outcomes 
using EORTC QLQ-C30 and QLQ-CR29. 
6. Toxicity, as measured by CTCAE v. 5.0. 
 
Exploratory Endpoints: 
1. Association of pre-treatment SCCA and post-treatment 
SCCA with PFS and OS at 6 months. 
2. Evaluate the effect of hypofractionated IMPT on levels of 
serum inflammatory markers. 
Study Population: 
Twenty patients with locoregionally recurrent rectal cancer who 
have had prior pelvic RT for rectal cancer will be enrolled. 
Phase: 
N/A 
Description of Sites / 
Facilities Enrolling: 
Washington University School of Medicine  
Description of Study 
Intervention: 
Reirradiation will consist of hypofractionated IMPT for 5 
fractions. Assessments include digital rectal exam (DRE) and MRI 

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pelvis within 6 weeks to 3 months post-completion of reirradiation. 
QOL assessments will be performed pre-treatment and at several 
time points after the end of treatment. 
Study Duration: 
61 months 
Participant Duration: 
36 months (recruitment) + 13 months (participation and follow-up) 
+ 12 months (analysis) 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose-painted hypofractionated intensity-modulated proton therapy dose levels: 
 
Dose Level 
Number of 
fractions of 
IMPT 
PTV 
Dose/fx 
(Gy) 
PTV Total 
Dose (Gy) 
PTV Standard 
BED  (Gy10) 
PTV EQD2 
-1 
5 
5 
25 
37.50 
31.25 
1 
Starting Level 
5 
6 
30 
48.00 
40.00 
2 
5 
7 
35 
59.50 
49.58 
3 
5 
8 
40 
72.00 
60.00 
 
Note – the first 6 evaluable patients enrolled will be treated at Dose Level 1 
Please refer to section 10.0 
 
 
Digital rectal 
exam, optional 
endoscopy with 
biopsy  
(proctoscopy, 
sigmoidoscopy, or 
colonoscopy), and 
MRI pelvis: 
 
Within 6 weeks to 3 
months post 
reirradiation  
Radiation: 
 
Hypofractionated IMPT 
for 5 fractions 
 
 
R
E
G
I
S
T
E
R  
Eligibility: 
 
Locoregionally 
recurrent rectal cancer 
 
Prior pelvic RT for 
rectal cancer 
 
May also receive 
salvage surgery and/or 
chemotherapy 
 
ECOG PS 0-2 

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SCHEDULE OF ACTIVITIES 
 
 
Screening 
Pre-
treatment8 
Radiation 
1-2 Weeks 
post RT 
6-8 Weeks 
post RT 
3 Mo post 
RT1 
6 Mo post 
RT1 
9 Mo post 
RT1 
12 Mo post 
RT1 
  
Informed consent 
X2 
 
 
 
 
 
 
 
 
 
H&P / PS / weight / 
DRE13 
X2 
 
X3 
X 
X 
X 
X 
X 
X 
 
MRI pelvis4 
X2 
 
 
 
X5 
X 
X 
X 
 
CT chest / abdomen 
/ pelvis with 
contrast6 
X2 
 
 
 
X6 
 
X 
X 
X 
 
Endoscopy7 
X2 
 
 
 
X15 
 
 
 
 
OPTIONAL biopsy 
X2, 15 
 
 
 
X 
 
 
 
 
CBC w/diff 
X2 
X2 
 
 
X9 
 
X 
 
 
 
CMP 
X2 
X2 
 
 
X9 
 
X 
 
 
 
CEA 
 
X 
 
 
X9 
 
X 
 
 
 
SCCA 
 
X 
 
 
X9 
 
X 
 
 
 
CRP 
 
X 
 
 
X9 
 
X 
 
 
 
LDH 
 
X 
 
 
X9 
 
X 
 
 
 
Pregnancy test 
X10,11 
 
 
 
 
 
 
 
 
 
Radiation therapy 
 
 
X12 
 
 
 
 
 
 
 
EORTC QLQ-C30 
 
X 
 
X 
 
X 
X 
X 
X 
 
EORTC QLQ-C29 
 
X 
 
X 
 
X 
X 
X 
X 
 
Adverse events 
 
X 
X3 
X 
X 
X 
X 
X 
X 
 
1. +/- 2 weeks 
2. No more than 60 days prior to registration.  Screening and baseline labs can be the same draw provided the timing aligns. 
3. Performed once during radiation therapy.  
4. Cross-sectional imaging with either MRI or CT is acceptable. 
5. MRI pelvis and CT chest/abdomen with contrast may be obtained 6 weeks to 3 months after radiation completion with a RECIST read at 3 months only.  
6. If PET/CT scan is done, then CT chest/abdomen/pelvis not required. 
7. Endoscopy with colonoscopy, sigmoidoscopy, or proctoscopy will be performed if feasible after screening. 
8. Baseline labs and QOL assessments should be performed within 30 days of radiation therapy.  
9. Labs should be drawn once 6 weeks to 3 months after radiation completion but should be drawn before surgery if the patient undergoes salvage surgery.  
10. Mandatory for women of childbearing potential.  
11. Within 14 days of registration. 
12. 5 fractions over 1 week. 
13. DRE only to be done if feasible.15. OPTIONAL endoscopy with biopsy performed 6 weeks to 3 months after completion of RT; for research purposes only. 
15. OPTIONAL screening biopsy to be performed at time of baseline SOC endoscopy. 
 
 

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1 
BACKGROUND 
 
1.1 
Recurrent Rectal Cancer 
 
Advances in the management of locally advanced rectal cancer in the recent decades, such 
preoperative chemotherapy (CRT) (1, 2) in conjunction with total mesorectal excision 
(TME) (3, 4), have led to marked improvements in patient outcomes, with a 10-year overall 
survival of approximately 40%-60%  (4, 5). The improvement in overall survival is in large 
part due to reductions in local-regional recurrences (LRF), which have decreased from 10-
25% (6, 7) to 4-8% (4, 8–10).  
 
While the clinical outcomes of locally advanced rectal cancer have improved as a whole, 
select patients, such as patients with advanced pathologic T and N stages (11, 12), 
lymphovascular or perineural invasion (11), low-lying rectal primaries (11), and involved 
or “threatened” circumferential margins (CRM) (13), remain at increased risks for 
locoregional failures (LRFs). Patients with locoregionally recurrent rectal cancer (LRRC) 
carry significant disease morbidity and have a poor prognosis (14). They may experience 
intractable pelvic or sciatic pain, bleeding, fistulas, intestinal obstruction, fecal discharge, 
dysuria, urinary tract dysfunction, and chronic pelvic sepsis (15), which compromise 
quality of life (16). 
 
The management of patients with LRRC poses a clinical dilemma. Since the majority of 
these patients have been previously treated with multimodality therapy, which causes 
fibrosis in the treatment field, salvage therapy options are limited. Complete surgical 
resection confers the best chances for long-term survival (6, 17, 18), but R0 resections can 
only be achieved in approximately 50-66% of the patients (14, 18) since recurrences near 
critical neuro-vascular structures and/or occupying large volumes are often unresectable.  
 
While LRFs mostly occur in the central pelvis after incomplete TMEs, LRFs after 
preoperative chemoradiation and TME occur more in the lateral pelvis, such as in the iliac, 
obturator, paraaortic, and retroperitoneal lymph nodes (19–21). Surgical salvage of lateral 
pelvic failures may require extensive resections such as pelvic exenteration and 
extravascular lateral pelvic sidewall resections (14), which cause significant perioperative 
and postoperative morbidity and mortality (16) while only achieving modest improvements 
in overall survival (OS) (6, 17, 18).  
 
1.2 
Reirradiation 
 
Given the clinical challenges and limitations with salvage surgery, investigators have 
explored pelvic reirradiation with and without salvage surgery and chemotherapy in the 
setting of LRRC (22–24). Reirradiation of the pelvis poses significant risks due to the 
cumulative effects on the organs at risk (OARs), such as the residual rectum, bladder, 
small, and large bowel, and the maximum lifetime dose to OARs for which toxicities 
outweigh the benefits of local-regional control remain undefined (25). Studies have 
reported reirradiation using conventional fractionation (1.8-2.0 Gy/fraction daily) (26–32) 
and hyperfractionation (1.2-1.5 Gy/fraction twice a day) (26, 33–37).  

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Metanalyses of these reirradiation studies showed pooled 1-, 2-, and 3-year OS rates for 
patients who received reirradiation and surgery were 86%, 72%, and 52%, respectively 
(24). The pooled grade ≥3 acute and late complication rate was 12% in patients who 
underwent reirradiation alone and was 26% in patients who underwent reirradiation and 
surgery (24). However, the 3-year OS was merely 24% in patients who received 
reirradiation alone (24). Since the low doses of 30-45 Gy delivered via conventional or 
accelerated hyperfractionation with photon therapy are generally insufficient to eradicate 
gross disease and are considered to the be palliative without salvage surgery (24).  
 
1.3 
Hypofractionated Radiation Therapy 
 
Technologic advances have improved patient immobilization, tumor tracking, and 
radiation delivery, allowing for larger doses to be given to tumors safely with reduced 
margins and steep gradients outside the target volume. Hypofractionated radiation therapy, 
or radiation treatments with greater than 2 Gy per fraction, delivers a higher biologically 
effective dose (BED). Hypofractionated radiation techniques such as stereotactic body 
radiotherapy (SBRT) have been shown to increase local control in primary lung (38, 39), 
pancreatic (40–43), and liver (44–46) cancers, as well as in brain metastases (47).  
 
In primary rectal cancer, the use of hypofractionated short-course preoperative radiation 
therapy to 25 Gy in 5 once daily fractions has been shown to have similar disease control 
and toxicities compared to conventionally fractionated long-course preoperative 
chemoradiation in the Polish rectal trial (48, 49) and the Australian Trans-Tasman 
Radiation Oncology Group Trial (9), and has been adopted as the standard of care at our 
institution. Reirradiation of recurrent rectal cancers with conventionally fractionated or 
hyperfractionated regimens has resulted in poor local control outcomes (30, 33, 35, 36). 
We aim to improve local control of recurrent rectal cancer by using a hypofractionated 
regimen. 
 
1.4 
Proton Therapy 
 
To improve clinical outcomes for LRRC, proton therapy may be considered for 
reirradiation to reduce dose to previously irradiated OARs and allow for dose escalation 
(50). Compared to x-ray photon therapy, proton therapy has decreased proximal dose 
deposition (51) and virtually no exit dose distal to the target volume (52), resulting in 
reduced integral dose and clinical toxicities. Reirradiation with proton therapy has been 
reported in various disease sites, such as glioma (53), head and neck (54–57), esophageal 
(58), NSCLC (59–61), sarcoma (62), chordoma (63), pancreatic (64), and liver cancers 
(65). In rectal cancer, dosimetric studies have illustrated the ability of proton therapy to 
reduce radiation dose to the bone marrow, small bowel, and urinary bladder while 
maintaining clinical efficacy (66–71).  
 
Preliminary studies have reported the feasibility of proton therapy for reirradiation of 
LRRC (30, 72). At the University of Pennsylvania, seven patients with LRRC who 
previously received 50.4 Gy of RT underwent double-scatter proton beam therapy to a 

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mean dose of 61.2 Gy (range, 45–64.8 Gy), with a maximum total dose sum of 109.8 Gy 
(range, 95.4–151.2 Gy) (30). At a median follow-up of 19 months, 57% of patients had a 
durable partial or complete radiographic response and four were still alive (30). Dosimetric 
comparison to VMAT showed that the bowel exposure at the V10Gy and V20Gy levels 
was significantly reduced by 85% and 55%, respectively, and doses to 200 and 150 cm3 of 
bowel were also reduced (30). Grade 3 acute toxicity was observed in 3 patients (1 
abdominal pain and 3 diarrhea) and small bowel obstruction developed in 2 patients (30). 
A Japan case report series also reported the use of carbon ion RT and proton therapy in 
three patients with LRRC (72).  
 
Given the paucity of prospective data on reirradiation with proton therapy for rectal cancer, 
we propose to conduct a study to evaluate the safety and efficacy of reirradiating patients 
with LRRC using pencil beam scanning proton beam therapy (PBSPT). PBSPT delivers 
intensity-modulated proton therapy (IMPT), which is achieved by narrow beam spots that 
are delivered to the patient in a scanning pattern. Compared to double-scatter proton 
therapy, IMPT allows improved dose-conformity not only at the distal region of the target, 
but also to the proximal region of the target from a given field and allows further sparing 
of the OARs located proximal to the target (73–75). We propose reirradiation with 
hypofractionation to improve local tumor control (23, 28, 76–78).  
 
1.5 
Patient-Reported Outcomes (PROs) 
 
Patient-reported outcomes will be assessed using the quality of life (QOL) questionnaires 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Quality 
of Life of Cancer Patients (79, 80) (Appendix B) and EORTC QLQ-CR29 Colorectal QOL 
(81) (Appendix C). The QOL questionnaires will be answered by the patients prior to the 
start of proton reirradiation, 1-2 weeks after RT, 3 months, 6 months, 9 months, and 12 
months post completion of RT. 
 
 
1.5.1 EORTC QLQ-C30 Quality of Life of Cancer Patients 
 
The EORTC QLQ-C30 Quality of Life of Cancer Patients is a validated, widely 
utilized QOL questionnaire in general oncology for adult patients (79, 80). The 
EORTC QLQ-C30 consists of a 30-question questionnaire, which assesses patient 
well-being with five functional scales (the physical, role, emotional, cognitive, 
social, and global). It also includes three symptom scales (fatigue, pain, 
nausea/vomiting) and six single items (dyspnea, sleep disturbance, appetite loss, 
diarrhea, constipation, and financial impact) (79, 80). Single-item QL scores for 
overall physical condition (question 29), overall quality of life (question 30), and 
the global and social functioning scales have been shown to be prognostic for 
overall survival in adult patients with advanced malignancies (82) 
 
1.5.2 EORTC QLQ-CR29 Colorectal QOL 
 
Developed in 2007 (83) as an update to QLQ-CR38 (84), the EORTC QLQ-CR29 
questionnaire is a supplemental module designed to be delivered alongside the  core 

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QLQ-C30 to assess QOL for patients with colorectal cancer. 
  
The QLQ-CR29 contains 29 questions, including items in 4 scales (urinary 
frequency, blood/mucus in stools, stool frequency, body image) and 19 single  items 
(urinary incontinence, dysuria, abdominal pain, buttock pain, bloating, dry mouth, 
hair loss, taste, anxiety, weight, flatulence, fecal incontinence, sore skin, 
embarrassment, stoma care problems, sexual interest for men, sexual interest for 
women, impotence, dyspareunia) (83). There are 11 items allocated for specific 
sub-populations, including males, females, and stoma patients. Scores of the QLQ-
CR29 can be linearly transformed to provide a score from 0 to 100, with  higher 
scores representing higher levels of functioning on the functional scales, greater 
degrees of symptomatology on the symptom scales and improved QOL on the 
global QOL scale (83). 
 
1.6 
Squamous cell carcinoma antigen and inflammatory markers 
 
Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor that belongs to the 
clade B subset of serpins and includes 2 isoforms, SCCA1-1 and SCCA1-2. SCCA 
isoforms are commonly detected in the serum of patients with solid organ squamous- or 
adenocarcinomas, such as breast cancer (85), cervical cancer (86), ovarian cancer (87), and 
hepatocellular carcinoma (88). SCCA is also upregulated in human colorectal cancer (89). 
Recent research demonstrated that SerpinB3, together with COX-2 and β-Catenin, are 
positively correlated and associated with more advanced tumor stage in colorectal cancer 
(90). Therefore, we intend to explore the prognostic value of SCCA prospectively in 
patients with locoregionally recurrent rectal cancer receiving hypofractionated radiation 
therapy. 
 
Additionally, epidemiological studies revealed that chronic inflammation predispose 
individuals to different cancers (91).  Accordingly, non-steroidal anti-inflammatory drugs 
(NSAIDs) decreases the incidence of colorectal cancer (92, 93).  Studies have also shown 
the prognostic significance of serum inflammatory markers, such as C-reactive protein (94) 
and lactate dehydrogenase (LDH) (95, 96), in association with treatment response and 
survival.  Therefore, we also propose to evaluate the changes in CRP and LDH following 
reirradiation with IMPT and assess their prognostic value for clinical endpoints.  
 
1.7 
Study Design  
 
1.7.1 Overall Design 
 
Patients will be enrolled on a prospective dose escalation protocol whereby they 
will receive hypofractionated IMPT.  Radiotherapy dose escalation in this study 
will be defined as intensification of dose through increasing dose per fraction while 
maintaining the total same total number of fractions.  
 

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Dose 
Level 
Number of 
fractions of 
IMPT 
PTV 
Dose/fx 
(Gy) 
PTV Total 
Dose (Gy) 
PTV 
Standard 
BED  (Gy10) 
PTV EQD2 
-1 
5 
5 
25 
37.50 
31.25 
1 
Starting 
Level 
5 
6 
30 
48.00 
40.00 
2 
5 
7 
35 
59.50 
49.58 
3 
5 
8 
40 
72.00 
60.00 
 
IMPT = intensity-modulated proton radiotherapy, fx = fractions, RBE = Relative 
Biological Effectiveness, BED10 = Biologically effective dose using an α/β=10 and 
the formula BED=nd(1+(d/[ α/β])) where n=# of fx and d=dose/fx, EQD2 = 
Equivalent dose at 2 Gy/fx. 
 
1.7.2 Scientific Rationale for Study Design  
 
The standard phase I 3+3 dose-escalation design is poorly suited for trials of 
radiotherapy, for which toxicities may occur up to several months after treatment. 
In this case, the 3+3 design, or any design that requires all patients to have 
completed observation for toxicity, is subject to openings and closings as patients 
present after a dose level potentially has filled, but before sufficient time has 
elapsed to be certain that treatment has not produced dose-limiting toxicities (DLT).  
 
As such, dose escalation for this trial will be guided by the Time-to-Event Continual 
Reassessment Method (TITE-CRM). TITE-CRM seeks to determine the target 
dose, defined as the dose most closely identified with the target rate, which is the 
largest acceptable probability of toxicity, determined a priori by the investigators 
based on the relative costs and benefits of the treatment (typically between 5% and 
25%). As the trial progresses and patients do or do not experience toxicities at 
different doses, the estimates of probability of toxicity are recalculated using a 
Bayesian expectation, and subsequent patients are assigned to doses under the 
principle to always treat at the target dose.   
 
In a Monte Carlo simulation of 60,000 phase I trials comparing 3+3 design to TITE-
CRM in studies with delayed toxicity, the TITE-CRM trials were significantly 
shorter when toxicity observation times are long, treated more patients at or above 
the maximum-tolerated dose, identified the MTD more accurately, but did not 
expose patients to significant additional risk (97). Additionally, given that TITE-
CRM concentrates most of the accrual around the target dose, early estimates of 
efficacy are possible. 
 
1.7.3 Justification for Dose  
 
In order to minimize toxicity, elective lymph nodes will not be treated. Only the 
dose to the gross tumor volume (GTV) will be escalated. This will minimize the 

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volume of tissue receiving the escalated dose. The starting dose to planned tumor 
volume (PTV) will be 30 Gy in 5 fx of 6 Gy/fx. Dose per fraction will be escalated 
in 1 Gy/fx increments. Such increments translate into approximately 11 Gy10 
increments of BED up to a target dose of 40 Gy(RBE) in 5 fx of 8 Gy/fx for a PTV2 
BED of 72 Gy10.    
 
Given the potential for significant toxicity with hypofractionated radiation at these 
doses, suggested dose limits to organs at risk (OARs) will be defined using BED-
adjusted conversions of published limits for both conventionally fractionated and 
hypofractionated regimens scaled appropriately for 5 fractions.   
 
Such dose limits are being employed as a means to minimize the likelihood of 
toxicity, but true tolerance to OARs are not yet known for such hypofractionated 
schemes. Therefore, prioritization will be employed for planning purposes taking 
into account the balance between tumor coverage and relative consequences of 
toxicity to specific OARs. A simultaneous integrated protection method using a 
planning organ at risk volume around luminal structures such as uninvolved bowel 
will be utilized to reduce the dose of radiation to nearby luminal organs to safe 
levels (97).  
 
 
2 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
To determine the MTD of 
reirradiation using 
hypofractionated IMPT. 
 
 
The maximum tolerated dose 
(MTD) of reirradiation using 
hypofractionated IMPT for 
patients with locoregionally 
recurrent rectal cancer will be 
defined as the dose associated 
with a 35% probability of 
dose-limiting toxicity (DLT).  
Toxicity will be coded using 
CTCAE v5, and DLT will be 
defined as any toxicity listed 
below that occurs within 6 
months from the start of 
treatment and is considered 
possibly, probably or definitely 
related to proton reirradiation:  
 
• Any grade 5 toxicities 
• Any grade 4-5 GI 
toxicities 
• Bowel obstruction  
Given the paucity of 
prospective data on 
reirradiation with proton 
therapy for locoregionally 
recurrent rectal cancer, this is 
a study aimed to evaluate the 
safety and efficacy of 
reirradiation using pencil 
beam scanning proton 
intensity-modulated proton 
therapy (IMPT). 
Hypofractionated radiation 
therapy may increase in the 
risk of treatment-related 
toxicities to spinal cord, 
intestines, kidneys, bowel, or 
skin. We aim to determine the 
maximally tolerated dose of 
hypofractionated radiation 
therapy by increasing the 
boost dose up to a potential 

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• Grade 3-5 
o Diarrhea 
o Anal, colonic, or 
bowel ulcers  
o Bladder perforation 
o Any fistula 
formations 
o Peripheral 
motor/sensatory 
neuropathy of the 
pelvis above 
baseline 
o Osteonecrosis/soft 
tissue necrosis  
o Radiation dermatitis 
o Hematuria 
o Hematochezia 
o Bowel/pelvic 
hemorrhage   
o Reproductive tract 
toxicity 
  
maximum of 40 Gy in 5 
fractions. We will monitor 
patients for toxicity. A dose 
limiting toxicity is defined as 
a high-grade toxicity 
occurring up to 6 months 
from the start of therapy in 
any of the organs above. 
Secondary 
1. To determine the clinical 
complete response rate of 
patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
1. The clinical complete 
response rate as measured 
by DRE, endoscopy, and 
cross-sectional imaging. 
 
We will report the preliminary 
estimate of the local-relapse 
free survival, progression-free 
survival, and overall survival 
rate. If a phase II study is 
eventually performed. The 
survival rates of the patients 
in the phase I study and phase 
II study will be combined for 
efficacy assessments.  
 
Tolerability of the treatment 
regimen (phase I endpoint) 
will determine if further trials 
testing this regimen will be 
performed. 
 
Little data exist on patient-
reported quality of life for 
patients with locoregionally 
recurrent rectal cancer treated 
with proton therapy. We aim 
to report the patients’ results 
2. To estimate median 
freedom from 
locoregional progression 
(FFLP) in patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
 
2. Freedom from locoregional 
progression (FFLP), 
defined as time from end of 
RT to date of first instance 
of local or regional tumor 
progression at 12 months. 
 
3. To estimate median 
overall survival (OS) in 
patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
 
3. Overall survival at 12 
months. 

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4. To estimate median 
progression-free survival 
(PFS) in patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
4. Progression-free survival, 
defined as time from end of 
RT to the earliest date of 
locoregional progression, 
distant progression, or 
death from any cause, at 12 
months.  
 
and compare results as a part 
of this proton dose-escalation 
trial. 
 
The toxicity profile of this 
radiation therapy regimen for 
reirradiation of locoregionally 
recurrent rectal cancer is 
unknown. 
5. To evaluate patient 
reported outcomes (PRO) 
in patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT 
via QOL questionnaires. 
 
5. To determine patient 
reported quality of life 
outcomes using EORTC 
QLQ-C30 and QLQ-CR29. 
 
6. To evaluate the toxicity 
profile of 
hypofractionated IMPT in 
patients with 
locoregionally recurrent 
rectal cancer.  
 
6. Toxicity, as measured by 
CTCAE v 5.0. 
Exploratory Objectives 
1. To explore the prognostic 
value of serum SCCA in 
patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
 
1. Association of pre-
treatment SCCA and post-
treatment SCCA with PFS 
and OS at 6 months. 
To our knowledge there is no 
prospective data on SCCA 
and serum inflammatory 
markers in patients with 
recurrent rectal cancer. 
2. To evaluate the changes in 
serum inflammatory 
markers, CRP and LDH, 
in patients with 
locoregionally recurrent 
rectal cancer who receive 
hypofractionated IMPT. 
 
2. Evaluate the effect of 
hypofractionated IMPT on 
levels of serum 
inflammatory markers. 
 
 
3 
STUDY POPULATION  
 
3.1 
Inclusion Criteria 
In order to participate in this study, a patient must meet all of the criteria listed in this 
section: 

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1. History of biopsy-proven adenocarcinoma of the rectum, anus or rectosigmoid junction 
of any stage now with recurrent disease in the pelvis. 
2. One prior course of radiation therapy to the pelvis for rectal cancer.  
3. ECOG performance status 0-2. 
4. At least 18 years of age. 
5. 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. 
6. Able to understand and willing to sign an IRB-approved written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
In order to participate in this study, a patient must not meet any of the criteria listed in 
this section: 
 
1. Patients with pre-existing radiosensitizing conditions, such as connective tissue 
disorders (i.e. lupus, scleroderma) and genetic mutations (i.e. ataxia-telangiectasia). 
2. A history of other malignancy with the exception of malignancies for which all 
treatment was completed at least 2 years before registration and the patient has no 
evidence of disease, basal cell or squamous cell carcinoma of the skin that 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. 
3. More than one prior course of radiation to the pelvis for rectal cancer.  
4. Prior radiation to the pelvis for disease other than rectal cancer. 
5. Tumor in the rectum/colon requiring radiation therapy to the full circumference of the 
rectum/colon. 
6. Current treatment with any investigational agents. 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, or unstable angina pectoris. 
8. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative 
urine or serum pregnancy test within 14 days of study entry. 
 
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 
REGISTRATION AND ENROLLMENT PROCEDURES 
 
 
The following steps must be taken before enrolling patients to this study: 
 
1. Registration of consented patient in the Siteman Cancer Center OnCore database 

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2. Assignment of unique patient number (UPN) 
Confirmation of patient eligibilityPatients must not start any protocol intervention or 
procedures prior to signing of informed consent. 
 
4.1 
Registration in OnCore Database 
 
Patient registration to the Siteman Cancer Center OnCore database must occur within one 
business day of the patient signing consent. 
 
 
4.2 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  The 
UPN must not include patient initials or other identifying information.  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
4.3 
Confirmation of Patient Eligibility  
 
Patient eligibility will be confirmed using the information listed below: 
 
1. 
Completed eligibility checklist, signed and dated by a member of the study 
team 
2. 
Copy of appropriate source documentation confirming patient eligibility 
 
4.4 
OnCore Subject Status Definitions 
Note: subject status should not be updated in OnCore until the subject is actively in that 
status; future dates are not allowed. 
 
Subject Status 
Definition 
Consented 
Patient has signed an IRB approved consent for the trial. 
Eligible 
Patient eligibility has been confirmed by Washington 
University PI or delegate. 
Not Eligible 
Patient did not meet eligibility criteria for the trial. Note that if 
a patient is determined to be eligible but never initiates study 
participation, they are not considered a screen fail. 
On Study 
Patient is confirmed eligible for the study and enrolled.  
On Treatment 
Patient is receiving study therapy. On Treatment date should 
be the date of the first study treatment. 
Off Treatment 
Patient has discontinued study therapy. Off Treatment date 
should be the last day any study treatment was administered. 
On Follow Up 
One day post RT to one year post RT 
Off Study 
Patient has fully discontinued all study procedures (including 
any follow-up procedures and/or review of medical record for 
outcomes data). 
 
 

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4.5 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently enrolled in the study (status of On Study).  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
event (if applicable).   
 
4.6 
Strategies for Recruitment and Retention  
 
The radiation therapy technology necessary to deliver this treatment regimen is only 
available at the main campus facility at the Center for Advanced Medicine. Follow-up can 
be done at the center nearest to the patient’s home at our community practice sites, such as 
Barnes-Jewish West County Hospital, Siteman Cancer Center South County, Barnes 
Jewish St Peters Hospital and potentially others. This approach reduces travel and expense 
and improves compliance. There will be no additional expense for the patient for 
participating in the clinical trial. 
 
 
5 
TREATMENT PLAN 
 
5.1 
Hypofractionated IMPT 
 
5.1.1 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 machine downtime or other issues. Radiotherapy as administered 
during this study may take up to 10 business days without being considered a 
protocol deviation.  The use of Intensity Modulated Radiation Therapy (IMRT) 
with photon beam therapy is permitted at the discretion of the treating investigator 
in order to avoid extended treatment delays due to logistical reasons (e.g. machine 
downtime). 
 
Radiotherapy will consist of five fractions, delivered once daily, with pencil beam 
scanning proton beam therapy. Treatment with passive-scatter proton beam therapy 
is not allowed. Single Field Optimization (Single Field Uniform Dose) plans are 
preferred over Multi-Field Optimization plans. Beam angles should be selected that 
minimize traversing bowel gas. The use of rectal balloons filled with water is 
optional. 
 
The dose to the PTV will be escalated, starting from 30 Gy in 5 fx of 6 Gy/fx. Dose 
per fraction will be escalated in 1 Gy/fx increments. Such increments translate into 

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approximately 11 Gy10 increments of BED up to a target dose of 40 Gy(RBE) in 5 
fx of 8 Gy/fx for a = BED of 72 Gy10.    
 
Daily imaging with cone beam CT to verify accurate setup is mandatory. The target 
coverage goal is that 95% of the PTV receives at least 95% of the prescription dose 
while not violating OAR dose constraints and the maximum dose should be <115% 
of the prescription dose.  
  
5.1.2 Treatment Planning Procedures 
 
Treatment planning will be performed on a non-contrast CT scans. CT scans with 
small bowel contrast and/or IV contrast are allowed, but the contrast CT scans will 
have to be fused to the planning non-contrast scans. Fusion of the diagnostic MRI 
pelvis with the simulation CT is encouraged, but not required. Diagnostic PET/CT 
scans are optional. Dose volume histogram (DVH) information for the target 
volumes, small bowel, and uninvolved colon and uninvolved rectum (defined to be 
large bowel outside the clinical target volumes) is mandatory.  This is to assist in 
interpreting outcome, including morbidity. LET optimization will be encouraged in 
the inverse planning of IMPT when the technology becomes available.  
 
5.1.3 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.  
 
5.1.4 Gross Tumor Volume (GTV), Clinical Target Volume (CTV), and 
Planning Target Volume (PTV) Definitions 
 
GTV should include all gross recurrent disease including lymph node metastases 
as determined by CT, PET/CT, MRI or biopsy.  
 
The creation of a CTV is at the discretion of the treating radiation oncologist, but 
generally should be minimized to only gross disease and a margin 2-5 mm to 
account for microscopic spread. Elective lymph nodes should not be treated.  
 
PTV is generated by a uniform 0.5 cm expansion about CTV or GTV if no CTV 
was created. 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. 
 

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5.1.5 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 PTV.  
 
These dose constraints are a general guideline. They are soft constraints that assume 
that the patient’s prior DICOM data is unavailable and that each listed organ 
received an EQD2 of 50 Gy previously. If prior DICOM data is available, then the 
modeled dose to the organs from the prior treatment plan would take precedence.  
 
Tissue 
Contouring Instructions 
Vol 
(cc) 
Vol 
Max 
(Gy) 
Max** 
Point 
Dose (Gy) 
Spinal Cord  
Entire bony canal including at least 1 cm 
superior and inferior to PTV. 
<0.35 cc 10 
 
11.5 
Cauda Equina 
Based on the bony limits of the spinal canal 
starting superiorly at the bottom of the 
spinal cord (typically around L2) and 
ending at the inferior extent of the thecal sac 
(typically S3). 
< 5 cc 
12 
14 
Skin 
The outer 0.5 cm of the body surface 
anywhere within the whole-body contour. 
<10 cc 
22.5 
28.5 
Small bowel* 
+ 5 mm 
Any and all loops of small bowel as one 
structure within 1 cm of the PTV in any 
direction. 
<30 cc 
20 
32 
Uninvolved 
Colon* + 5 mm 
One structure including wall and contents of 
lumen starting 1 cm superior to PTV and 
ending 10 cm below PTV. 
<20 cc 
28.5 
40 
Uninvolved 
Rectum + 5 
mm 
One structure including wall and contents of 
lumen subtracting out the GTV or CTV (if 
CTV is created). 
<3.5 cc 
<20 cc 
<62.7% 
50  
32.5  
16  
55  
Bladder wall 
Contour the bladder wall and all urine 
ending inferiorly at the base of the prostate. 
<15 cc 
 
20 
25 
Ureter 
Entire organ. 
n/a 
n/a 
30 Gy 
Femoral heads 
Entire femoral head and proximal femur. 
<10 cc 
15 
n/a 
Penile bulb 
Contour starting superiorly at the inferior 
aspect of the pelvic diaphragm (urethral 
sphincter) and extending inferiorly and 
anteriorly up to 3 cm 
<3 cc 
15 
n/a 

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Sacral Plexus 
Outlining the space defined medially by the 
sacral foramina from S1-S3 including 
contouring within the sacral foramina, 
posteriorly along the limits of the true pelvis, 
laterally to 2-3 cm lateral to the sacral 
foramina, and anteriorly about 3-5 mm from 
the posterior limits of the contour. 
< 5 cc 
12 
14 
Prostate 
Entire organ 
n/a 
n/a 
25 
 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
5.2 
Dose Escalation Schema and MTD Definition 
 
Refer to Section 10 for a description of the TITE-CRM design and dose escalation rules as 
well as for the protocol definition of MTD. 
 
5.2.1 Dose-Limiting Toxicities (DLTs) 
 
Dose-limiting toxicities (DLTs) are defined as any toxicity listed below that 
occurs within 6 months from the start of treatment and is considered possibly, 
probably, or definitely related to proton reirradiation:  
• Any grade 5 toxicities 
• Any grade 4-5 GI toxicities 
• Bowel obstruction  
• Grade 3-5 
o Diarrhea  
o Anal, colonic, or bowel ulcers  
o Bladder perforation 
o Any fistula formation 
o Peripheral/motor sensatory neuropathy of the pelvis above baseline 
o Osteonecrosis/soft tissue necrosis 
o Radiation dermatitis 
o Hematuria 
o Hematochezia 
o Bowel/pelvic hemorrhage   
o Reproductive tract toxicity 
 
5.3 
Study Procedures 
 
5.3.1 Screening Evaluations  
 
The following procedures must occur during screening: 
 
1. Complete history and physical including assessment of ECOG performance 
status, weight, and digital rectal exam within 60 days prior to registration 
(Appendix A). 

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2. CBC with differential and complete metabolic panel within 60 days prior to 
registration. 
3. Urine or serum pregnancy test for female patients that are of childbearing 
potential within 14 days prior to registration. 
4. CT chest/abdomen/pelvis or staging within 60 days prior to registration. If 
PET/CT scan is done, then CT chest/abdomen/pelvis not required. 
5. MRI of the pelvis within 60 days prior to registration. 
6. Endoscopy with colonoscopy, sigmoidoscopy, or endoscopy of the 
locoregionally recurrent tumor within 60 days of registration (recommended if 
feasible)  
7. OPTIONAL biopsy at time of SOC endoscopy.  
8. Charlson Comorbidity Index score will be calculated based on patient 
comorbidities and age. 
 
5.3.2 Pre-RT Evaluations 
 
No more than 30 days before the start of radiation treatment, the following 
procedures must occur: 
3. CBC with differential and CMP 
4. Study labs (CEA, SCCA, CRP, LDH) 
5. QOL questionnaires (Appendices B, C) 
6. Assessment of baseline symptoms  
    
5.3.3 On Therapy Evaluations 
 
The following evaluations will occur while the patient is receiving radiation 
therapy: 
 
• One on-treatment visit during the 5 fractions of RT including a physical exam, 
vital signs, assessment of ECOG performance status, and digital rectal exam.  
• Physician-reported assessment of patient symptoms will be done using CTCAE 
version 5.0 once during radiation therapy (preferably during fraction 4 or 5). 
 
5.3.4 Post-Radiation Evaluations 
 
All patients will be followed from time of enrollment until 1 year post radiation  
Mandatory follow-up time points are as below.  In the event that an in-person 
evaluation is not possible, or if not indicated by the treating investigator, a 
telehealth visit may be performed in its place. 
• 1-2 weeks post-RT 
• 6-8 weeks post-RT 
• 3 months post-RT (+-/- 2 weeks) 
• 6 months post-RT (+/- 2 weeks) 
• 9 months post-RT (+/- 2 weeks) 
• 12 months post-RT (+/- 2 weeks) 
 

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5.3.4.1 Treatment Response Assessment 
 
The following assessments should be performed 6 weeks to 3 months after 
radiation (but should be completed before surgery if the patient will be 
undergoing salvage surgery) and again 6 months after radiation: 
• MRI pelvis 
• CT chest/abdomen with contrast (if a PET is performed, a CT is 
not required) 
• CBC with differential and CMP 
• Study labs (CEA, SCCA, CRP, LDH) 
 
In addition, MRI pelvis and CT chest/abdomen with contrast should be 
performed at 9 and 12 months after radiation.  Endoscopies are optional 
after radiation therapy.  
 
5.3.4.2 Adverse Events and PRO QOL  
 
Patients will be clinically evaluated after completion of radiation therapy at 
the time points listed above. Physician reported assessment of patient 
symptoms will be done using the NCI-CTCAE v5.0 at each time point. 
Patient evaluation by a physician should occur sooner for any symptoms 
concerning for treatment-related toxicity or disease recurrence/progression.  
PROs will be assessed at all time points (except the 6-8 weeks post-RT time 
point) using the QOL questionnaires (Appendices B, C).   
 
5.4 
Definitions of Evaluability 
 
Endpoint 
In order to be evaluable for this endpoint, a 
patient must… 
Maximum tolerated dose 
Have received at least one fraction of study 
radiation.  Patients will be evaluated for DLTs 
from the start of treatment through 6 months 
after the start of treatment.  DLT is defined in 
Section 5.2.1. 
Clinical complete response rate. 
 
Have received at least one fraction of study 
radiation and undergone response assessment by 
DRE, endoscopy, and/or cross-sectional 
imaging. 
Freedom from locoregional 
progression (FFLP) at 12 months. 
Have received at least one fraction of study 
radiation and undergone response assessment. 
Overall survival at 12 months. 
Have received at least one fraction of study 
radiation 
Progression-free survival at 12 
months.  
Have received at least one fraction of study 
radiation and undergone response assessment. 

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Patient reported quality of life. 
 
Have completed the EORTC QLQ-C30 and/or 
QLQ-CR29 QOLs at pre-treatment and a 
minimum of one post-treatment time point 
Toxicity 
Have received at least one fraction of study 
radiation.  Patients are evaluated from first 
receiving study radiation until 12 months after 
the conclusion of radiation. 
Association of pre-treatment SCCA 
and post-treatment SCCA with PFS 
and OS at 6 months. 
Have had blood drawn for SCCA at screening 
and after completion of study radiation 
Levels of serum inflammatory 
markers. 
Have had blood drawn for CRP and LDH after 
completion of study radiation 
 
5.5 
Supportive Care Guidelines 
 
Standard antiemetics, anti-diarrheals, and pain medications may be provided at the 
discretion of the treating radiation oncologist(s) and physicians who evaluate the patients 
for follow up.  Grade 3-5 adverse events may require hospitalization and inpatient 
management.  
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative urine or serum pregnancy test within 14 days prior to the first fraction of 
radiation therapy.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and 30 days following the fraction of radiation therapy.  
 
If a patient is suspected to be pregnant, radiation therapy should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 30 days after the last fraction of radiation, the investigator must be notified in order 
to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 

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In the absence of treatment delays due to adverse events, treatment may continue for 5 
fractions or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
5.8 
Duration of Follow-up 
 
Patients will be followed for 12 months following the completion of IMPT or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event. Follow-up is described in 
Section 5.3.4. Patients will be followed by office visits, phone calls, and review of medical 
record.  Any additional follow-up and imaging will be obtained off-study as per routine 
clinical policies of the treating physician. 
 
5.9 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 5 business days and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to 
and/or should continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 

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o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix D for definitions and Appendix E for a grid of reporting 
timelines. All investigators treating patients on this study are responsible for ensuring that serious 
adverse events (as defined in Appendix B) are reported to the Sponsor-Investigator within an 
adequate timeframe for the event to be assessed by the Sponsor-Investigator for reporting to 
HRPO, QASMC, and/or FDA.  Note that for investigator-initiated studies, the term “Sponsor-
Investigator” refers to the investigator holding the IND. 
 
 
 
Adverse events will be tracked from start of treatment through 12 months after completion of 
radiation therapy. All adverse events must be recorded on the toxicity tracking case report form 
(CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• Toxicities that are definitely or highly likely related to salvage surgery and/or salvage 
chemotherapy 
 
Refer to the data submission schedule in Section 7 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 6.1. 
 
6.1 
WU PI Reporting Requirements 
 
6.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
6.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI (or designee) is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  

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(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 qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
6.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 6.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
7 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Treatment Summary Form 
End of treatment 
DLT Form 
6 months post-treatment 
PRO Form 
Prior to starting treatment, 1-2 weeks post-treatment, 3 
months post-treatment, 6 months post-treatment, 9 
months post-treatment, 12 months post-treatment 
Toxicity Form 
Continuous 
Follow Up Form 
1-2 weeks post-treatment, 6-8 weeks post-treatment, 3 
months post-treatment, 6 months post-treatment, 9 
months post-treatment, 12 months post-treatment 
Tumor Measurement Form 
Baseline, 6-8 weeks post-treatment OR 3 months post-
treatment 
Progression Form 
Time of disease progression 
Death Form 
Time of death 
MedWatch Form 
See Section 6.0 for reporting requirements 
 
7.1 
Adverse Event Collection in the Case Report Forms 
 

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All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 6.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
8 
MEASUREMENT OF EFFECT 
 
8.1 
Antitumor Effect – RECIST 1.1 
 
For the purposes of this study, patients should be re-evaluated for response at the specified 
times in section 5.3.4. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
8.1.1 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 

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‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 
8.1.2 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 

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Conventional CT and MRI:  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI 
is performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or 
serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because they 
are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection 
is an endpoint. 
 

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Tumor markers:  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in clinical complete response.  Specific guidelines for both CA-
125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 
cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 
1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated 
with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease).  
New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring.  The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
  

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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
8.1.3 Response Criteria 
 
8.1.3.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions 
is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
8.1.3.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in clinical complete response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 

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the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
8.1.3.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 

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Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
8.1.3.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
 
9 
DATA AND SAFETY MONITORING 
 
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.  
.  The first report is required either 30 days after the enrollment of the 5th participant (if sooner 
than 6 months after study activation) or 6 months after study activation (provided at least one 
patient has been enrolled; if zero patients have been enrolled at the 6-month mark, the first report 
will be required one year after accrual opens provided at least one patient has been enrolled). 
 
 
The Principal Investigator will review all patient data at least monthly and provide a semi-annual 
report to the Quality Assurance and Safety Monitoring Committee (QASMC).  This report will 
include: 
• Study demographic information (local protocol number, protocol title, list of primary 
study team members, study sites, primary and secondary sponsors, IND/IDE status, 
date of most recent QA audit, and study status and history (including activation and 
suspension dates) 
• Accrual information, including study-wide target accrual and actual accrual, 
anticipated and/or actual accrual end date, and accrual by year by site (if applicable) 
• Subject status information presented in both cumulative format (total number of 
subjects who consented, enrolled, screen failed, started intervention, discontinued 

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intervention, went off study, expired) and current format (number of subjects in 
screening, on intervention, in follow-up, or off study at time of report) 
• Protocol objectives and the number of participants who are evaluable for each 
objective 
• History of study (including summaries of substantive amendments, accrual 
suspensions and reasons, protocol exceptions, errors, and breaches of confidentiality) 
• Summary of exceptions, noncompliance reports, and unanticipated problems reported 
to the IRB 
• Early stopping rules and data describing whether the stopping rules have been met (if 
applicable) 
• Interim analysis plans and the results of the interim analysis (if applicable) 
• Separate SAE and worst grade toxicity tables, each separated by site (if applicable) 
and arm/cohort/dose level (if applicable) 
• Participant-level response and survival data by arm/cohort/dose level (if applicable) 
• Summary of specimen collection (percentage of participants who have had specimens 
collected at each required time point) 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety of participants or the 
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. 
 
 
10 
STASTISTICAL CONSIDERATIONS 
 
10.1 
 Phase I Methodology for Primary Endpoint 
 
10.1.1 Background of TITE-CRM and trial rules 
 
The Time-to-Event Continual Reassessment Method (TITE-CRM) proposed by 
Cheung and Chappell is an adaptive Phase I design (98). In a TITE-CRM clinical 
trial, patients enroll as they become available to be studied. Each participant is 
assigned to a dose level from a set of dose levels pre-defined by investigators and 
is monitored for DLTs over time. The design is adaptive in that the dose level 
assigned to a newly enrolled patient depends on the dose level assignments and 
dose limiting toxicity outcomes of the patients already in the study. A patient's 
observation period ends at the occurrence of a DLT or, if a DLT does not occur, 
after a fixed time T of follow-up. The trial ends when a fixed number of patients, 
n, have been observed. Once the final patient has been observed, the MTD can be 
estimated using the available data.  
 

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The TITE-CRM differs from the traditional CRM in that the estimation process is 
weighted to account for the proportion of the observation period that each currently 
enrolled patient has been observed. By not requiring complete observation before 
the enrollment of the next patient, new participants can be assigned a dose and begin 
evaluation as they become available, subsequently shortening the overall duration 
of the study. 
 
The Biostatistics Unit at the University of Michigan Comprehensive Cancer Center 
has developed a program titecrm.sas for SAS 9 (SAS Institute, Inc.; Cary, NC) that 
makes all of the calculations necessary to determine dose allocation of a trial in 
real-time. They have also developed simulation programs that allow the user to 
determine the efficacy of the trial based on a priori estimates of the probabilities of 
toxicity and necessary sample sizes.   
 
In order to properly utilize this type of trial, a few assumptions and many rules must 
be determined before the start of the trial. The main assumption that must be 
determined is how many different dose levels will be included in the trial and a 
priori estimates of the probability of a DLT at each of those dose levels. For this 
trial, we have 5 dose levels listed below (d1,…, d5), with initial toxicity probability 
estimates (p1,…, p5) ranging from 0.05 to 0.25, respectively.  The following table 
shows the dose design with associated estimated probabilities of toxicity. 
 
Dose Level 
Number of 
fractions of 
IMPT 
PTV 
Dose/fx 
(Gy) 
PTV 
Total 
Dose 
(Gy) 
PTV 
Standard 
BED  (Gy10) 
PTV 
EQD2 
-1 
5 
5 
25 
37.50 
31.25 
1 
Starting 
Level 
5 
6 
30 
48.00 
40.00 
2 
5 
7 
35 
59.50 
49.58 
3 
5 
8 
40 
72.00 
60.00 
 
10.1.2 TITE-CRM design 
 
    
The starting dose can have a large impact on the properties of the design. After the 
trial is completed, most information about the MTD will be obtained if many 
patients are treated at or near the MTD. Thus, the sooner the choice of dose can 
converge on the MTD the more effective the trial will be. However, due to the 
uncertainty of the MTD in the reirradiation of locoregionally recurrent rectal 
cancer, we will start at the two dose levels lower than the expected MTD to 
prioritize safety.  Therefore, our starting dose for this trial will be PTV total dose 
of 30 Gy.   
 
The next thing to be considered is the dose escalation rules. For this trial, we will 
only allow a single dose level escalation per new patient enrolled on the trial.  

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Therefore, if the previous patient was treated at dose level, dk, then a new patient 
can only be treated at dose levels dk+1 or lower.  In order to determine at which level 
to treat the new patient, we will use a weighted, cumulative time of exposure 
approach.   
 
The total length of follow-up for DLT for any patient is 6 months from the start of 
radiation therapy. In order to efficiently and effectively determine the MTD, we 
allow for a dose change when the cumulative time of exposure is 6 months. 
Additionally, since previously published data shows that most toxic events occur 
within the first 6 months from start of treatment, we also implement a linear 
weighting function wherein the first 6 months accounts for 75% of the follow-up 
where the last 3 months attributes 25% of the follow-up information.  The dose for 
the next patient is selected so that the estimated probability at that dose is close to 
the target level.  
 
A feature of the dose escalation part of the TITE-CRM program is the flexibility in 
specifying the margin for the dose selection. This allows the selection of the dose 
level for the next patient that may have an estimated probability of toxicity larger 
than the target level but less than the target level plus the margin. It finds the dose 
closest to the target probability even if it has a higher estimated probability. For this 
trial we set the admissible margin to be 5%, therefore, the MTD will be chosen as 
the dose that yields a posterior toxicity estimate closest to 35% while being between 
30% and 40%. The admissible margin is also used to help determine stopping rules 
for the trial.   
 
In order to account for the possibility of poor initial outcomes we will employ a 
run-in of 6 patients, meaning that the minimum number of treated patients will be 
6. If after these 6 patients, or any other time during the trial, the lowest dose level 
has a posterior probability higher than 40% then the trial will stop.   
 
10.2 
 Simulation and Sample Size Calculations 
 
The TITE-CRM manual details methods for utilizing trial simulation in order to obtain 
estimated posterior probabilities on toxicity estimates.  We utilized the simulation program 
to determine the efficacy of our trial and obtain estimates for needed sample size. While 
there is no exact power calculation for this type of trial, the effectiveness of the trial’s 
sample size can be determined by looking at the stability of the posterior probability under 
different prior probabilities.  
 
We ran 1000 simulations under various increasing and decreasing prior probability 
estimates utilizing the previously described rules and assumptions for this trial and saw 
sufficient stability in posterior probability estimates with a sample size of 20 patients with 
a run-in of 6 patients. Simulations showed that approximately 95% of the time the trial will 
come to completion and the MTD will fall between the 3rd and 5th dose level 89% of the 
time.  Therefore, we will use a fixed sample size of 20 patients for this trial. The posterior 
probability distribution of these 1000 simulations follow in the next table.  

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Dose Level 
Estimated 
initial 
toxicity 
Mean 
Posterior 
toxicity (SD) 
d-1 
0.25 
0.328 (0.434) 
1 
(Starting 
Dose) 
0.30 
0.38 (0.453) 
2 
0.35 
0.43 (0.463) 
3 
0.40 
0.479 (0.464) 
Summary of simulation with estimated posterior probabilities. SD, Standard Deviation 
 
10.2.1 Workflow  
 
The first patient will be enrolled on the trial and treated at PTV total dose 30 Gy, 
which is one dose level below the hypothesized MTD. That patient will be entered 
into the titecrm.sas program and follow-up will begin from start of treatment.  
 
For the purposes of this trial, the patient will be followed from start of treatment 
until the patient completes 12months of follow-up, has a DLT, or is lost to follow-
up. If any of these endpoints occur, the statistician will be notified and the date 
corresponding to the event will be entered into the program. While there is a 
maximum follow-up of 6 months for observation of possible toxicities, sometimes 
patients have a delay in their treatment resulting in the need for a prolonged 
observation period. This delay will be accounted for, as needed, for this study to 
ensure a complete 6-month follow-up.  
 
When a new patient is enrolled on the trial, the statistician will be notified of the 
date of enrollment. At that time the statistician will update the follow-up for all 
patients currently on the trial and determine the dose that will be administered for 
the new patient. We will utilize the cumulative time of exposure method, which 
will allow the contribution of patients with no DLT at this time to be partially 
weighted consistent with their time observed.  We will also utilize the weight 
function to place more emphasis on the first 6 months follow-up (75% weight) 
compared to the last 3 months of follow-up (25% weight).  At this point, the 
program provides a summary of the number of patients treated at each dose so far, 
along with the number of DLTs that have occurred. The posterior probability and 
95% credible intervals of dose limiting toxicity for each dose level is calculated.  
At this point, the model determines the dose level that has an estimated toxicity rate 
closest to 35% within the 5% admissible margin.   
 
The newly enrolled patient will be enrolled in the corresponding dose level if that 
dose level is within one dose level from the dose level the most current patient is 
enrolled on.  If the suggested dose level is more than one dose level from the current 
dose level the next patient will be enrolled on the dose level that is closest to the 
current level in the direction of the dose level determined from the estimated 

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posterior probability. This continues until the trial has accrued all 20 patients or, if 
after 6 patients are enrolled, the estimated posterior.   
 
10.2.2 Recommended Phase 2 Dose 
 
The MTD will be estimated using the proposed TITE-CRM model. After the phase 
I study, the MTD will be chosen as the dose that yields a posterior toxicity estimate 
closest to 35% while being between 30% and 40%. 
 
10.2.3 Replacement of Subjects that are not Evaluable  
 
Patients who withdraw from the dose escalation component of the trial for any other 
reason than toxicity and who have not already developed a dose-limiting toxicity 
(DLT) at that point will be replaced by recruiting another patient at the same dose 
level. 
 
10.2.4 Stratification Factors 
 
There is no stratification in this trial.  
 
10.2.5 Analysis Plan  
 
The primary endpoint of the study is to determine the maximum tolerated dose 
(MTD) of reirradiation using hypofractionated IMPT for patients with 
locoregionally recurrent rectal cancer. The MTD will be defined as the dose 
associated with a 35% probability of dose-limiting toxicity (DLT) as described 
above.   
 
The secondary endpoints are clinical complete response rate, freedom from 
locoregional progression (FFLP), overall survival (OS), progression-free survival 
(PFS), PRO QOL, and adverse events as defined by CTCAE version 5.  
 
Descriptive statistics will be calculated on all variables. Frequencies will be 
computed for all binary/categorical variables, and continuous variables will be 
summarized using medians, quartiles, and ranges. Next all variables will be 
compared with the historical data using Chi-square tests for binary/categorical 
variables and t-tests for continuous variables. 
 
All the survival events will be measured from the end of radiation therapy and 
subjects who do not develop events will be censored at the last follow-up. Patients 
with distant metastasis will be continued to be followed for locoregional tumor 
recurrence until the last follow-up or time of death whether. Death will be analyzed 
as a competing cause in FFLP. Kaplan-Meier curves will be performed to compare 
the freedom from locoregional progression (FFLP), progression-free survival (PFS) 
and overall survival (OS). Cox proportional hazard model with log-rank test will 
be used to explain the correlation between explanatory variables and survival times. 

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Adjusted hazard ratios (HR) and the corresponding 95% confidence intervals (CI) 
will be reported.  
 
PRO QOL questionnaires (Appendix B and C) will be tabulated for each domain 
and summed to generate a composite global QOL score. Repeated measures 
ANOVA will be used to compare QOL scores collected at baseline and at 1-2 
weeks, 3 months, 6 months, 9 months, and 12 months after RT.  
 
Adverse events or treatment-related toxicities will be classified as acute (<3 months 
after RT completion) toxicities and late (3-12 months after RT completion) 
toxicities. Adverse events, along with their maximum grade and relationship to 
study treatment, will be tabulated and assessed descriptively for patterns of 
occurrence. Frequency tables will include frequencies and percentages at the patient 
level as well as at the AE level. Point estimates for proportions will be reported, 
along with small sample confidence interval estimates.  
 
All analyses will be performed in R (RFoundation for Statistical Computing) or in 
SAS (SAS Institute, Inc.; Cary, NC). 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: EORTC QLQ-C30 Quality of Life of Cancer Patients 
 
 

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APPENDIX C: EORTC QLQ-CR29 Colorectal QOL 
 
 

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APPENDIX D: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
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 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 

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APPENDIX E: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Unanticipated problem 
involving risk to participants 
or others 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
Report via email after 
IRB acknowledgment 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 
10 working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
 

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working day.  Otherwise, report at the time of 
continuing review. 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
 

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APPENDIX F: Study-Specific DSM Tables 
 
Protocol Objectives and Subject Evaluability 
Objective 
# of patients evaluable for this 
endpoint to date 
Primary 
To determine the MTD of reirradiation using 
hypofractionated IMPT. 
Secondary 
To determine the clinical complete response rate of 
patients with locoregionally recurrent rectal cancer who 
receive hypofractionated IMPT. 
 
To estimate median freedom from locoregional 
progression (FFLP) in patients with locoregionally 
recurrent rectal cancer who receive hypofractionated 
IMPT. 
 
To estimate median overall survival (OS) in patients with 
locoregionally recurrent rectal cancer who receive 
hypofractionated IMPT. 
 
To estimate median progression-free survival (PFS) in 
patients with locoregionally recurrent rectal cancer who 
receive hypofractionated IMPT. 
 
To evaluate patient reported outcomes (PRO) in patients 
with locoregionally recurrent rectal cancer who receive 
hypofractionated IMPT via QOL questionnaires. 
 
To evaluate the toxicity profile of hypofractionated 
IMPT in patients with locoregionally recurrent rectal 
cancer. 
 
Exploratory 
To explore the prognostic value of serum SCCA in 
patients with locoregionally recurrent rectal cancer who 
receive hypofractionated IMPT. 
 
To evaluate the changes in serum inflammatory markers, 
CRP and LDH, in patients with locoregionally recurrent 
rectal cancer who receive hypofractionated IMPT 
 
 
 
Interim Analysis and Early Stopping Rules 
Does the study design include an interim toxicity analysis? 
No 
Does the study design include an interim futility analysis? 
No 
Are there early stopping rules that outline circumstances under which the study must be 
suspended or closed? 
Yes 
If yes, describe. 

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In order to account for the possibility of poor initial outcomes we will employ a run-in of 6 
patients, meaning that the minimum number of treated patients will be 6. If after these 6 
patients, or any other time during the trial, the lowest dose level has a posterior toxicity 
probability higher than 40% then the trial will stop. 
 
Please complete the table below. 
 
Have any patients 
experienced a DLT? 
If yes, provide UPN(s). 
If yes, specify AE. 
 
 
 
 
 
 
 
Treatment Response 
UPN 
Dose 
Level 
On tx 
date 
# fx 
received 
DLT? 
Best 
response 
Replaced? 
Date of 
progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival 
UPN 
Off tx 
date 
Reason off tx 
Date of 
death 
Cause of death