Clinical trial NCT04786600
Conditions: Metastatic Colorectal Cancer
Keywords: metastatic colorectal cancer precision oncology personalized medicine ctDNA
Sponsor: University of Florida
Start date: 2022-03-14; Completion date: 2024-03-19
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, phase 2 study will investigate the use of the Signatera ctDNA assay versus the standard scan-based approach to guide treatment in patients with metastatic colorectal cancer. The aim of this study will be to measure and compare the overall survival, progression-free survival, and best overall response while on study of patients whose treatment has been guided by these two approaches.

Detailed description:

Arms: arm 1: Subjects on this arm will be tested with the Signatera ctDNA assay while receiving treatment on a pre-specified sequence of FDA-approved drugs and drug combinations. Subjects will move through this sequence based on the results of the ctDNA assay. Subjects will move to a new drug or drug combination in the sequence when the ctDNA assay indicates a significant increase in ctDNA level. Subjects will also have imaging scans every 12 weeks while on each drug or drug combination and subjects will move to a new drug or drug combination if these scans indicate disease progression. arm 2: Subjects on this arm will be treated with the same pre-specified sequence of FDA-approved drugs and drug combinations as those on the ctDNA assay- guided intervention arm. Subjects will move through the sequence based on the results of imaging scans, moving to a new drug or drug combination if imaging shows progressive disease.
Interventions: intervention 1: Signatera ctDNA assay intervention 2: pre-specified sequence of FDA-approved drugs and drug combinations
Intervention descriptions: intervention 1: Subjects will be tested with the Signatera ctDNA assay every 2 weeks. intervention 2: Subjects will receive treatment with a pre-specified sequence of FDA-approved drugs and drug combinations

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Randomized Therapeutic Optimization Trial for Subjects with Refractory Metastatic 
colorectal Cancer using ctDNA: Rapid 1 Trial 
 
Protocol Number: 
UF-STO-GI-012  
 
Protocol Version Number: 
3.4 
 
Coordinating Center:  
 
University of Florida 
 
Principal Investigator:   
 
Sherise Rogers. MD, MPH 
University of Florida 
1600 SW Archer Road 
Gainesville, FL 32608 
Telephone: (352) 273-7828 
Email: Sherise.Rogers@medicine.ufl.edu 
 
 
 
 
 
 
 
 
 
  
Statistician: 
 
 
 
Dr. XiangYang Lou, PhD  
University of Florida Health Cancer Center 
 
Protocol Manager: 
 
            CRO Project Management Office 
pmo@cancer.ufl.edu  
 
Clinical Phase: 
Phase II 
 
IND Status: 
N/A 
 
NCT#  
 
 
 
NCT04786600 
 
Keywords:  
Gastrointestinal, GI, Colorectal Cancer, Precision Oncology, 
Personalized Medicine, ctDNA 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This protocol was designed and developed by the University of Florida Health Cancer Center.  The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further disclosed by them. 
 


 
 
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TABLE OF CONTENTS 
 
 
Page 
STUDY SCHEMA ................................................................................................................................................. 11 
PROTOCOL SYNOPSIS .................................................................................................................................... 12 
1. 
BACKGROUND .......................................................................................................................................... 18 
1.1 
Metastatic Colorectal Cancer ..................................................................................................... 18 
1.2 
Circulating Tumor DNA (ctDNA) ............................................................................................... 19 
1.3 
Current Study .................................................................................................................................... 21 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 22 
2.1 
Primary.................................................................................................................................................. 22 
2.1.1. 
Primary Objective ............................................................................................................... 22 
2.1.2  
Primary Endpoint ................................................................................................................ 22 
2.2 
Secondary ............................................................................................................................................ 22 
2.2.1 
Secondary Objectives ....................................................................................................... 22 
2.2.2 
Secondary Endpoints ........................................................................................................ 22 
2.3 
Exploratory .......................................................................................................................................... 22 
3. 
STUDY DESIGN ......................................................................................................................................... 23 
3.1 
Study Overview ................................................................................................................................. 23 
4. 
SELECTION OF SUBJECTS ..................................................................................................................... 24 
4.1 
Number of Subjects ........................................................................................................................ 24 
4.2 
Inclusion Criteria .............................................................................................................................. 24 
4.3 
Exclusion Criteria .............................................................................................................................. 26 
4.4 
Inclusion of Women and Minorities ........................................................................................ 27 
5. 
REGISTRATION PROCEDURES ............................................................................................................ 27 
6. 
STUDY PROCEDURES ............................................................................................................................. 27 
6.1 
Schedule of Events .......................................................................................................................... 28 
6.2 
End of Treatment (EOT) Evaluations ....................................................................................... 31 
6.3 
Follow up/Survival Evaluations .................................................................................................. 31 
7. 
Protocol-specified treatment ............................................................................................................. 32 
7.1 
Treatment Schedule/Administration ....................................................................................... 32 


 
 
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7.1.1 
Dose Calculations ............................................................................................................... 33 
7.2 
Supportive Care ................................................................................................................................ 33 
7.2.1 
Supportive Care Guidelines............................................................................................ 33 
7.2.2 
Concomitant Therapy ....................................................................................................... 33 
7.2.3 
Prohibited Concomitant Therapy ................................................................................ 34 
7.3 
Dose Modifications ......................................................................................................................... 35 
8. 
TREATMENT DISCONTINUATION .................................................................................................... 35 
8.1 
Screen Failures .................................................................................................................................. 35 
8.2 
Criteria For Protocol-Specified Treatment Discontinuation ......................................... 35 
8.3 
Replacement of Subjects .............................................................................................................. 36 
9. 
BIOLOGICAL SPECIMENS AND CORRELATIVES ......................................................................... 37 
9.1 
Source of Specimens ...................................................................................................................... 37 
9.2 
Correlative Studies of Biospecimens ....................................................................................... 37 
9.3 
Preparation, Shipment and Storage of Specimens .......................................................... 37 
9.3.1 
Tumor Tissue ........................................................................................................................ 38 
9.3.2 
Blood Samples ..................................................................................................................... 38 
9.3.3 
Microbiota Samples ........................................................................................................... 39 
10. 
protocol-specified treatment INFORMATION ........................................................................ 39 
10.1 FOLFIRI + Bevacizumab ................................................................................................................ 39 
10.1.1 
Identification and Physical Description .................................................................... 39 
10.1.2 
Administration ..................................................................................................................... 39 
10.1.3 
Storage, Handling, and Dispensing ............................................................................ 39 
10.1.4 
Contraindications ................................................................................................................ 40 
10.1.5 
Special Warnings and Precautions for Use ............................................................. 40 
10.1.6 
Adverse Effects..................................................................................................................... 41 
10.2 Cetuximab or Panitumumab ....................................................................................................... 41 
10.2.1 
Identification and Physical Description .................................................................... 41 
10.2.2 
Administration ..................................................................................................................... 41 
10.2.3 
Storage, Handling and Dispensing ............................................................................. 42 
10.2.4 
Contraindications ................................................................................................................ 42 


 
 
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10.2.5 
Special Warnings and Precautions for Use ............................................................. 42 
10.2.6 
Adverse Effects..................................................................................................................... 42 
10.3 TAS-102 ................................................................................................................................................ 43 
10.3.1 
Identification and Physical Description .................................................................... 43 
10.3.2 
Administration ..................................................................................................................... 43 
10.3.3 
Storage, Handling and Dispensing ............................................................................. 43 
10.3.4 
Contraindications ................................................................................................................ 43 
10.3.5 
Special Warnings and Precautions for Use ............................................................. 43 
10.3.6 
Adverse Effects..................................................................................................................... 43 
10.4 Regorafenib ........................................................................................................................................ 44 
10.4.1 
Identification and Physical Description .................................................................... 44 
10.4.2 
Administration ..................................................................................................................... 44 
10.4.3 
Storage, Handling and Dispensing ............................................................................. 44 
10.4.4 
Contraindications ................................................................................................................ 44 
10.4.5 
Special Warnings and Precautions for Use ............................................................. 44 
10.4.6 
Adverse Effects..................................................................................................................... 44 
10.5 Capecitabine ...................................................................................................................................... 45 
10.5.1 
Identification and Physical Description .................................................................... 45 
10.5.2 
Administration ..................................................................................................................... 45 
10.5.3 
Storage, Handling and Dispensing ............................................................................. 45 
10.5.4 
Contraindications ................................................................................................................ 45 
10.5.5 
Special Warnings and Precautions for Use ............................................................. 45 
10.5.6 
Adverse Effects..................................................................................................................... 46 
10.6 FOLFIRI .................................................................................................................................................. 46 
10.7 FOLFOX/CAPOX ................................................................................................................................ 46 
10.7.1 
Identification ......................................................................................................................... 46 
10.7.2 
Administration ..................................................................................................................... 46 
10.7.3 
Storage, Handling, and Dispensing ............................................................................ 47 
10.7.4 
Contraindications ................................................................................................................ 47 
10.7.5 
Special Warning and Precautions................................................................................ 47 


 
 
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10.7.6 
Adverse Effects..................................................................................................................... 48 
11. 
ADVERSE EVENTS ................................................................................................................................. 49 
11.1 Definitions ........................................................................................................................................... 49 
11.1.1 
Adverse Event ....................................................................................................................... 49 
11.1.2 
Serious Adverse Event ...................................................................................................... 50 
11.1.3 
Non-Serious Adverse Event ........................................................................................... 51 
11.2 Period of Observation.................................................................................................................... 51 
11.3 Documenting and Reporting of Adverse Events by Investigator .............................. 51 
11.3.1 
Assessment of Causal Relationship to the Study ................................................. 52 
11.3.2 
Intensity of Adverse Events ............................................................................................ 53 
11.3.3 
Action Taken with Drug(s) .............................................................................................. 53 
11.3.4 
Definition of Outcome ..................................................................................................... 54 
11.4 Immediately Reportable Events ................................................................................................ 54 
11.4.1 
Serious Adverse Events .................................................................................................... 54 
11.4.2 
Other Events Requiring Immediate Reporting ...................................................... 55 
11.4.3 
Reporting to Natera .......................................................................................................... 56 
12. 
STATISTICAL METHODS .................................................................................................................... 56 
12.1 Data collection and management plan ................................................................................. 56 
12.2 Stratification ....................................................................................................................................... 56 
12.3 Sample Size Justification .............................................................................................................. 56 
12.4 Analysis of Primary Endpoint...................................................................................................... 57 
12.5 Analysis of Secondary Endpoints / Safety Data ................................................................. 57 
12.6 Analysis of Exploratory Endpoints ............................................................................................ 58 
12.7 Interim Analysis ................................................................................................................................ 58 
12.8 Data Integrity and Safety Committee ..................................................................................... 58 
12.9 Data Monitoring ............................................................................................................................... 59 
12.10 Principal Investigator Responsibilities .................................................................................... 60 
13. 
EMERGENCY PROCEDURES ............................................................................................................. 60 
13.1 Emergency Contact ......................................................................................................................... 60 
13.2 Emergency Identification of Investigational Products .................................................... 60 


 
 
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13.3 Emergency Treatment ................................................................................................................... 60 
14. 
ADMINISTRATIVE, ETHICAL, and REGULATORY CONSIDERATIONS ............................ 61 
14.1 Good Clinical Practice .................................................................................................................... 61 
14.2 Institutional Review Board ........................................................................................................... 61 
14.3 Compliance with Laws and Regulations ................................................................................ 61 
14.4 Delegation of Investigator Responsibilities ......................................................................... 62 
14.5 Subject Information and Informed Consent ........................................................................ 62 
14.6 Confidentiality ................................................................................................................................... 63 
14.7 Protocol Amendments .................................................................................................................. 63 
14.8 Case Report Forms .......................................................................................................................... 63 
14.9 Record Retention ............................................................................................................................. 64 
15. 
REFERENCES ........................................................................................................................................... 65 
16. 
APPENDICES ........................................................................................................................................... 66 
Appendix A: PROTOCOL VERSION HISTORY / SUMMARY OF CHANGES .......................... 67 
Appendix B: PERFORMANCE STATUS CRITERIA ............................................................................. 69 
Appendix C: RECIST GUIDELINES (VERSION 1.1) ........................................................................... 70 
Appendix D: SUBJECT PILL DIARIES ..................................................................................................... 77 
Appendix E: TREATMENT REGIMEN ..................................................................................................... 81 
Appendix F: PROPOSED TIMELINE ....................................................................................................... 84 
 


 
 
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ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CRC 
Colorectal Cancer 
CL 
clearance 
Clcr 
Creatinine clearance 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
clinical trials management system 
CRO 
Clinical Research Office 
CtDNA 
Circulating Tumor DNA 
CTO 
Clinical Trials Office 
DISC 
Data Integrity and Safety Committee 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DPD 
Dihydropyrimidine dehydrogenase 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
EOT 
End of Treatment 
FDG 
fluorodeoxyglucose positron emission 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FSH 
follicle stimulating hormone 
5FU 
fluorouracil 
GCP 
Good Clinical Practice 
H&E 
Haemotoxylin and Eosin (stained slides) 


 
 
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HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg  
kilogram(s) 
LDH 
lactic dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSAE 
non-serious adverse event 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PMO 
Project Management Office 
PI 
principal investigator 
PK 
pharmacokinetics 
PR 
partial remission 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 


 
 
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SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
Tmax 
time to maximum plasma concentration 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell  
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 


 
 
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Protocol Signature Page 
 
A Phase II Randomized Therapeutic Optimization Trial for Subjects with Refractory 
Metastatic colorectal Cancer using ctDNA: Rapid 1 Trial 
 
 
Study Principal Investigator:  
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
Location of Facility (City/State) 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB 
procedures, the Declaration of Helsinki, ICH Good Clinical 
Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations 
governing the conduct of clinical studies. 
 
 
 
 
 
 
 


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If measurable 
ctDNA- 
Randomization 
• Blood collected for post-hoc assessment of ctDNA 
every 4 weeks until Progressive Disease (PD) by scan. 
• CT imaging with RECIST read every 12 weeks. 
 
If no 
measurable 
ctDNA, do not 
randomize.  
These 
subjects will 
be followed 
for survival 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual Goal: 78 randomized 
 
Follow all subjects in both arms until death 
Primary Endpoint= Overall Survival (OS) 
 
Informed Consent / Screening / 
Cycle 1 Day 1 
 
Arm A 
ctDNA  
Guided Intervention 
 
N= 39 
 
Arm B 
Scan  
Guided Intervention 
 
N= 39 
 
• ctDNA assay every 2 weeks until an intervention shows a 
significant decrease (see section 7.1), then every 4 weeks 
until Progressive Disease (PD) by scan or significant ctDNA 
increase. 
• CT imaging with RECIST read every 12 weeks. 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase II Randomized Therapeutic Optimization Trial for 
Subjects with Refractory Metastatic colorectal Cancer using 
ctDNA: Rapid 1 Trial 
Funding 
Source(s): 
 University of Florida 
Rationale: 
Patients with advanced CRC after progressing through first line 
therapy, have a number of FDA-approved therapeutic options 
that are associated with a clinical benefit for a substantive 
minority of patients.  Present clinical practice is to try these 
various interventions in a step-wise empiric fashion using 
scans every 3 months to determine the effectiveness of each 
intervention.  This process requires 3-4 months between 
therapeutic interventions from which the patient may derive 
no clinical benefit, unless the selected therapeutic agent by 
chance happens to provide some level of benefit.  As is most 
often the case, a patient’s performance status may decline and 
thus limit the number of possible interventions to only 1 or 2 
before further intervention is precluded.  This empiric 
approach that is dependent on relatively infrequent scans 
(every few months) not only limits the number of possible 
therapeutic attempts, but often misses the intervention that 
may provide meaningful benefit due to the limited number of 
possible therapeutic attempts.  Additionally, the 3 months of 
exposure to each non-beneficial therapeutic result in entirely 
unnecessary toxicity. 
An alternative approach makes use of frequent ctDNA 
monitoring after each given intervention to gage the 
effectiveness of the intervention and thus abbreviates the 
interval between therapeutic attempts to 2-3 weeks rather 
than 4 months as required using scans.  This rapid assessment 
by ctDNA allows each patient to be exposed to each potential 
beneficial intervention for a relatively brief period of time, thus 
limiting toxicity, while allowing a far larger number of 
interventions to be attempted to find the intervention or 
interventions that provide the greatest clinical benefit for each 
patient.  This is essentially a means to “personalize” available 
therapeutics for each patient.    


 
 
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Objectives: 
Primary:    
To determine the difference in overall survival (OS) of adults 
with metastatic colorectal cancer after treatment with 
oxaliplatin, between use of the ctDNA guided assay (Signatera 
Test) and routine scan-guided treatment. 
 
Secondary:   
To measure and compare progression free survival (PFS) and 
best overall response (OR) in subjects with ctDNA-guided 
treatment compared to routine scan-guided treatment. 
 
To investigate the dynamics of ctDNA vs scan evidence of 
disease status. 
 
Exploratory:   
To investigate the relationship of the microbiome and other 
novel biomarkers relative to patient outcomes. 
Study Design: 
This is a prospective, single center, two-arm randomized trial.  
Accrual Goal: 
A total of 78 randomized subjects, with a maximum enrollment 
cap of 100 subjects to account for any withdrawals or screen 
failures. 
Inclusion Criteria: 
Individuals eligible for study participation must meet the 
following criteria:  
A. A histologic confirmation of adenocarcinoma of the 
colon or rectum with RECIST measurable metastatic 
disease not currently candidates for oligometastatic 
definitive management (i.e., potentially curative surgery 
or ablation). 
B. Must have at least received first-line oxaliplatin-based 
therapy for metastatic disease, or a clinically acceptable 
and documented reason they did not, and progressed 
or were intolerant to the therapy. Individuals who 
recurred within 6 months of completion of oxaliplatin 
based adjuvant chemotherapy are also eligible. Subjects 


 
 
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may enroll at any line of therapy past this first line so 
long as the patient’s next clinically reasonable 
prescribed treatment would be FOLFIRI + 
Bevacizumab/biosimilar, Anti-EGFR therapy (with or 
without irinotecan), OR Lonsurf.  
C. Subjects must have tissue from either the primary 
and/or metastatic deposit available for submission at 
enrollment. Tissue can be from either a biopsy or 
resection surgery, whichever is most recent, but must be 
from the past five years.  See Section 9.3.1 for tissue 
block and slide specifications.  
D. Subjects must have tissue and blood shipped to Natera 
at least 10 days prior to the anticipated treatment start 
date.   
E. Subjects must have had molecular profiling to 
determine tumor RAS, BRAF and MMR/MSI status. 
F. Subjects with known or suspected Gilbert’s disease 
must be formally tested for UGT1A1*28 with results 
available to study team prior to treatment initiation. 
G. Any clinically relevant (as deemed by the PI) adverse 
events related to prior therapies must have resolved to 
Grade 1 or less (CTCAE 5.0) at study enrollment. 
H. Both males and females ≥ eighteen years of age.  
I. An ECOG Performance Status less than or equal to 2. 
J. A life expectancy of at least 6 months. 
K. Adequate organ function as defined as: 
• Absolute neutrophil count (ANC) ≥ 1,500/µL 
• Hemoglobin ≥ 9g/dL 
• Platelets ≥ 100,000/µL 
• Total bilirubin ≤ 1.5 ULN or direct bilirubin ≤ 1 x ULN 
• Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 x ULN; if liver metastases 
present, then AST and ALT must be ≤ 5 x ULN 


 
 
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• Serum creatinine ≤ 1.5 x ULN or calculated creatinine 
clearance ≥ 59 mL/min/1.73m using Cockcroft-Gault 
equation 
L. Subjects must not have more than one active 
malignancy at the time of enrollment (Subjects with a 
prior or concurrent malignancy whose natural history or 
treatment does not have the potential to interfere with 
the safety or efficacy assessment of the investigational 
regimen [as determined by the treating physician and 
approved by the PI] may be included).  
M. Written informed consent obtained from the subject 
and the subject agrees to comply with all the study-
related procedures. 
N. Women of childbearing potential (WOCBP) must be 
using an adequate method of contraception to avoid 
pregnancy throughout the study and for at least 12 
weeks after the last dose of the protocol-specified 
treatment to minimize the risk of pregnancy.  Prior to 
study enrollment, women of childbearing potential must 
be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors 
for an unintentional pregnancy.   
 
WOCBP includes any woman who has experienced 
menarche and who has not undergone successful 
surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or who is not post-
menopausal. Post-menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive 
months without another cause, or 
• For women with irregular menstrual periods who 
are taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone 
(FSH) level of greater than 35 mIU/mL. 


 
 
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O. Males with female partners of child-bearing potential 
must agree to use physician-approved contraceptive 
methods (e.g., abstinence, condoms, vasectomy) 
throughout the study and should avoid conceiving 
children for 12 weeks following the last dose of the 
protocol-specified treatment. 
Exclusion Criteria: 
Subjects with any of the following will not be eligible for study 
participation:  
A. Subject with colorectal cancer known to be 
Microsatellite High (MSI-H), deficient in DNA mismatch 
repair genes (dMMR), or BRAF (V600E) mutated. 
B. Females or males of childbearing potential who are 
unwilling or unable to use an acceptable method to 
avoid pregnancy for the entire study period and for at 
least 12 weeks after the last dose of the protocol-
specified treatment.  
C. Females who are pregnant or breastfeeding. 
D. History of any other disease, metabolic dysfunction, 
physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of protocol 
therapy or that might affect the interpretation of the 
results of the study or that puts the subject at high risk 
for treatment complications, in the opinion of the 
treating physician.   
E. Prisoners or subjects who are involuntarily incarcerated, 
or subjects who are compulsorily detained for treatment 
of either a psychiatric or physical illness. 
F. Prior radiation therapy must have been completed 14 
days prior to study entry. 
G. Prior chemotherapy or biologic therapy must have been 
completed 21 days prior to study entry. 


 
 
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H. Subject has known Dihydropyrimidine Dehydrogenase 
(DPD) deficiency. 
Efficacy 
Assessments: 
RECIST (version 1.1), ctDNA assay, overall survival assessments 
Statistical 
Considerations: 
A total of 39 randomized patients in each arm randomized 1:1 
will provide an 80% power to detect a HR of 0.55 (target 
median OS of 11 months) using an alpha of 0.1.   
We will use Overall Survival (OS) as the primary endpoint and 
assume a median OS of 6 months with the standard approach 
based on the experimental arm of the CORRECT Trial (Grothey 
et al, Lancet 2013) using single agent regorafenib in the same 
population as is being enrolled in the present trial.  
An interim futility analysis will occur after 26 patients are 
enrolled onto each arm.  The trial would be stopped if the 
futility boundary is exceeded or an additional 13 patients 
would be enrolled onto each arm if futility is not exceeded. 
Estimated 
Enrollment 
Period: 
36 months 
Estimated Study 
Duration: 
48 months 


 
 
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1. BACKGROUND 
1.1 
Metastatic Colorectal Cancer 
Colorectal cancer (CRC) accounts for about 150,000 new cases annually in the US, of 
which about 50,000 patients succumb to their cancer.  For patients with metastatic CRC, 
the 5-year survival is on the order of 10% with only a small minority of patients able to 
undergo surgical resection with curative intent.  For the overwhelming majority of 
patients, palliative treatment with systemic chemotherapy represents the standard of 
care with an associated median survival of about 30 months.  Patients with advanced 
disease are typically treated with the combination of a fluoropyrimidine (5-FU or 
capecitabine) with oxaliplatin or irinotecan plus bevacizumab for the first 2 lines of 
therapy.  In cases of left-sided primary disease, anti-EGFR antibodies (cetuximab or 
panitumumab) may be employed instead of bevacizumab.  After progressing through 
the first 2 lines of therapy, patients have a number of NCCN supported/FDA approved 
therapeutic options that are associated with a clinical benefit for a substantive minority 
of patients.  Present clinical practice is to try these various interventions in a stepwise 
empiric fashion using scans every 3 months to determine the effectiveness of each 
intervention.  This process requires 3-4 months between therapeutic interventions from 
which the patient may derive no clinical benefit unless the selected therapeutic agent by 
chance happens to provide some level of benefit.  As is most often the case, a patient’s 
performance status may decline and thus limit the number of possible interventions to 
only 1 or 2 before further intervention is precluded.  This empiric approach that is 
dependent on relatively infrequent scans not only limits the number of possible 
therapeutic attempts but often misses the intervention that may provide meaningful 
benefit due to the limited number of possible therapeutic attempts.  Additionally, the 3 
months of exposure to each non-beneficial therapeutic will result in entirely unnecessary 
toxicity, both physical and financial. 
 
An alternative approach makes use of frequent ctDNA monitoring performed 2 weeks 
after a given intervention to gage the effectiveness of the intervention and thus 
abbreviating the interval between therapeutic attempts to 2-3 weeks rather than 3-4 
months as required with the present approach using imaging scans.  This rapid 
assessment by ctDNA allows each patient to be exposed to each potential beneficial 
intervention for a relatively brief period of time, thus limiting toxicity, while allowing a 
far larger number of interventions to be attempted to find the intervention or 
interventions that provide the greatest clinical benefit for each patient.  This is 
essentially a means to “personalize” available therapeutics for each patient.  
 


 
 
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1.2 
Circulating Tumor DNA (ctDNA) 
Using a single tumor mutation to assay for ctDNA, Tie and colleagues (Ann Oncology 
2015) demonstrated a close relationship between pretreatment ctDNA levels and 
imaging using the sum of the longest tumor diameters as shown in Figure 1 below. 
 
 
Figure 1 
 
In this same investigation it was found that a 10-fold or greater decrease in ctDNA was 
associated with a RECIST response in 64% of patients whereas a less than 10-fold 
decrease was associated with a response in 25% of patients. 
 
Osumi and colleagues (Nature 2019) used mutations in 14 colon-cancer associated 
genes to assay for ctDNA in 29 patients with metastatic CRC undergoing second line 
therapy.  They found that changes in ctDNA levels at 2 and 8 weeks closely mirrored 
image detected disease status as shown in Figure 2 below. 
 
 
Figure 2 
 


 
 
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Taken together, these data support a strong relationship between ctDNA levels and 
disease status as measured by conventional imaging in patients with metastatic CRC.   
 
The Signatera ctDNA assay (Natera Inc San Carlos, CA) is CLIA-approved and utilizes 
paraffin embedded tumor tissue from either the primary CRC or a metastatic site 
subjected to NGS to identify 16 truncal mutations specific for a given individuals cancer.  
These mutations are then assayed in the blood using PCR technology and serve as a 
quantitative measure of tumor burden that may be followed over time as an indicator of 
benefit associated with any given therapeutic intervention.  In patients with active 
metastatic CRC the assay detected ctDNA in 100% of 25 patients investigated whereas 
patients achieving a PR (15 patients) or NED (12 patients) following chemotherapy had 
ctDNA positivity rates of 60% and 33% respectively (Kasi et.al. ASCO 2020). In patients 
with oligometastatic CRC, the Signatera assay was positive in all patients at pre-op at a 
median level of 36.5 mean tumor molecules (MTM) per ml. This % dropped to 49% of 
patients post-op with a median MTM of 5.6 with a further decrease during adjuvant 
therapy to 33% of patients with a median MTM of 2.2 supporting the role of ctDNA 
monitoring as a metric of disease burden (Hook et.al. ESMO 2020).  A second study 
presented at ESMO 2020 by Loupakis and colleagues enrolled 100 patients with 
advanced CRC undergoing resection with curative intent and followed with the 
Signatera ctDNA assay. As shown in Figure 3, patients who were ctDNA negative 
following resection had a far superior outcome relative to those who remained ctDNA 
positive. This lends further support to the use of ctDNA as a valid measure of tumor 
burden in patients with metastatic CRC. 
 
  
Figure 3 


 
 
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1.3 
Current Study 
We propose a prospective randomized phase 2 study design comparing the usual 
empiric scan-driven approach vs interventions guided by ctDNA assessments, both 
arms using a pre-specified order of treatment.  Eligible patients will have progressed 
or have demonstrated intolerance to first-line oxaliplatin -based therapies, or had a 
clinically acceptable and documented reason why they did not receive the therapy. 
Overall Survival (OS) will be the primary endpoint assuming a median OS of 6 
months with the standard approach based on the experimental arm of the CORRECT 
Trial (Grothey et al Lancet 2013) using single agent regorafenib in a similar patient 
population as is being enrolled in the present trial. 
 
Subjects may start treatment once all eligibility criteria are confirmed (Section 4).  
However, subjects will not be randomized until and unless Natera results from the 
baseline assay results in measureable ctDNA.  In the event no ctDNA is measured, 
the subject will NOT be randomized and instead will receive routine care outside the 
study and be followed for survival.   
 
Patients randomized to Arm A, the ctDNA guided arm, will have ctDNA assayed 
every 2 weeks real-time until a given intervention demonstrates a significant 
decrease in ctDNA, at which time, testing frequency would be decreased to every 4 
weeks until either scans demonstrate PD or the ctDNA levels rise significantly.  Once 
a patient progresses on a given intervention, they will initiate therapy in a pre-
specified order as listed in Appendix E as soon as any significant toxicity from the 
prior therapy allow the next treatment to safely begin, as determined by the treating 
physician. This sequential approach will continue until all interventions are exhausted 
or the patient’s performance status declines to a point where further interventions 
are not feasible, or the patient withdraws from the study.   
 
For patients randomized to Arm B, the control arm, ctDNA samples will be obtained 
every 4 weeks until they are off study for retrospective batch analysis.  All patients 
will be scanned at 12-week intervals.  Based on the results of scans, therapeutic 
interventions will be administered in a pre-specified order with the agents listed in 
Appendix E. 


 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1 
Primary 
2.1.1. Primary Objective 
To determine the difference in overall survival (OS) of adults with metastatic 
colorectal cancer after treatment with oxaliplatin, between use of the ctDNA 
guided assay (Signatera Test) and the routine scan-guided approach. 
  
2.1.2  Primary Endpoint 
Overall Survival (OS), defined as time between date of randomization and death 
2.2 
Secondary 
2.2.1 Secondary Objectives 
• To measure and compare progression free survival (PFS) and best overall 
response (OR) in subjects with ctDNA-guided treatment compared to 
routine scan-guided treatment. 
• To investigate the dynamics of ctDNA vs scan evidence of disease status. 
 
2.2.2 Secondary Endpoints 
• Progression Free Survival (PFS), defined as time between date of 
randomization and disease progression or death (whichever comes first) 
• Best Overall Response (OR) during the entire period of study participation 
 
2.3 
Exploratory 
To investigate the relationship of the microbiome and other novel biomarkers 
relative to patient outcomes. 
 
 


 
 
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3. STUDY DESIGN 
3.1 
Study Overview 
This is a prospective, single center, two-arm randomized trial. A total of 78 subjects are 
planned, with a maximum enrollment cap of 100 subjects to account for any 
withdrawals, screen failures, or subjects with no measurable ctDNA. Subjects in Arm A 
will be administered drugs/regimens in a pre-specified order as listed in Appendix E, as 
appropriate. Subjects may enroll at second or subsequent lines of therapy so long as the 
patient’s next clinically reasonable prescribed treatment would be FOLFIRI+ 
Bevacizumab/biosimilar, Anti-EGFR therapy (with or without irinotecan), OR Lonsurf; 
subjects will enter the pre-specified treatment order (Appendix E) anywhere between 
T1-T3, as appropriate given mutation status and prior lines of therapy. These subjects 
will be treated with a different agent based on Signatera’s ctDNA assay, moving to a 
new drug/regimen when the assay indicates non-response and prior relevant toxicity for 
the next treatment has resolved to an acceptable point per the treating physician. If an 
intervention is identified that shows a significant decrease in ctDNA, frequency of 
testing would be decreased to approximately every four weeks until either (a) scans 
demonstrate progressive disease, or (b) ctDNA levels rise significantly. Each therapeutic 
intervention will use the most recent ctDNA as the new baseline.  These subjects will 
continue until all interventions are exhausted, further interventions are not feasible, or 
subject withdraws from the study. 
 
Subjects in Arm B will also be administered drugs/regimens in a pre-specified order, 
identical to the process in Arm A, as listed in Appendix E.  These subjects will be treated 
based on imaging results every 12 weeks, moving to a new drug when scans show PD, 
as is the current routine practice. ctDNA samples will be obtained from these patients 
approximately every 4 weeks for retrospective batch analysis. All subjects will undergo 
imaging scans at the usual 12-week intervals for comparison to the ctDNA assays. 
Evaluations will be taken at baseline and at each of the study visits.  All subjects will be 
followed for overall survival. 
 
In the event that ctDNA results (Arm A) or RECIST reads (Arm B) are not received in time 
to make a treatment decision at a study visit, clinical judgement of the treating physician 
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Furthermore, In the event initial ctDNA results are not available from Natera within the 
randomization window, the subject will remain on their first regimen until the results are 
received and subject is able to be randomized.  In this event, the pre-randomized 
subject will have their ctDNA tested at 2 weeks past Cycle 1 Day 1, but results will not be 
released to the study team unless the subject is confirmed to be randomized to Arm A 
upon receipt of initial screening results. 
 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study, 
however, only subjects with measurable ctDNA will be randomized.  Others will receive 
routine care outside the study and only be followed for survival. 
 
Total duration of subject enrollment will be approximately 36 months.  Total duration of 
the study is expected to be approximately 48 months. 
4. SELECTION OF SUBJECTS 
Subjects with a diagnosis of Metastatic Colorectal Cancer who meet the following 
inclusion and exclusion criteria will be eligible for participation in this study.  Per UFHCC 
guidelines, exceptions to inclusion and exclusion criteria are not permitted.  For questions 
concerning eligibility, please contact the PMO (pmo@cancer.ufl.edu). 
4.1 
Number of Subjects 
78 subjects are expected to participate in this study, with a maximum enrollment cap of 
100 subjects to account for any withdrawals or screen failures. 
4.2 
Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible for study participation:  
A. A histologic confirmation of adenocarcinoma of the colon or rectum with RECIST 
measurable metastatic disease not currently candidates for oligometastatic 
definitive management (i.e., potentially curative surgery or ablation). 
B. Must have at least received first-line oxaliplatin-based therapy for metastatic 
disease, or a clinically acceptable and documented reason they did not, and 
progressed or were intolerant to the therapy. Individuals who recurred within 6 
months of completion of oxaliplatin based adjuvant chemotherapy are also 
eligible. Subjects may enroll at any line of therapy past this first line so long as 


 
 
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the patient’s next clinically reasonable prescribed treatment would be FOLFIRI + 
Bevacizumab/biosimilar, Anti-EGFR therapy (with or without irinotecan), OR 
Lonsurf. 
C. Subjects must have tissue from either the primary and/or metastatic deposit 
available for submission at enrollment.   Tissue can be from either a biopsy or 
resection surgery, whichever is most recent, but must be from the past five years. 
See Section 9.3.1 for tissue block and slide specifications.   
D. Subjects must have tissue and blood shipped to Natera at least 10 days prior to 
the anticipated treatment start date.   
E. Subjects must have had molecular profiling to determine tumor RAS, BRAF and 
MMR/MSI status. 
F. Subjects with known or suspected Gilbert’s disease must be formally tested for 
UGT1A1*28 with results available to study team prior to treatment initiation. 
G. Any clinically relevant (as deemed by the PI) adverse events related to prior 
therapies must have resolved to Grade 1 or less (CTCAE 5.0) at study enrollment. 
H. Both males and females ≥ eighteen years of age. 
I. An ECOG Performance Status less than or equal to 2. 
J. A life expectancy of at least 6 months. 
K. Adequate organ function as defined as: 
• Absolute neutrophil count (ANC) ≥ 1,500/µL 
• Hemoglobin ≥ 9g/dL 
• Platelets ≥ 100,000/µL 
• Total bilirubin ≤ 1.5 ULN or direct bilirubin ≤ 1 x ULN 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
ULN; if liver metastases present, then AST and ALT must be ≤ 5 x ULN 
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 59 
mL/min/1.73m using Cockcroft-Gault equation 
L. Subjects must not have more than one active malignancy at the time of 
enrollment (Subjects with a prior or concurrent malignancy whose natural history 
or treatment does not have the potential to interfere with the safety or efficacy 
assessment of the investigational regimen [as determined by the treating 
physician and approved by the PI] may be included).  
M. Written informed consent obtained from the subject and the subject agrees to 
comply with all the study-related procedures. 


 
 
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N. Women of childbearing potential (WOCBP) must be using an adequate method 
of contraception to avoid pregnancy throughout the study and for at least 12 
weeks after the end of protocol-specified treatment to minimize the risk of 
pregnancy. Prior to study enrollment, women of childbearing potential must be 
advised of the importance of avoiding pregnancy during trial participation and 
the potential risk factors for an unintentional pregnancy.   
 
WOCBP includes any woman who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is 
defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive months without another 
cause, or 
• For women with irregular menstrual periods who are taking hormone 
replacement therapy (HRT), a documented serum follicle-stimulating 
hormone (FSH) level of greater than 35 mIU/mL. 
O. Males with female partners of child-bearing potential must agree to use 
physician-approved contraceptive methods (e.g., abstinence, condoms, 
vasectomy) throughout the study and should avoid conceiving children for12 
weeks following the last dose of the protocol-specified treatment. 
4.3 
Exclusion Criteria 
Subjects with any of the following will not be eligible for study participation:  
A. Subject with colorectal cancer known to be Microsatellite High (MSI-H), deficient 
in DNA mismatch repair genes (dMMR), or BRAF (V600E) mutated. 
B. Females or males of childbearing potential who are unwilling or unable to use an 
acceptable method to avoid pregnancy for the entire study period and for at 
least 12 weeks after the last dose of the protocol-specified treatment.  
C. Females who are pregnant or breastfeeding. 
D. History of any other disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of protocol therapy or that might affect the 
interpretation of the results of the study or that puts the subject at high risk for 
treatment complications, in the opinion of the treating physician. 


 
 
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E. Prisoners or subjects who are involuntarily incarcerated, or subjects who are 
compulsorily detained for treatment of either a psychiatric or physical illness. 
F. Prior radiation therapy must have been completed 14 days prior to study entry. 
G. Prior chemotherapy or biologic therapy must have been completed 21 days prior 
to study entry. 
H. Subject has known Dihydropyrimidine Dehydrogenase (DPD) deficiency. 
4.4 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
5. REGISTRATION PROCEDURES 
All consented subjects must be entered into the University of Florida’s Clinical Trial 
Management System (OnCore) prior to assignment of a subject identification number.  
The study team must submit the completed study specific eligibility checklist, 
supporting source documentation and a copy of the signed informed consent 
document(s) to the UFHCC Project Management Office (PMO; PMO@cancer.ufl.edu) or 
their assigned Project Manager.  Upon receipt of a completed eligibility packet, the 
designated Project Manager will review the source to verify eligibility and assign a 
subject number.  No subject may be enrolled until his/her eligibility packet is complete 
and eligibility is verified by PMO.  If eligibility cannot be confirmed, the project manager 
will query the site for clarification or additional documents as needed.  Subjects failing 
to meet all study eligibility requirements will not be able to participate in the trial. 
 
All eligible and enrolled subjects will receive a unique subject number. This number will 
be used to identify the subject throughout the study. Subjects withdrawn from the study 
will retain their subject number.   
6. STUDY PROCEDURES 
Written informed consent must be obtained prior to performing any study-specific 
evaluations or tests. Tests or evaluations performed as standard of care within the 
specified screening period, but prior to informed consent, may be accepted for this 
study and need not be repeated.  Screening measurements will be obtained within 30 
days prior to start of treatment.  
In the event a subject must be re-screened, tissue already shipped to Natera for 
purposes of this trial need not be re-shipped. However, a new blood sample must be 
sent to Natera if the last ctDNA blood collection >14 days from the start of treatment. 


 
 
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Unless a new consent is provided that requires re-consent, re-screened subjects need 
not sign a new, duplicate consent form prior to re-screening procedures. 
Additionally, a second microbiome collection will not be required for subjects 
undergoing re-consent at screening, so long as the collection occurred within 90 days 
prior to treatment start and there have been no significant changes in patient status or 
treatment. 
 
6.1 
Schedule of Events


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                                    Visit: 
 
Procedure: 
SCREENING 
(≤ 30 days prior 
to C1D1) 
TREATMENT BASELINE 
Treatment X, Cycle 
1, Day 111  
CYCLE 2, DAY 1 AND 
ONWARD (SEE APPENDIX E) 
(+/- 3 days) 
 
EVERY12WEEKS POST 
CYCLE 1, Day 1 
(+/- 7 days) 
END OF 
TREATMENT (EOT)7 
 
FOLLOW UP 
(30 ± 7  DAYS AFTER LAST 
DOSE OF TREATMENT)8 
SURVIVAL FOLLOW UP 
EVERY 3 MONTHS (90 
± 7 DAYS) 
Informed Consent (not subject to 30-
day screening window) 
X 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
Brief Physical Exam 
 
X 
X 
 
X 
 
 
Vital Signs (VS) 
X 
X 
X 
 
X 
 
 
ECOG PS 
X 
 
 
 
 
 
 
Research Blood, including buffy coat 
and plasma collection10 
X 
X 
X 
 
X 
 
 
Safety labs including CMP, CBC w/diff1 
X 
X 
X 
 
X 
 
 
Pregnancy Test (Urine or Serum)2  
X 
 
X12 
 
 
 
 
Microbiome Samples14 
X14 
 
 
X14 
 
 
 
Diagnostic Imaging Scan/TA3 
X 
 
 
X 
X 
 
 
FFPE / H&E Tumor Tissue Submission4 
X 
 
 
 
 
 
 
Tumor Marker Assessment 
(Carcinoembryonic Antigen (CEA) test) 
X 
X 
X 
 
X 
 
 
Randomization13 
 
X 
 
 
 
 
 
Administration of Drug5 
 
X 
X 
 
 
 
 
ctDNA assessment6 
X 
X 
X 
 
X 
 
 
Concomitant Medication Review9 
X 
X 
X 
 
X 
X 
 
Adverse Event Review9 
 
X 
X 
 
X 
X 
 
Survival Assessment15 
 
 
 
 
 
 
X 
Abbreviations: VS=vital signs (blood pressure, temperature, pulse and respiratory rates, weight and height); CBC/diff=complete blood count and white blood cell differential; CMP=12 item complete 
metabolic profile (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, alkaline phosphatase, AST, ALT, total bilirubin); 
1 Safety labs will be performed as per institutional standards while subject is on each agent, if more or additional labs are required to monitor safety 
2 Women of child bearing potential only 
3 TA= Tumor Assessment using RECIST 1.1 criteria.  A baseline tumor evaluation must be performed within 4 weeks before a subject begins protocol-specified treatment. 


 
 
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4 Tumor tissue sample from previously routine biopsy or resection, whichever is most recent, required at enrollment, and must be shipped no fewer than 10 days prior to start of therapy.  Details on 
specifications, including alternative submission requirements, can be found in section 9.3.1. 
5 Arm A- Subjects will be administered drugs/regimens in a pre-specified order as listed in Appendix E. Subjects will be treated with one of these agents moving to a new drug/regimen when the ctDNA 
assay or scan indicates non-response. Arm B- Subjects will be administered drugs/regimens in a pre-specified order as listed in Appendix E. Subjects will be treated with one of these agents moving to a 
new drug/regimen when CT scan indicates non-response. 
6 ctDNA collection should  occur as close as possible prior to dosing. In the event a subject’s screening ctDNA occurred within 14 days of their baseline visit (C1D1 of their first on-study regimen), a 
second ctDNA test at baseline is not required.  Arm A- ctDNA collected every 2 weeks as per Appendix E.   If an intervention is identified that shows a significant decrease in ctDNA, testing frequency 
will be decreased to every four weeks until either scans demonstrate progressive disease or ctDNA levels rise significantly. Arm B- ctDNA collected for post-hoc assessment every 4 weeks per Appendix 
E until Progressive Disease (PD) by scan. At screening for both arms, schedule ctDNA sample collection as early as possible to allow for confirmation of sufficient quantity of samples for assay creation 
prior to Cycle 1 Day 1. Per Natera, turnaround time for the initial assay is up to twenty (20) business days. In addition, per Natera, turnaround time for subsequent assays is up to ten (10) business days. 
In the event that ctDNA results (Arm A) or RECIST reads (Arm B) are not received in time to make a treatment decision at a study visit, clinical judgement of the treating physician will be followed until 
the next study visit or opportunity to modify the treatment plan.  No Measurable ctDNA at Baseline- No further ctDNA will be collected  
7 Subjects will continue until all interventions are exhausted, further interventions are not feasible, or subject withdraws from the study.  EOT visit will be completed within 30 days of discontinuation. 
8 If EOT visit is done 30 days after last dose of treatment, follow up visit may be omitted. 
9 ConMeds include use of probiotics, nutritional supplements, antibiotics, and other holistic supplements to inform the planned correlative analyses on microbiota samples. ConMeds and AE 
assessments should also occur on any PRN visit to oncology during study period.  Adverse events to be collected from randomization to follow up visit, for events deemed to be associated with the 
study 
10 Research blood to be collected at same visits that ctDNA is collected; See laboratory manual for more details. “Visits” refer to the table header “visit” in the SOE- i.e. the visit “Screening” would 
encompass all 30 days prior to C1D1, so blood draws occurring during that time period count as part of that “visit”, and do not necessarily need to be collected on the same day. 
11 Subject may begin initial treatment (i.e., Treatment 1 Cycle 1 Day 1) while awaiting initial assay results from Natera.  However, subjects may not be randomized until confirmation is received from 
Natera that the subject has measureable ctDNA.  Randomization should begin within 14 days of treatment start. In the event a subject has assessments (Physical Exam, ECOG, Labs, and other 
procedures per protocol) collected at screening within 7 days of their C1D1 of their first regimen overall, those procedures will not need to be repeated at their C1D1 of their first regimen overall. 
12 As clinically indicated and per institutional practice 
13  Randomization should begin prior to or within 14 days after treatment start.  In the event initial ctDNA results are not available from Natera within this 14-day randomization window, the subject 
will remain on their first regimen until the results are received and subject is able to be randomized.  In this event, the pre-randomized subject will have their ctDNA tested at 2 weeks past Cycle 1 Day 1, 
but results will not be released to the study team unless the subject is confirmed to be randomized to Arm A upon receipt of initial screening results. Subjects without measurable ctDNA will not be 
randomized and will only be followed for survival 
14 Microbiome samples will be collected at two timepoints: screening (sample must be received prior to C1D1 dosing) and 12 weeks after C1D1 (sample must be received within (+/-) 14 days of first 
scan).   There will be no reportable protocol deviation for microbiome specimens not collected or collected outside of collection window. Such variance poses no risk to patient safety or primary study 
endpoints. 
15 Subjects who did not have measurable ctDNA, will only receive quarterly survival follow-up visits.  These may be completed via telephone or in person. 


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6.2 
End of Treatment (EOT) Evaluations 
Subjects will continue until all interventions are exhausted, further interventions are not 
feasible, subject withdraws from the study, or when the physician and/or subject decides 
it is not appropriate to continue based on subject disease status.  EOT visit will be 
completed within 30 days of protocol-specified treatment completion.  End of treatment 
evaluations will also be performed within 30 days if the subject is discontinued as per 
section 8.2. 
6.3 
Follow up/Survival Evaluations 
Subjects will have a follow-up visit for the evaluation of adverse events 30 days (± 7 
days) after the last dose of study medication.  
 
If the subject is unavailable to travel to the institution, the visit may be made via 
telephone or telehealth interview to review adverse event resolution or the occurrence 
of any new adverse events.  Additionally, external or internal medical records may be 
consulted with permission of the subject to complete remote visit reporting. 
 
If a subject is removed from the study for reasons other than disease progression (per 
imaging and/or ctDNA), imaging/disease assessments will continue per protocol until 
documented progression or until, at the investigator's discretion, further off-protocol 
treatment is begun. All subjects will continue to be followed for survival. Following 
discontinuation of the study for any reason, report the date the first off-protocol anti-
cancer therapy is administered. 
 
If a subject becomes unreachable during the course of the study, the investigator or 
study team will make a reasonable effort to contact the subject and document each 
attempt (in accordance with Section 4.3.4 of the ICH E-6 GCP).  If these attempts are not 
successful, the subject may be documented as “lost to follow up.”  For subjects lost to 
follow-up, the termination date will be the date of last contact with the subject. Vital 
statistics will still be monitored through public reporting databased for survival status. 
 


 
 
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7. PROTOCOL-SPECIFIED TREATMENT 
7.1 
Treatment Schedule/Administration 
All subjects will be treated with agents/regimens in a pre-specified order with the 
drugs/regimens listed in Appendix E.  Subjects may enroll at second or subsequent lines 
of therapy, so long as the patient’s next clinically reasonable prescribed treatment would 
be FOLFIRI+ Bevacizumab/biosimilar, Anti-EGFR therapy (with or without irinotecan), OR 
Lonsurf. Accordingly, subjects will begin treatment on agents T1-T3 and proceed in the 
pre-specified order in Appendix E. All visits will be recorded as Treatment X (sequential 
number) Cycle Y Day Z. For example, the first day of treatment after moving past the 
first treatment in Appendix E will be represented as T2C1D1.  
Subjects on arm A will move through the treatment algorithm based on the results of 
Signatera’s ctDNA assay, moving to a new drug/regimen when the assay indicates non-
response.  Routine imaging, approximately every 12 weeks per treatment regimen, and 
clinical assessments for toxicity may also be used to indicate a non-response or need for 
new treatment and the latter will override ctDNA results in the event of a discrepancy 
(i.e., ctDNA going down, scans showing overt progression).  Prior toxicities relevant to 
the next treatment must have first resolved to an acceptable point per the treating 
physician before starting the next treatment. If an intervention is identified that shows a 
significant decrease in ctDNA (or scan), testing frequency will be decreased to every four 
weeks until either scans demonstrate progressive disease or ctDNA levels rise 
significantly, defined as a 10% increase from baseline or 50% increase from nadir.  Each 
therapeutic intervention will use the most recent ctDNA as the new baseline.  These 
subjects will continue on the algorithm until all interventions are exhausted, further 
interventions are not feasible, or subject withdraws from the study. 
 


 
 
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For Arm B, subjects will be treated with the same agents/regimens in the same pre-
specified order as subjects in Arm A and as listed in Appendix E. However, these subjects 
will have treatment changes based on traditional imaging results every 12 weeks or 
unacceptable toxicity, moving to a new drug when scans show progressive disease or 
treatment intolerance, as is the current routine practice. Prior toxicities relevant to the 
next treatment must have first resolved to an acceptable point per the treating physician 
before starting the next treatment. These subjects will continue on the algorithm until all 
interventions are exhausted, further interventions are not feasible, or subject withdraws 
from the study. Blood will be collected for ctDNA every 4 weeks from these subjects 
throughout study participation, but analyses will be performed post-hoc.    
 
Subjects without measurable ctDNA will receive standard of care treatment 
management and be followed only for overall survival. 
 
7.1.1 Dose Calculations 
Dose calculations will be performed per institutional and treating physician practice, in 
consultation with the published literature, package insert and good clinical practice.  
Appendix E includes general, standard dosing for each regimen but should not overrule 
institutional standard practice. 
 
7.2 
Supportive Care 
 
7.2.1 Supportive Care Guidelines 
Full supportive care may be provided as is routine for patients receiving these 
agents, including transfusions of blood and blood products, antibiotics, antiemetics, 
growth factors, antidiarrheals, analgesics, etc., when appropriate. Bisphosphonates 
or denosumab are allowed for subjects with bone metastases. These should follow 
institutional guidelines. 
 
7.2.2 Concomitant Therapy  
Relevant medical history should be obtained at screening and include prior 
medications and treatment history.  All medications taken within four weeks prior to 
screening, regardless of indication, should be recorded.  All anti-cancer agents 
previously taken should be recorded.  Additionally, special care will be taken to 


 
 
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record use of probiotics, nutritional supplements, antibiotics, and other holistic 
supplements to inform the planned correlative analyses on microbiota samples. 
 
Any therapy or medication (except the protocol-specified treatment), administered 
from screening until thirty days after the last dose of any the protocol-specified 
treatment, is considered a concomitant therapy or medication. However, if another 
course of anti-cancer therapy is initiated prior to the thirty-day follow-up period visit, 
a record of concomitant medications will no longer be performed. If the use of any 
concomitant treatments (medications or procedures) becomes necessary, the 
treatment must be recorded, including the name of the drug or treatment, dose, 
route, date, indication for use, expected duration, and frequency of treatment. 
Assessment and documentation of concomitant medications will be done at each 
visit. 
7.2.3 Prohibited Concomitant Therapy 
Supportive care measures consistent with optimal subject care will be permitted 
throughout the study, as long as the therapy is not included in this section as 
prohibited. 
 
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase of this trial:   
  
• Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol  
• Immunotherapy not specified in this protocol  
• Chemotherapy not specified in this protocol  
• Investigational agents other than the protocol-specified treatment in this trial. 
Participation in other clinical trials may be allowed with approval by the PI  
• The use of palliative RT for symptom management is allowable consistent with 
good clinical practice, but continued participation in the study will be determined 
on a case-by-case basis with the PI or study leadership team. Once a lesion is 
irradiated, it will no longer be included in the RECIST assessment for response. In 
general, a requisite to radiate a lesion may indicate progression of disease.  This 
decision will be made on a case by case basis by discussion of the treating 
physician and the study investigators. 
• Cancer-Related Surgery, except those allowed at discretion of the PI 
•  Medications listed in the eligibility criteria and in the package insert for the anti-


 
 
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cancer agent being administered (see section 10 for a summary). 
 
7.3 
Dose Modifications 
The National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE Version 5.0) for 
Adverse Events (CTCAE) will be used to grade toxicity 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).    
 
Dose modifications based on toxicity will be performed per institutional guidelines, as all 
are standard of care/ FDA approved treatments. 
 
8. TREATMENT DISCONTINUATION 
8.1 
Screen Failures  
Subjects who sign informed consent, but do not meet eligibility criteria, or withdraw 
prior to eligibility being verified, and undergo at least some of the screening procedures 
will be considered screen failures. Subjects who sign informed consent and are verified 
as eligible, but do not proceed to formal registration will also be considered screen 
failures.  A record of screen failures will be maintained by the study site. 
8.2 
Criteria For Protocol-Specified Treatment Discontinuation 
Subjects who discontinue participation in the clinical study on their own or subjects who 
are withdrawn by the investigator, for reasons other than completion of treatment, 
disease progression or toxicity, will be defined as premature withdrawals.   
 
A subject will be discontinued from protocol therapy under the following circumstances:  
• Any adverse event which, in the Investigator’s opinion, requires termination of the 
study. 
• The subject becomes pregnant.  Pregnancy will be reported along the same timelines 
as a serious adverse event. 
• The subject uses illicit drugs or other substances, or takes part in activities that may, 
in the opinion of the Investigator, have a reasonable chance of contributing to 
toxicity or otherwise interfering with results. 
• The development of a second malignancy that requires treatment, which would 
interfere with this study. 
• The subject is lost to follow-up. 


 
 
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• Development of an intercurrent illness or situation which would, in the judgment of 
the investigator, affect assessments of clinical status and study endpoints to a 
significant degree. 
• Administration of prohibited anti-cancer therapy or medication (Section 7.2.3) 
administered from screening until 30 days following EOT. 
• Substantial non-compliance with the requirements of the study.  
• Interruption in treatment for greater than twenty-eight continuous days, due to 
toxicity, or sixty continuous days for any other reason. 
• Subject desire to discontinue therapy. 
 
The Investigator will make every reasonable effort to keep each subject in the study 
unless it is in the subject’s best interests to discontinue participation.  If a subject is 
removed from the study or declines further participation, all EOT evaluations should be 
performed if the subject is willing and able to be assessed.  A description of the 
reason(s) for withdrawal from the study must be recorded on the case report form (CRF).  
The Investigator should also ensure that all subjects are followed up for survival status 
after their final visit. 
 
Subjects who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All subjects who discontinue because of adverse events or 
clinically significant laboratory abnormalities should be followed up until they recover or 
stabilize, and the subsequent outcome recorded.  If any subject should experience a 
serious adverse event during the trial or within 30 days of stopping the study, the 
Investigator will inform the UF Health Data Integrity and Safety Committee.   
 
8.3 
Replacement of Subjects 
Subjects may be replaced if they are not screen failures, have not completed any doses 
of treatment for any reason, and are not discontinued for disease progression, toxicity, 
or any of the reasons listed in section 8.2.  This includes subjects who otherwise meet all 
eligibility criteria, are randomized, but fail to have measurable ctDNA reported by the 
Signatera assay.  All subjects who fail to have measurable ctDNA will be observed for 
survival and included in the final study results.     
Only subjects who received at least one dose of protocol treatment will be included in 
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9. BIOLOGICAL SPECIMENS AND CORRELATIVES 
9.1 
Source of Specimens 
Correlative study specimens will be collected from patients per the schedule of events.  
Processing and short-term storage for secondary and exploratory analyses will follow the 
instructions outlined in the Study Laboratory or Procedure Manual for this study.  
 
Biospecimen collection and submission is required as a component of subject 
participation in the study.  
9.2 
Correlative Studies of Biospecimens 
Each subject will be asked to provide stool, oral and urine microbiome samples at each 
of two time points. This should provide a maximum of 312 samples.  Processing, storage 
and analyses will be conducted through the UFHCC Microbiome Biorepository.  
Microbiota samples will be examined for their microbiota content with the intention of 
making associations between the microbiota and each clinical outcome measure 
including OS, PFS, RR and toxicity. Research blood collection will be obtained at the time 
points indicated for post-hoc analysis including alternate assay validation for tumor 
circulating DNA, germline genetic and genomic profiling, and other biomarkers.  
9.3 
Preparation, Shipment and Storage of Specimens 
See Study Laboratory or Procedure Manual for collection, processing and shipping 
instructions for all tissue, stool, oral swab, urine and blood specimens.   
All tissue, stool, urine, oral swab, and blood samples will be labelled with the subject’s 
unique study number and physically stored.  During the life of the study, these 
biospecimens remain available only to the study team. For analyses that require research 
collaborations outside of UF, only de-identified specimens will be shared. Samples will 
be stored for the life of the study and will then be destroyed or transferred to a 
biospecimen bank for general research use, if subject agrees to enroll in the separate 
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At study enrollment, all subjects will be given the option to provide permission for all 
biospecimens collected and stored during this study, including those residual specimens 
remaining after completion of all planned exploratory analyses, to remain available for 
long-term research use (i.e., beyond the life of this study) (IRB# 201901513). Thus, future 
research on remaining biospecimens after the study-specific analyses have been 
completed can only be considered by subjects providing their additional consent on an 
IRB- approved study consent form for optional biobanking. Future specific use of those 
biomaterials will require secondary IRB approval. At the closure of this treatment trial, 
any biospecimens remaining from subjects who have provided consent for long-term 
storage/use will be transferred to a biobank (or destroyed if samples or resources are 
inadequate). For subjects who decline secondary long-term storage, their biomaterials 
will be destroyed at the completion of the treatment trial and will not be transferred. 
 
9.3.1 Tumor Tissue 
Subjects must have tissue from either the primary and/or metastatic deposit available 
for submission at enrollment.  Tissue may be provided from either a biopsy or surgical 
resection, whichever is most recent, and should have been collected within the past 5 
years prior to enrollment.  To create the assay, Natera requires an FFPE tissue block with 
>25mm2 of surface area and one H&E stained slide (preferred).  However, 6-10 (10-
micron) slides OR 12-20 (5-micron) slides and one H&E stained slide (10-micron 
thickness) is acceptable.   
 
9.3.2 Blood Samples 
Natera 
Natera requires two 10mL Streck tubes and one 6mL EDTA tube for initial assay creation.  
These will be collected at screening.  For subsequent ctDNA testing timepoints, Natera 
requires two 10mL Streck tubes only.   
 
Research Samples 
EDTA tubes will be collected and processed for research buffy coat and plasma samples 
at each visit specified in the Schedule of Events.  
 


 
 
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9.3.3 Microbiota Samples 
Urine and oral microbiome specimens will be collected in clinic. Kits will be provided to 
patients for self-collection of stool. These will be distributed to patients prior to the 
collection date indicated by the Schedule of Events.  Instructions for collection and kit 
return will be included as well as self-addressed and pre-paid postage. Subjects may 
also choose to bring the collection and kit to their study doctor at their scheduled visit. 
 
10. PROTOCOL-SPECIFIED TREATMENT INFORMATION 
All agents prescribed as part of this study are FDA-approved for colorectal cancer.  
Complete prescribing information can be found in the product’s package insert.  The 
information below is a summary of that information. 
10.1 FOLFIRI + Bevacizumab 
FOLFIRI is a combination of folinic acid (leucovorin), fluorouracil (5FU), and irinotecan 
(Camptosar).  Bevacizumab is the generic name for Avastin.  
 
10.1.1 Identification and Physical Description 
All three medications that compose FOLFIRI are liquid and administered via 
intravenous infusion.  Bevacizumab is administered as an intravenous infusion, as a 
clear to slightly opalescent, colorless to pale brown solution in a single-dose vial.  
10.1.2  Administration 
FOLFIRI is administered as an intravenous infusion. Folinic acid (leucovorin) is given 
over two hours before fluorouracil on Day 1 and irinotecan is given over 90 minutes 
on Day 1.  Fluorouracil (5-FU) continuous infusion is given via an at-home infusion 
pump over 46 hours, beginning Day 1 and ending on Day 3.  A cycle lasts 14 days. 
 
Bevacizumab is administered as an intravenous infusion. The first infusion is 
administered over 90 minutes. The subsequent infusion is administered over 60 
minutes if the first infusion is tolerated. Then, administer all subsequent infusions 
over 30 minutes if second infusion over 60 minutes is tolerated. A cycle last 14 days. 
 
10.1.3 Storage, Handling, and Dispensing 
Leucovorin: Prior to reconstitution, store below 40 °C (104 °F), preferably between 
20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer. Protect 
from light. 
Irinotecan: Store at controlled room temperature 15°C to 30°C (59° to 86°F). Protect 
from light. 


 
 
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Fluorouracil (5-FU): Store at room temperature 15° to 30°C (59° to 86°F). Protect 
from light. 
Bevacizumab: Store diluted Avastin solution at 2°C to 8°C (36°F to 46°F) for up to 8 
hours. Discard any unused portion left in a vial, as the product contains no 
preservatives.  
 
10.1.4 Contraindications 
Leucovorin is contraindicated for pernicious anemia and other megaloblastic 
anemias secondary to the lack of vitamin B12.  
 
Avoid the use of strong CYP3A4 inducers with FOLFIRI if possible; substitute non-
enzyme–inducing therapies at least 2 weeks prior to initiation of nal-IRI.  Avoid the 
use of strong CYP3A4 or UGT1A1 inhibitors, if possible; discontinue strong CYP3A4 
inhibitors at least 1 week prior to starting therapy. 
 
The following drugs are noted in the irinotecan prescribing information as 
interacting with irinotecan, and should be avoided: St. John’s Wort, CYP3A4 
inducing anticonvulsants (phenytoin, phenobarbital, and carbamazepine), 
ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and verapamil.  
Because 5-FU interacts with warfarin, caution should be exercised if concomitant  
use is necessary. 
 
None for Bevacizumab 
 
10.1.5 Special Warnings and Precautions for Use 
FOLFIRI: Individuals who are homozygous for the UGT1A1*28 allele are at increased 
risk for neutropenia following initiation of treatment. 
 
Bevacizumab: Gastrointestinal Perforations and Fistula, Surgery and Wound Healing 
Complications, Hemorrhage, Arterial Thromboembolic Events (ATE), Venous 
Thromboembolic Events (VTE), Hypertension, Posterior Reversible Encephalopathy 
Syndrome (PRES), Renal Injury and Proteinuria, Infusion-Related Reactions, Embryo-
Fetal Toxicity, Ovarian Failure, and Congestive Heart Failure. 
 


 
 
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10.1.6 Adverse Effects 
The most common adverse effects with FOLFIRI (>15%) include nausea/vomiting, 
diarrhea, neutropenia, mucositis, hair loss, anemia, hand-foot syndrome, 
thrombocytopenia, weakness, and fever.  Supportive care will be administered per 
routine care. 
 
Bevacizumab: Most common adverse reactions incidence (incidence > 10%) are 
epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, 
hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.   
10.2 Cetuximab or Panitumumab 
Cetuximab is the generic name for the U.S. Brand name drug Erbitux. Other names are 
C225, IMC-C225, MOAB C225. Eli Lilly and Co. 
Panitumumab is the generic name for the brand name Vectibix, which is manufactured 
by Amgen, Inc.  
10.2.1 Identification and Physical Description 
Cetuximab is a recombinant human/mouse chimeric monoclonal antibody used to 
treat cancers of the colon and rectum. It is also used to treat head and neck cancer.  
 
Panitumumab is an epidermal growth factor receptor antagonist indicated as a 
single agent for the treatment of metastatic colorectal carcinoma with disease 
progression on or following fluoropyrimidine, oxaliplatin, and irinotecan 
chemotherapy regimens.  
 
10.2.2 Administration 
Cetuximab is given as an intravenous infusion.  The recommended initial dose is 500 
mg/m2 administered as a 120-minute intravenous infusion.  The recommended 
subsequent dosage is 250 mg/m2 weekly as 60-minute infusion every 14 days until 
disease progression or unacceptable toxicity. 
 
Panitumumab is given as an intravenous infusion. The recommended dose is 6 
mg/kg over 60 minutes every 14 days. 
 


 
 
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10.2.3 Storage, Handling and Dispensing 
Cetuximab: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze or shake. 
Preparations in infusion containers are stable for up to 12 hours refrigerated at 2°C 
to 8°C (36°F to 46°F) and up to 8 hours at room temperature of 20°C to 25°C (68°F 
to 77°F). 
 
Panitumumab: Store vials in original carton under refrigeration at 2°C to 8°C (36°F 
to 46°F) until time of use. Protect from direct sunlight.  The diluted infusion solution 
should be used within 6 hours of preparation if stored at room temperature, or 
within 24 hours of dilution if stored at 2°C to 8°C (36°F to 46°F).  
 
10.2.4 Contraindications 
None 
10.2.5 Special Warnings and Precautions for Use 
Cetuximab:  
Subjects may be pre-treated with an H1 receptor antagonist if there is concern for 
an infusion reaction.  Serum electrolytes will be monitored during and after 
administration as outlined in the FDA package insert.   
 
Lack of benefit with cetuximab has been observed in patients with colorectal tumors 
harboring a KRAS mutation.  Thus, as noted in Appendix E, this treatment will be 
skipped if subject is harboring a KRAS mutation. 
 
Panitumumab: 
Limit sun exposure. Not indicated for use in combination with chemotherapy. 
Discontinue Vectibix in patient developing interstitial lung disease, pneumonitis, or 
lung infiltrates. Monitor electrolytes during and for 8 weeks after completion of 
Vectibix therapy and institute appropriate treatment.  
 
10.2.6 Adverse Effects  
Cetuximab: The most common adverse reactions (incidence ≥25%) include: 
cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, 
diarrhea, and infection.  Supportive care will be administered as per routine care. 


 
 
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Panitumumab: The most common adverse reactions (≥20%) are skin toxicities (i.e. 
erythema, dermatitis acneiform, pruritus, exfoliation, rash, and fissures), paronychia, 
hypomagnesemia, fatigue, abdominal pain, nausea, diarrhea, and constipation.  
 
10.3 TAS-102 
Drug Name: TAS-102 (Lonsurf), TAIHO Oncology, Inc.  
10.3.1 Identification and Physical Description 
Lonsurf is a combination of trifluridine and tipiracil, indicated for the treatment 
of patients with metastatic colorectal cancer.  The drug is provided as 15mg or 
20mg round white or red tablets. 
 
10.3.2 Administration 
Lonsurf is a tablet that is taken orally.  The recommended dose is 35 mg/m2 twice 
daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. Lonsurf 
should be taken within 1 hour after completion of morning and evening 
meals.  
 
10.3.3 Storage, Handling and Dispensing 
Tablets should be stored at room temperature (68°F to 77°F). 
 
10.3.4 Contraindications 
None 
 
10.3.5 Special Warnings and Precautions for Use 
Lonsurf may cause severe myelosuppression, consisting of anemia, neutropenia, 
thrombocytopenia, and febrile neutropenia. Obtain complete blood counts prior to 
and on Day 15 of each cycle, and more frequently as clinically indicated. Lonsurf will 
be withheld for febrile neutropenia, Grade 4 neutropenia, or platelets less than 
50,000/mm3 and resumed at a reduced dose, as per the FDA package insert.  
 
10.3.6 Adverse Effects 
The most common adverse reactions (≥10%) include anemia, neutropenia, 
asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, 
abdominal pain, and pyrexia.  Supportive care will be administered as per routine 
care. 


 
 
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10.4 Regorafenib 
Regorafenib is the generic name for the brand name Stivarga, which is manufactured by 
Bayer. 
10.4.1 Identification and Physical Description 
Regorafenib is a kinase inhibitor used for patients with metastatic colorectal cancer 
and liver cancer.  Tablets are supplied in bottles of 28 tablets. 
  
10.4.2 Administration 
Regorafenib is taken orally once per day.  The usual adult dose for colorectal cancer 
is 160 mg orally once a day for the first 21 days of each 28-day cycle until disease 
progression or unacceptable toxicity.   This drug should be taken at the same time 
each day with food.  
 
10.4.3 Storage, Handling and Dispensing 
Store at room temperature (approximately 77°F).  To protect from moisture, keep 
tablets in the original bottle and do not remove the desiccant.  Discard any unused 
tablets 7 weeks after opening the bottle.  
10.4.4 Contraindications 
None. 
10.4.5 Special Warnings and Precautions for Use 
If subjects have wild type KRAS mutation, they should be first treated with an anti-
EGFR therapy consistent with Appendix E. 
 
Subjects should avoid taking strong CYP3A4 inducers or CYP3A4 inhibitors or 
inhibitors while on this medication. 
 
10.4.6 Adverse Effects 
The most common adverse reactions (≥30%) include asthenia/fatigue, decreased 
appetite and food intake, hand-foot skin reaction (HFSR) [palmar-plantar 
erythrodysesthesia (PPE)], diarrhea, mucositis, weight loss, infection, hypertension, 
and dysphonia.  Supportive care will be provided as per routine care. 
 


 
 
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10.5 Capecitabine  
The brand name of capecitabine is Xeloda. 
10.5.1 Identification and Physical Description 
Capecitabine is a nucleoside metabolic inhibitor with antineoplastic activity used to 
treat multiple cancers, including colorectal cancer.  The drug is supplied as film-
coated oblong tablets. 
 
10.5.2 Administration 
Capecitabine is taken twice daily for the first 14 days of each 21-day cycle.  Food 
has been shown to reduce both the rate and extent of absorption of capecitabine. 
10.5.3 Storage, Handling and Dispensing 
Capecitabine should be stored in a tight container at room temperature 
(approximately 77°F).  The bottle must remain tightly closed.  Tablets should not be 
cut or crushed. 
10.5.4 Contraindications 
Contraindications for use include known hypersensitivity to capecitabine or any 
ingredient in the formulation.  
 
Additionally, the following drugs are known to interact with capecitabine: 
anticoagulants, phenytoin, leucovorin, and CYP2C9 substrates. 
10.5.5 Special Warnings and Precautions for Use 
Do not initiate capecitabine therapy if baseline ANC <1500/mm3 and/or baseline 
platelet count <100,000/mm3. 
 
Patients receiving capecitabine who also take oral coumarin-derivative 
anticoagulants, such as warfarin and phenprocoumon, should have their 
anticoagulant response (PT/INR) monitored frequently in order to adjust the 
anticoagulant dose accordingly.  
 
Cardiotoxicity is common in patients with a prior history of coronary 
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Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic 
Epidermal Necrolysis (TEN), have been reported. XELODA should be permanently 
discontinued in patients who experience a severe mucocutaneous 
reaction during treatment. 
 
There is an increased risk of severe or fatal adverse reactions to capecitabine in 
patients with low or absent Dihydropyrimidine Dehydrogenase (DPD) activity. 
10.5.6 Adverse Effects 
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, 
nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. 
Supportive care will be provided as per routine care. 
 
10.6 FOLFIRI 
FOLFIRI is a combination of folinic acid (leucovorin), fluorouracil (5FU), and irinotecan 
(Camptosar).  See details for FOLFIRI noted above in section 10.1 
 
10.7 FOLFOX/CAPOX  
FOLFOX is a combination of folinic acid (leucovorin), fluorouracil (5FU), and oxaliplatin 
(Eloxatin). 
 
CAPOX is a combination of Capecitabine (Xeloda) and Oxaliplatin (Eloxatin). 
 
10.7.1 Identification  
All three medications that compose FOLFOX are liquid and administered via 
intravenous infusion. Eloxatin is a platinum-based drug used in combination with 
infusional 5-fluoracil/leucovorin, which is indicated for adjuvant treatment of Stage 
III colon cancer in patients who have undergone complete resection of the primary 
tumor, and treatment of advanced colorectal cancer.  
For CAPOX, Oxaliplatin is administered via intravenous infusion, while Capecitabine 
is administered orally.  
 
10.7.2 Administration 
FOLFOX: Folinic acid 400mg/m2 IV over two hours before fluorouracil (Day 1), 
Oxaliplatin IV 85mg/m2 over two hours on Day 1, commonly at the same time as 
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2 days (total 2,400mg/m2 over 46–48 hours) IV continuous infusion, via an at-home 
infusion beginning Day 1 and ending on Day 3.  The time between doses of 
oxaliplatin should be 14 days.  
 
CAPOX: Day 1: Capecitabine 850 – 1000 mg/m2, by mouth, twice daily, for the first 
14 days of each 21-day cycle.  Oxaliplatin IV 130 mg/m2 over 2 hours on Day 1.   
 
10.7.3 Storage, Handling, and Dispensing 
FOLFOX: Oxaliplatin: Unopened vials should be stored at 15°C -30°C; protect from 
light. Leucovorin: Prior to reconstitution, store below 40 °C (104 °F), preferably 
between 20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer. 
Protect from light. Fluorouracil (5-FU): Store at room temperature 15° to 30°C (59° 
to 86°F). Protect from light. 
 
CAPOX: Oxaliplatin: Unopened vials should be stored at 15°C -30°C; protect from 
light. Capecitabine: Store in a tight container at room temperature (approximately 
77°F).  The bottle must remain tightly closed.  Tablets should not be cut or crushed. 
 
10.7.4 Contraindications 
FOLFOX: Known allergy to Eloxatin or other platinum compounds. 
 
CAPOX: Capecitabine: Known hypersensitivity to capecitabine or any ingredient in 
the formulation. Additionally, the following drugs are known to interact with 
capecitabine: anticoagulants, phenytoin, leucovorin, and CYP2C9 substrates. 
Oxaliplatin: Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, 
contrast dye, frusemide, NDSAIDs), Neurotoxic drugs (e.g. vincristine, paclitaxel).  
 
10.7.5 Special Warning and Precautions 
FOLFOX: Allergic Reactions: Monitor for development of rash, urticaria, erythema, 
pruritis, bronchospasm, and hypotension. Neuropathy: Reduce the dose or 
discontinue Eloxatin if necessary. Pulmonary Toxicity: May need to discontinue 
Eloxatin until interstitial lung disease or pulmonary fibrosis are excluded. 
Hepatotoxicity: Monitor liver function tests.  
 
CAPOX:  


 
 
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Oxaliplatin: Patients should be warned about cold avoidance prior to receiving 
oxaliplatin; ice for mucositis prophylaxis should not be used. Oxaliplatin may cause 
dizziness or visual disturbances in some patients; exercise caution when driving or 
operating machinery. Patients with risk factors for dehydration, pre-existing renal 
dysfunction or on nephrotoxic agents. Patients with a history of cardiovascular 
disease. Patients taking anticoagulants such as warfarin.  
Capecitabine: Do not initiate capecitabine therapy if baseline ANC <1500/mm3 
and/or baseline platelet count <100,000/mm3. Patients receiving capecitabine who 
also take oral coumarin-derivative anticoagulants, such as warfarin and 
phenprocoumon, should have their anticoagulant response (PT/INR) monitored 
frequently in order to adjust the anticoagulant dose accordingly.  Cardiotoxicity is 
common in patients with a prior history of coronary artery disease.  Severe 
mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal 
Necrolysis (TEN), have been reported. XELODA should be permanently 
discontinued in patients who experience a severe mucocutaneous 
reaction during treatment. 
 
10.7.6 Adverse Effects 
FOLFOX: Most common adverse reactions (incidence ≥ 40%) were peripheral 
sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in 
transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. 
 
CAPOX: Hypersensitivity reaction, Laryngo-pharyngeal dysesthesia, Cardiotoxicity, 
Nausea and vomiting, Taste and smell alternation, Neutropenia, Thrombocytopenia, 
Diarrhea, Oral mucositis, Palmer-planter erythrodysaesthesia (PEE) – hand-foot 
syndrome (HFS), Peripheral neuropathy, Fatigue, Actinic keratoses flare, 
Photosensitivity, Ocular changes, Abdominal pain, Anemia, Nail changes, Alopecia-
partial, and Hyperbilirubinaemia. Capecitabine: Most common adverse reactions 
(≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, 
fatigue/weakness, and hyperbilirubinemia.  


 
 
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11. ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Event 
The term “adverse event” (AE) includes any sign, symptom, syndrome, or illness that 
appears or worsens in a subject during the period of observation in the clinical study 
and that may impair the wellbeing of the subject. The term also covers laboratory 
findings or results of other diagnostic procedures that are considered to be clinically 
significant (e.g., that requires unscheduled diagnostic procedures or treatment 
measures, or result in withdrawal from the study).  An AE is therefore any unfavorable 
and unintended symptom associated with the study, whether or not related to a study 
procedure. 
 
The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of a 
concomitant illness/condition; 
• An effect of a protocol-specified procedure; or 
• A combination of 2 or more of these factors. 
 
No causal relationship with the clinical study is implied by the use of the term “adverse 
event.” 
 
The Investigator or his/her designee will probe, via discussion with the subject, for the 
occurrence of AEs during each subject visit and record the information in the site’s 
source documents.  AEs will be recorded in the subject CRF.  AEs will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
the study, or if unrelated, the cause. 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures 
for conditions that require surgery. The condition(s) for which the surgery is required 
may be an adverse event. Planned surgical measures permitted by the clinical study 
protocol and the condition(s) leading to these measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective findings, this 
diagnosis will be recorded as an adverse event and not the abnormal objective findings 
(e.g., viral hepatitis will be recorded as the adverse event and not the transaminase 
elevation). If a definitive diagnosis is not available, then the sign(s) (e.g., clinically 
significant elevation of transaminase levels) or symptom(s) (e.g., abdominal pain) will be 


 
 
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recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
11.1.2 Serious Adverse Event 
A serious adverse event is one that at any time during the period of observation: 
• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. “Medically important” should be marked only if no other serious 
criteria are met. 
 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not 
consistent with the currently known adverse event profile of the disease under study or 
the investigational agent(s). 
 
NOTE: The following hospitalizations are not considered SAEs in UFHCC clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that 
was planned before study entry. Appropriate documentation is required in these 
cases. 
• admission encountered for another life circumstance that carries no bearing on 


 
 
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health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). Any grade ≥ 3 adverse 
events per CTCAE is generally considered severe AE. This is not the same as “serious,” 
which is based on the outcome or action criteria usually associated with events that 
pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
11.1.3 Non-Serious Adverse Event 
A non-serious adverse event is any adverse event not meeting any of the serious 
adverse event criteria. 
11.2 Period of Observation 
Following randomization, all SAEs must be collected. Collection of all SAEs must 
continue for 30 days after the last study visit. The investigator should notify the DISC of 
any SAE occurring after this time period that is believed to be related to a protocol-
specified procedure.  Adverse events will not be collected for subjects who do not have 
measurable ctDNA, or prior to documentation of the presence of measurable ctDNA at 
baseline, because they will move straight into routine care and only be contacted every 
approximately 3 months for survival status. 
 
The investigator will also begin collecting non-serious adverse event (NSAE) information 
once randomized, for those who have measurable ctDNA. Randomized subjects, 
including those who were prematurely discontinued from the study, will be followed for 
any adverse events that occur during the study until 30 days following the last study 
visit (i.e., until the Follow-up Visit).  However, if another course of anti-cancer therapy is 
initiated outside the context of this study and prior to the 30-day follow-up period visit, 
collection of adverse events will no longer be performed, with the exception of events 
that may be possibly, probably, or definitely related to the study or are clinically 
significant.  
11.3 Documenting and Reporting of Adverse Events by Investigator 
All adverse events at least possibly related to the study and occurring after 
randomization, until the Follow Up Visit, must be fully recorded in the subject’s case 
record form. 
 


 
 
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Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator, should be reported as an adverse event.  Each event should 
be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis 
that encompasses the component signs and symptoms. If only nonspecific signs or 
symptoms are present, then these should be recorded as separate diagnoses on the 
pages of the case report form. 
 
All subjects who have adverse events must be monitored to determine the outcome. 
The clinical course of the adverse event will be followed according to accepted 
standards of medical practice, even after the end of the period of observation, until a 
satisfactory explanation is found or the Principal Investigator considers it medically 
justifiable to terminate follow-up. Should the adverse event result in death, a full 
pathologist’s report should be supplied, if possible. 
11.3.1 Assessment of Causal Relationship to the Study 
The Investigator will provide an assessment of the potential causal relationship between 
adverse events and study by determining whether or not there is a reasonable 
possibility that the event was caused by the study. Because all treatments used in this 
study are standard of care, and would be provided in the same order at the same dose 
outside the study as part of routine care, side effects deemed to be associated with 
treatment will not be recorded or collected.  The relationship or association of the 
adverse event to the study will be characterized as not related, unlikely related, possibly 
related, probably related, or related:   
 
Not Related: There is not a temporal relationship to the study or the adverse event is 
clearly due only to the progression of the underlying disease state, intercurrent illness, 
concomitant medication, concurrent therapy or other known cause. 
 
Unlikely Related:  There is little or no chance that the study caused the adverse event; 
the event is most likely due to another competing cause, including intercurrent illness, 
progression or expression of the disease state, or a reaction to a concomitant 
medication or concurrent therapy appearing to explain the reported adverse event.  
 
Possibly Related:  The association of the adverse event with the study is unknown; 
however, the adverse event is not reasonably attributed to any other condition.  


 
 
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Probably Related:  When a reasonable temporal relationship exists between the adverse 
event and the study; significant symptoms abate upon discontinuation of the study and 
there is a reasonable explanation based on known characteristics of thestudy and there 
is no clear association with preexisting disease or therapy, intercurrent illness, 
concurrent therapy or other factor(s). 
 
Related:  When the adverse event is a known side effect of a protocol-specified 
procedure or there is a temporal relationship to the suspected protocol-specified 
procedure; or the adverse event reappears upon re-entry into the study ; or the 
significant symptoms of the adverse event abate upon discontinuation of the study. 
11.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be graded according 
to the most up-to-date CTCAE version. For all other adverse events not described in the 
CTCAE, the intensity will be assessed by the Investigator using the following categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible. 
 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care 
probable. 
 
Death (Grade 5) – the event resulted in death. 
11.3.3 Action Taken with Drug(s) 
The action the Investigator took with protocol-specified treatment as a result of the 
event should be recorded as one of the following: 
 
None – No action was taken with regard to the protocol-specified treatment as a result 
of the adverse event. 
 
Interrupted – protocol-specified treatment was stopped due to the adverse event, but 


 
 
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was later resumed at the same dose. 
 
Dose decreased – The dose of protocol-specified treatment was decreased as a result of 
the adverse event. 
 
Permanently discontinued – The subject was withdrawn from the study due to the 
adverse event. 
 
Only one item should be chosen. If multiple actions apply, the following “worst case” 
scenario hierarchy should be used to determine the preferred entry: permanently 
discontinued > dose decreased > interrupted. 
11.3.4 Definition of Outcome 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
 
Resolved with sequelae – The subject recovered from the adverse event with observable 
residual effects. 
 
Not resolved – The adverse event was present at the time of last observation. 
 
Death – The subject died as a result of the adverse event. 
11.4 Immediately Reportable Events 
11.4.1 Serious Adverse Events 
Serious adverse events (SAEs) during the period of observation must be reported to the 
UFHCC CRO Project Management Office (PMO; pmo@cancer.ufl.edu), and entered into 
OnCore, within 24 hours of discovery of the event. All SAEs regardless of “relatedness” 
will need to be reported to DISC by PMO within 5 business days of discovery of the 
event.  If only limited details are known, these should be reported within that time frame 
and follow up reports can be submitted for elaboration, clarifications, or corrections.  
Any email correspondence must be kept in the trial file at the study site. The site 
investigator is responsible for informing the IRB and/or the Regulatory Authority of the 
SAE as per local requirements.   
 
Follow-up information will be submitted to the UFHCC CRO PMO (pmo@cancer.ufl.edu), 
stating that this is a follow-up to a previously reported SAE and giving the date of the 


 
 
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original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-
up information should describe whether the event has resolved or continues, if and how 
it was treated, and whether the participant continued or withdrew from study 
participation.  PMO will confirm that the event and any necessary follow-ups are 
reported to the UFHCC Data and Safety Integrity Committee (DISC), the sponsor, and 
any other regulatory authorities as required (FDA, etc.)  
 
11.4.2 Other Events Requiring Immediate Reporting  
All pregnancies, regardless of outcome, must be reported to the UFHCC CRO Project 
Management Office (PMO; pmo@cancer.ufl.edu), including pregnancies that occur in 
the female partner of a male study subject. All pregnancies must be followed to 
outcome.  Pregnancies and follow-ups will be submitted by PMO to DISC, the sponsor if 
required, and any other regulatory authorities required. 
 
Although overdose and cancer are not always serious by regulatory definition, these 
events should also be reported to the UFHCC CRO Project Management Office (PMO; 
pmo@cancer.ufl.edu), in addition to other institutional officials per safety reporting 
requirements, in an expedited manner.  In case the overdose did not result in any 
adverse event, the Investigator should report this as “overdose, no adverse event” and 
provide the intended amount, as well as the actual amount, of drug administered.  In the 
event of overdose or exaggerated response, appropriate supportive measures should be 
employed.  Actual treatment should depend on the severity of the clinical situation and 
the judgment and experience of the treating physician.  Overdose events and follow-ups 
will be submitted by PMO to DISC, the study sponsor if required, and any other 
regulatory authorities required. 
 
Pregnancies and overdoses should be documented and reported per the reporting 
guidelines below. 
 
 
Institution Immediate Reporting Information 
 
SAEs and pregnancies must be reported to the UFHCC CRO Project 
Management Office (PMO), or assigned designee at: 
  
Email: pmo@cancer.ufl.edu  
 
As well as entered in OnCore, the study CTMS. 
 


 
 
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11.4.3 Reporting to Natera 
The UFHCC CRO Project Management Office (PMO) will forward any SAE to Natera as 
agreed upon in the contract.  PMO will forward both initial and follow-up versions of 
each report. Reports will be marked with the study ID, product, and description of event. 
Only SAEs that are related to the procedure (blood draw) will be reported, and only 
those that are unexpected.  
 
Natera AE Reporting Information 
 
Contact: Dr. Alexey Aleshin 
Email: aaleshin@natera.com 
12. STATISTICAL METHODS 
The sections below provide an overview of the statistical considerations and analyses. 
 
12.1 Data collection and management plan  
Data will be collected via paper source documents and the medical record, and will 
subsequently be entered into a validated EDC (REDCap) which will be monitored and 
audited on a regular basis to ensure accuracy.  Data will be accessible only to certified 
members of the research team, under the supervision of the PI, and will be fully de-
identified prior to analysis.  All paper records will be archived for a pre-specified length 
of time as per applicable regulations and federal laws. 
 
12.2 Stratification 
Eligible patients will be randomized 1:1 between the two arms with stratification for RAS 
status (Mutated vs. non-mutated), line of therapy (2nd line vs. 3rd line or later) and initial 
stage at diagnosis (stage IV at diagnosis vs. less than stage IV).  
12.3 Sample Size Justification 
A sample size of 26 in each group in stage 1 and 39 in final stage can detect a hazard 
ratio of 0.55 comparing ctDNA-guided treatment (median survival times: 11 months) 
and scan-guided treatment group (median survival times: 6 months) assuming 3 years 
for patient accrual and 1 year for follow up to achieve 0.1 type-1 error rate and 80% 
power. The calculation is based on one-sided Z-test group sequential testing via 
simulation, equally incremented 2 stages, two-sided symmetric futility boundary, 


 
 
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O’Brien-Flemming beta spending function and binding futility. The futility boundaries of 
p-value are in the table below: 
Stage 
Sample Size 
(ctDNA-guided) 
Sample Size 
(scan-guided) 
Upper Futility 
Boundary 
Lower Futility 
Boundary 
1 
26 
26 
0.46225 
0.46225 
2 
39 
39 
0.05268 
0.05268 
 
12.4 Analysis of Primary Endpoint 
The study primary endpoint is Overall Survival (OS) defined as time between date of 
randomization and death/censoring. Stratified log-rank test or weighted log-rank test 
will be used to compare OS between ctDNA-guided treatment group and scan-guided 
treatment group. Stratification factors are described in Section 12.2. 
 
12.5 Analysis of Secondary Endpoints / Safety Data 
Secondary endpoints include: Progression Free Survival (PFS), defined as time between 
date of randomization and disease progression or death (whichever comes first); Best 
Overall Response (OR), defined as proportion of patients having each category of 
response (Complete Response, Partial Response, Stable Disease, and Progressive 
Disease) during the period of study participation. To compare secondary endpoints 
between ctDNA-guided treatment group and scan-guided treatment group, stratified 
log-rank test or weighted log-rank test will be used for PFS; Cochran-Mantel-Haenszel 
(CMH) test will be used for best OR. Weighted kappa will be used to assess the 
agreement between ctDNA vs. response assessment per RECIST. 
 
The incidence, severity and reversibility of toxicities will be performed on all subjects 
who receive any dose of study medication. Non-serious adverse events that occur more 
than 30 days after the administration of the last dose of treatment will not be included. 
The safety and tolerability of treatment is determined by reported AEs, physical 
examinations, laboratory tests, and ECGs. AEs will be summarized with the incidence and 
percentage of subjects with at least one occurrence of a preferred term (NCI - CTCAE 
Version 5 grade) will be included. The number of AEs reported will also be summarized. 
Causality (relationship to the protocol-specified treatment) will be summarized 
separately. Duration of AE will be determined and included in listings along with action 
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Laboratory results will be classified according to NCI-CTCAE, Version 5.0. Incidence of 
laboratory abnormalities will be summarized; laboratory results not corresponding to an 
NCI- CTCAE Version 5.0 term will not be graded. Laboratory toxicity shifts from baseline 
to worst grade will also be provided. The results from physical examination and vital 
sign measurement will be tabulated. Descriptive statistics by arm will be provided as 
appropriate and monitored by the safety stopping rule. 
 
12.6 Analysis of Exploratory Endpoints 
Exploratory analysis of microbiome and other biomarkers will be descriptive in nature. 
  
12.7 Interim Analysis 
An interim analysis for futility will be performed after the first 26 subjects are enrolled 
onto each arm in the trial.  The futility boundaries are shown in Section 12.3.  The trial 
will be stopped if the futility boundary is exceeded, otherwise an additional 13 patients 
will be enrolled onto each arm if futility is not exceeded to enroll the full sample of 78 
subjects.  Enrollment will not be suspended during futility or safety interim analyses. 
 
An interim analysis for safety will be performed after the first 20 subjects are enrolled in 
each arm based on clinical considerations. At this time, the proportion of Grade 3 or 
higher toxicity events in the experimental arm and the control arm will be calculated, 
and if there are more than 50% Grade 3 or higher toxicity events in either arm, accrual 
will be held for safety review.  If deemed safe and appropriate, enrollment will continue 
up to 78 subjects.   
12.8 Data Integrity and Safety Committee 
This protocol will be reviewed and monitored by the University of Florida Health Cancer 
Center Data Integrity and Safety Committee (UFHCC DISC) in accordance with their 
policies and procedures.  They will review and monitor study progress, toxicity, safety 
and other data from this trial. Questions about subject safety or protocol performance 
will be addressed with the sponsor-investigator, statistician and study team members. 
Should any major concerns arise, the DISC will offer recommendations regarding 
whether or not to suspend the trial. 
 
UFHCC DISC data and safety monitoring activities include:  
• Review of clinical trial conducted for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the 
protocol  
• Review of reports generated by data quality control review process  


 
 
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• Notification of the sponsor-investigator of recommended action  
• Notification of sites coordinated by the UFHCC of adverse events requiring 
expedited reporting and subsequent committee recommendations for study 
modifications 
 
In compliance with the UFHCC data and safety monitoring plan, the PI will provide a 
Data Integrity and Safety Committee Report to DISC at the predetermined timelines for 
the level of risk category assigned during the initial SRMC (Scientific Review and 
Monitoring Committee) review, which occurs prior to initial IRB approval. 
 
UFHCC investigator-initiated protocols will be classified into one of the following 
categories of risk by the SRMC (see SRMC manual for further details): 
 
 
Level 1 – Low risk Investigator Initiated interventional trials. 
 
Level 2 – Moderate risk Investigator Initiated or externally sponsored 
interventional (such as drug, biologic or device) trials using FDA approved or 
commercially available compounds or interventions. 
Level 3 – High risk Investigator Initiated or externally sponsored interventional 
trials (such as investigator-sponsored INDs, Phase I trials, studies requiring 
biosafety approval, or other areas that may be designated by NIH as high risk). 
Level 4 – Complex trials involving very high risk to subjects and a high level of 
complexity such as first in human or gene transfer studies. 
 
The risk level assigned by SRMC will determine the appropriate level of DISC monitoring 
required, with increased monitoring required for higher-risk trials.  
 
Findings will be communicated to all study sites by UFHCC CRO. 
 
12.9 Data Monitoring 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or 
project management officers will perform remote monitoring and may make monitoring 
visits to the trial sites periodically during the trial to confirm that all sites are complying 
with the protocol. Source documents will be reviewed for completion and validated 
against data submitted electronically via Electronic Data Capture. The site 
investigator/institution guarantee access to source documents by UFHCC or its designee 
and appropriate regulatory agencies.  As part of the responsibilities assumed by 
conducting this study, the Principal Investigator (PI) agrees to maintain and have 
available for monitoring adequate case records (accurate source documents and CRFs) 
for the subjects treated under this protocol. 
 


 
 
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The trial site may also be subject to quality assurance audit by any collaborating 
sponsors or their designee as well as inspection by appropriate regulatory agencies.  
 
It is important for the site investigator and their relevant personnel to be available 
during the monitoring visits and possible audits and for sufficient time to be devoted to 
the process. 
12.10 Principal Investigator Responsibilities 
Per UF IRB requirements, the PI is personally responsible for conducting and supervising 
the conduct of human subjects research by “protecting the rights, safety, and welfare of 
subjects under the investigator’s care.” The PI also must ensure that all the research 
conducted is done so in an ethical manner and in accordance with all federal, state, and 
local laws and regulations, institutional policies, and the requirements of the IRB. 
 
Oversight is defined as “management by overseeing the performance or operation of a 
person or group; watchful care, superintendence, general supervision”. Any person 
serving as a PI has voluntarily accepted these responsibilities and is expected to fully 
comply with these requirements, as outlined in the UFHCC Guidance: Principal 
Investigator Responsibilities and Oversight. 
 
The PI will be primarily responsible for continuous monitoring of adverse events, 
protocol violations, and other immediate protocol issues. The study coordinator will 
collect information on subjects enrolled through the use of electronic or paper adverse 
event (AE) forms, CRFs, and Informed Consent forms.  
13. EMERGENCY PROCEDURES 
13.1 Emergency Contact 
In emergency situations, the treating physician should contact the Principal Investigator 
by telephone at the number listed on the title page of the protocol. 
13.2 Emergency Identification of Investigational Products 
This is a non-blinded, randomized study. Thus, there will be no need for unmasking 
procedures. 
13.3 Emergency Treatment 
During and following a subject’s participation in the study, the treating physician and/or 
institution should ensure that adequate medical care is provided to a subject for any 
adverse events, including clinically significant laboratory values, related to the study. 


 
 
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14. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
 
14.1 Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and 
Co-Investigators abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonization (ICH) Guideline E6 and in accordance with the general 
ethical principles outlined in the Declaration of Helsinki.  
 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review Board 
(IRB) approval before initiation of the study.  
 
The Principal Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities. 
 
All potential serious breaches must be reported immediately to the UFHCC Project 
Management Office (PMO, pmo@cancer.ufl.edu, who will then report the breach to 
UFHCC DISC) and the IRB of record, if applicable. A serious breach is a breach of the 
conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
14.2 Institutional Review Board 
Before study initiation, the investigator must have written and dated approval from the 
IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The 
investigator should also provide the IRB with a copy of the Investigator Brochure or 
product labeling, information to be provided to subjects, and any updates. The 
investigator should provide the IRB with reports, updates, and other information (e.g., 
amendments, and administrative letters) according to regulatory requirements or 
institution procedures. 
14.3 Compliance with Laws and Regulations 
It is intended that the proposed study be conducted according to the International 
Conference on Harmonization E6 Guideline for Good Clinical Practice (GCP) and the 


 
 
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Declaration of Helsinki.  Please refer to the International Conference on Harmonization 
and GCP:  
http://www.fda.gov/oc/gcp/guidance.html; Declaration of Helsinki:   
http://www.fda.gov/oc/health/helsinki89.html; Code of Federal Regulations, Title 
21: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm]  
 
All UF Health Cancer Center investigator-initiated trials, meeting the criteria of the 
FDAAA’s applicable clinical trials, will be registered with ClinicalTrials.gov by the Project 
Management Officer (PMO) or assigned designee.  All studies must be registered prior 
to enrollment of the first participant.  The Project Management Officer or assigned 
designee will maintain the responsibility of updating trials registered with 
ClinicalTrials.gov.  Per FDA requirement, information must be updated at least every 
twelve months and the registry must be updated within thirty days of any changes in 
recruitment status or completion of the study. The PMO will determine if registration 
and updates to the NCI CTRP are required. 
14.4 Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are 
adequately informed about the protocol, any amendments to the protocol, the 
protocol-specified treatment, and their study-related duties and functions. The Principal 
Investigator will maintain a list of Co-Investigators and other appropriately qualified 
persons to whom s/he has delegated significant study-related duties.  
 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (e.g., loss of medical licensure; debarment). Systems with 
procedures that ensure the quality of every aspect of the study will be implemented. 
 
14.5 Subject Information and Informed Consent 
Before being enrolled in this clinical trial, the subject must consent to participate after 
the nature, scope, and possible consequences of the clinical study have been explained 
in a form understandable to him or her. An informed consent document that includes 
both information about the study and the consent form will be prepared and given to 
the subject. This document will contain all ICH, GCP, and locally required regulatory 
elements. The document must be in a language understandable to the subject and must 
specify the person who obtained informed consent. 


 
 
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After reading the informed consent document, the subject must give consent in writing. 
The written informed consent will be obtained prior to conducting any study-related 
procedures or tests. The subject’s consent must be confirmed at the time of consent by 
the personally dated signature of the person conducting the informed consent 
discussions and a copy of the consent form (preferably signed) must be given to the 
subject for their records.  
The PI will retain the original signed consent document. The PI will not undertake any 
measures specifically required only for the clinical study until valid consent has been 
obtained. 
14.6 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual.   
 
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection law. 
14.7 Protocol Amendments 
Once the study has started, amendments should be made only in exceptional cases.  
Protocol amendments will not be implemented without prior written IRB approval. All 
amendments will be submitted to the IRB and SRMC (as applicable), and written 
verification that the amendment was submitted and subsequently approved is to be 
obtained, and notification will be sent out to the applicable study teams, prior to 
implementing the amendment.   
 
On an emergency-basis, to eliminate an immediate safety hazard to a subject, a protocol 
deviation may be implemented immediately, provided the IRB and UFHCC CRO PMO 
(pmo@cancer.ufl.edu) are notified within 5 business days with a full justification and 
description of the event.    
 
14.8 Case Report Forms 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the 
study.  Study specific Case Report Forms (CRFs) will document protocol-required 


 
 
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outcomes for safety monitoring and data analysis.  All study data will be entered 
electronically in an Electronic Data Capture system in accordance with the protocol 
schedule of events and guidelines developed in the Data Management Plan for the 
study, using a secure access account.   
All protocol data is the sole property of UFHCC and should not be made available in any 
form to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from UFHCC. 
14.9 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed subject consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
 
UF Health Cancer Center requires that all study documentation be maintained for at 
least 6 years from the date of final study publication.  No study records may be 
destroyed without prior authorization from UF. 
 
 


 
 
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15. REFERENCES 
1. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously 
treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. Lancet, Jan 2013; 381(9863): 303-312. 
 
2. Hook N et al. Cancer Care and a Tale of Three Molecular “Genomic” Tests. Natera, Inc. 
European Society of Human Genetics. ESMO. June 2020. 
 
3. Kasi A, et.al. Deaths among pancreatic cancer in-hospital, and the utilization of 
palliative care. An American Society of Clinical Oncology Journal, May 2020; 38 (15).   
 
4. Loupakis F, et al. Personalized circulating tumour DNA assay for the detection of 
minimal residual disease in CRC patients after resection of metastases. ESMO. 
September 2020.  
 
5. Osumi H, Shinozaki E, Yamaguchi K, et al. Early change in circulating tumor DNA as a 
potential predictor of response to chemotherapy in patients with metastatic colorectal 
cancer. Nature, 2019; 9(17358).  
 
6. Tie J et al. Circulating tumor DNA as an early marker of therapeutic response in 
patients with metastatic colorectal cancer. Annals of Oncology, Aug 2015; 26(8): 1715-
1722 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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16. APPENDICES 
 
 
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Appendix A: PROTOCOL VERSION HISTORY / SUMMARY OF CHANGES 
Protocol 
Version 
Number 
Protocol Version Date 
Affected Section(s) 
Summary of Revisions Made 
1.0 
February 24, 2021 
N/A- Initial protocol 
1.1 
June 11, 2021 
Table of Contents 
Update page numbers 
Protocol Synopsis 
Inclusion Criteria K Creatinine 
Clearance Value  
Section 4.2 
Inclusion Criteria K Creatinine 
Clearance Value 
1.2 
July 14, 2021 
Section 3.1 
Updated treatment decisions 
Section 6, 6.1 
Updated screening period 
Updated Footnote 6 
Appendix E 
Updated proposed timeline 
1.3 
August 9, 2021 
Title Page 
PI change 
2.0 
November 17, 2021 
Protocol Synopsis 
Inclusion Criteria D 
Section 1.3 
Eligible subjects 
Section 3.1 
Measurable ctDNA update 
Section 4.2 
Inclusion Criteria D 
Section 7.1 
Update for non-measurable ctDNA 
Section 12.2 
Updated to 3rd line or later 
3.0 
December 1, 2021 
Protocol Synopsis 
Updated primary objective language 
and Inclusion Criteria B 
Section 1.3 
Updated eligible subjects language 
Section 2.1.1 
Updated primary objective language 
Section 3.1 
Included later line of therapy in agent 
entry 
Section 4.2 
Updated inclusion Criteria B 
Section 6 
Added re-screen procedures 
Section 6.1 
Updated screening window, and 
abbreviations 4, 6 and 14. 
Section 7.1 
Included later line of therapy in agent 
entry 
Section 11 
Updated adverse event reporting, 
since all treatments are standard of 
care 
Appendix D 
Clarified subject’s starting treatment # 
3.1  
August 2nd, 2022 
Protocol Synopsis and 
Section 4.2 
Rephrased inclusion criteria D  
Section 6 
Rephrased ctDNA re-collection if >14 
days from start of trt 


 
 
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Section 6.1 
Updated Footnote 6 to provide 
clarification on screening/baseline 
ctDNA sampling  
 
Updated Footnote 10 to clarify “visits” 
for the research blood collection 
timepoint 
 
Updated Footnote 11 to clarify which 
procedures need not be repeated for 
C1D1 assessments in the event the 
visit occurs in close proximity to the 
screening visit 
Sections 11.2 and 
11.4.1 
Updated SAE reporting guidelines 
3.2 
August 18th, 2022 
Section 3.1 and Section 
6.1 Footnote 13 
Added in the event that the initial 
ctDNA results are not available within 
the 14-day randomization window. 
3.3 
November 15th, 2022 
Title Page 
Updated biostatistician 
Appendix D 
Added subject pill diaries 
3.4 
July 24th, 2023 
Appendix E  
Updated to allow the addition of 
Bevacizumab or biosimilar anti-VEGF 
therapy to treatment regimen at 
physician discretion.  
 
Corrected typographical error in 
Appendix lettering throughout 
protocol. 


 
 
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Appendix B: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease 
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) 
80 
Normal activity with effort; some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active 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 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
 
 


 
 
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Appendix C: RECIST GUIDELINES (VERSION 1.1) 
 
Response and progression will be evaluated in this study using the international criteria proposed by 
the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST Guideline (version 1.1). 
 
Measurability of Tumor at Baseline 
Tumor lesions/lymph nodes will be categorized at baseline as measurable or non-measurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion. 
 
Measurable 
Tumor lesions: Measured in at least 1 dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (slice 
thickness ≤5 mm) 
• 10 mm caliper measurement by clinical exam (non-measurable lesions if cannot be accurately 
measured with calipers) 
• 20 mm by chest X-ray. 
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 thickness recommended to be ≤5 
mm). 
 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
 
Special Considerations for Lesion Measurability 
Bone Lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI, can be considered 
measurable lesions if the soft tissue component meets the definition of measurability. 
• Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 


 
 
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• Simple cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) 
• Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability. If non-cystic lesions are presented in the same 
subjects, these are preferred for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
• Tumor lesions situated at a previously irradiated area, or in an area subjected to other loco-
regional therapy, are non-measurable unless there has been demonstrated progression in the 
lesion. 
 
Baseline Documentation of Target and Non-Target Lesion 
 
Target Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 lesions 
total (and a maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline. Non-nodal target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative of 
all involved organs, and can be reproduced in repeated measurements.  Measurable lymph nodes are 
target lesions if they meet the criteria of a short axis of ≥15 mm by CT scan. All measurements are to 
be recorded in the CRF in millimeters (or decimal fractions of centimeters). 
 
Non-target Lesions 
All other lesions (or sites of disease) are identified as non-target lesions (chosen based on the 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline. Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’ In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the CRF (for example, 
multiple liver metastases recorded as 1 liver lesion).  Lymph nodes with short axis ≥10 mm but <15 
mm should be considered non-target lesions.  Nodes that have a short axis <10 mm are considered 
non-pathological and are not recorded or followed. 
 
Specifications by Methods of Measurement 
 
All measurements should be recorded in metric notation, using a ruler or calipers if clinically assessed. 
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 should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessed by clinical exam. 
 


 
 
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An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given subject. If prior to enrollment it is known a subject is not able to undergo CT scans with 
intravenous contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT 
or MRI (with or without intravenous contrast) should be used to evaluate the subject at baseline and 
follow-up should be guided by the tumor type under investigation and the anatomic location of the 
disease. 
 
Clinical Lesions: Clinical lesions will be considered measurable only when they are superficial and ≥10 
mm diameter as assessed using calipers (for example, skin nodules). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion is 
recommended. When lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray when progression is an important endpoint.  
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
CT and MRI: CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan assumes that CT slice thickness 
is ≤5 mm. When CT scan have slice thickness >5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (for example, for body 
scans). If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
 
Ultrasound: Ultrasound should not be used to measure lesion size. 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. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint. 
 
Tumor Markers: Tumor markers alone cannot be used to assess tumor response. If markers are initially 
above the upper normal limit, they must normalize for a subject to be considered in complete 
response (CR). 
 


 
 
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Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and 
complete response (CR) in rare cases if required by protocol (for example, residual lesions in tumor 
types such as germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (for example, with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease (SD) in order to differentiate between response (or SD) and progressive 
disease (PD). 
 
PET Scan (FDG-PET, PET CT): PET is not recommended for lesion assessment. If a new lesion is found 
by PET, another assessment must be done by CT, unless the PET CT is of diagnostic quality. If CT is 
done to confirm the results of the earlier PET scan, the date of progression must be reported as the 
earlier date of the PET scan. 
 
Bone Scan: If lesions measured by bone scan are reported at baseline, it is necessary to repeat the 
bone scan when trying to identify a complete response (CR) or partial response (PR) in target disease 
or when progression in bone is suspected. 
 
Response Criteria 
 
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 diameter 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 (including the baseline sum if that is the smallest).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of 1 or more new lesions is also considered progression. For equivocal findings of 
progression (for example, very small and uncertain new lesions; cystic changes or necrosis in existing 
lesions), treatment may continue until the next scheduled assessment. If at the next scheduled 
assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 
 
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. 
 


 
 
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Not Evaluable (NE): When an incomplete radiologic assessment of target lesions is performed or there 
is a change in the method of measurement from baseline that impacts the ability to make a reliable 
evaluation of response. 
 
Evaluation of Non-target Lesions 
 
Complete Response: Disappearance of all non-target lesions. All lymph nodes must be non-
pathological or normal in size (<10 mm short axis). 
 
Non-CR/ non-PD: Persistence of 1 or more non-target lesions and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease: Unequivocal progression of existing non-target lesions. The appearance of 1 or 
more new lesions is also considered progression. 
 
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the protocol-specified 
treatment until the earliest of objective progression or start of new anticancer therapy, considering 
any requirement for confirmation. The subject’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the appearance of 
new lesions. The best overall response will be calculated via an algorithm using the assessment 
responses provided by the investigator over the course of the trial. 
 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. (When no 
imaging/measurement is done at all at a particular time point, the subject is not evaluable (NE) at that 
time point.) Table 17.2.1 provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disease at baseline. 
 
Table 17.2.1- Time Point Response: Subjects with Target or Measurable Disease 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 


 
 
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Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
   Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease 
 
Table 17.2.2 is to be used when subjects have non-measurable disease only. 
 
Table 17.2.2- Time Point Response: Subjects with Non-Target or Non-Measurable Disease 
 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluable 
No 
NE 
Unequivocal 
Yes or No 
PD 
Any 
Yes 
PD 
   Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; SD = stable 
disease. 
   a non-CR/non-PD is preferred over SD for non-target disease due to SD being increasingly used as 
an endpoint for assessment in trials; to assign this category when no lesions can be measured is not 
advised. 
 
Frequency of Tumor Re-Evaluation 
 
A baseline tumor evaluation must be performed within 4 weeks before a subject begins the protocol-
specified treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment. Normally, all target and non-
target sites are evaluated at each assessment using the same method. However, bone scans may need 
to be repeated only when CR is identified in target disease or when progression in bone is suspected. 
 
Duration of Response 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for CR 
or PR (whichever is first recorded) until the first date that disease is recurrent or objective progression 
is observed (taking as reference for PD the smallest measurements recorded on study). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
 


 
 
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Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, that is the reference for calculation of PD). 
 
 


 
 
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Appendix D: SUBJECT PILL DIARIES 
EXAMPLE:  
 
 
 
 
Date  
Time  
Number of Lonsurf Taken 
Comments 
Day 1 
01/01/2022 8:30 AM 
2 
Felt nauseated an hour after taking, did 
not vomit, took a Zofran  
 
PM 
 
CYCLE # 
 
Cycle Start Date:  
Dose Level:   
 
 
Cycle End Date: 
 
 
Weeks 1 
and 2  
Date  
Time  
Number of Lonsurf 
tablets Prescribed 
 
AM#:        PM#: 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome side 
effects)  
Number of Lonsurf 
tablets taken 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Day 8  
 
 
AM 
 
 
 
PM 
 
 
Day 9  
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11  
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
 
 
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CYCLE # 
 
Cycle Start Date: 
 
Dose Level:  
 
 
 
Cycle End Date: 
 
 
Week 1 
Date  
Time  
Number of Stivarga 
tablets Prescribed 
 
AM#:        PM#: 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome side 
effects)  
Number of Stivarga 
tablets taken 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Week 2 
Date 
Time 
Number of Stivarga 
tablets taken 
Comments 
Day 8  
 
 
AM 
 
 
 
PM 
 
 
Day 9  
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11  
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 
 
PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
 


 
 
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Week 3 
Date  
Time  
Number of Stivarga 
tablets taken 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome side 
effects)  
Day 15 
 
 
AM 
 
 
 
PM 
 
 
Day 16 
 
 
AM 
 
 
 
PM 
 
 
Day 17 
 
 
AM 
 
 
 
PM 
 
 
Day 18 
 
 
AM 
 
 
 
PM 
 
 
Day 19 
 
 
AM 
 
 
 
PM 
 
 
Day 20 
 
 
AM 
 
 
 
PM 
 
 
Day 21 
 
 
AM 
 
 
 
PM 
 
 
 
 
 
[SUBJECT AND/OR STUDY STAFF VERIFYING SIGNATURE  
&  DATE] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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CYCLE # 
 
Cycle Start Date: 
 
Dose Level:  
 
 
 
Cycle End Date: 
 
 
Week 1 
Date  
Time  
Number of Xeloda 
tablets Prescribed 
 
AM#:        PM#: 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome side 
effects)  
Number of Xeloda 
tablets taken 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Week 2 
Date 
Time 
Number of Xeloda 
tablets taken 
Comments 
Day 8  
 
 
AM 
 
 
 
PM 
 
 
Day 9  
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11  
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 
 
PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
 
 
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Appendix E: TREATMENT REGIMENa 
Sequence of 
Treatment 
Regimen 
Medication Name: 
Generic (Trade)a 
Dosage, Frequency, and 
Administration 
ctDNA 
testing 
timepoints 
Cycle 
Length 
Notes and Special Precautions 
T1. 
 
Subjects 
may start at 
T1-T3; 
regardless 
of where 
they start, 
the T-
number 
corresponds 
to the drug, 
NOT line of 
therapy. 
FOLFIRI – Folinic acid 
(leucovorin), 
fluorouracil (5FU) and 
irinotecan (Camptosar) 
 
 
 
and 
 
 
 
 
Bevacizumab  
Folinic acid (leucovorin) is given 
at 400mg/m2 over two hours and 
irinotecan 180mg/m2 IV over 30–
90 minutes on Day 1, both prior 
to 5FU.  Fluorouracil (5-FU) 
400mg/m2 IV push day 1, then 
1,200mg/m2/day × 2 days (total 
2,400mg/m2 over 46–48 hours) IV 
continuous infusion, via at-home 
infusion beginning Day 1 and 
ending on Day 3.   
 
Bevacizumab: Injection of 100 
mg/4 mL (25 mg/mL) or 400 
mg/16 mL (25 mg/mL) in a 
single-dose vial. For Metastatic 
Colorectal Cancer, given 5 mg/kg 
every 2 weeks.  
Day 1 
14 days 
 
 
 
 
 
 
 
 
 
 
 
14 days  
Individuals who are known to be homozygous for the 
UGT1A1*28 allele are at increased risk for neutropenia 
following initiation of treatment.  See FDA package insert for 
dosing specifications. 
 
 
 
 
See FDA package insert for specifics on warnings and 
precautions. 
T2 
Anti-EGFR therapy 
[Cetuximab (Erbitux) or 
Panitumumab 
(Vectibix)] in 
combination with 
Irinotecanb at 
physician discretion  
Cetuximab: 500 mg/m2 IV over 
120 minutes every 14 days.  First 
dose requires test dose.   
 
Panitumumab: 6 mg/kg, IV over 
60 minutes. every 14 days. 
Day 1 
14 days 
SKIP and move to Treatment Regimen #3 (Lonsurf) if subject is 
harboring a KRAS mutation or subject has already been 
previously treated with Cetuximab or Panitumumab and 
irinotecan. 
 
Serum electrolytes (magnesium) should be monitored during 
and after administration as outlined in the FDA package insert. 
T3 
TAS-102 (Lonsurf) in 
combination with 
Bevacizumab at 
physician discretion 
Lonsurf: 35 mg/m2 twice daily on 
days 1 to 5 and 8 to 12 of each 
28-day cycle. 
 
Day 1 and 
Day 15 
28 days 
n/a 


 
 
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Version 3.4 
Bevacizumab: Injection of 100 
mg/4 mL (25 mg/mL) or 400 
mg/16 mL (25 mg/mL) in a 
single-dose vial. For Metastatic 
Colorectal Cancer, given 5 mg/kg 
every 2 weeks. 
T4 
Regorafenib (Stivarga) 
160 mg orally once a day for the 
first 21 days of each 28-day cycle. 
Day 1 and 
Day 15 
28 days 
n/a 
T5 
Capecitabine (Xeloda)  
850–1,250mg/m2 orally twice 
daily for the first 14 days of each 
21-day cycle. 
Day 1 
21 days 
Patients receiving capecitabine who also take oral coumarin-
derivative anticoagulants, such as warfarin and 
phenprocoumon, should have their anticoagulant response 
(PT/INR) monitored frequently in order to adjust the 
anticoagulant dose accordingly.  See FDA package insert. 
T6 
FOLFIRI – Folinic acid 
(leucovorin), 
fluorouracil (5FU) and 
irinotecan (Camptosar) 
Folinic acid (leucovorin) is given 
at 400mg/m2 over two hours and 
irinotecan 180mg/m2 IV over 30–
90 minutes on Day 1, both prior 
to 5FU.  Fluorouracil (5-FU) 
400mg/m2 IV push day 1, then 
1,200mg/m2/day × 2 days (total 
2,400mg/m2 over 46–48 hours) IV 
continuous infusion, via at-home 
infusion beginning Day 1 and 
ending on Day 3.   
Day 1 
14 days 
Individuals who are known to be homozygous for the 
UGT1A1*28 allele are at increased risk for neutropenia 
following initiation of treatment.  See FDA package insert for 
dosing specifications. 
 
 
T7 
7a. FOLFOX – Folinic 
acid (leucovorin), 
oxaliplatin (Eloxatin), 
and fluorouracil (5FU)  
 
Or 
 
7b. CAPOX – 
Capecitabine (Xeloda), 
FOLFOX: Folinic acid 400mg/m2 
IV over two hours before 
fluorouracil (Day 1), 
Oxaliplatin IV 85mg/m2 over two 
hours on Day 1, commonly at the 
same time as folinic acid. 
Fluorouracil (5-FU) 400mg/m2 IV 
push day 1, then 
1,200mg/m2/day × 2 days (total 
2,400mg/m2 over 46–48 hours) IV 
Day 1 
14 days 
 
 
 
 
 
 
 
 
 
Monitor for persistent neuropathy / neurosensory 
events and adjust as necessary. 
 
 


 
 
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Version 3.4 
and oxaliplatin 
(Eloxatin) 
continuous infusion, via an at-
home infusion beginning Day 1 
and ending on Day 3.   
 
CAPOX: Capecitabine 850 – 1000 
mg/m2, by mouth, twice daily, for 
the first 14 days of each 21-day 
cycle.  Oxaliplatin IV 130 mg/m2 
over 2 hours on Day 1.   
 
 
 
 
 
 
21 days 
Next 
Return to Treatment 
Regimen #1 (FOLIRI 
and Bevacizumab and 
repeatc 
 
 
 
 
 
a Actual dosage should be prescribed per institutional standards; this table only outlines common dosing administration practices. 
b Only for RAS wild-type tumors.  Irinotecan is routinely dosed at 150-180 mg/m2 IV over 30 minutes every 14 days 
c This round of FOLFIRI and Bevacizumab should be administered even if subject was treated with FOLFIRI and Bevacizumab in the past.  If 
sequence is repeated, treatment numbers should be indicated as T2.1, T2.2, T2.3, etc. representing the first, second and third treatments, 
respectively, of treatment round #2.  


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Appendix F: PROPOSED TIMELINE 
 
Month 
 
Milestone 
(Target) 
Approximate Date 
 
Activation 
August 1, 2021 
1* 
First patient, First Visit 
September 1, 2021 
20* 
Safety Interim Analysis Target 
(N=40, 20 in each arm) 
March 31, 2023 
26* 
Futility Interim Analysis 
(N=52, 26 in each arm) 
October 1, 2023 
36 
Complete enrollment 
August 1, 2024 
40 
Last Patient, Last Visit  
December 1, 2024 
48 
Final Report Filed 
May 1, 2025 
 
*Enrollment is expected to occur at a rate of 2-3 subjects per month