Clinical trial NCT04853043
Conditions: Colorectal Cancer
Sponsor: University of Utah
Start date: 2021-11-03; Completion date: 2024-05-03
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A prospective, multi-center, phase II study of 21 patients to evaluate the efficacy of the epidermal growth factor receptor (EGFR) inhibitor, Cetuximab in patients with metastatic colorectal cancer (mCRC) harboring Adenomatous polyposis coli (APC), tumor protein p53 (TP53) and RAS mutations.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Cetuximab
Intervention descriptions: intervention 1: Cetuximab will be administered every 2 weeks (14 days). The initial dose of 500 mg/m2 is to be administered by IV infusion over 120 minutes on the first day of the treatment. In the absence of infusion reactions, subsequent doses are to be administered over 60 minutes biweekly. Each cycle will be defined as 14 days of treatment.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 59 
 
 
APK MUTANT: A Single Arm Phase II study of Cetuximab in Third 
Line for Mutant APC, TP53 and RAS patients with Refractory 
Metastatic Colorectal Cancer 
 
Principal Investigator 
Vaia Florou, MD 
Assistant Professor, Division of Oncology 
Huntsman Cancer Institute  
2000 Circle of Hope  
SLC, UT, 84112  
vaia.florou@hci.utah.edu 
Statistician 
Michael Schell, Ph.D 
Biostatistics and Bioinformatics Department 
Moffitt Cancer Center, FL 
Michael.schell@moffitt.org 
Sponsor  
Huntsman Cancer Institute 
Coordinating Center 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
HCI-RCO@utah.edu 
Investigational Product 
Cetuximab 
Commercial Agent 
Cetuximab 
Drug Manufacturer 
Eli Lilly 
Drug Manufacturer 
Protocol ID 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 2 of 59 
IND  
Exempt 
NCT number 
NCT04853043 
HCI IRB number 
141689 
Protocol Version 
Version 3: 28APR2022 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 3 of 59 
DOCUMENT HISTORY 
Document 
Date 
Overall Rationale 
Original Protocol  
24MAY2021 
Not applicable  
Protocol Amendment 
02NOV2021 
SAE Reporting 
Clarification/Inclusion 
Criteria 
Protocol Amendment 
28APR2022 
Accrual number and 
inclusion criteria updates 
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 4 of 59 
Table of Contents 
DOCUMENT HISTORY ................................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................................. 6 
PROTOCOL SIGNATURE ............................................................................................................................ 7 
ABREVIATIONS ........................................................................................................................................... 8 
1 
PROTOCOL SUMMARY .................................................................................................................... 11 
 
Synopsis ...................................................................................................................................... 11 
 
Schema ....................................................................................................................................... 14 
 
Schedule of Events ..................................................................................................................... 15 
2 
OBJECTIVES AND ENDPOINTS....................................................................................................... 18 
 
Primary Objective ........................................................................................................................ 18 
 
Secondary Objectives ................................................................................................................. 18 
 
Exploratory Objectives ................................................................................................................ 18 
3 
BACKGROUND AND RATIONALE ................................................................................................... 18 
 
Metastatic colorectal cancer and Epidermal Growth Factor Receptor Inhibitors ........................ 18 
 
Investigational Intervention ......................................................................................................... 20 
4 
STUDY DESIGN ................................................................................................................................. 22 
 
Study Duration............................................................................................................................. 22 
 
End of Study ................................................................................................................................ 23 
5 
STUDY POPULATION ....................................................................................................................... 23 
 
Inclusion Criteria ......................................................................................................................... 23 
 
Exclusion Criteria ........................................................................................................................ 25 
 
Registration ................................................................................................................................. 26 
 
Contraception .............................................................................................................................. 26 
 
Screen Failures ........................................................................................................................... 27 
 
Strategies for Recruitment .......................................................................................................... 27 
6 
STUDY INTERVENTION .................................................................................................................... 27 
 
Administration Schedule ............................................................................................................. 27 
 
Cetuximab ................................................................................................................................... 28 
 
Dose Interruptions ....................................................................................................................... 29 
 
Dose Reductions ......................................................................................................................... 30 
 
Dose Modifications Guidelines .................................................................................................... 30 
 
Supportive Care .......................................................................................................................... 33 
 
Concomitant Medications and Therapies .................................................................................... 33 
 
Duration of Therapy .................................................................................................................... 34 
 
Lost to Follow-Up .................................................................................................................... 36 
7 
STUDY ASSESSMENTS .................................................................................................................... 36 
 
General Assessments ................................................................................................................. 36 
 
Safety Assessments .................................................................................................................... 38 
 
Efficacy Assessments ................................................................................................................. 39 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 5 of 59 
 
Correlative Studies ...................................................................................................................... 40 
 
Remote Visits/Telehealth ............................................................................................................ 40 
8 
ADVERSE EVENTS ........................................................................................................................... 40 
 
Definitions .................................................................................................................................... 40 
 
Adverse Event Reporting ............................................................................................................ 41 
 
Special Situations ........................................................................................................................ 46 
 
Data Safety Monitoring Committee ............................................................................................. 47 
9 
STATISTICAL CONSIDERATIONS ................................................................................................... 48 
 
Sample size determination .......................................................................................................... 48 
 
Population for Analyses .............................................................................................................. 49 
 
Primary Endpoint ......................................................................................................................... 49 
 
Secondary Endpoints .................................................................................................................. 49 
10 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................... 50 
 
Human Subjects Protection ......................................................................................................... 50 
 
Institutional Review ..................................................................................................................... 50 
 
Investigator Responsibilities ........................................................................................................ 50 
 
Protocol Amendments ................................................................................................................. 50 
 
Protocol Deviations ..................................................................................................................... 51 
11 
DATA HANDLING .......................................................................................................................... 51 
 
Recording and Collection of Data ............................................................................................... 51 
 
Data Management ....................................................................................................................... 51 
12 
PUBLICATION PLAN ..................................................................................................................... 52 
13 
REFERENCES ................................................................................................................................ 53 
 
List of Tables 
Table 1: Cetuximab Reduction Levels ........................................................................................................ 30 
Table 2: Cetuximab Dose Delays Due to Cutaneous Toxicity .................................................................... 31 
Table 3 : Laboratory Assessments ............................................................................................................. 38 
Table 4 : Severity Assessment ................................................................................................................... 42 
Table 5: Statistical Plan ............................................................................................................................... 48 
Table 6 : RECIST 1.1 response criteria ...................................................................................................... 56 
Table 7 : Best Overall Response Classification .......................................................................................... 57 
 
List of Appendices 
Appendix 1: ECOG Performance Status23 .................................................................................................. 55 
Appendix 2: RECIST 1.1 ............................................................................................................................. 56 
 
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 6 of 59 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor, funding agency and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 7 of 59 
PROTOCOL SIGNATURE  
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of 
the federal government. I will promptly submit the protocol to the IRB for review and approval. 
Once the protocol has been approved by the IRB, I understand that any modifications made during 
the study must first be approved by the IRB prior to implementation except when such modification 
is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the obligations 
of confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic Research 
Integrity and Compliance Administration (ERICA) system. For this reason, the Principal 
Investigator at Huntsman Cancer Institute will not have a hand-written signature on this signature 
page.  
Instructions to multi-site Principal Investigators at locations other than Huntsman Cancer Institute: 
SIGN and DATE this signature page and PRINT your name. Return the original, completed and 
signed, to the HCI Research Compliance Office. Retain a copy in the regulatory binder.  
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator 
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
 
____________________________________ 
Name of Institution 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 8 of 59 
ABREVIATIONS 
Abbreviation 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCVA 
Best-corrected distance visual acuity 
BICR 
Blinded Independent Central Review 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
CQ 
Chloroquine 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 9 of 59 
Abbreviation 
Definition/Explanation 
DILI 
Drug-Induced Liver Injury 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NIH 
National Institute of Health 
PD 
Pharmacodynamic(s) 
PDAC 
Pancreatic Ductal Adenocarcinoma  
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 10 of 59 
Abbreviation 
Definition/Explanation 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SD-OCT 
Spectral-domain ocular coherence tomography 
T1/2 
Terminal elimination half-life 
TdP 
Torsades de Pointes 
Tmax 
Time of maximum observed concentration 
ULN 
The upper limit of normal 
VF 
Visual field 
WBC 
White blood cell 
  
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 11 of 59 
1 
PROTOCOL SUMMARY 
 
Synopsis 
Title: 
APK Mutant: A Single Arm Phase II study of Cetuximab in Third Line 
for Mutant APC, TP53 and RAS patients with Refractory Metastatic 
Colorectal Cancer (mCRC) 
Protocol Short Title 
APK Mutant 
Study Description: 
Single arm, open label study 
Phase: 
II 
Objectives: 
 
Primary Objective:  
To evaluate the progression free survival (PFS) among patients 
treated with cetuximab in APC, TP53 and RAS mutated refractory 
metastatic colorectal cancer. 
Secondary Objectives: 
To evaluate the overall survival (OS) among patients treated with 
cetuximab with APC, TP53 and RAS mutated refractory metastatic 
colorectal cancer. 
Exploratory objective: To correlate APC, TP53, RAS and BRAF 
status using ultrasensitive cell free DNA (cfDNA) duplex sequencing 
assay and tissue next generation sequencing to monitoring disease 
response in patients with metastatic CRC 
Endpoints: 
Primary Endpoint:  
The primary endpoint is progression free survival (PFS). PFS will be 
measured from the date of first dose of study drug until first 
documented radiographic evidence of disease progression by 
RECIST criteria 1.1, clinical progression per investigator judgement, 
start of new anti-cancer therapy, or death from any cause. 
Secondary Endpoints: 
The secondary endpoint is overall survival (OS). OS will be measured 
from the date of first dose of study drug until death from any cause. 
Patients who show a response to treatment (CR, PR, or SD) may 
continue treatment (with disease reassessment every 8 weeks) until 
disease progression or the occurrence of unacceptable toxicities. 
Study Population: 
Key Inclusion Criteria 
 
Male or female subject aged ≥ 18 years. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 12 of 59 
 
Histologically confirmed metastatic colorectal 
adenocarcinoma with mutant APC, TP53 and RAS genes as 
determined by the local CLIA-certified laboratory are eligible. 
Patients with wild type RAS, APC or TP53 are ineligible. 
 
Progression or unwanted toxicities on at least 2 prior lines of 
treatment including 5-Flourouracil, oxaliplatin and irinotecan 
based regimen. 
 
Study participants must have measurable disease by 
RECIST 1.1 criteria by CT or MRI. 
 
ECOG Performance Status ≤ 2. 
 
Study participants with treated and/or stable brain 
metastases are allowed. 
 
Study participants must have anticipated life expectancy > 3 
months. 
 
Adequate organ function as defined as:  
o Hematologic: 
 
Absolute neutrophil count (ANC) ≥ ≥1000/µL 
 
Platelet count ≥ 100,000/mm3 
 
Hemoglobin ≥ 9 g/dL 
o Hepatic:  
 
Serum Bilirubin ≤ 2 x ULN or ≤ 3 x ULN  for 
subjects with Gilbert’s syndrome. 
 
Aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤ 3.0 times the upper limit 
of normal (ULN; or 5.0 times the ULN in the 
setting of liver metastases) 
o Renal: 
 
Serum creatinine ≤1.5 times the ULN, or 
creatinine clearance (measured via 24-hour 
urine collection) ≥40 mL/minute (that is, if 
serum creatinine is >1.5 times the ULN, a 24-
hour urine collection to calculate creatinine 
clearance must be performed) 
Key Exclusion Criteria: 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 13 of 59 
 
Prior use of systemic anti-EGFR therapy including cetuximab 
or panitumumab is not allowed. Note: Prior use irinotecan, 
oxaliplatin, regorafenib or TAS-102 is allowed 
 
Study participants with new or progressive brain metastases 
(active brain metastases) or leptomeningeal disease who 
need immediate CNS specific treatment during first cycle of 
treatment as determined by the treating physician. 
o Note: Brain metastases or cranial epidural disease 
adequately treated with radiotherapy and/or surgery 
and stable for at least 4 weeks before the first dose of 
study treatment will be allowed on trial. Subjects must 
be neurologically asymptomatic and without 
corticosteroid treatment at the time of the first dose of 
study treatment.   
 
Known prior severe hypersensitivity attributed to compounds 
of chemical or biologic composition similar to those of 
cetuximab, or if the patient had red meat allergy/tick bite 
history (NCI CTCAE v5.0 Grade ≥ 3).  
 
Live attenuated and inactive vaccinations within 4 weeks of 
the first dose of study treatment and while on trial is 
prohibited. COVID-19 vaccines are allowed. 
Study Intervention: 
Cetuximab 500 mg/m2 IV every 2 weeks infused over 120 minutes 
Study Duration: 
Approximately 24 months 
Participant Duration: 
Until RECIST 1.1 disease progression, clinical progression per 
investigator judgement, or intolerable toxicity whichever comes first 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 14 of 59 
Metastatic CRC 
who progressed 
on prior 
FOLFOX/FOLFIRI 
+ Bevacizumab 
INFORMED CONSENT 
 
 
Schema 
 
  
 
mAPC + mTP53 + mRAS  
(mutant KRAS/NRAS/HRAS) 
Cetuximab 
Every 2 weeks 
until progression 
or unacceptable 
toxicity 
Follow up 
every 3 
months  
until death, end of 
the study, or 
withdrawal of 
consent, whichever 
comes first.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 15 of 59 
 
Schedule of Events 
 
Protocol Activities 
 
Screening1 
 
On-Treatment Period: One Cycle= 14 days
Post Treatment Period
Cycle 12 
Cycle 2  
Cycle 3+ 3 
EOT4  
Safety Follow up5 
Long Term 
Follow-Up 
 
Day of Cycle 
(Visit Window)
(-28 days) 
(± 3 days) 
(±3 days) 
(±3 days) 
(+ 7 days) 
(±7 days) 
Informed consent 
x 
 
Demographics 
x 
 
 
 
 
 
 
Medical History 
x 
 
Cancer History6 
x 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
Registration7 
x 
 
 
 
 
 
 
Clinical Assessments 
Vital signs8 
x 
X 
X 
X 
X 
X 
 
Physical 
examination9 
x 
X 
X 
X 
X 
X 
 
ECOG Performance 
status 
x 
X 
X 
X 
X 
X 
 
Adverse event 
collection 
x 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
x 
X 
X 
X 
X 
X 
 
Survival follow up10 
 
 
 
 
 
 
X 
Laboratory Studies 
Hematology11 
X 
X 
X 
X 
X 
X 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 16 of 59 
Chemistry panel12 
X 
X 
X 
X 
X 
X 
 
Magnesium level 
X 
X 
X 
X 
X 
X 
 
CEA13 
X 
X 
X 
X 
X 
 
Serum pregnancy 
test14 
X 
X 
 
Disease Assessments 
Imaging (CT/MRI)15 
X 
Every 8 weeks from C1D1 
X16 
 
RECIST 1.1 
measurement17 
X 
 Every 8 weeks from C1D1 
X17 
 
 
Treatment Compliance 
Cetuximab 
 
X 
X 
X 
 
 
 
Correlative Studies 
NGS18 
X 
 
 
 
 
 
 
Blood CfDNA19 
 
X at C1D1 and then every 8 weeks (see footnote)  
 
 
 
1 Screening procedures must be completed ≤ 28 days prior to C1D1 unless noted otherwise. 
2 C1D1 procedures do not need to be repeated if screening procedures were performed ≤ 7 days of the start of treatment. 
3 Treatment will continue until progression or unacceptable toxicity. 
4 The end of treatment visit should occur when the decision to discontinue treatment is made. If this visit overlaps with a regularly scheduled visit, only the 
procedures listed in the calendar for the EOT visit will be performed. All end of treatment procedures should be completed ≤ 7 days after the decision to 
discontinue treatment has been made 
5 All patients will have a safety follow-up visit 30 days (± 7 days) after last dose of study drug, unless the subject had an EOT visit conducted 30 days after 
discontinuation of treatment.  
6 History of the malignancy understudy will be collected at the screening visit with special attention to prior regimens (duration of therapy, best response on 
therapy, date of discontinuation, and reason for discontinuation), surgery, radiation therapy, and sequence. 
7 To register eligible subjects on study, complete a Clinical Trials Office Subject Registration Form and submit to CTORegistrations@hci.utah.edu. 
8 Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, weight, and body temperature. Height will be captured at 
screening only. 
                                               


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 17 of 59 
                                                                                                                                                                                                                 
9 If necessary to facilitate scheduling, the physical exam may occur one day prior to study treatment. 
10 Subjects will be contacted every 3 months (±14 days) after study treatment discontinuation until death, end of the study, or withdrawal of consent, whichever 
comes first. 
11 Hematology includes CBC with differential and platelets. Labs may be performed ≤ 3 days prior to a scheduled day one visit except for cycle one day one labs 
which may be completed ≤ 7 days prior to cycle one day one. 
12 Chemistry includes a Complete Metabolic Panel (Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, 
Calcium, Carbon Dioxide, Creatinine, Chloride, Glucose, Total Potassium, Protein, Sodium, and Urea Nitrogen). Labs may be performed ≤ 3 days prior to a 
scheduled day one visit except for cycle one day one labs which may be completed ≤ 7 days prior to cycle one day one. 
13 CEA is the tumor marker that will be drawn on day one of each cycle.  
14 Pregnancy test (serum) must be obtained at screening ≤ 7 days prior to C1D1 for all women of childbearing potential and as clinically indicated while on 
treatment. 
15 Disease assessment will be repeated every 8 weeks (± 7 days) regardless of dose holds or delays. Subjects who discontinue treatment for reasons other than 
progression will continue to have disease assessments until documented clinical or radiographic progression or initiation of subsequent therapy. 
16 Scans will be completed per investigator discretion and do not need to be repeated if performed within 8 weeks of the EOT visit. 
17 Recist 1.1 Assessments will be done at each imaging assessment. 
18 Previously completed next generation sequencing data will be collected to confirm APC, TP53, and RAS mutational status. NGS will be performed as part of 
standard of care testing and does not need to be repeated during the screening period. NGS previously performed in any CLIA certified laboratory will be 
accepted. 
19  Whole blood will be collected on C1D1 prior to study therapy and then every 8 weeks (± 7 days) coinciding with the disease assessment. When samples are 
due to be collected on the same day as treatment administration, samples will be collected prior to study therapy. 
 
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 18 of 59 
2 
OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
To evaluate the progression free survival (PFS) among patients treated with cetuximab in 
APC, TP53 and RAS mutated refractory metastatic colorectal cancer. 
Primary Endpoint: The primary endpoint is progression free survival (PFS). PFS will be 
measured from the date of first dose of study drug until first documented radiographic 
evidence of disease progression by RECIST criteria 1.1, clinical progression per investigator 
judgement, start of new anti-cancer therapy, or death from any cause.  
 
Secondary Objectives 
To evaluate the overall survival (OS) among patients treated with cetuximab in APC, TP53 
and RAS mutated refractory metastatic colorectal cancer. 
Secondary Endpoint: The secondary endpoint is overall survival (OS). OS will be measured 
from the date of first dose of study drug until death from any cause. Patients who show a 
response to treatment (CR, PR, or SD) may continue treatment (with disease reassessment 
every 8 weeks) until disease progression or the occurrence of unacceptable toxicities. 
 
Exploratory Objectives 
To correlate the plasma APC, TP53, RAS, and BRAF status with tissue testing using 
ultrasensitive cell free DNA (cfDNA) duplex sequencing assay for monitoring disease 
response in patients with metastatic CRC. 
Exploratory Endpoint: The mutation status in the blood or serum is analyzed by duplex 
sequencing assay. This ultrasensitive assay quantitatively detects the variant allele fraction 
(VAF) of APC, TP53, RAS, and BRAF in plasma to monitor response to therapy. The tumor 
is analyzed by using CLIA certified next generation sequencing techniques. 
3 
BACKGROUND AND RATIONALE 
 
Metastatic colorectal cancer and Epidermal Growth Factor Receptor Inhibitors 
Colorectal cancer (CRC) is the second leading cause of cancer death in United States.1 
Metastatic CRC is usually fatal and treatment options are limited including chemotherapy, 
targeted therapy and immune therapy. Two well-characterized EGFR inhibitors (EGFRi; 
cetuximab, panitumumab) are FDA approved as first- and second-line targeted therapies for 
metastatic colorectal cancer (mCRC).2-5 Despite approval, utilization has been modest, 
primarily because of drug restriction to the wild-type (WT) RAS subpopulation.6 Early 
colorectal cancer clinical trial studies involving cetuximab/panitumumab, either as 
monotherapies or as combination therapies, reported that a statistically significant drug 
response was generally observed in WT KRAS patients—but not in mutant (MUT) KRAS 
patients. On the other hand, despite selection, about half of patients with a WT KRAS still fail 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 19 of 59 
to respond to EGFRi treatments, 7,8 suggesting that additional genes, beyond KRAS, may 
negatively contribute to EGFRi response. Recently, mutations in NRAS and BRAF were 
reported to account for EGFRi therapy resistance in some WT KRAS colorectal cancers. More 
recently, left-sided colorectal cancers have been reported to be more favorably associated 
with response to cetuximab/panitumumab than right-sided tumors, as indicated by increased 
response rate (RR), better progression-free survival (PFS), and/ or overall survival (OS).9-14 A 
molecular basis of the laterality of anti-EGFR sensitivity, however, is still poorly understood.  
 Cetuximab Sensitivity Score (CTX-S) 
To model EGFRi sensitivity, a pre-specified cetuximab-sensitivity signature (CTX) score was 
developed and validated in two independent sets of CRC patient samples derived from clinical 
trials15,16 and one set of in vitro cetuximab-treated CRC cell lines.17 We then used it to stratify 
468 tumors in association with concomitant somatic mutations. We found that out of 1321 
sequenced cancer-associated genes, mutations in APC and TP53 were the only genes 
significantly and positively correlated with cetuximab sensitivity scores in all patients (n=468) 
and MSS patients (n=407) (adjusted FDR P<0.0001 for both genes) (Table 1).18   
   Rationale for selection of APC, TP53, RAS patient population 
An integrated analysis–targeted gene sequencing for 1,321 cancer related genes, global gene 
expression, and microsatellite instability (MSI) analyses was performed across a large cohort 
of human colorectal cancers (n= 468). Among several mutated genes identified, striking 
pairwise, statistically significant, correlations were observed between APC, TP53, RAS, and 
BRAF that ultimately suggested a prognostic role for APC.16  
Given the paucity of available clinical trial tissue samples with EGFRi exposure, we elected to 
use a cetuximab sensitivity (CTX-S) gene expression score as a surrogate for cetuximab 
response data in our colorectal cancer cohort, TCGA, and other published data. We found 
that the presence of MUT AP had a striking positive effect on the CTX-S scores of 
KRAS/NRAS–mutated (K/N)-tumors in Moffitt colorectal cancers. Note that because the great 
majority of RAS mutations in colorectal cancers are KRAS mutations (~40%) and the 
frequency of NRAS mutations is much lower (~5%), for simplicity, we used K* to represent 
both KRAS and NRAS mutations (K/N). Although WT RAS tumors (n = 264) had significantly 
higher CTX-S scores (P < 0.0001 for two-tailed Welch t test) than MUTRAS tumors (n=111) 
in which the mutant APK subpopulation was excluded, the APK triply mutated tumors (n= 91) 
had even higher scores (P < 0.0001).18 
When restricted to Moffitt stage IV tumors (n = 110), a striking difference remained for mutated 
K* tumors between the APK* and non-APK* subpopulations. In the TCGA colorectal cancers, 
the mutant APK* tumors and WT RAS tumors had no significant difference in CTX-S scores, 
but both had significantly higher scores than other RAS-mutated tumors. These data suggest 
that some APK* patients (heretofore not treated) may be sensitive to CTX treatment. 
Based on above data which suggest APC, TP53, RAS as potential biomarkers of cetuximab 
response, we propose current phase II study to evaluate efficacy of cetuximab in refractory 
mCRC. 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 20 of 59 
 
 
Investigational Intervention 
 Cetuximab 
Cetuximab is a chimeric human/mouse IgG1 monoclonal antibody that targets epidermal 
growth factor receptor (EGFR). It binds specifically to the epidermal growth factor receptor 
(EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the 
binding of epidermal growth factor (EGF) and other ligands, such as transforming growth 
factor– alpha.  Binding of ERBITUX to the EGFR blocks phosphorylation and activation of 
receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and 
decreased matrix metalloproteinase and vascular endothelial growth factor production.  The 
EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor 
tyrosine kinases including EGFR (HER1), HER2, HER3, and HER4.  The EGFR is 
constitutively expressed in many normal epithelial tissues, including the skin and hair follicle.  
Over-expression of EGFR is also detected in many human cancers including those of the 
colon and rectum. 
Physical and Chemical Properties 
Cetuximab is an epidermal growth factor receptor binding FAB. Cetuximab is composed of 
the Fv (variable; antigen-binding) regions of the 225 murine EGFr monoclonal antibody 
specific for the N-terminal portion of human EGFr with human IgG1 heavy and kappa light 
chain constant (framework) regions. Cetuximab is a clear colorless liquid, with the empirical 
formula C6484H10042N1732O2023S36 and an approximate molecular weight of 152 kDa. 
Pharmaceutical Properties and Formulation  
Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small 
amount of easily visible, white, amorphous, Cetuximab particulates. Each single-use, 50-mL 
vial contains 100 mg of Cetuximab at a concentration of 2 mg/mL and is formulated in a 
preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium 
phosphate dibasic heptahydrate, 0.42 mg/mL sodium phosphate monobasic monohydrate, 
and Water for Injection, USP. Refer to the most recent version of the Investigator’s Brochure 
for more information.  
 Pre-Clinical Experience 
In vitro assays and in vivo animal studies have shown that ERBITUX inhibits the growth and 
survival of tumor cells that over-express the EGFR. No anti-tumor effects of cetuximab were 
observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to 
irinotecan or irinotecan plus 5-fluorouracil in animal studies resulted in an increase in anti-
tumor effects compared to chemotherapy alone. 
 Dose Rationale  
A pharmacokinetic (PK) study by Tabernero et al. suggested no major differences between 
cetuximab 250 mg/m2 every week and cetuximab 500 mg/m2 every 2 weeks. Follow up 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 21 of 59 
clinical study in 2008 by Pfeiffer et.al also suggest Cetuximab 500 mg/m2 every 2 week 
regimen as safe, convenient, and well tolerated regimen in CRC.19 In addition, a population 
pharmacokinetic (PK) modeling analyses compared the predicted exposures of cetuximab 
500 mg every 2 weeks to observed cetuximab exposures in patients who received 
cetuximab 250 mg weekly.20 Also, pooled analyses of overall response rates, progression-
free survival, and overall survival from published literature in patients with CRC and Head 
and Neck cancer, and overall survival analyses using real-world data in patients with mCRC 
who received either the weekly cetuximab or every 2 week regimens.21 In these exploratory 
analyses, the observed efficacy results were consistent across dosage regimens and 
supported the results of the population PK modeling analyses. Based on above studies, 
FDA recently approved a new dosage regimen of 500 mg/m2 as a 120-minute intravenous 
infusion every two weeks for cetuximab.22 
 Clinical Experience 
The clinical safety of cetuximab is studied in number of prior phase III clinical trials in mCRC. 
The most common adverse events are included as below: 
Acne-like Rash: The most common adverse event associated with cetuximab administration 
is acne-like rash. Acne-like rash usually occurs on the face, upper chest, and back, but 
occasionally extends to the extremities and is characterized by multiple follicular or pustular 
appearing lesions characterized histologically as a lymphocytic peri folliculitis or suppurative 
superficial folliculitis. The onset of rash is generally within the first 2 weeks of therapy.  
 
A number of therapeutic interventions have been attempted, including oral and topical 
antibiotics, topical steroids, and rarely, oral steroids. The value of these measures is unknown 
since definitive clinical trials have not be performed. The etiology of the acne-like skin rash is 
believed to be the result of cetuximab binding to EGFR in the epidermis. 
 
Nail Disorder: Nail disorders were reported in 6.4% of patients receiving cetuximab as a single 
agent. The nail disorder is characterized as paronychial inflammation with associated swelling 
of the lateral nail folds of the toes and fingers. The most commonly affected digits are the 
great toes and thumbs. According to investigators, the nail disorder persists for up to 3 months 
after discontinuation of cetuximab. Soaks in aluminum acetate (Burow’s) solution BID-QID will 
prevent secondary infection. Symptom relief may be achieved with standard bandages or with 
the application of liquid bandages (cyanoacrylate preparations). Preliminary analysis in 
patients treated at usually doses (400 mg/m2 initial dose, followed by 250 mg/m2 weekly), 
revealed that the incidence of nail disorders is greater in patients who received more than 6 
infusions (approximately 10%) compared to patients treated with 6 or less infusion of 
cetuximab (approximately 3%). 
 
Allergic Reactions: The majority of the allergic/hypersensitivity reactions described have been 
grade 1 to 2 toxicities with less occurrences of grade 3-4. All reactions responded promptly to 
appropriate medical intervention. 
 
Infusion Reaction: Infusion reactions are distinct from allergic or hypersensitivity reactions, 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 22 of 59 
although some of the manifestation are overlapping. Infusion reactions generally develop 
during or shortly after the infusion. Mild infusion reactions (chills, fever, dyspnea) have been 
reported in 23% of patients receiving cetuximab as a single agent. Severe infusion reactions 
(airway obstruction [bronchospasm, stridor, hoarseness], urticaria, hypotension) were 
reported in 2% of patients receiving single agent cetuximab. Infusion reactions occur most 
often with the first dose. 
 
Pulmonary Toxicity: Interstitial lung disease has been reported in less than 1% of patients who 
have received cetuximab for advanced colorectal cancer, and in one patient with head and 
neck cancer. 
 
Cardiac Toxicity: Recent reports described the occurrence of cardiac dysfunction, chest pain, 
and/or cardiac ischemia/infarction. These events occurred in patients who were receiving 
cetuximab in addition to 5-FU-containing therapy. Cardiac ischemia/infarction and acute 
cardiomyopathy are known side effects of 5-fluorouracil-based chemotherapy. It is presently 
unclear if the addition of cetuximab may increase the risk of 5-FU-related cardiac events. 
Other Toxicities: Other reported or potential toxicities associated with cetuximab include: 
Skin—Pruritus (10%), alopecia 
Gastrointestinal—Diarrhea 
(28%, 
2% 
grade 
3/4), 
nausea/vomiting 
(29%), 
stomatitis/mucositis (11%), anorexia, constipation 
Metabolites—Hypomagnesemia (rarely grade 4 requiring aggressive IV repletion) 
Pulmonary—Interstitial pneumonitis was reported in 3 of 633 (<0.5%) patients; one patient 
died as a consequence. 
EENT—Conjunctivitis (7%)  
Constitutional—Fatigue/malaise, asthenia, infection 
Musculoskeletal—Back pain  
Hematologic— Anemia, leukopenia 
CNS—Headache (25%, 3% grade 3/4) 
 
4 
STUDY DESIGN 
This is a prospective, multi-center, phase II study of up to 25 patients to evaluate the efficacy 
of the EGFR inhibitor, cetuximab in patients with mCRC harboring APC, TP53 and RAS 
mutations. The study will be conducted at Intermountain Healthcare and Huntsman Cancer 
Institute at the University of Utah, Salt Lake City, Utah.   
 
Study Duration 
The estimated duration of the study from start of screening to last participant completed the 
study and duration of participation is approximately 24 months 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 23 of 59 
 
End of Study  
A subject is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Events. 
The study will end when the last subject completes the last visit or last contact, discontinues 
from the study, or is lost to follow-up, whichever occurs first. In addition, the sponsor may 
terminate the study at any time. If at any time, the sponsor terminates the study any subjects 
receiving clinical benefit from the study intervention may roll over to an expanded access 
protocol to ensure continued access to the study medication.  
5 
STUDY POPULATION 
Potential study participants must meet all inclusion criteria and no exclusion criteria to be 
deemed eligible for trial participation. To ensure subject safety, all subjects must be deemed 
eligible at the time of study registration and must continue to meet eligibility criteria up to cycle 
one day one dosing. This eligibility checklist is used to determine subject eligibility and will be 
filed with the enrolling investigator’s signature in the subject research chart. 
 
Inclusion Criteria 
1. _____ Male or female subject aged ≥ 18 years. 
2. _____ Histologically confirmed metastatic colorectal adenocarcinoma with mutant APC, 
TP53 and RAS genes as determined by the local CLIA-certified laboratory are eligible. 
All RAS mutations are allowed (KRAS, NRAS, HRAS). Patients with wild type RAS, APC 
or TP53 are ineligible. 
3. _____ Progression or unwanted toxicities on at least 2 prior lines of treatment including 
5-Flourouracil, oxaliplatin and irinotecan based regimen 
4. _____ Study participants must have measurable disease by RECIST 1.1 criteria by CT 
or MRI. 
5. _____ ECOG Performance Status ≤ 2. 
6. _____ Study participants with treated and/or stable brain metastases are allowed 
7. _____ Study participants must have anticipated life expectancy > 3 months 
8. _____ Adequate organ function as defined as:  
 
Hematologic: 
o Absolute neutrophil count (ANC) ≥ ≥1000/µL 
o Platelet count ≥ 100,000/mm3 
o Hemoglobin ≥ 9 g/dL 
 
Hepatic: 
o Serum Bilirubin ≤ 2 x ULN or ≤ 3 x ULN  for subjects with Gilbert’s syndrome. 
o Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times 
the upper limit of normal (ULN; or 5.0 times the ULN in the setting of liver 
metastases) 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 24 of 59 
 
Renal: 
o Serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 
24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 
times the ULN, a 24-hour urine collection to calculate creatinine clearance 
must be performed) 
9. _____ For female subjects: Because the teratogenicity of cetuximab is not known, the 
patient, if sexually active must have a negative serum pregnancy test or surgically sterile 
or using effective contraception (hormonal or barrier methods) or evidence of post-
menopausal status. The post-menopausal status will be defined as having been 
amenorrheic for 12 months without an alternative medical cause. The following age-
specific requirements apply:  
 
Women < 50 years of age:  
o Amenorrheic for ≥ 12 months following cessation of exogenous 
hormonal treatments; and  
o Luteinizing hormone and follicle-stimulating hormone levels in the 
post-menopausal range for the institution; or 
o Underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
 
Women ≥ 50 years of age: 
o Amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments; or 
o Had radiation-induced menopause with last menses >1 year ago; or 
o Had chemotherapy-induced menopause with last menses >1 year 
ago; or 
o Underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy). 
10. _____ Female subjects of childbearing potential must have a negative pregnancy test 
within 7 days prior to enrollment and male subjects with a sexual partner of childbearing 
potential must agree to use a highly effective method of contraception throughout the 
study and for at least 2 months after last study treatment administration. 
11. _____ Male subjects must agree to use a condom during intercourse for the duration of 
study therapy and for at least 2 months after last study treatment administration. 
12. _____ Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior 
cancer therapy, unless considered clinically not significant by the treating investigator. 
13.  _____ Able to provide informed consent and willing to sign an approved consent form 
that conforms to federal and institutional guidelines. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 25 of 59 
 
Exclusion Criteria 
1. _____ Prior use of systemic anti-EGFR therapy including cetuximab or panitumumab is 
not allowed but prior use irinotecan, oxaliplatin, regorafenib or TAS-102 is allowed 
2. _____ Study participants with prior or concurrent malignancy whose natural history or 
treatment have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen, as determined by the investigator 
3. _____ Study participants with new or progressive brain metastases (active brain 
metastases) or leptomeningeal disease who need immediate CNS specific treatment 
during first cycle of treatment as determined by the treating physician. 
Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy 
and/or surgery and stable for at least 4 weeks before the first dose of study treatment 
will be allowed on trial. Subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of the first dose of study treatment.   
4. _____ Current evidence of uncontrolled, significant intercurrent illness including, but not 
limited to, the following conditions: 
 
The patient has clinically relevant coronary artery disease or history of 
myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia 
or uncontrolled cardiac insufficiency. 
 
The patient has uncontrolled or poorly-controlled hypertension (>180 mmHg 
systolic or > 130 mmHg diastolic. 
 
Any other condition that would, in the Investigator’s judgment, contraindicate the 
subject’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, 
unable to swallow medication, [subjects may not receive the drug through a 
feeding tube], social/ psychological issues, etc.) 
 
5. _____ Known HIV infection with a detectable viral load within 6 months of the anticipated 
start of treatment. 
Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 
months of the anticipated start of treatment are eligible for this trial. 
6. _____ Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination, radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis 
C.  
Note: Subjects with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects 
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA. 
7. _____ Medical, psychiatric, cognitive, or other conditions that may compromise the 
subject's ability to understand the subject information, give informed consent, comply 
with the study protocol or complete the study. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 26 of 59 
8. _____ Known prior severe hypersensitivity attributed to compounds of chemical or 
biologic composition similar to those of cetuximab, or if the patient had red meat 
allergy/tick bite history (NCI CTCAE v5.0 Grade ≥ 3).  
9. _____ Live attenuated and inactive vaccinations within 4 weeks of the first dose of study 
treatment and while on trial is prohibited. COVID-19 vaccines are allowed 
10. _____ The patient is pregnant or breast-feeding. 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
this study.  
 
____________________________  
_________       
_______ 
Investigator Signature  
 
 
Date 
  
            Time 
 
 
Registration 
Subjects must meet all of the eligibility requirements before registration. Study-related screening 
procedures can only begin once the subject has signed the consent form. Subjects must not 
begin protocol treatment prior to registration. 
Treatment should start as soon as logistically possible after registration. 
To register eligible subjects on study, complete a Clinical Trials Office Subject Registration 
Form and submit to CTORegistrations@hci.utah.edu. 
For sites outside of Huntsman Cancer Institute, submit registration forms to 
MultisiteRegistrations@hci.utah.edu  
 
Contraception 
Due to the known abortifacient and teratogenic effects of Cetuximab, a form of highly effective 
contraception is required for the duration of study therapy. Female subjects of childbearing 
potential must use a form of highly effective contraception from the start of study therapy until 2 
months after the last dose of study therapy. Male subjects with a partner of childbearing 
potential must agree to use a method of highly effective contraception from the start of study 
therapy until 2 months after the last dose of study therapy.  
Acceptable highly effective contraceptive methods include: 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Intra-uterine devise (IUD) or hormone-releasing system (IUS) 
 
Any hormonal (estrogen combined with progesterone or progesterone alone) 
contraception associated with inhibition of ovulation: implanted, oral, intravaginal, 
transdermal, or injectable. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 27 of 59 
 
Spermicide with a compatible barrier method (i.e. diaphragm, sponge, or male or female 
condoms). 
 
Abstinence from heterosexual intercourse. 
Due to concern for drug transfer through seminal fluid, male subjects must agree to use a 
condom during heterosexual and homosexual intercourse from the start of study therapy until 2 
months after the last dose of study therapy.  
 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but do 
not meet subject eligibility criteria. These subjects will not be entered into the study or begin 
study intervention. However, minimal information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements. Minimal information includes, but may not be limited to, demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE) experienced 
during screening, but prior to being deemed ineligible. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened at the Investigator’s discretion.  
 
Strategies for Recruitment 
Investigators will identify potential subjects in the setting of their outpatient clinics, in tumor 
boards and referrals from other medical oncologists. All potentially eligible patients irrespective 
of their age, gender, and race will be screened. This study will be posted on clinicaltrials.gov. 
 Number of Subjects 
Up to 25 patients to get 21 evaluable patients for efficacy as defined in Section 9.2.2. 
 Number of Study Sites 
This is a multi-center study conducted at Intermountain Healthcare and Huntsman 
Cancer Institute.   
6 
STUDY INTERVENTION 
 
Administration Schedule 
The treatment plan includes single agent cetuximab. Cetuximab will be administered every 2 
weeks (14 days). The initial dose of 500 mg/m2 is to be administered by IV infusion over 120 
minutes. Each cycle will be defined as 14 days of treatment. 
Sites should make every effort to target infusion timing to be as close to 120 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 120 minutes: -5 min / +10 min). 
In an effort to prevent a hypersensitivity reaction, all patients should be premedicated with 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 28 of 59 
diphenhydramine hydrochloride 50 mg (or an equivalent antihistamine) by IV given 
approximately 30-60 minutes prior to the first dose of cetuximab. Premedication may be 
administered prior tosubsequent doses, but at the Investigator’s discretion, the dose of 
diphenhydramine (or a similar agent) may be reduced. 
Patients should be closely monitored for treatment-related adverse events, especially 
hypersensitivity reactions, during the infusion and the post-infusion observation hour. For the 
duration that patients are on protocol therapy, adverse event monitoring will be done 
continuously. Patients will be evaluated for adverse events at each visit and are to be 
instructed to call their physician to report any clinically significant adverse events between 
visits.  
 
Cetuximab 
 Investigational Product Supplies 
The Investigational Drug Services Pharmacy at Huntsman Cancer Institute and Intermountain 
Healthcare Principal Investigator will ensure appropriately trained and delegated personnel will 
receive, inventory, and stored all investigational products per applicable laws and regulations.  
 Preparation and Dispensing 
The investigator or qualified personnel who are familiar with procedures that minimize undue 
exposure to themselves and to the environment will prepare, handle and dispense all 
investigational supplies. Appropriate records will be kept to accurately show all dispensing 
activates and Investigational Product (IP) will be supplied only to subjects deem eligible for 
study therapy. IP may not be dispensed to subjects who have not been enrolled in the trial.  
Drug preparation: The calculated amount of cetuximab should be withdrawn from the 
appropriate number of vials and injected into an empty sterile container (glass, PVC or non-PVC 
plastic) for IV infusion. Cetuximab should not be mixed with other drugs or diluted with infusion 
solutions. Do not shake. Cetuximab should be administered through a 0.22 micrometer in-line 
filter. The solution should be clear and colorless and may contain a small amount of easily 
visible white amorphous cetuximab particulates. DO NOT SHAKE OR DILUTE. Cetuximab can 
be administered via infusion pump or syringe pump but must not be administered as an IV push 
or bolus. Cetuximab should be piggybacked to the patient’s infusion line. Prime the infusion line 
with cetuximab before starting the infusion. Use 0.9% saline solution to flush the line at the end 
of the infusion. In this study cetuximab will be administered at dose 500 mg/m2 as an IV infusion 
over 120 minutes the initial dose followed by 120 minutes subsequent doses. 
Drug dosing guidelines: The total administered dose of chemotherapy may be rounded up or 
down within a range of 5% of the actual calculated dose. It is not necessary to change the dose 
of chemotherapy or cetuximab administered unless the calculated dose changes by ≥10%. 
Drug Disposal: The unused portions of injectable chemotherapeutic agents supplied as single-
dose preparations will be discarded within eight hours of vial entry to minimize the risk of 
bacterial contamination.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 29 of 59 
 Accountability and Compliance 
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol. At the discretion of the principal investigator, a subject may be 
discontinued from the trial for non-compliance with follow-up visits or study drug.  
Information pertaining to study drug compliance (i.e., date time, and dose) will be recorded in 
the corresponding electronic case report form (eCRF) by the study team.  
Any reason for non-compliance will be documented in the subject’s research chart and the 
corresponding eCRF. At the discretion of the principal investigator, a subject may be 
discontinued from the trial for non-compliance with study visits or study drug. 
All doses of Cetuximab will be administered at the investigational site by qualified medical staff.  
The start and stop times of the infusion, along with the total volume administered, will be 
recorded in the subjects’ medical records. Additionally, the start and stop times of any 
interruptions to infusions and/or changes in the rate of infusion will be recorded in the subject’s 
medical records. Any reasons that a dose other than the protocol-specified dose, rate, or dosing 
schedule was administered should be documented in the subject’s research chart. 
Depending on the patient’s BSA, 7-9 vials for bi-weekly doses will be needed. A suggested 
initial shipment is 20 vials. Will allow 5-7 business days for shipment of drug from receipt of the 
request.  
All products will be shipped via Federal Express in a temperature-controlled container. 
Shipments will be made on Monday through Thursday for delivery Tuesday through Friday. 
There will be no weekend, holiday or Monday delivery of drugs. The cetuximab supplies are 
study-specific but not patient-specific. Cetuximab ordered may be used for multiple patients on 
this study.  
Inside each shipping container, a disposable electronic unit (TagAlert) to ensure the product has 
remained at the appropriate temperature during shipping may be included. This unit may be 
attached to an information card. The LCD display will show “OK” (indicating no alarm has been 
triggered) or a black bar and the number(s) 1-4 (indicating an alarm/alarms have been 
triggered). 
 
Dose Interruptions 
Dose interruptions for study treatment-related AEs are allowed as per the dose modification 
recommendations (Section 6.5). Doses of Cetuximab that were not administered due to toxicity 
will not be replaced within the same cycle. In addition to dose interruption, the need for a dose 
reduction at the time of treatment resumption should also be considered based on the dose 
modifications recommendations. If a toxicity-related dose delay lasts for > 28 days, treatment 
will be discontinued permanently and the subject should be removed from study treatment. If a 
subject requires a dose hold for > 28 days for a non-treatment related adverse event or situation 
(i.e. radiation therapy) the subject may continue on study only after approval and discussion 
with the Principal Investigator and Medical Monitor. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 30 of 59 
 
Dose Reductions 
Following dosing interruption due to treatment-related toxicity, the study drug may need to be 
resumed at a reduced dose as per the dose modification recommendations. Dose reduction 
should proceed by decreasing the administered dose by one dose level per Table 1. 
Once the study treatment has been reduced for a given patient, all subsequent cycles will be 
administered at that dose level. Intra-patient dose re-escalation is not allowed except as 
described in the toxicity management guidelines, Section 6.5 
Table 1: Cetuximab Reduction Levels 
Dose Level  
Cetuximab
Dose Level 0  
500 mg/m2
Dose Level -1 
400 mg/m2 
Dose Level -2 
300 mg/m2 
Dose Level -3 
250 mg/m2 
 
Dose Modifications Guidelines 
Subjects experiencing adverse events attributed to study drug may undergo dose modifications 
for toxicity management. Dose modification guidelines are provided below for adverse events 
considered to be related to study medication. If either medication requires reduction below Dose 
Level -3 for toxicity management, study therapy will be discontinued This study will utilize the 
CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for adverse event 
and serious adverse event reporting. 
Hematological toxicities:  
  No cetuximab dose modifications will be made for hematologic toxicity.  
Gastrointestinal toxicities: 
 
No cetuximab dose modifications will be made for diarrhea, mucositis, nausea, or 
vomiting.  
Pulmonary Toxicity  
 
For grade 2 or worsening pulmonary symptoms unrelated to underlying cancer, 
cetuximab therapy should be stopped and symptoms investigated. Cetuximab therapy 
may resume when symptoms resolve to ≤ grade 1.  
 
For ≥ grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, skip 
cetuximab until interstitial lung disease is ruled out. Discontinue all protocol therapy if 
interstitial lung disease is confirmed.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 31 of 59 
Hypomagnesemia 
 
Hypomagnesemia has been seen with cetuximab. Should hypomagnesemia occur, 
magnesium supplementation should be provided. No dose adjustment is required; 
however, continue careful monitoring. 
Cutaneous Toxicity 
 
Acne is the most common cutaneous toxicity noted with cetuximab. While there is no 
clear evidence of benefit, over-the-counter or prescription acne medications designed to 
treat the acne-like rash may be used for patients who experience the acne-like rash 
associated with EGFR inhibitors. The investigator could also consider concomitant 
treatment with topical and/or oral antibiotics; topical corticosteroids are not 
recommended 
Table 2: Cetuximab Dose Delays Due to Cutaneous Toxicity 
 
Cetuximab 
Outcome 
Cetuximab dose 
modification 
Grade 3 Rash 
1st occurrence 
Skip infusion 1-2 weeks 
If improvement 
Continue 500mg/m2 
If no improvement 
Discontinue cetuximab 
2nd  occurrence 
Skip infusion 1-2 weeks 
If improvement 
Reduce to 400mg/m2 
If no improvement 
Discontinue cetuximab 
3rd occurrence 
Skip infusion 1-2 weeks 
If improvement 
Reduce to 300mg/m2 
If no improvement 
Discontinue cetuximab 
4th occurrence 
Skip infusion 1-2 weeks 
If improvement 
Reduce to 250 mg/m2 
If no improvement 
Discontinue cetuximab 
5th occurrence 
Discontinue cetuximab 
 
 
Grade 4 Rash  
 
Discontinue cetuximab 
 
 
There will be no dose level reductions below a biweekly dose of 250 mg/m2 for cetuximab. 
Cetuximab dose reductions are permanent, that is, there will not be any re-escalation of dose. 
Discontinue cetuximab if doses are skipped for more than 4 consecutive weeks. 
Nail disorders 
 
For grade 3 nail disorders, cetuximab may be skipped for up to 3 weeks and if no 
improvement, reduce dose to 400 mg/m2 for 1st occurrence, 300 mg/m2 for 2nd 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 32 of 59 
occurrence, 250 mg/m2 for 3rd occurrence and discontinue cetuximab if there is no 
improvement after 3 weeks.  
Hypersensitivity and infusion reactions 
 
Note that the NCI CTCAE defines these reactions differently: “Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 
although some of the manifestations are common to both AEs. An acute infusion 
reaction may occur with an agent that causes cytokine release (e.g., monoclonal 
antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.” See the “Syndromes” section of the CTCAE version 5.0 for a 
complete list of signs and symptoms of “Cytokine release syndrome/acute infusion 
reaction;” and see the “Allergy/Immunology” section for a description of hypersensitivity. 
 
Dose modifications for hypersensitivity reactions to Cetuximab: 
• 
For grade 1 hypersensitivity reactions (transient rash, drug fever < 38°C): 
Decrease the infusion rate by 50% until symptoms resolve, then resume at the 
initial planned rate. 
• 
For grade 2 hypersensitivity reactions (urticaria, drug fever ≥ 38°C and/or 
asymptomatic bronchospasm): Stop infusion. Administer H1 and/or H2 blockers, 
and/or steroids according to institutional policy. Restart the infusion when 
symptoms resolve and pretreat before all subsequent doses. Treat according to 
institutional policy. 
• 
For grade 3 or grade 4 hypersensitivity reactions: Stop the infusion. Discontinue 
all protocol treatment and notify the Principal investigator or Medical Monitor.  
Infusion reactions 
• 
For grade 1 or 2 cetuximab infusion reactions: Stop the infusion until symptoms 
resolve, then restart cetuximab at a 50% lower rate of infusion. All subsequent 
doses should be administered at the lower infusion rate. 
• 
For ≥ grade 3 cetuximab infusion reactions: Discontinue cetuximab permanently.  
Other non-hematologic toxicities 
 
For all other ≥ grade 3 non-hematologic toxicities not described above, hold all protocol 
treatment and monitor toxicity at least weekly. If toxicity resolves to ≤ grade 1 or baseline 
within 4 weeks, treatment may be resumed with cetuximab at one lower dose level. 
Dose Modification for Obese Patients 
 
There is no clearly documented adverse impact of treatment of obese patients when 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 33 of 59 
dosing is performed according to actual body weight. Therefore, all dosing is to be 
determined solely by the patient’s actual weight without any modification. This will 
eliminate the risk of calculation error and the possible introduction of variability in dose 
administration. Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol deviation. 
 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the study. 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded. GCSFs may be used for the management of treatment-
emergent neutropenia at the investigator's discretion and according to the current American 
Society of Clinical Oncology (ASCO) guidelines. The use of hematopoietic growth factors is at 
the discretion of the treating physician and according to local institutional standards. For 
example:  study participants who enter the study on stable doses of erythropoietin or 
darbepoetin may continue this treatment, and patients may start either drug during the study at 
the discretion of the treating physician. 
 
Concomitant Medications and Therapies 
All administered concomitant medications (including herbal supplements) and non-medicinal 
therapies (including transfusions) used 28 days prior to Cycle One Day One, and until 30 days 
after the last dose of study therapy will be recorded in the subject’s research chart and 
corresponding eCRF. All medications, including those used to treat adverse events, chronic 
conditions or diseases, or as supportive therapy should be documented in the eCRF.  
Allowed Therapy 
Loperamide: For symptoms of diarrhea and/or abdominal cramping that occur at any time 
during a treatment cycle with cetuximab, patients will be instructed to begin taking 
loperamide. Loperamide should be started at the earliest sign of (1) a poorly formed or loose 
stool or (2) the occurrence of 1 to 2 more bowel movements than usual in 1 day or (3) an 
increase in stool volume or liquidity. Loperamide should be taken in the following manner: 4 
mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock until diarrhea-free 
for at least 12 hours. Patients may take loperamide 4 mg every 4 hours during the night. The 
maximum daily dose of loperamide is 16 mg/day. Patients should be provided with 
loperamide at the initial treatment visit so that they have sufficient supply on hand in case 
antidiarrheal support is required. Additional antidiarrheal measures may be used at the 
discretion of the treating physician. Patients should be instructed to increase fluid intake to 
help maintain fluid and electrolyte balance during episodes of diarrhea.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 34 of 59 
Antiemetics: Patients should receive antiemetics before cetuximab according to the treating 
physician and institutional guidelines.  
Ancillary Therapy  
Hormonal/Other Chemotherapeutic Agents: Treatment with hormones or other 
chemotherapeutic agents may not be administered except for steroids given for adrenal failure; 
hormones administered for non-disease-related conditions (e.g., insulin for diabetes); and 
intermittent use of dexamethasone as an antiemetic.  
 Radiotherapy 
 
If deemed necessary by the treating investigator, palliative radiation therapy for a single site of 
bone or brain metastasis is allowed. The radiation field must not affect any of the target lesions 
designated for disease assessment. Protocol treatment will be held during radiation therapy and 
will be re-started 2 weeks following the conclusion of therapy.  
 Prohibited Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the active treatment period. Subjects are prohibited from receiving the following therapies 
during the treatment phase of this trial:  
 
Anti-cancer systemic chemotherapy or biological therapy;  
 
Other investigational agents;  
 
Radiation therapy (with the exception noted above); 
 
Any live-attenuated vaccine therapies for the prevention of infectious disease (e.g. MMR, 
or rotavirus); COVID-19 vaccines are allowed. 
If a subject requires treatment with one or more of the listed prohibited medications, the subject 
may need to be taken off study therapy. Each case will be considered and if possible, the 
investigator should discuss with the DSMC and Medical Monitor prior to initiating prohibited 
therapy. 
 
Duration of Therapy 
Subjects will receive study treatment until treatment discontinuation criteria is met. Upon 
meeting treatment discontinuation criteria, subjects will continue on the study in follow-up until 
study discontinuation criteria are met.  
 Criteria for the Discontinuation of Treatment (“Off Treatment”) 
Subjects may withdraw from treatment or the study overall at any time at their request, or they 
may be withdrawn at the discretion of the Investigator or Sponsor for safety, behavioral reasons, 
or the inability of the subject to comply with the protocol-required schedule of study visits or 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 35 of 59 
procedures. In addition to the drug-specific discontinuation criteria listed in section 6, the 
following will result in treatment discontinuation: 
 
The subject requests to discontinue the study treatment and/or study procedures;  
 
Clinical deterioration that, in the opinion of the investigator, increases the risk to the 
subject; 
 
Confirmed disease progression based on radiographic progression per RECIST 1.1;  
 
Adverse events or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from study treatment; 
 
Significant noncompliance with the protocol schedule or treatment administration in the 
opinion of the investigator; 
 
Pregnancy; 
 
Patients with grade 4 hypertension must not receive further treatment with cetuximab. 
 Criteria for the Discontinuation of Study (“Off Study”) 
Subjects will be taken off study for the following: 
 
Completed study follow-up period; 
 
Participant or legally authorized representative requests to be fully withdrawn from the 
study;  
 
If, in the investigator's opinion, the continuation of the trial would be harmful to the 
subject's well-being; 
 
The subject is lost to follow-up;  
 
Screen failure; 
 
Death. 
 Withdrawal of consent 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
Subjects who withdraw consent for further participation in the study will not receive any further 
study medications or further study observation.  
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent to 
all further participation in the study including any further follow-up (e.g., survival contact 
telephone calls). Survival status may be obtained from public records for subjects who have 
withdrawn from any further follow-up contact. 
 Long Term Follow-Up 
Upon discontinuation of study therapy, subjects will be followed for survival and the initiation of 
subsequent anticancer therapy from the date of study therapy initiation until death, end of the 
study, or subject withdrawal of consent, whichever comes first. Subjects or their legally 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 36 of 59 
authorized representatives will be contacted every three months (±14 days) from end of study 
treatment until death, end of the study, or subject withdrawal of consent, whichever comes first. 
Survival and subsequent treatment status may be collected by public records, medical records, 
or by contacting the subject or their legally authorized representative by phone. All efforts 
should be made to contact the subject at these time points. Refer below for Lost to Follow-Up 
guidelines. 
 Lost to Follow-Up 
Subjects will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the subject’s 
status at that time. Subjects who refuse to continue participation in the study, including 
telephone contact, should be documented as “withdrawal of consent” rather than “lost to follow-
up.” Investigators should document attempts to re-establish contact with missing subjects 
throughout the study period. If contact with a missing subject is re-established, the subject 
should not be considered lost to follow-up and evaluations should resume according to the 
protocol. 
When a subject is lost to follow-up, site personnel should check hospital records, the subjects’ 
current physician, and a publicly available death registry to obtain a current survival status.  
In the event that the subject has actively withdrawn consent, the survival status of the subject 
can be obtained by site personnel from publicly available death. 
7 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances, outside of 
the control of the Investigator that may make it unfeasible to perform the test. In these cases, 
the Investigator will take all steps necessary to ensure the safety and well-being of the subject. 
When a protocol-required test cannot be performed, the Investigator will document the reason 
for this and any corrective and preventive actions that he or she has taken to ensure that normal 
processes are adhered to as soon as possible. 
 
General Assessments 
 Participant Consent 
Before the initiation of any study procedures, all potential subjects or their legal representative 
must be fully informed of the risks and potential benefits of trial participation and demonstrate 
understanding. An informed consent document must be signed and dated by the participant or 
their legal representative indicating that they understand the risks and consent to participation 
and treatment on the study. The Principal Investigator or their appropriately trained and 
delegated study personnel conducting the informed consent discussion must also sign and date 
the document. A copy of the signed document should be provided to the subject. 
Procedures, laboratory tests, or imaging performed as part of the standard of care prior to 
subject consent may contribute to the assessment of eligibility and/or screening procedures if 
performed during the screening period.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 37 of 59 
 Medical History 
The investigator or appropriately trained and delegated study personnel will collect medical 
history to the extent that supports the assessment of eligibility. The medical history will include 
any active conditions and any conditions deemed to be clinically significant by the treating 
investigator. The use of symptom terms should be discouraged; if possible, terms describing the 
principal condition or syndrome should be used.  
When collecting medical history specific attention should be given to: 
 
Prior history of cancer, family history of cancer 
 
History of Coronary Artery Disease 
 
Alcohol history (never used alcohol, current alcohol user, former alcohol user) 
 
Smoking history (never smoked, current smoker, former smoker) 
 
Pack years (average number of packs per day and number of years smoked) 
 
Current employment status (employed, retired, student, unknown, other) 
 
Insurance status (private insurance, Medicare, Medicaid, VA, military, not insured, self-
pay, unknown, other) 
 Cancer History 
The oncologic history of the malignancy understudy will be collected at the screening visit and 
will include prior regimens (duration of therapy, the best response on therapy, date of 
discontinuation, and reason for discontinuation), surgery, radiation therapy, and sequence. The 
details of genomic sequencing, site of metastases will be collected.  
 Concomitant Medications 
All medications currently being used by a study participant, regularly or as needed, must be 
reviewed and documented by the investigator or qualified designee. Specific attention should be 
given to medications with a protocol required washout as described in the exclusion criteria and 
any medication taken 28 days prior to cycle one day one. Refer to Section 6.7.2 for prohibited 
medications.  
During protocol therapy, any medications taken by the patient or used to treat an adverse event 
will be documented in the subject’s research chart and the corresponding eCRF. If a new 
anticancer therapy is initiated during study follow-up, the new therapy should also be recorded 
in the subject’s research chart and corresponding eCRF.  
 Tumor Mutation Testing 
It is required that all subjects have histological confirmation and documentation of APC, TP53, 
RAS mutation through local laboratory testing. The mutational status must be confirmed by a 
Clinical Laboratory Improvement Amendments (CLIA) approved test using either tumor tissue or 
ctDNA done as part of standard of care testing. Additionally as part of exploratory aim, the blood 
based cell free DNA assay to test for APC, TP53, KRAS,NRAS, HRAS, BRAF will be assessed 
every 8 weeks coinciding with CT imaging. The cell free DNA assay is performed using 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 38 of 59 
ultrasensitive duplex sequencing assay at Intermountain Precision Genomics. The duplex 
sequencing results have a mean duplex depth >22,000x per replicate; and peak duplex depth 
>35,000x per replicate. 
 
Safety Assessments 
 Physical Examinations and Vital Signs 
Subjects will have physical examinations to include major body systems, vital signs (blood 
pressure, heart rate, respiration rate, pulse oximetry, and body temperature), assessment of 
ECOG performance status (see Appendix 1), weight, and height (height will be measured at 
screening only) at the time points described in the Schedule of Events. If necessary to facilitate 
scheduling, the physical exam may occur one day before study treatment.  
 Adverse Events 
Adverse events experienced during trial participation will be collected per the Schedule of 
Events and Adverse Events Section. Each study participant will be questioned about the 
occurrence of adverse events in a non-leading manner. Should the treating investigator feel that 
the adverse event is attributed to study therapy, dose modification guidelines in the Dose 
Modification Section will be followed.  
 Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the Study 
Calendar and when clinically indicated. Laboratory tests may be performed up to 3 days before 
the scheduled clinic visit. All safety laboratory analyses will be performed by the local laboratory 
for each study center. When applicable, all safety laboratory assessments must be reviewed by 
the treating investigator before study drug administration. When applicable, results from the 
pregnancy test must also be available for review before dosing.  
Table 3 : Laboratory Assessments 
Laboratory Assessments 
Complete Blood Count with 
Platelet Count and 
Differential 
 
White Blood Cell Count 
 
Hemoglobin 
 
Platelets 
 
Absolute Neutrophil Count 
 
Absolute Lymphocytes
 Chemistry 
 
Complete Metabolic Panel 
o Sodium 
o Potassium 
o Chloride 
o Carbon Dioxide 
o Alkaline Phosphatase 
o Aspartate Aminotransferase 
o Alanine Aminotransferase 
o Urea Nitrogen 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 39 of 59 
o Glucose 
o Creatinine 
o Calcium 
o Protein 
o Albumin 
o Bilirubin 
 
Magnesium level 
Pregnancy
 
Beta-hCG Qualitative Serum 
Tumor Marker
 
CEA 
Bloodmarker
 
CfDNA 
 
Efficacy Assessments 
 Disease Assessment 
Disease assessments must include all known or suspected sites of disease; therefore, the 
decision for body areas to be scanned will depend on the extent of disease. The minimum 
recommended body areas to be scanned is chest, abdomen, and pelvis. Response will be 
defined by RECIST 1.1 (Appendix 3). 
Disease assessments will be evaluated radiologically and conducted at baseline (within 28 days 
before the first dose of study treatment) and then every 8 weeks thereafter regardless of dose 
holds or delays. Disease assessments will continue until disease progression. Subjects who 
discontinue treatment for reasons other than progression will continue to have disease 
assessments until documented clinical or radiographic progression or initiation of subsequent 
therapy.  In addition, radiological tumor assessments will be conducted whenever disease 
progression is suspected (e.g. symptomatic deterioration) or when clinically indicated. The 
schedule of tumor assessments should be fixed according to the calendar, starting with cycle 
one day one, regardless of treatment delays or interruptions due to toxicity. 
Brain CT or MRI scans are required at baseline for all subjects with stable brain lesions and for 
those for whom Central Nervous System (CNS) involvement is suspected. If stable brain 
metastases are present at baseline, brain imaging should be repeated at each tumor 
assessment. Otherwise, brain imaging will be conducted post-baseline only when clinically 
indicated. 
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons. Consistent imaging modality should be used for all disease assessments. 
 Photography of Cutaneous Lesions 
Cutaneous lesions not evaluable by CT or MRI will be documented by color digital photography, 
including a ruler to estimate lesion size. Photographs must be taken in a manner that protects 
subject identity and confidentiality (e.g. covering eyes or defining marks or characteristics). 
Cutaneous lesions may be considered target lesions if they meet RECIST v1.1 criteria, 
otherwise they may be considered non-target lesions. Photographs of cutaneous lesions will be 
taken at screening and on the same day as a tumor assessment visit, or at the first clinic visit 
following each tumor assessment 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 40 of 59 
 
Correlative Studies 
To support exploratory objectives and correlative studies, blood samples will be collected at the 
time points indicated on the Schedule of Events. Any blood remaining after completion of the 
indicated testing will be stored for future unspecified research. With the participant’s approval 
and as approved by the Institutional Review Board (IRB), de-identified biological samples will be 
stored at Huntsman Cancer Institute’s and Intermountain Healthcare Biorepository. These 
samples could be used to research the causes of cancer, its complications, and other conditions 
for which individuals with cancer are at increased risk, and to improve treatment.  
At the time of consent, subjects will be given the opportunity to opt-out of the use of their 
samples for future research. During the conduct of the study, an individual participant can 
choose to withdraw consent to have biological specimens stored for future research. However, 
the withdrawal of consent with regard to biosample storage may not be possible after the study 
is completed.   
 Blood Samples 
A blood sample will be obtained from patients to perform duplex DNA sequencing for APC, 
TP53, KRAS, BRAF, HRAS, and NRAS mutations. Up to 10 mLs of blood will be collected at 
the time-points indicated on the Schedule of Events and processed to cfDNA. These 
samples will be used to identify predictive biomarkers for response and resistance. 
 
Remote Visits/Telehealth 
Some study visits and/or procedures may be conducted remotely in the following 
circumstances: 
 
Telehealth visits do not present an increased risk to the participant. 
 
All necessary data for the trial can be collected. 
 
Procedures do not include research related imaging, lab samples, and/or pathology 
which should be conducted in person. 
Note: The method of telehealth should be documented in the participants’ charts.  
8 
ADVERSE EVENTS 
 
Definitions 
 Adverse events 
21 CRF 312.32, ICH GCP, and OHRP define an adverse event as any untoward medical 
occurrence whether or not considered treatment-related. This definition extends to the 
worsening of any preexisting condition or symptom. All adverse events experienced during trial 
participation should be documented in the subject’s research chart and corresponding eCRF 
Laboratory abnormalities should not be listed as adverse events unless deemed clinically 
significant by the investigator or qualified designee. An abnormal test result or findings should 
not be recorded as an adverse event unless the following conditions are met: 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 41 of 59 
 
Associated with clinical symptoms; and/or 
 
Requires intervention (medical, surgical, or additional diagnostic testing); and/or 
 
Results in a change in study drug dosing; and/or 
 
Deemed by the investigator or qualified designee to be an adverse event. 
 Serious Adverse Events 
 A serious adverse event is defined as any untoward event that is: 
 
Fatal; 
 
Life-threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Medically significant; 
 
Causes a congenital abnormality or birth defect; 
 
Requires or prolongs inpatient hospitalization. 
Investigator judgment must be used to assess an event as medically significant. The event may 
not be life-threatening or cause disability but may jeopardize the subject and require intervention 
to prevent the other SAE outcomes. 
The following situations should not be reported as an SAE: 
 
Hospital admission not associated with a precipitating AE such as: 
o Treatment for a preexisting condition not associated with a new AE or the 
worsening of a preexisting condition; 
o Admission for social or administrative reasons; 
o Optional admission or elective surgery; 
o Observation; 
o Preplanned treatments or surgical procedures as noted at baseline; 
o Admission for the administration of blood products. 
 
Adverse Event Reporting 
The investigator and qualified designees are responsible for the detection, documentation, 
reporting, and follow-up of all adverse events experienced by subjects during trial participation. 
AEs and SAEs will be recorded from the initiation of study therapy until 30 days after last dose 
of study therapy or until new anti-cancer therapy is started. The following information will be 
required for each adverse event: 
 
Event severity as graded by the CTCAE v.5;  
 
The causality assessment to study medication per the below definitions; 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 42 of 59 
 
Expectedness 
 
Event duration; 
 
Any action taken to treat or manage the event; 
 
Event outcome. 
 Severity Assessment 
The severity of adverse events should be assessed by CTCAE v.5. If an event is not listed in 
CTCAE v.5 then the assessment of severity should follow the general guidelines listed in table 
3. 
Table 4 : Severity Assessment 
Grade 
Severity Description 
1 
Mild event that generally does not require intervention. 
2 
Moderate event that may require intervention. 
3 
Severe event that requires intervention. 
4 
Life-threatening event that requires urgent intervention. 
5 
Death. 
Events meeting grade 4 or 5 severity description should be reported promptly as SAEs unless 
otherwise indicated in Section 8.1.1  
 Causality Assessment 
The Investigator should assess the causality or relationship of AEs and SAEs to study therapy. 
The Investigator should consider if there is evidence that the investigational product caused the 
event taking into consideration timing, organ system affected, type of event, and possible 
alternative etiologies. The relationship of the AE to study treatment will be reported as listed 
below. These categories will be defined as follows: 
 
Definitely related – a clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent disease or other drugs or chemicals. The response to the withdrawal of the 
drug (dechallenge) should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if 
necessary. 
 
Probably related – a reasonable time sequence to the administration of the drug, unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 43 of 59 
 
Possibly related – a reasonable time sequence to administrations of the drug, but which 
could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
 
Unlikely related –a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
 
Not related – there is no evidence of a causal relationship between the study drug and 
the event and in which other drugs, chemicals or underlying disease explain the event. 
Adverse events reported as definitely, probably, and possible, related to study therapy will be 
reported as related. In cases when the Investigator is unsure of the causality of an AE, the event 
will be considered related to study therapy unless deemed otherwise by the DSMC. 
 Expectedness 
The Investigator will be responsible for determining whether or not an adverse event was 
expected or unexpected. Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert (PI) or current Investigator Brochure (IB). Unexpected 
adverse events are those not listed in the PI or current IB or not identified. This includes 
adverse events for which the specificity or severity is not consistent with the description in the PI 
or IB. For example, under this definition, hepatic necrosis would be unexpected if the PI or IB 
only referred to elevated hepatic enzymes or hepatitis. 
  Action Taken and Outcome 
Start and stop dates will be required for all adverse events and serious adverse events. The 
action taken in response to the event should also be recorded in the subject’s research chart 
and corresponding eCRF. Event action terms include none, medication administered, non-drug 
therapy administered, surgery, hospitalization, or other with the option to specify. If a new 
medication is added the medication should also be added to the concomitant medications log. 
All adverse events should be followed until stabilization or resolution. Event outcomes may be 
classified as resolved, resolved with sequelae, ongoing, or death.  
 Reporting Serious Adverse Events 
All serious adverse events should be reported as soon as possible but no later than one 
business day after the Investigator becomes aware. All SAEs must be reported on the 
MedWatch 3500A form and submitted to compliance@hci.utah.edu. The HCI Clinical Site 
Monitor will, in turn, submit the MedWatch form to the Medical Monitor. The RCO will 
summarize and present all reported SAEs according to the Data and Safety Monitoring Plan at 
the monthly DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of event 
causality, event grade, and the expectedness of the event. Although the Investigator may not 
know all the information at the time of the event, the available information should be reported. 
An SAE follow-up may be submitted at a later date once more information is known. It is 
required that follow-up reports be submitted until the SAE is resolved. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 44 of 59 
The HCI DSMC will notify all participating sites of all unexpected and related SAEs via the 
Research Compliance Office (RCO). The RCO will also notify all investigators at remote clinical 
sites participating in a multisite trial of any other safety updates, including external safety 
reports, manufacturer’s reports, and updates to the investigator’s brochure. 
 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the Event 
Description (Section B.5) of the MedWatch 3500A form: 
 
Protocol number and title description 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics (Section B.6) 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Expectedness of the event (i.e., expected or unexpected event). 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes available, 
however, a follow-up report should be submitted within 7 days of knowledge of event resolution. 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as a follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
 
Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The subject identifiers are important so that the new information is added to 
the correct initial report) 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 FDA Notifications 
This study is IND exempted.  
 IRB Notification 
The University of Utah IRB requires any unanticipated problems that may increase the risk to 
research participants be promptly reported. All study-therapy related, unexpected adverse 
events whose nature, severity, or frequency is not consistent with either: 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 45 of 59 
 
The unknown or foreseeable risk of adverse events that are described in the protocol 
related-documents, such as the IRB-approved research protocol, applicable investigator 
brochure, the current IRB-approved informed consent document, and/or other relevant 
sources of information, such as product labeling and package inserts; or 
 
The expected natural progression of any underlying disease or condition of the 
subject(s) experiencing the adverse event. 
Adverse events meeting this criterion must be promptly reported to the IRB within 10 business 
days of awareness.  
 Drug Manufacturer Notifications 
 
All serious adverse events regardless of relationship to study drug must be reported to 
Eli Lilly.   
 
SAE reports should be documented on a MedWatch form and can be faxed or emailed 
the local safety representative using the following information:  
o Local fax number: 866-644-1697 
o Local telephone number:  317-453-3402 
o Email: mailindata_gsmtindy@lilly.com 
  
 
Investigator and Institution agree: 
o To provide Lilly with a copy of all information Investigator and/or Institution 
submit to regulators related to any adverse events for the Study Drug that 
occur during the Study that Investigator and/or Institution have not otherwise 
provided Lilly. 
o To notify Lilly, sub-investigators, and the IRB of any problems involving risk to 
Study patients and report new safety information to IRBs in accordance with 
applicable requirements; 
o To notify Lilly within fifteen (15) business days of Investigator and/or Institution 
receiving notification of any “serious” and “unexpected” adverse event 
experienced by a patient participating in the Study and receiving Study Drug 
that is possibly related, based on Investigator’s assessment, to the Study Drug.   
 
For purposes of this requirement, “serious” means:   
 
(1) death;  
 
(2) in-patient hospitalization or prolonged hospitalization; 
 
(3) life-threatening;  
 
(4) persistent or significant disability or incapacity; 
 
 (5) congenital anomaly or birth defect;  
 
or (6) other serious events that may jeopardize the patient and 
may require medical or surgical intervention to prevent one of 
the other five listed outcomes and “unexpected” means an 
adverse drug event that is not consistent with applicable product 
information in the current labeling for the Study Drug.  
 
Serious adverse events should be reported to Lilly using a 
Medwatch form to Lilly.  Investigator and Institution further agree 
to make available promptly to Lilly such records as may be 
necessary and pertinent for Lilly to further investigate an 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 46 of 59 
adverse event in the Study that is possibly associated with the 
Study Drug 
 
Special Situations 
 Pregnancy or Breastfeeding  
Pregnancy and breastfeeding exposure should be tracked from the start of study therapy until at 
least 5 half-lives after the last dose of study drug.  
Although pregnancy is not considered an adverse event, any exposure to the investigational 
products during pregnancy or breastfeeding must be reported promptly. Exposure may occur by 
a woman actively receiving study therapy or the partner of a male subject actively receiving 
study therapy becomes pregnant. Any possible pregnancy or breastfeeding exposure during 
study therapy and up to 2 months after the last dose of study therapy or up to the start of 
subsequent anticancer therapy (whichever happens first) must be reported within one business 
day of awareness regardless of the occurrence of an SAE. Should a woman on study therapy 
become pregnant, she should immediately discontinue study treatment. 
Women exposed to IP during pregnancy or while breastfeeding will be followed for pregnancy 
outcome and neonate health. Pregnancy outcomes may meet criteria as an SAE if ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly occurs. Congenital anomalies that occur in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death should be reported as an SAE. Any neonatal 
deaths that occur up to 30 days after birth or breastfeeding exposure should be reported as an 
SAE. Further follow-up on birth outcomes and neonate health will be handled on a case-by-case 
base. 
 Hy’s Law Cases 
It is important to identify possible cases of Drug-Induced Liver Injury (DILI) early. Total bilirubin, 
AST, and ALT should be regularly monitored for elevations indicative of liver damage. Subjects 
who experience a transaminase elevation above three times the ULN should be monitored 
frequently to determine if the elevation is transient. Transient elevations are an indication of 
adaption and these subjects may be identified as “adaptors.” However, should a transaminase 
elevation be followed by total bilirubin (TBili) increase, a DILI could be occurring. Any laboratory 
abnormalities meeting the following criteria should be reported within 24 hours of awareness: 
 
AST or ALT elevation > 3 x ULN; and 
 
Total bilirubin > 2 x ULN; and 
 
Absence of cholestasis; and  
 
No alternative explanation for the elevations (e.g., impaired glucuronidation capacity 
caused by genetic [Gilbert syndrome]; viral hepatitis A, B, or C, preexisting or acute liver 
disease; or another drug capable of causing the observed injury). 
Investigators should conduct reasonable investigations to rule out other possible etiologies. 
Investigators should take into consideration the subject's use of ethanol, acetaminophen, 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 47 of 59 
recreational drugs, herbal supplements, and medical history. A potential Hy’s Law case will not 
be considered a confirmed case until all results and considerations have excluded alternative 
etiologies.  
Possible cases of DILI will be promptly reported to the FDA prior to full work up to rule out other 
etiologies. Reporting should be completed on a MedWatch 3500A form and should include all 
available information, including the likelihood that the drug caused the event. Subjects should 
be closely followed until the resolution of the event.  
Subjects who experience possible DILI should be managed per the Dose Modification 
Guidelines.  
 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) at HCI is charged with ensuring the risk/benefit 
balance for subjects undergoing study therapy. The purpose of the DSMC is to ensure subject 
safety and make recommendations for study conduct to ensure subject safety and data integrity. 
The DSMC is chaired by a medical oncologist and may include, but is not limited to, 
representatives from medical oncology, oncological sciences, biostatistics, and pharmacy. 
The roles and responsibilities of the DSMC are described in the NCI-approved Data and Safety 
Monitoring (DSM) plan. The activities of the committee include reviewing adverse events 
(including SAEs), deviations, important medical events, and approving cohort/dose escalations. 
Amendments that increase risk, increase treatment exposure, or impact study objectives will 
also be reviewed by the DSMC. If the DSMC and/or the PI have concerns about unexpected 
safety issues or AE trends, the study may be stopped and an unplanned safety data analysis 
may be conducted. Enrollment will not resume until the issues are resolved. The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office. 
All trials will be assigned an oncologist member of the DSMC to serve as a medical monitor. In 
rare cases, an external medical monitor may be assigned. The Medical Monitor will be notified 
of all serious adverse events (SAEs). Specific notifications will also be issued when a dose-
limiting toxicity is encountered and when the RP2D is defined. Approval from the Medical 
Monitor is required for all dose escalations. All serious adverse events (SAEs) occurring in 
subjects treated at HCI or its affiliates will also be reviewed by the full DSMC monthly.  
Each trial is assigned a research compliance officer who will be responsible for monitoring the 
trial and reporting to the DSMC. The assessed risk level of the trial will determine the frequency 
with which monitoring occurs. The Research Compliance Officer monitor will review the study 
status and summarize enrollment, toxicities, SAEs, dose-escalation, statistical endpoints (e.g., 
stopping rules), deviations, and any other pertinent information for the full DSMC membership at 
the regularly scheduled meetings.  
Audits will be conducted for all trials one year after enrollment begins and annually thereafter. 
Audits may be conducted more frequently as requested by the DSMC, Institutional Review 
Board (IRB), Protocol Review and Monitoring Committee (PRMC), Research Compliance Office 
management, or the Principal Investigator.  
DSMC oversite will be tailored to the assessed risk level of the trial. Trials are categorized 
amongst three risk levels: high, moderate, and low.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 48 of 59 
This trial has been classified as high risk and therefore will be monitored by RCO and reviewed 
by DSMC after the first subject is enrolled and then quarterly thereafter. 
9 
STATISTICAL CONSIDERATIONS 
 
Sample size determination 
Assuming a parametric exponential survival model, with a minimum 12-month follow-up and a 
10% significance level (1-sided), 21 patients will achieve an 90% power for PFS analysis, 
assuming a null hypothesis median survival of 1.7 months and an alternative hypothesis median 
survival of 4 months. The null hypothesis is based on the literature for median progression free 
survival noted in multiple randomized phase III trials who received no additional therapy. The 
sample size estimation for this and alternative designs are summarized in the following Table 4. 
(see the line below shaded in Table 4). 
 
Table 5: Statistical Plan 
Numeric Results  
Test Based on Theta-hat with Fixed Running Time t0 and Without Replacement Sampling.  
H0: Theta = Theta0. Ha: Theta = Theta1 < Theta0. Reject H0 if Theta-hat ≤ ThetaC. 
 
 
Time 
 
 Target Actual Target Actual Theta 
Power 
N 
t0 Theta0 Theta1 
Alpha 
Alpha 
Beta 
Beta 
C 
 
0.80684 
21 12.000 
0.4 
0.2 0.05000 0.05000 0.20000 0.19316 
0.3 
 
0.90532 
28 12.000 
0.4 
0.2 0.05000 0.05000 0.10000 0.09468 
0.3 
 
0.80420 
15 12.000 
0.4 
0.2 0.10000 0.10000 0.20000 0.19580 
0.3 
 
0.90396 
21 12.000 
0.4 
0.2 0.10000 0.10000 0.10000 0.09604 
0.3 
 
 
References 
Bain, L.J. and Engelhardt, M. 1991. Statistical Analysis of Reliability and Life-Testing Models. Marcel Dekker. New York. 
Epstein, Benjamin. 1960. 'Statistical Life Test Acceptance Procedures.' Technometrics. Volume 2.4, pages 435-446. 
Juran, J.M. 1979. Quality Control Handbook. McGraw-Hill. New York. 
Schilling, Edward. 1982. Acceptance Sampling in Quality Control. Marcel-Dekker. New York. 
Report Definitions 
Power is the probability of rejecting a false null hypothesis. 
N is the size of the sample drawn from the population. 
Alpha is the probability of rejecting a true null hypothesis. 
Beta is the probability of accepting a false null hypothesis. 
Theta0 is the Mean Life under the null hypothesis. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 49 of 59 
Theta1 is the Mean Life under the alternative hypothesis. 
t0 is the test duration time. It provides the scale for Theta0 and Theta1. 
r is the number of failures. 
Summary: 
A sample size of 21 achieves 90% power to detect the difference between the null hypothesis 
mean lifetime of 0.4 and the alternative hypothesis mean lifetime of 0.2 at a 0.10000 
significance level (alpha) using a one-sided test based on the elapsed time. Failing items are 
not replaced with new items. The study is terminated when it has run for 12.000 time units. 
 
Population for Analyses 
 Evaluable for toxicity 
Study participants who have received at least one treatment with cetuximab infusion will be 
evaluable for toxicity. 
 Evaluable for Efficacy  
Study participants who have at received at least 2 doses of cetuximab and have had one set 
of restaging CT scans or documented clinical progression will be evaluable for efficacy 
All study participants who have received one dose of cetuximab will be included in safety 
data sets.  
Study participants who fail to receive at least 2 doses of cetuximab and have at least one 
set of CT scans or documented clinical progression will be replaced to ensure 21 response 
evaluable patients. 
 
Primary Endpoint 
The progression free survival (PFS) is the primary endpoint. PFS will be measured from study 
entry until first documented radiographic disease progression by RECIST criteria 1.1, clinical 
progression per investigator judgement, start of new anti-cancer therapy, or death from any 
cause.  
 
Secondary Endpoints 
Overall Survival (OS) will be assessed as the time between trial initiation and death of any 
cause. Subjects will be followed for OS after the initiation of therapy until death from any cause. 
Subjects lost to follow-up will be censored at the time of last known follow-up. Subjects still alive 
will be censored after five years from the date of study therapy initiation. Kaplan-Meier methods 
will be used to analyze OS.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 50 of 59 
10 ETHICAL AND REGULATORY CONSIDERATIONS 
 Human Subjects Protection 
The study will be conducted in accordance with the protocol, 21 CFR, HIPAA regulations, the 
Belmont Principles, ICH Guidelines for Good Clinical Practice (GCP), and the Declaration of 
Helsinki. Informed consent will be obtained from all research participants or their legally 
authorized representative before performing any study procedures using the most recent IRB 
approved version.  
 Personal Data Protection 
All parties will take all necessary actions required for the protection of subject personal data. 
Subjects enrolled in the study will be assigned a subject number and will be reference by this 
number. Directly identifiable data will be omitted from reports, publications, and other 
disclosures. All personal data will be store at the study site in encrypted electronic and/or paper 
form stored in a locked and secured facility. The site will be responsible for maintaining a list of 
subjects linking each subject with their subject number. Data will only be accessed by 
appropriate personnel and will be password protected or securely stored in a locked room. In 
the case of a potential breach of personally identifiable data, the site will take responsibility to 
ensure appropriate action is taken according to institutional practice and applicable laws and 
regulations.  
 Institutional Review 
Before the initiation of the study, the Investigator will have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant documents, 
(e.g., recruitment advertisements, questionnaires, if applicable), from the IRB. All 
correspondence with the IRB should be retained in the Investigator’s regulatory file. Changes to 
the protocol or approved documents may not be made until IRB approval has been received. 
However, if a change is necessary to eliminate immediate hazards to the subjects, prospective 
approval is not necessary.  
The investigator or designee should provide the IRB with reports, updates and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 Investigator Responsibilities 
The Investigator is responsible for ensuring the trial is conducted in compliance with the current 
IRB approved version of the protocol, GCP, the Declaration of Helsinki, and any applicable 
national and local laws and regulations.   
 Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval. However, prospective IRB 
approval will not be sought when an amendment is required to eliminate immediate risk to 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 51 of 59 
subjects on study. In these cases, amendments will be retrospectively submitted to the IRB for 
review and approval. 
Any amendments to the protocol that significantly affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the study will be submitted to the FDA for review. 
 Protocol Deviations 
A deviation will be defined as any noncompliance with ICH GCP or the clinical protocol 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the study staff. As a result of the deviation, a corrective action must be implemented to 
ensure future deviation does not occur. It is the Investigator’s responsibility to identify and report 
deviations from ICH GCP or protocol requirements. These deviations and corrective action 
should be documented in the subject’s research chart, the associated eCRF, and reported to 
the IRB per their policy.  
11 DATA HANDLING 
 Recording and Collection of Data 
Primary source documentation will come directly from the subject’s medical record. All source 
documentation should be attributable, legible, contemporaneous, original, accurate, complete, 
and available. All documentation should be signed and dated by applicable personnel. Relevant 
source data will be transcribed into the electronic case report forms (eCRFs) and should be 
completed as soon as possible after data availability. The eCRFs will be part of a computerized 
database grounded in the protocol requirements and study objectives. The database will be 
designed to comply with 21 CFR Part 11.  
The Investigator has ultimate responsibility for ensuring that all data collected and recorded is 
accurate and consistent. He/she will need to sign off on all eCRFs to attest that all data 
recorded on them is true. A separate screening log of all the subjects screened for participation 
in the study must also be maintained and should include gender, age, eligibility status, the 
reason for ineligibility (if applicable), and study allocated subject number (if applicable). 
 Data Management 
To accommodate evaluations, inspections, and/or audits from regulatory authorities, the 
Investigator must maintain all study records including subject identity, source documentation, 
original signed consent form, safety reporting forms, monitoring logs, IP accountability records, 
relevant correspondence (e.g., letters, emails, meeting minutes, etc.), and any other documents 
pertaining to the conduct of the study. The Investigator must also agree to the maintain source 
documents for a minimum of two years after regulatory approval of the investigational product 
per 21 CFR 312.57. For the duration of record maintenance, records must be stored in a secure 
location and protected from the elements. If for any reason the Investigator at another 
participating institution is no longer able to retain study records, the HCI Investigator Sponsor 
should be notified before any destruction so that the records can be transferred to an 
acceptable designee. Once retention requirements have been met, the participating site 
Investigator must get HCI Investigator Sponsor approval before the destruction of any records.  


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 52 of 59 
12 PUBLICATION PLAN 
In accordance with U.S. regulations and the best interest of research ethics and transparency, 
this study will be registered on ClinicalTrials.gov before subject enrollment. US Basic Results 
will also be reported and available on ClinicalTrials.gov within one year of the primary 
completion date, regardless of formal journal publication. All results will be reported objectively, 
accurately, balanced, and completely, regardless of the study outcome.  
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 53 of 59 
13 REFERENCES 
 
1. 
Siegel RL, Miller KD, Fuchs HE, et al: Cancer Statistics, 2021. CA: A Cancer 
Journal for Clinicians 71:7-33, 2021 
 
2. 
De Roock W, Claes B, Bernasconi D, et al: Effects of KRAS, BRAF, NRAS, and 
PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory 
metastatic colorectal cancer: a retrospective consortium analysis. The Lancet Oncology 11:753-
762, 2010 
 
3. 
Douillard J-Y, Oliner KS, Siena S, et al: Panitumumab–FOLFOX4 Treatment and 
RAS Mutations in Colorectal Cancer. New England Journal of Medicine 369:1023-1034, 2013 
 
4. 
Lievre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of 
response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-5, 2006 
 
5. 
Sartore-Bianchi A, Martini M, Molinari F, et al: PIK3CA mutations in colorectal 
cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer 
Res 69:1851-7, 2009 
 
6. 
Allegra CJ, Jessup JM, Somerfield MR, et al: American Society of Clinical 
Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With 
Metastatic Colorectal Carcinoma to Predict Response to Anti–Epidermal Growth Factor 
Receptor Monoclonal Antibody Therapy. Journal of Clinical Oncology 27:2091-2096, 2009 
 
7. 
Malapelle U, Carlomagno C, de Luca C, et al: KRAS testing in metastatic 
colorectal carcinoma: challenges, controversies, breakthroughs and beyond. J Clin Pathol 67:1-
9, 2014 
 
8. 
Mosakhani N, Lahti L, Borze I, et al: MicroRNA profiling predicts survival in anti-
EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and 
BRAF. Cancer Genet 205:545-51, 2012 
 
9. 
Arnold D, Lueza B, Douillard JY, et al: Prognostic and predictive value of primary 
tumour side in patients with RAS wild-type metastatic colorectal cancer treated with 
chemotherapy and EGFR directed antibodies in six randomized trials. Annals of Oncology 
28:1713-1729, 2017 
 
10. 
Holch JW, Ricard I, Stintzing S, et al: The relevance of primary tumour location in 
patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. European 
Journal of Cancer 70:87-98, 2017 
 
11. 
Lenz H-J, Ou F-S, Venook AP, et al: Impact of Consensus Molecular Subtype on 
Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 
(Alliance). Journal of Clinical Oncology 37:1876-1885, 2019 
 
12. 
Modest DP, Stintzing S, von Weikersthal LF, et al: Exploring the effect of primary 
tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic 
colorectal cancer: analysis of FIRE-3 (AIOKRK0306). Oncotarget 8:105749-105760, 2017 
 
13. 
Tejpar S, Stintzing S, Ciardiello F, et al: Prognostic and Predictive Relevance of 
Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: 
Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncology 3:194-201, 2017 
 
14. 
von Einem JC, Heinemann V, von Weikersthal LF, et al: Left-sided primary 
tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 54 of 59 
metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO 
KRK-0104 trial. J Cancer Res Clin Oncol 140:1607-14, 2014 
 
15. 
Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of Epiregulin and 
Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal 
Cancer Patients Treated With Cetuximab. Journal of Clinical Oncology 25:3230-3237, 2007 
 
16. 
Schell MJ, Yang M, Missiaglia E, et al: A Composite Gene Expression Signature 
Optimizes Prediction of Colorectal Cancer Metastasis and Outcome. Clinical Cancer Research 
22:734-745, 2016 
 
17. 
Medico E, Russo M, Picco G, et al: The molecular landscape of colorectal cancer 
cell lines unveils clinically actionable kinase targets. Nature Communications 6, 2015 
 
18. 
Yang M, Schell MJ, Loboda A, et al: Repurposing EGFR Inhibitor Utility in 
Colorectal Cancer in Mutant <em>APC</em> and <em>TP53</em> Subpopulations. Cancer 
Epidemiology Biomarkers &amp; Prevention 28:1141-1152, 2019 
 
19. 
Pfeiffer P, Nielsen D, Bjerregaard J, et al: Biweekly cetuximab and irinotecan as 
third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, 
oxaliplatin and 5-fluorouracil. Annals of Oncology 19:1141-1145, 2008 
 
20. 
Tabernero J, Ciardiello F, Rivera F, et al: Cetuximab administered once every 
second week to patients with metastatic colorectal cancer: a two-part 
pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol 21:1537-1545, 
2010 
 
21. 
Lamy F-X, Batech M, Boutmy E, et al: Comparative effectiveness of weekly 
versus every-2-weeks cetuximab in metastatic colorectal cancer in a US-insured population. 
Journal of Comparative Effectiveness Research 9:1117-1129, 2020 
 
22.
 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s277s280lbl.pdf:  
 
23. 
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. American journal of clinical oncology 5:649-655, 1982 
 
 
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 55 of 59 
Appendix 1: ECOG Performance Status23 
 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hour 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care. Confined to bed or chair 
5 
Dead 
 
 
 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 56 of 59 
Appendix 2: RECIST 1.1 
 
Response to study therapy will be evaluated using RECIST v1.1 criteria. The following 
definitions and criteria should be used for the baseline evaluations of existing disease, and the 
ongoing evaluation of tumor responses.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
the longest diameter (LD) ≥ 10 mm using CT, MRI, or caliper measurements or ≥20 mm with an 
x-ray. A lymph node must be ≥15 mm in short axis when assessed by CT scan 
Non-measurable lesions - all other lesions including small lesions (LD < 10 mm with CT, MRI, 
or caliper measurements or <20 mm with x-ray). 
Documentation of “Target” and “Non-Target” Lesions 
 
All measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 
Target lesions should be selected based on their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques 
or clinical assessments). 
 
A sum of the LD for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as the reference by which to characterize the 
objective tumor response. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 
Table 6 : RECIST 1.1 response criteria 
Evaluation of target lesions 
Complete Response (CR) 
The disappearance of all target lesions  
(Must persist for a minimum of four weeks) 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD  
(Must persist for a minimum of four weeks) 
Progressive Disease (PD)
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 57 of 59 
Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
 
Evaluation of non-target lesions 
Complete Response (CR) 
The disappearance of all non-target lesions 
Stable Disease (SD) 
Persistence of one or more non-target lesion(s) 
Progressive Disease (PD)
 
The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
Evaluation of Best Overall Response 
Per RECIST 1.1 “in non-randomised trials where response is the primary endpoint, confirmation 
of PR or CR is needed to deem either one the ‘best overall response’.” Select the following 
language as appropriate. 
The best overall response is the best response observed until progression/recurrence and is 
determined as indicated in the table below: 
Table 7 : Best Overall Response Classification  
 
Target Lesions 
Non-Target 
Lesions 
Evaluation of New 
Lesions 
Best Overall 
Response 
CR 
CR 
No 
CR 
CR 
SD 
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 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 58 of 59 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
and NE = inevaluable. 
 
The best overall response is the best response observed until progression or recurrence. 
However, for response (CR or PR) to be reported the response must be confirmed on a 
subsequent scan at least 4 weeks from the original scan demonstrating response. Best overall 
response will be determined based on the table below: 
Overall response 
Best overall response 
First time point 
Subsequent time point 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable. 


Protocol: APK MUTANT 
Version: 28APR2022 
 
 
Page 59 of 59 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the subject had PR, not CR at the first time point. Under these circumstances, 
the original CR should be changed to PR and the best response is PR.