PULSE: A Randomized, Phase II Open Label Study of PanitUmumab RechaLlenge Versus Standard Therapy After Progression on Anti-EGFR Therapy in Patients With Metastatic and/or Unresectable RAS Wild-Type Colorectal Cancer
Phase: PHASE2
Conditions: Metastatic Colon Adenocarcinoma, Metastatic Colorectal Carcinoma, Metastatic Rectal Adenocarcinoma, Stage III Colon Cancer AJCC v8, Stage III Colorectal Cancer AJCC v8, Stage III Rectal Cancer AJCC v8, Stage IIIA Colon Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIA Rectal Cancer AJCC v8, Stage IIIB Colon Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIB Rectal Cancer AJCC v8, Stage IIIC Colon Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8, Stage IIIC Rectal Cancer AJCC v8, Stage IV Colon Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Rectal Cancer AJCC v8, Stage IVA Colon Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVA Rectal Cancer AJCC v8, Stage IVB Colon Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVB Rectal Cancer AJCC v8, Stage IVC Colon Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8, Stage IVC Rectal Cancer AJCC v8, Unresectable Colon Adenocarcinoma, Unresectable Colorectal Carcinoma, Unresectable Rectal Adenocarcinoma
Sponsor: Academic and Community Cancer Research United

 
 
ACCRU-GI-1623 
Academic and Community Cancer Research United (ACCRU) 
 
PULSE: A Randomized, Phase II Open Label Study of PanitUmumab RechaLlenge Versus 
Standard Therapy after Progression on Anti-EGFR Therapy in Patients with Metastatic and/or 
Unresectable RAS Wild-Type Colorectal Cancer  
 
For any communications regarding this protocol, please contact the person indicated on the 
Protocol Resource page. This is a stand-alone document found on the ACCRU web site 
(
). 
 
Study Chairs 
 
ACCRU: 
 
  
 
   
 
 
 
Sponsor/Investigator:  
 
 
Study Co-chairs: 
 
 
 
 
 
 
 
Correlative Science Co-chair:  
 
 
  
 
Statistician:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Availability 
Commercial Agents: Trifluridine/tipiracil (TAS-102), regorafenib 
Drug Company Supplied: Panitumumab (IND Exempt) 
 Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
 
 
 
 
 
 
Document History 
(effective date) 
Initial Version 
April 29, 2019 
Amendment 1 
August 4, 2020 

 
2  
ACCRU-GI-1623 
Amendment 1 
 
 
 
Index 
 
Schema 
1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors  
 6.0 
Registration/Randomization Procedures 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modification Based on Adverse Events  
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Appendix I – Patient Information Sheets 
Appendix II – Linear Analogue Self Assessment (LASA) 
Appendix III – Examples of CYP3A4 Inducers and Inhibitors 
Appendix IV(A) – Patient Medication Diary: Regorafenib 
Appendix IV(B) –  Patient Medication Diary: TAS-102 
Appendix V – Submission of Safety Data Regarding the Study Drug Panitumumab 
  
 

3                                                                                        ACCRU-GI-1623 
Amendment 1 
 
Schema 
 
NOTE: Patients must be registered to ACCRU-GI-1611(COLOMATE) and have received the COLOMATE 
Companion Trial Recommendation Form prior to being registered on this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Cycle length = 28 days  
*Treat until progression or maximum of 24 cycles 
 
Generic name:   Panitumumab 
Brand name(s):  Vectibix 
Availability: Amgen 
Generic name:   TAS-102 
Brand name(s):  TAS-102 Trifluridine FTD)/ 
Tipiracil (TPI) (TAS-102, Lonsurf®) 
 
Availability: Commercial 
Generic name:   Regorafenib 
 
Brand name(s):  Stivarga 
Availability: Commercial  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm A* 
Panitumumab 
 (N=60) 
Randomization 
PD at any time 
Unacceptable adverse   
 
 events   
 
 
 EM** 
Patient refusal 
Investigator’s decision 
 
** EM= Event Monitoring 
 
 
Arm B* 
Standard Therapy (regorafenib 
or TAS-102) (N=60) 
 

 
 
4  
 
 
Amendment 1 
1.0 
Background  
 
1.1 
Treatment 
 
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States 
[1]. Current FDA-approved treatment options for refractory metastatic CRC include 
regorafenib and trifluridine/tipiracil (TAS-102). Compared to placebo, regorafenib and 
TAS-102 both offer a median progression free survival (PFS) benefit of less than 10 
days, and an overall survival (OS) benefit of less than 2 months (see Table 1) [2, 3]. The 
objective response rate (ORR) for both therapies is less than 2%. 
 
Table 1. Treatment Options for Patients with Treatment Refractory Metastatic CRC 
Clinical trial 
Therapies 
Patients 
(N) 
ORR 
(%) 
Median 
PFS 
(months) 
Median OS 
(months) 
CORRECT 
Regorafenib 
Placebo 
505 
255 
1.0% 
0.4% 
1.9 
1.7 
6.4 
5.0 
RECOURSE 
TAS-102 
Placebo 
534 
266 
1.6% 
0.4% 
2.0 
1.7 
7.1 
5.3 
 
Approximately half of all patients with metastatic CRC have KRAS or NRAS (RAS) wild-
type tumors, and these patients are eligible to receive the epidermal growth factor 
receptor (EGFR) monoclonal antibodies panitumumab or cetuximab. Anti-EGFR 
therapies improve survival in the first line [4-6], second-line [7, 8], and treatment 
refractory settings [9-11], but nearly all patients develop resistance. In recent years 
several reports have suggested that patients with RAS wild-type metastatic CRC who 
develop EGFR antibody resistance may benefit from EGFR antibody rechallenge [12-
14]. In a prospective non-randomized phase II study of cetuximab rechallenge (n=39), the 
response rate was 54%, with a median PFS of 6.6 months [15]. Despite these encouraging 
results there is limited evidence from randomized trials establishing the clinical value of 
this approach. Efforts are ongoing to better understand sub-populations who may benefit 
from EGFR antibody rechallenge.  
 
1.2 
Drivers of EGFR Antibody Resistance 
 
To establish the benefit of EGFR antibody rechallenge, it is critical to avoid treatment in 
patients with known drivers of EGFR antibody resistance. These genomic drivers of 
primary and acquired EGFR antibody resistance are well described. The first-line PRIME 
and CRYSTAL trials established mutations in KRAS and NRAS exons 2-4 as predictive 
biomarkers for lack of benefit from anti-EGFR antibody therapy [16, 17]. Based on these 
findings, the FDA labels for cetuximab and panitumumab were updated to exclude anti-
EGFR therapy in patients with known RAS mutations. Other genomic alterations may 
also predict resistance to anti-EGFR therapy. BRAF V600E mutations are found in 5-10% 
of metastatic CRC tumors. Several retrospective studies suggest that BRAF mutations 
predict poor response to anti-EGFR therapy [18-20], though these studies are often 
limited by small patient numbers. ERBB2 (also known as HER2) amplification may also 
predict resistance to anti-EGFR therapies [21-23].  
 
Blood-based genomic profiling has identified several drivers of acquired resistance. MET 
amplification emerges under the selective pressure of anti-EGFR therapy, and may be 
targetable with FDA-approved and investigational anti-MET therapies [12, 24-28]. EGFR 
ectodomain (ECD) mutations prevent binding of EGFR antibodies, and may be sensitive 
to novel anti-EGFR therapies [22, 29, 30]. KRAS and NRAS mutations are the most 
common drivers of acquired resistance [31-33]. RAS mutated clones are dependent on the 
presence of EGFR antibodies for their selective advantage, and their frequency declines 
when EGFR antibodies are withdrawn [12]. In a series of 130 patients with RAS wild-
type metastatic CRC treated with EGFR antibodies, plasma samples were able to detect 
acquired RAS and EGFR mutations in blood. This same analysis demonstrated 
exponential decay of the RAS and EGFR relative mutant allele frequency (rMAF), with a 
half-life of 3.4 months and 6.9 months, respectively [34]. Accordingly, these results 
provide a rationale for the study of EGFR antibody rechallenge. 
 
1.3 
Blood-based molecular profiling to Identify Patients for EGFR Antibody Rechallenge 
 

 
 
5  
 
 
Amendment 1 
Several recent studies have demonstrated that molecular profiling of cell free DNA 
(cfDNA) could be useful for identifying patient sub-populations most likely to benefit 
from EGFR antibody rechallenge. As part of an investigator-initiated trial at Duke 
University (NCT02008383), comprehensive blood-based genomic profiling was 
performed on patients with EGFR-refractory, RAS wild-type metastatic CRC. This 
profiling effort utilized the Guardant360TM assay (Guardant Health, Redwood City, CA), 
a >70-gene NGS-based blood test. Among the 69 patients with EGFR-refractory disease 
who received blood-based genomic profiling, 18 patients (26%) had no detectable 
resistance-conferring mutation or amplification [35].  
 
Recent studies have further shown that cfDNA profiling is an effective diagnostic tool to 
identify patients likely to benefit from EGFR antibody rechallenge. In a single-arm phase 
II study conducted in Italy (CRICKET), 28 patients with RAS wild-type metastatic CRC 
who received first-line FOLFIRI/cetuximab and second line FOLFOX/bevacizumab were 
assigned to third line irinotecan/cetuximab [36]. Six patients (21.5%) experienced partial 
response, with a median PFS of 3.4 months and a median overall survival (OS) of 9.8 
months. Utilizing droplet digital (dd) PCR, 12 patients had a baseline RAS mutation 
detected in blood, and 13 patients had no baseline RAS mutation detected. The response 
rate for patients who were RAS wild-type in blood was 38%, with a median PFS of 4.0 
months and a median survival of 12.5 months. The use of cfDNA to identify patients 
likely to benefit from EGFR antibody rechallenge is further supported by results of a 
phase II randomized trial comparing the novel EGFR antibody admixture SYM004 
versus investigator choice (IC) therapy in patients with EGFR refractory metastatic CRC 
[37]. In the intent-to-treat (ITT) population, there was no survival benefit for SYM004 
compared to IC. However, a retrospective analysis of patients who were 
RAS/BRAF/EGFR mutation negative in blood found improved survival in patients treated 
with SYM004 compared with IC (median OS, 12.8 and 7.3 months, respectively).  
 
Collectively, these results support the potential clinical benefit of EGFR antibody 
rechallenge, and suggest that cfDNA profiling may identify patients most likely to 
benefit.  
 
 
2.0 
Goals  
 
2.1 
Primary 
 
2.11 
To compare the overall survival (OS) in molecularly selected patients with 
metastatic CRC receiving panitumumab rechallenge versus standard therapy 
(TAS-102 or regorafenib).  
 
2.2 
Secondary 
 
2.21 
To compare the progression free survival (PFS) in molecularly selected patients 
with metastatic CRC receiving panitumumab rechallenge versus standard therapy 
(TAS-102 or regorafenib). 
 
2.22 
To define the objective response rate (ORR) in patients receiving panitumumab 
rechallenge versus standard therapy (TAS-102 or regorafenib). 
 
2.23 
To define the clinical benefit rate (CBR= complete response + partial response + 
stable disease ≥ 6 months) in patients receiving panitumumab rechallenge versus 
standard therapy (TAS-102 or regorafenib). 
 
2.24 
To compare the safety and tolerability of panitumumab rechallenge versus 
standard therapy (TAS-102 or regorafenib). 
 
2.25 
To compare QOL between panitumumab rechallenge versus standard therapy 
(TAS-102 or regorafenib) as measured by the linear analogue self-assessment 
(LASA) questionnaires. 
 
2.3 
Correlative Research 
 
2.31 
To assess plasma pharmacodynamics biomarkers of response and resistance to 
therapy. 

 
 
6  
 
 
Amendment 1 
 
2.32 
To explore any correlation between tissue and blood based biomarkers and 
clinical outcomes. 
 
3.0 
 Patient Eligibility  
 
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy 
 
3.1  
Registration – Inclusion Criteria  
 
3.11 
Registered to COLOMATE ACCRU-GI-1611 and: 
a) COLOMATE Companion Trial Recommendation Form indicates patient 
qualifies to be screened for a COLOMATE companion trial.   
b) COLOMATE Companion Trial Recommendation Form date of completion is 
 30 days prior to randomization. 
 
3.12 
Age ≥18 years. 
3.13 
Histologically and/or cytologically confirmed adenocarcinoma of the colon or 
rectum that is metastatic and/or unresectable.  
 
3.14 
Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) 
and in BRAF codon 600, based on tumor tissue taken from primary or metastatic 
site prior to receipt of anti-EGFR therapy. 
 
3.15 
Progression, intolerance, or contraindication to a fluoropyrimidine (e.g., 5-
fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal 
antibody (bevacizumab, ramucirumab, or aflibercept), and an anti-PD-1 
monoclonal antibody (nivolumab or pembrolizumab) if tumor has deficient 
mismatch repair proteins (dMMR) or is microsatellite instability-high (MSI-H). 
 
3.16 
Disease progression after treatment with an anti-EGFR monoclonal antibody 
(cetuximab and/or panitumumab) for at least 4 months (minimum of 8 biweekly 
treatments or 16 weekly treatments at full or partial dose).  
 
 
NOTE: Treatments do not need to be administered consecutively. 
 
NOTE: Dose reductions or delays are permitted. 
 
3.17 
Greater than 90 days has elapsed between the most recent treatment with an anti-
EGFR therapy (cetuximab or panitumumab) and blood collection for 
COLOMATE ACCRU-GI-1611. 
 
3.18 
At least one site of disease that is measurable by RECIST criteria (as defined in 
Section 11.0) that has not been previously irradiated; if the patient has had 
previous radiation to the target lesion(s), there must be evidence of progression 
since the radiation.  
 
3.19a  Life expectancy ≥ 3 months per estimation of investigator. 
 
3.19b ECOG Performance Status (PS) 0, 1, or 2. (Form is available on the ACCRU 
web site). 
 
3.19c 
The following laboratory values obtained 7 days prior to randomization.  
 
 
Absolute neutrophil count (ANC) ≥1500/mm3without colony stimulating 
factor support 
 
Platelet count 75,000/mm3 
 
Hemoglobin >8.0 g/dL 
 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
 
Aspartate transaminase (AST)  2.5 x ULN ( 5 x ULN for subjects with 
liver involvement of their cancer) 
 
Aminotransferase (ALT)  2.5 x ULN ( 5 x ULN for subjects with liver 
involvement of their cancer) 
 

 
 
7  
 
 
Amendment 1 
 
Calculated creatinine clearance must be > 30 ml/min using the Cockcroft-
Gault formula below: 
 
3.19d  Women of child bearing potential and male partners of women of child bearing 
potential must agree to use two medically accepted methods of contraception, 
one of them being a barrier method during the study and for 2 months after the 
last dose of study drug(s). 
 
3.19e 
Negative serum pregnancy test done ≤7 days prior to randomization, for women 
of childbearing potential only. 
 
NOTE: Women of childbearing potential include women who have experienced 
menarche and who have not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not 
postmenopausal. Postmenopause is defined as amenorrhea ≥ 12 consecutive 
months. NOTE: women who have been amenorrheic for 12 or more months are 
still considered to be of childbearing potential if the amenorrhea is possibly due 
to prior chemotherapy, anti-estrogens, ovarian suppression or any other 
reversible treatment. 
 
3.19f 
Ability to complete questionnaire(s) by themselves or with assistance.  
 
3.19g Capable of understanding and complying with the protocol requirements and has 
signed the informed consent document. 
 
3.19h Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19i 
Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6.0, 14.0 and 17.0).  
 
3.19j 
Willing to allow transfer of tissue and blood samples, clinical information, and 
outcome data collected from this trial for future research (see Sections 6, 14, and 
17). 
 
3.2 
Registration – Exclusion Criteria  
 
3.21  
Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or 
chemotherapy for cancer < 21 days prior to randomization. 
 
3.22 
Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin).  
 
3.23 
Maximum mutant allele frequency (highest allele frequency reported for any 
gene mutation) (MAF) less than 2% by Guardant360 assay. 
 
NOTE: Refer to COLOMATE Companion Trial Recommendation Form for information 
regarding 3.23 and 3.24. 
 
3.24 
Detection of at least one of the following gene mutation(s) or amplification(s) by 
Guardant360 assay. 
 
 
BRAF mutation mutant allele frequency (MAF) > 0.5% 
 
EGFR mutation (MAF > 0.5%). Note: EGFR S492R, K467, and R451C 
mutations are not an exclusion  
 
ERBB2 (HER2) mutation (MAF > 0.5%) or amplification 
 
KRAS mutation (MAF > 0.5%) or amplification 
 
MET mutation (MAF > 0.5%) or amplification 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

 
 
8  
 
 
Amendment 1 
 
NRAS mutation (MAF > 0.5%) or amplification 
 
3.25 
Prior treatment with both TAS-102 and regorafenib (prior treatment with either 
TAS-102 or regorafenib is permitted). 
 
3.26 
Unable to swallow oral tablets (crushing of study treatment tablets is not 
allowed). 
 
3.27 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. Note: This includes impaired heart function 
or clinically significant heart disease.  
 
3.28 
Not recovered to baseline or CTCAE v5.0 ≤ Grade 1 from toxicity due to all 
prior therapies except alopecia, oxaliplatin-related neuropathy, asymptomatic 
electrolyte abnormalities, and other non-clinically significant adverse events. 
 
3.29a 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
 
 
Pregnant women 
 
Nursing women 
 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
 
3.29b Patients with known CNS metastases. Note: Patients with radiated or resected 
lesions are permitted, provided the lesions are fully treated and inactive (based on 
repeat imaging ≥ 30 days after completion of definitive treatment), patients are 
asymptomatic, and no steroids to control symptoms related to CNS metastases 
have been administered for at least 30 days. 
 
3.29c 
Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days 
prior to randomization (≤ 56 days for hepatectomy, open thoracotomy, major 
neurosurgery) or anticipation of need for major surgical procedure during the 
course of the study. 
 
3.29d Serious, non-healing wound, ulcer, or bone fracture. 
 
3.29e 
History of stroke (cerebrovascular accident), transient ischemic attack (TIA), 
myocardial infarction (MI), unstable angina, cardiac or other vascular stenting, 
angioplasty, or cardiac surgery ≤ 6 months prior to randomization.  
 
3.29f 
History of cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers, calcium channel blockers, or digoxin ≤ 6 months prior to 
randomization.  
 
3.29g Known history of congestive heart failure – New York Heart Association 
(NYHA) ≥ Class II.  
 
3.29h Known history of HIV seropositivity, acute or chronic active hepatitis B or C 
infection, or other serious chronic infection requiring ongoing treatment. 
 
3.29i 
History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or 
evidence of interstitial lung disease on baseline chest CT scan. 
 
3.29j 
Subjects with any previously untreated or concurrent cancer that is distinct in 
primary site or histology from colorectal cancer except cervical cancer in-situ, 
treated basal cell carcinoma, or superficial bladder tumor. Note: Subjects 
surviving a cancer that was curatively treated and without evidence of disease or 
biochemical relapse (undetectable PSA for prostate cancer) for 3 or more years 
before randomization are allowed. All cancer treatments must be completed at 
least 3 years prior to randomization. 
 

 
 
9  
 
 
Amendment 1 
3.29k Uncontrolled hypertension (systolic pressure > 150 mm HG or diastolic pressure 
> 90 mm Hg [NCI-CTAE v5.0] on repeated measurement despite optimal 
medical management.  
 
3.29l 
Evidence or history of bleeding diathesis or coagulopathy. 
 
3.29m Any hemorrhage or bleeding event ≥ NCI CTCAE v5.0 Grade 3, ≤ 4 weeks prior 
to randomization. 
 
3.29n Ongoing active infection > Grade 2 NCI-CTCAE v5.0. 
 
3.29o Known or suspected allergy or hypersensitivity to any of the study drugs, study 
drug classes, or excipients of the formulation given during the course of this trial.  
 
 
EXCEPTION: Cetuximab 
 
3.29p Any known history of malabsorption condition. 
 
3.29q Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results.  
 
3.29r 
Use of any herbal remedy (e.g. St. John’s wort) ≤ 7 days prior to randomization. 
 
3.29s 
Use of strong CYP3A4 inducers or inhibitors ≤ 7 days prior to randomization. 
See Appendix III. 

10                                                                                        ACCRU-GI-1623 
Amendment 1 
 
 
4.0 
Test Schedule 
 
Screening Phase 
Active Monitoring Phase 
 
 
 
Tests and procedures 
 
≤28 days 
prior to 
randomizat
ion 
≤7 days 
prior to 
randomizat
ion 
Baseline 
(Prior to 
Cycle 1 
Day 1 
treatment) 
Day 15 
of each 
cycle8 
(± 3 
days) 
Prior to 
dosing on 
Day 1 of 
≥ cy 2 
(± 3 days) 
Prior to 
dosing at 
restaging 
(C3 and 
every other 
cycle after) 
End of Tx 
(within 30 
days after 
last dose of 
study drug) 
History and exam, wt, ECOG PS  
X 
 
 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Adverse event assessment 
X 
 
 
X1 
X1 
 
X 
CBC/ differential: WBC, hemoglobin, 
hematocrit, platelets, neutrophil count, 
lymphocyte count, monocyte count, eosinophil 
count 
 
X 
X11 
X 
X 
  
X 
Chemistry: Sodium, potassium, chloride, CO2, 
BUN, creatinine, glucose, calcium, SGOT 
(AST), SGPT (ALT), total bilirubin, alk phos, 
albumin, total protein 
 
X 
X11 
X 
X 
  
X 
Magnesium 
 
X 
 
X5 
X5 
 
X5 
Tumor Blood Bio-Markers (CEA) 
 
X 
 
 
X  
(C2 only) 
X 
(at each 
restaging) 
 
Serum Pregnancy test2 
 
X 
X11 
 
 
X 
 
Tumor measurement (CT or MRI of the chest, 
abdomen and pelvis)3 
X 
 
 
 
 
X 
 
COLOMATE Companion Trial 
Recommendation Form12 
X 
 
 
 
 
 
 
Mandatory blood sample – whole blood4, 9,R 
 
 
X 
 
 
  
 
Mandatory blood sample –plasma4,9, R 
 
 
X 
 
X  
(C2 only) 
X 
(at each 
restaging) 
X 
Mandatory tissue sample– archival tumor 
paraffin6,R  
 
 
X 
 
 
 
 

 
 
11  
 
ACCRU-GI-1623 
 
Amendment 1 
 
Screening Phase 
Active Monitoring Phase 
 
 
 
Tests and procedures 
 
≤28 days 
prior to 
randomizat
ion 
≤7 days 
prior to 
randomizat
ion 
Baseline 
(Prior to 
Cycle 1 
Day 1 
treatment) 
Day 15 
of each 
cycle8 
(± 3 
days) 
Prior to 
dosing on 
Day 1 of 
≥ cy 2 
(± 3 days) 
Prior to 
dosing at 
restaging 
(C3 and 
every other 
cycle after) 
End of Tx 
(within 30 
days after 
last dose of 
study drug) 
Mandatory Patient Questionnaire Booklet 
(Appendix II)10 
 
 
X 
 
X 
 
X 
Patient Medication Diary (Appendix IV)13 
 
 
 
 
X 
X 
X 
Optional Blood sample-cfDNA Guardant 
3604,7,R 
 
 
 
 
 
 
X 
1 
The adverse event assessment will be evaluated at the end of each cycle prior to the beginning of the next cycle and at day 15 visit for the first 6 cycles. Please note: only the maximum 
grade will be needed for data entry. 
2 
For women of childbearing potential only. Must be done  7 days prior to randomization. 
3 
Use same imaging throughout the study. 
4 
Kits are required for this collection. Refer to Section 14.0.  
5 
Only for patients receiving panitumumab. 
6 
Receipt of archival tumor tissue is not required for study randomization and initiation of therapy. However, it is mandatory to receive the required tissue within 90 days from 
randomization.  See section 17.0. 
7 
Patients have the option to complete cfDNA testing at study completion and will be allowed to re-register with protocol ACCRU-GI-1611. Site will access results by creating an 
account at
 Sites will be notified by Guardant Health via email when results are available in the portal. Refer to Section 13.7. See detailed instructions 
on the ACCRU website under Manuals and Forms.  
8 
May discontinue day 15 visit beginning cycle 7. Additional visits and laboratory studies are permitted as per institutional practice and as clinically appropriate. 
9     Patient must be registered prior to collection.  
10   Patient questionnaire will be completed at baseline and each cycle (Appendix II). Patient questionnaire booklets must be used; copies are not acceptable for this submission. The 
booklet order form is located on the ACCRU website under Manuals and Forms. 
11   If screening tests occur  7 days prior to C1D1, they do not have to be repeated prior to dosing.  
12 The COLOMATE Companion Trial Recommendation Form must indicate that the patient has met molecular eligibility to screen. The patient must be registered to the companion 
study ≤30 days from date of COLOMATE Companion Trial Recommendation Form completion. If the COLOMATE Companion Trial Recommendation Form recommends a 
different companion study, patient may still enroll.   
13 The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution OR compliance must be documented in 
the medical record by any member of the care team. 
R Research funded. 
 
Event Monitoring: survival follow-up will be done every 3 months (± 7 days) until 3 year after randomization.

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
5.0 
Stratification Factors:  
 
5.1 
Primary tumor location: right (cecum, ascending colon, hepatic flexure, and 
transverse colon) vs left (splenic flexure, descending colon, sigmoid colon, 
rectosigmoid junction, and rectum). 
  
5.2 
Prior TAS-102 or regorafenib: Yes vs No.  
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, fax (
) a completed eligibility checklist to the 
Academic and Community Cancer Research United (ACCRU) Registration 
Office between 8 a.m. and 4:30 p.m. central time Monday through Friday.   
 
NOTE: ACCRU-GI-1611 (COLOMATE) treating physician will provide COLOMATE 
Companion Trial Recommendation Form which will include the Patient ID that 
must be used for this study.   
 
6.12 
Correlative Research  
 
 
Mandatory 
 
A mandatory correlative research component is part of this study. The 
patient will be automatically registered onto this component (see Sections 
3.0, 14.0 and 17.0). 
 
Optional 
 
An optional correlative research component is part of this study. There will 
be an option to select if the patient is to be registered onto this component 
(see Section 14.0). 
 
 
Patient has/has not given permission to give his/her blood sample for 
research testing.  
 
6.13 
Documentation of IRB approval must be on file in the Registration 
Office before an investigator may register any patients. Approvals 
should be uploaded using the online ACCRU Regulatory 
Management System (ARMS). 
 
 
In addition to submitting initial IRB approval documents, ongoing 
IRB approval documentation must be on file (no less than annually) 
with ACCRU. Approvals should be uploaded using the online 
ACCRU Regulatory Management System (ARMS). If the necessary 
documentation is not submitted in advance of attempting patient 
registration, the randomization will not be accepted and the patient 
may not be enrolled in the protocol until the situation is resolved.  
 
 
Submission of annual IRB approvals is required until the study has 
been closed through your IRB. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
6.14 
Prior to accepting the registration/randomization, the 
registration/randomization application will verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected 
health information  
 
 
 
6.15 
At the time of registration, the following will be recorded: 
 
Patient has/has not given permission to store and use his/her blood 
sample(s) for future research to learn about, prevent, or treat cancer. 
 
Patient has/has not given permission to store and use his/her blood  
sample(s) for future research to learn, prevent, or treat other health  
problems (for example: diabetes, Alzheimer’s disease, or heart disease). 
 
Patient has/has not given permission to store and use his/her tissue 
sample(s) for future research to learn about, prevent, or treat cancer. 
 
Patient has/has not given permission to store and use his/her tissue 
sample(s) for future research to learn, prevent, or treat other health 
problems (for example: diabetes, Alzheimer’s disease, or heart disease). 
 
Patient has/has not given permission for ACCRU to give his/her 
sample(s) to outside researchers. 
 
6.16 
Treatment cannot begin prior to randomization and must begin  7 days 
after randomization. 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within 
the guidelines specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.52) must be documented 
and graded. 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under 
the supervision of a medical oncologist. 
 
6.19b Study drug is available on site.  
 
6.19c 
Blood draw kit is available on site.  
 
 
Exclusion: Guardant 360 kit does not need to be on site at the time of 
registration.  
 
6.19d Patient questionnaire booklet is available on site; copies are not acceptable 
for this submission. 
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering 
membership, will be used as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the 
stratification factors will be recorded, and the patient will be assigned to 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
one of the following treatment groups using the Pocock and Simon [39] 
dynamic allocation procedure which balances the marginal distributions of 
the stratification factors between the treatment groups.  
 
 
Panitumumab  
 
Standard Therapy (regorafenib or TAS-102) 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
 
Arm 
Agent 
Dose Level 
Route 
Day 
ReRx 
A 
Panitumumab 
 
6 mg/kg 
IV 
Day 1 
Day 15 
Every 28 
Days 
 
 
B 
TAS-102 
 
35 mg/m2  
(max 80 mg/dose) 
Oral 
Twice daily, 
days 1-5 and 
days 8-12 
Every 28 
Days 
Regorafenib 
 
160 mg 
(alternative dosing 
permitted 
minimum 80 mg 
and max 160 mg) 
Oral 
Once 
daily, 
days 1-21 
Every 28 
Days 
 
 
7.11 
Arm A: Patients assigned to Arm A will receive panitumumab.  
 
7.12 
Arm B: Patients assigned to Arm B will receive either TAS-102 or 
regorafenib per treating physician discretion and will be dosed as per 
prescribing guidelines and at investigator discretion. Patients who have 
received TAS-102 prior to registration may only receive regorafenib. 
Patients who have received regorafenib prior to registration may only 
receive TAS-102.  Patients cannot switch between TAS-102 and 
regorafenib during protocol treatment.  
 
7.2 
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation as per the study calendar during treatment. Additional visits during 
treatment are not mandated by the study protocol, but are advised to optimize 
symptom management and provide optimal care. 
 
 
7.4 
Treatment by a local medical doctor (LMD) is not allowed  
 
7.5 
Study treatment  with panitumumab may be administered up to 3 days before or 
after the scheduled Day 1, Day 15 of each cycle due to administrative reasons. 
 
 
 
 
 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Subjects will be monitored continuously for AEs from the date of first dose of study drug 
and for 30 days after the last dose of study drug. Subjects will be instructed to notify their 
treating physician of any and all AEs. All AEs should also be managed with supportive care 
at the earliest signs of toxicity. Subjects should receive appropriate supportive care 
measures as deemed necessary by the Investigator. Suggested supportive care measures for 
the management of adverse events are outlined in Section 9.0.   
 
Subjects experiencing one or more AEs due to study drug(s) may require dose 
modification(s) as described in Sections 8.1, 8.2, and 8.3. If multiple adverse events are 
seen, administer dose based on greatest reduction required for any single adverse event 
observed. Reductions or increases apply to treatment given in the preceding cycle and are 
based on adverse events observed since the prior dose. At the discretion of the Investigator, 
dose modifications are permitted outside of those provided in the protocol if the Investigator 
feels it is in the interest of the subject’s safety (e.g., due to multiple toxicities, persistent 
toxicities, intercurrent illness, or short term compliance or monitoring issues, etc.). Subjects 
may need to be followed at least weekly when the study drug is held for clinically 
significant toxicity until the toxicity returns to Grade ≤ 1 or is determined to be controlled, 
chronic, or irreversible.  
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 4 weeks 
of the scheduled interruption, unless otherwise discussed with the Lead PI. The reason for 
interruption should be documented in the patient's study record.   
 
ALERT: ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Panitumumab: This section applies to adverse events associated with panitumumab. 
For adverse events associated with regorafenib, please refer to Section 8.2 and for 
TAS-102, please refer to Section 8.3.  
 
* 
Located at 
  
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 Dose Modifications – Dermatologic Toxicity 
 Table 8.11.  Dose Modifications during Vectibix Treatment 
Occurrence of Skin 
Symptom(s): 
≥ grade 3a 
Administration 
of Vectibix 
Outcome 
Dose Regulation 
Initial occurrence 
Stop 1 or 2 doses 
Improved (< grade 3) 
Continue infusion at 
100% of original dose 
Not recovered 
Discontinue 
At the second 
occurrence 
Stop 1 or 2 doses 
Improved (< grade 3) 
Continue infusion at 80% 
of original dose 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
Not recovered 
Discontinue 
At the third 
occurrence 
Stop 1 or 2 doses 
Improved (< grade 3) 
Continue infusion at 60% 
of original dose 
Not recovered 
Discontinue 
At the fourth 
occurrence 
Discontinue 
-- 
-- 
a Greater than or equal to Grade 3 is defined as severe or life-threatening 
Management of Skin Toxicities 
 
Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), topical 
steroid cream (not stronger than 1% hydrocortisone) and an oral antibiotic (e.g., doxycycline), as 
prescribed by the physician, may be useful in the management of skin toxicities.  Patients may be 
advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning 
during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every 
night.  Treatment of skin reactions should be based on severity and may include a moisturizer, 
sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% 
hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by the physician. 
Pulmonary Toxicity 
 
In the event of acute onset or worsening of pulmonary symptoms, consider withholding 
panitumumab. If Interstitial Lung Disease is confirmed, discontinue panitumumab. 
 
For Toxicities other than Dermatologic or Pulmonary 
 
Withhold panitumumab for any grade 3 or 4 panitumumab-related toxicity with the 
following exceptions: 
• Panitumumab will only be withheld for symptomatic grade 3 or 4 hypomagnesemia 
and/or hypocalcemia that persists despite aggressive magnesium and/or calcium 
replacement 
• Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that 
persists despite maximum supportive care.   
 
Diarrhea management (refer to the 9.4 for management) 
 
Electrolytes 
Subjects should be evaluated and managed as per local medical practice. If hypomagnesemia is 
present, replacement should be managed with either oral and/or parental replacement, according to 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
institutional practice and to the degree of hypomagnesemia present. It is recommended that the 
subject’s serum magnesium level should be maintained within the normal range, as much as 
possible, during study treatment. It is important to assess and manage serum potassium and calcium 
(adjusted for albumin) in subjects who have concomitant hypomagnesemia. Subject’s serum 
potassium and calcium parameters are recommended to be managed, as per local 
medical practice, and kept within the normal ranges, as much as possible, during study 
treatment. 
 
Criteria for Re-treatment with Panitumumab 
• For dermatologic toxicities (see Table 8.11) 
• For toxicities other than dermatologic: If panitumumab was withheld, administration 
may recommence once the adverse event has improved to ≤ grade 1 or returned to 
baseline. The reason for dose change of panitumumab is to be recorded on each subject’s CRF(s).  
 
 
8.2  
Regorafenib: This section applies to adverse events associated with regorafenib. For adverse 
events assorted with panitumumab, please refer to Section 8.1 and for TAS-102, please refer 
to Section 8.3. 
 
NOTE: This drug is standard of care and FDA approved and, therefore, these are suggested but not 
mandated.  
 
Discontinue regorafenib for the following conditions: 
 
Any grade arterial thromboembolic event,  
 
GI or other perforation or fistula formation,  
 
Intra-abdominal abscess,  
 
Wound dehiscence requiring medical or surgical therapy, 
 
Severe or life-threatening hemorrhage. 
 
Regorafenib Dose Modifications 
Dose Modification Level 
Regorafenib (Orally, daily, mg, days 1-21 of each 28 day cycle) 
 Initial dose 
160 
120 
80 
-1 
120 
80 
40 
-2 
80 
40 
discontinue 
-3 
40 
discontinue 
 
-4 
Discontinue 
 
 
 
 
 
 
 
 
 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Skin and 
subcutaneous tissue 
disorder 
 
Palmar-plantar erythrodysesthesia syndrome 
Grade 1 
Maintain current dose 
Grade 2 
1st occurrence: Hold until grade ≤ 1, then resume at 
current dose. If there is no recovery after a 4-week 
delay, treatment with regorafenib will be permanently 
discontinued. 
2nd or 3rd occurrence: Hold until grade ≤ 1, then resume 
at one dose level lower. Dose re-escalation is permitted 
at the discretion of the investigator if subject has 
completed one cycle at reduced dose without 
recurrence of event. If there is no recovery after a 4-
week delay, treatment with regorafenib will be 
permanently discontinued.  
4th occurrence: Discontinue 
Grade 3 
1st occurrence: Hold until grade ≤1 for a minimum of 7 
days then resume at two dose levels lower. Dose re-
escalation is permitted at the discretion of the 
investigator if subject has completed one cycle at 
reduced dose without recurrence of event. If there is no 
recovery after a 4-week delay, treatment with 
regorafenib will be permanently discontinued.  
2nd occurrence: Discontinue 
Grade 4 
Discontinue 
Vascular disorder 
Hypertension 
Grade ≤ 2 
asymptomatic 
Maintain current dose 
Grade 3 asymptomatic 
Maintain current dose 
Grade 2 or 3 
symptomatic 
1st occurrence: Hold until symptoms have resolve, then 
resume at one dose level lower. 
2nd occurrence: Discontinue 
Grade 4 
Discontinue 
Investigations 
  
Alanine aminotransferase (ALT), and/or Aspartate aminotransferase (AST), 
and/or Blood bilirubin increaseda 
Grade ≤ 2 
Maintain current dose 
Grade 3 
1st or 2nd occurrence: Hold until recovery to grade ≤ 2, 
then resume at one dose level lower if potential benefit 
outweighs the risk of hepatotoxicity. 
3rd occurrence: Discontinue 
Grade 4 
Discontinue 
 Platelet count decreased 
Grade 2 
Maintain current dose. 
Grade 3 
Hold until recovery to grade ≤ 1, then resume at one 
dose level lower. 
Grade 4 
Hold until recovery to grade ≤ 1, then resume at two 
dose levels lower. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
 Neutrophil count decreased 
Grade 2 
Maintain current dose. 
Grade 3 
Hold until recovery to grade ≤ 1, then resume at one 
dose level lower. 
Grade 4 
Hold until recovery to grade ≤ 1, then resume at two 
dose levels lower. Discontinue after second occurrence. 
Febrile neutropenia 
Grade 3 
Hold until resolution of fever and neutropenia to grade 
≤ 1, then resume at two dose levels lower.  
Discontinue after second occurrence. 
Grade 4 
Hold until resolution of fever and neutropenia to grade 
≤ 1, then resume at two dose levels lower.  
Discontinue after second occurrence. 
Gastrointestinal 
disorders 
 
Diarrhea 
Grade 1 
Maintain current dose 
Grade 2 
Hold until recovery to grade ≤ 1, then resume at one 
dose level lower. 
Grade 3 
1st or 2nd occurrence: Hold until recovery to grade  1, 
then resume at one dose level lower. 
3rd occurrence: Discontinue 
Grade 4 
1st occurrence: Discontinue or hold until recovery to 
grade  1, then resume at two dose levels lower. 
2nd occurrence: Discontinue 
Mucositis oral 
 
Grade 1 
Maintain current dose 
Grade 2 
Hold until recovery to grade ≤ 1, then resume at one 
dose level lower. 
Grade 3 
1st or 2nd occurrence: Hold until recovery to grade  1, 
then resume at one dose level lower. 
3rd occurrence: Discontinue 
Grade 4 
1st occurrence: Discontinue or hold until recovery to 
grade  1, then resume at two dose levels lower. 
2nd occurrence: Discontinue 
Small intestinal or colonic obstruction 
Grade 2 
Hold regorafenib for partial obstruction requiring 
medical intervention. Resume all study drugs at current 
dose when obstruction is resolved to grade  1. 
 
Grade 3 or 4 
Hold for all study drugs for complete obstruction. If 
surgery is necessary, subject may resume all study 
drugs at current doses after full recovery from surgery 
with permission of Principal Investigator. 
General disorders and 
administration site 
conditions 
Fatigue 
 
Grade 1 
Maintain current dose 
Grade 2 
Hold until recovery to grade ≤ 1, then resume at one 
dose level lower. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
Grade 3 
1st or 2nd occurrence: Hold until recovery to grade  1, 
then resume at one dose level lower. 
3rd occurrence: Discontinue 
Grade 4 
1st occurrence: Discontinue or hold until recovery to 
grade  1, then resume at two dose levels lower. 
2nd occurrence: Discontinue 
a Discontinue regorafenib for the following: 
 
Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN).  
 
Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more 
than 2 times ULN.  
 
Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction. 
 
* 
Located at 
  
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
8.3  
TAS-102: This section applies to adverse events associated with TAS-102. For adverse 
events associated with panitumumab, please refer to Section 8.1 and for regorafenib, please 
refer to Section 8.2. 
 
NOTE: This drug is standard of care and FDA approved and, therefore, these are suggested but not 
mandated. 
 
Complete blood cell counts prior to day 1 and on day 15 of each cycle are recommended. A 
maximum of 3 dose reductions are permitted to a minimum dose of 20 mg/m2 twice daily. Do not 
escalate TAS-102 dose after it has been reduced. 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Hematologic 
Neutrophil count decreased at cycle start 
 
Grade 2-3 
Delay treatment until ANC is ≥ 1500/mm3, then resume 
at same dose. 
 
Grade 4 
Delay treatment until ANC is ≥ 1500/mm3. If recovery 
≤ 1 week, resume at same dose. If recovery > 1 week, 
resume at 5mg/m2/dose lower than previous dose. 
Neutrophil count decreased during cycle 
 
Grade 4 
Withhold treatment until ANC is ≥ 1500/mm3. If 
recovery ≤ 1 week, resume at same dose. If recovery > 
1 week, resume at 5mg/m2/dose lower than previous 
dose. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
ACTION** 
Febrile neutropenia at cycle start 
Grade 3 
Delay treatment until ANC is ≥ 1500/mm3 and fever is 
resolved. After recovery, resume at 5mg/m2/dose lower 
than previous dose. 
Febrile neutropenia during cycle 
Grade 3 
Withhold treatment until ANC is ≥ 1500/mm3 and 
fever is resolved. After recovery, resume at 
5mg/m2/dose lower than previous dose. 
Platelet count decreased at cycle start 
Grade 2-3 
Delay treatment until platelet count is ≥ 75,000/mm3. 
After recovery, resume at same dose. 
 
Grade 4 
Delay treatment until platelet count is ≥ 75,000/mm3. If 
recovery ≤ 1 week, resume at same dose. If recovery > 
1 week resume at 5mg/m2/dose lower than previous 
dose. 
Platelet count decreased during cycle 
 
Grade 2-3 
Withhold treatment until platelet count is ≥ 
75,000/mm3. After recovery, resume at same dose. 
 
Grade 4 
Withhold treatment until platelet count is ≥ 
75,000/mm3. If recovery ≤ 1 week, resume at same 
dose. If recovery > 1 week resume at 5mg/m2/dose 
lower than previous dose. 
General Disorders 
and administration 
site conditions 
Fatigue 
Grade 3 
Delay until resolved to grade ≤ 1. Resume at 
5mg/m2/dose lower than previous dose. 
Grade 4 
Discontinuea 
Gastrointestinal 
disorders 
Mucositis oral  
Grade 3 
Delay until resolved to grade ≤ 1. Resume at 
5mg/m2/dose lower than previous dose. 
Grade 4 
Discontinuea 
a For all Grade 3 or 4 AEs except for Grade 3 nausea and/or vomiting controlled by antiemetic 
therapy or Grade 3 diarrhea responsive to antidiarrheal medication. 
 
* 
Located at 
  
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
(ASCO) Recommendations for the Use of WBC Growth Factors: American Society 
of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 
33:3199-3212.  
 
9.3 
Patients should receive full supportive care while on this study. This includes 
blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from 
the first day of study treatment administration until 30 days after the final dose 
will be recorded in the medical records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 
hours until diarrhea free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are 
allowed: hydration, octreotide, and antidiarrheals.  
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever 
or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be hospitalized for intravenous hydration and correction of 
electrolyte imbalances. 
 
9.5 
Management of regorafenib-related Adverse Events 
 
At first occurrence of palmar-planter erythrodysesthesia syndrome (PPES), 
independent of grade, prompt institution of supportive measures such as topical 
emollients, low potency steroids, or urea-containing creams should be 
administered. 
 
9.51 
Recommended prevention/management strategies for skin toxicities 
consistent with PPES are summarized below: 
 
Control of calluses 
 
Before initiating treatment with regorafenib: 
 
 
Check condition of hands and feet. 
 
Suggest a manicure/pedicure, when indicated. 
 
Recommend pumice stone use for callus or ‘rough spot’ removal. 
 
During regorafenib treatment: 
 
 Avoid pressure points. 
 Avoid items that rub, pinch or create friction. 
 
Use of creams 
 
 Over the counter moisturizing creams or ointments are allowed 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 For grades 2 or 3, topical analgesics (e.g. lidocaine 5% patches, 
lidocaine/prilocaine cream TID, lidocaine 2-5% creams) are to be 
considered for pain control. 
 Topical corticosteroids like clobetasol 0.05% should be instituted for 
subjects with Grade 2 or 3 PPES. 
 For grade 2/3 Oral NSAIDs (celecoxib, ibuprofen) may be used for pain 
control 
 
Tender areas should be protected as follows: 
 
 Use of thick socks/gloves to cover moisturizing creams 
 Wear well-padded footwear 
 Use insole cushions or inserts (e.g. silicon, gel) 
 Foot soaks with tepid or cool water  
 Use soft shoes or slippers (Crocs, TempurPedic slippers), avoid high 
heels and wood soles/heels 
 
Suggested PPES Reaction Treatment 
 
 
CTCAE v5 Grade 1 ((Minimal skin changes or dermatitis (e.g., 
erythema, edema or hyperkeratosis) without pain)) - Continue 
regorafenib at current dose.  
 
CTCAE v5 Grade 2 ((Skin changes (e.g., peeling, blisters, bleeding, 
edema, or hyperkeratosis) with pain, limiting instrumental ADL (or 
intolerable grade 2, defined as grade 2 AE that does not decrease to 
grade ≤1 after 2 weeks of therapy OR that is considered intolerable per 
patient))  
 
Oral (NSAIDs or narcotics) OR topical analgesia (lidocaine cream 
or patches PRN. 
 
CTCAE v5 Grade ≥3 ((Ulcerative dermatitis or skin changes with pain 
interfering with function. Severe skin changes (eg, peeling, blisters, 
bleeding, edema, or hyperkertosis) with pain; limiting self-care ADL)) 
 Topical steroid cream BID AND topical anesthetics 
 Oral (NSAIDs or narcotics) OR topical analgesia (lidocaine cream 
or patches PRN. 
 
9.6  
Hypomagnesemia: Panitumumab should be held for severe and/or life threatening 
hypomagnesemia. Consider IV replacement and magnesium oxide 400 mg PO BID. 
 
9.7 
Panitumumab-related skin rash. The treating physician may elect to preemptively 
treat subjects receiving panitumumab to mitigate or prevent skin toxicities. 
Doxycyline 100mg every 12 hours or equivalent, emollient, and hydrocortisone 1% 
cream is recommended, but not required for skin rash prophylaxis (Refer to Section 
8.1) 
 
 
9.8 
Hypertension: Early and aggressive medical management of hypertension is 
strongly recommended to minimize the need for dose holding and/or dose 
reductions. Addition or adjustment of blood pressure medications should be 
considered for blood pressure values persistently > 140/90. Symptomatic or 
asymptomatic patients with poorly controlled blood pressure (>150/100 on 3 
measurements over 2 weeks) for over one month (despite the addition and 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
adjustment of anti-hypertensive therapy) should have regorafenib held until their 
blood pressure is ≤140/90. 
 
9.9 
Prohibited Concomitant Therapy 
 
The following therapies are prohibited during the study (unless otherwise noted): 
 
 
Investigational drugs and devices 
 
Anti-cancer therapy, including but not limited to chemotherapy and hormonal 
therapy 
 
Radiation therapy, except for palliative radiotherapy at focal non-CNS sites 
which are not considered target lesions per RECIST 1.1, which may be given 
after consultation with the medical monitor, provided that there remain other 
sites of assessable disease accessible by RECIST 1.1 
 
Strong inhibitors or inducers of CYP3A4. Known strong inhibitors of 
CYP3A4 include, but are not limited to, ketoconazole, itraconazole, 
clarithromycin, erythromycin, atazanivir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, and voriconazole. Known inducers of 
CYP3A4 include, but are not limited to phenytoin, carbamazepine, 
barbiturates, and St. John’s Wort. Partial and more complete lists of strong 
inhibitors and inducers may be found in other reference material.  
 
Caution is required when using drugs that are human thymidine kinase 
substrates, e.g., zidovudine. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all adverse events to the 
sponsor as described within the protocol. Refer to the adverse event and serious adverse 
event sections of the protocol for detailed information. 
 
NOTE: Please see Appendix V for specific AE reporting regarding the study drug 
panitumumab for ACCRU personnel only. 
 
ACCRU is responsible for notifying FDA and all participating investigators in a written 
safety report of any of the following:  
 
 
Any suspected adverse reaction that is both serious and unexpected.  
 
Any findings from laboratory animal or in vitro testing that suggest a significant 
risk for human subjects, including reports of mutagenicity, teratogenicity, or 
carcinogenicity.  
 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not 
conducted by the sponsor, that suggest a significant risk in humans exposed to the 
drug.  
 
Any clinically important increase in the rate of a serious suspected adverse reaction 
over the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of 
investigational product(s)/study treatment through the safety follow-up visit are 
reported using the Event CRF. 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, electrocardiogram, radiological 
scans, vital signs measurements), including those that worsen from 
baseline, that are considered clinically significant in the medical and 
scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration 
even though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug 
interaction. 
 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are an adverse event. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. Hospitalization for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These 
events are typically to be considered serious.  
 

 
 
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Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team 
becoming aware of the event. All SAEs that occur after the subject has signed the main 
informed consent through the safety follow-up visit or 30 days after the last dose of protocol-
specified therapy, whichever is later, will be reported to Amgen and recorded in the case 
report form. SAEs must be reported to Amgen within 24 hours of discovery. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means in 
order to facilitate the review of safety data (may be requested by the FDA or the 
sponsor).  
 
Events NOT Meeting the Adverse Event Definition 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the adverse event. 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site: 
)  
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.  
b. Identify the grade and severity of the event using the CTCAE version 5.0.  
c. Determine whether the event is expected or unexpected (see Section 10.2).  
d. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Section 18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 

 
 
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10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the 
study specific consent form, package insert (if applicable), and/or the investigator 
brochure, (if an investigator brochure is not required, otherwise described in the 
general investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have 
not been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal 
relationship between the drug/device and the adverse event.  
 
Assessment of Causality 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies or study-mandated procedure and each 
occurrence of each adverse event/serious adverse event. 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and 
has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 

 
 
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investigator has minimal information to include in the initial report. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature 
and/or causality of the adverse event or serious adverse event as fully 
as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be recorded.  
 If a subject dies during participation in the study or during a recognized follow-up 
period as defined in Section 13.0, the investigator will provide a copy of any 
postmortem findings including histopathology. 
New or updated information will be recorded in the originally completed Event 
CRF. 
The investigator will submit any updated serious adverse event data within 
reporting timeline.  
 
 
10.31  Special Situations for Expedited Reporting  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 
Serious Adverse Events where the AE is EXPECTED. Any protocol 
specific reporting procedures MUST BE SPECIFIED BELOW and will 
supersede the standard Expedited Adverse Event Reporting Requirements: 
 
Note: These exceptions only apply if the adverse event does not result in 
hospitalization, immediately life-threatening or resulted in 
persistent/significant disability or death.  
 
If the adverse event results in hospitalization, immediately life-threatening 
or resulted in persistent/significant disability or death, then the standard 
expedited adverse events reporting requirements must be followed. 
 
 
 
 
 
 
 
 

 
 
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System Organ Class (SOC) 
Adverse event/Symptoms 
CTCAE Grade at 
which the event will 
not be expeditiously 
reported. 
Gastrointestinal Disorders 
Diarrhea 
Any Grade 
Dyspepsia 
Nausea 
Vomiting 
Colitis 
Grades 1-3 
Pancreatitis 
General disorders and 
administrations site conditions 
Anorexia 
Any Grade 
Asthenia 
Dehydration 
Fatigue 
Malaise 
Weight loss 
Hepatobiliary disorders 
Cholecystitis 
Grades 1-3 
Infections and infestations 
Lung Infection 
Grades 1-3 
Sinusitis 
Skin infection 
Urinary tract infection 
Investigations 
Alkaline phosphatase increased 
Any Grade 
Alanine aminotransferase increased 
Aspartate aminotransferase 
increased 
Lymphocyte count decreased 
Metabolism and nutrition 
disorders 
Hyperkalemia 
Any Grade 
Hypocalcemia 
Hypomagnesemia 
Hyponatremia 
Musculoskeletal and connective 
tissue disorders 
Arthralgia 
Any Grade 
Back pain 
Musculoskeletal and connective 
tissue disorder – Other (muscle 
spasms) 
Skin and subcutaneous tissue 
disorders 
Alopecia 
Any Grade 
Rash acneiform 
Rash maculo-papular 
Palmar-plantar erythrodysesthesia 
syndrome 
 
10.311 Death 
 
 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under 
an IND/IDE requires expedited reporting within 24-
hours. 

 
 
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 
Any death occurring greater than 30 days with an 
attribution of possible, probable, or definite to an 
agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
 
Reportable categories of Death  
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal: A disorder characterized by 
cessation of life during the first 28 days of 
life. 
 
 
Death NOS: A cessation of life that cannot be 
attributed to a CTCAE term associated with 
Grade 5. 
 
 
 
Sudden death NOS: A sudden (defined as instant 
or within one hour of the onset of symptoms) or 
an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with 
Grade 5. 
 
 
Death due to progressive disease that cannot be 
attributed to a CTCAE term associated with 
Grade 5 should be reported as Grade 5 “ 
Disease progression” under the system organ 
class (SOC) of General Disorders and 
Administration Site Conditions. Evidence that 
the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical 
deterioration associated with a disease process) 
should be submitted. 
 
10.312 Secondary Malignancy 
 
 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial 
neoplasm. 
 
 
All secondary malignancies that occur following treatment with 
an agent under an IND/IDE to be reported. Three options are 
available to describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 

 
 
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o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.313 Second Malignancy 
 
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial 
malignancy). Second malignancies require ONLY routine 
reporting. 
 
10.314 Pregnancy  
 
The investigator should report all pregnancies, including those of partners 
of male patients, within 24 hours to ACCRU by submitting the Pregnancy 
Notification Worksheet located on the ACCRU website under Manuals and 
Forms. The funding sponsor will be notified by ACCRU within 10 calendar 
days. The sponsor may ask for follow up evaluation of the pregnancy, fetus, 
and child.  
 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman and 
the newborn infant’s parent or legal guardian before any data collection can 
occur. A consent form will need to be submitted to the IRB for these 
subjects if a pregnancy occurs. If informed consent is not obtained, no 
information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In 
cases where the child/fetus experiences a serious adverse event other than 
fetal death, the child/fetus is the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation.  
 
10.4 Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial 
Agent 1, 2 
 

 
 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour; 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the 
initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 
       Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. 
Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
Follow site-specific reporting guidelines. 
Commercial agent expedited reports must be submitted to the FDA via MedWatch.3500A  
 
  
 

 
 
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Instructions for completing the MedWatch 3500A: 
 
 
Submit copies along with the ACCRU MedWatch Cover Sheet found on the ACCRU Website to the 
ACCRU SAE Coordinator via fax 
The 
ACCRU SAE Coordinator will forward to the funding sponsor via fax 
 
 
The ACCRU SAE Coordinator will forward to 
 as appropriate. 
The ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if required.  
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
in general, include any incident, experience, or outcome that meets all of 
the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
 
2. Related or possibly related to participation in the research (in this 
guidance document, possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of 
the physical or psychological harm associated with adverse events. In other 
cases, unanticipated problems place subjects or others at increased risk of 
harm, but no harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does 
not indicate that subjects should not get pregnant/impregnate others, then 
any pregnancy in a subject/patient or a male patient’s partner 
(spontaneously reported) which occurs during the study or within 120 days 
of completing the study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as 
required by your institutional policies.  
 
10.52 Baseline and Adverse Events Evaluations 
 
 
The following pre-treatment symptoms/conditions are to be graded at 
baseline and adverse events are to be graded at each evaluation using 
CTCAE v5.0 grading.  
 

 
 
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System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
Evaluation 
General disorders 
and 
administration 
site conditions 
Fatigue 
X 
X 
Gastrointestinal 
disorders 
Diarrhea 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash acneiform 
X 
X 
 
10.53 Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
 
Submit the following AEs not specified in Section 10.5   
 
10.531 Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment 
or procedure. 
 
10.533 Grade 5 AEs (Deaths) 
 
10.5331 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5332 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.54 Late occurring adverse events are any adverse events that occur during 
Survival Follow-Up reporting periods. These are reported in compliance 
with Section 4.0 and Section 18.  
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote 
for the table regarding measureable disease in Section 11.44, as it pertains to data collection 
and analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1) [38]. Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the short axis measurements in the case of lymph nodes are used in the 
RECIST guideline. 
 

 
 
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11.1 
Schedule of Evaluations: For the purposes of this study, patients should be 
reevaluated every 8 weeks.  
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21  Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter 
can be accurately measured as 2.0 cm with chest x-ray, or as ≥1.0 
cm with CT scan, CT component of a PET/CT, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter 
is ≥ 1.0 cm in diameter as assessed using calipers (e.g. skin nodules) 
or imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
11.213 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease.  
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to 
<1.5 cm). Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable as well. 
 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. In addition, lymph nodes that have a short axis <1.0 cm are 
considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:  
 
 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to 

 
 
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less than 2 cm must use CT imaging for both pre- and post-treatment 
tumor assessments.  
 
 
Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used at the same evaluation 
to assess the antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:  
 
 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  
 
 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the 
type and site of disease. The lesions should be measured on the same 
pulse sequence. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
 
PET-CT: If the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  
 
11.33 Measurement at Follow-up Evaluation:  
 
 
In the case of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum interval 
of 8 weeks (see Section 11.44). 
 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate 
between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
 
Cytologic and histologic techniques can be used to differentiate between 
PR and CR in rare cases (e.g., residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as 
“Target Lesions” and recorded and measured at baseline. These lesions 

 
 
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can be non-nodal or nodal (as defined in 11.21), where no more than 2 
lesions are from the same organ and no more than 2 malignant nodal 
lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified 
(as there often will be), there is no reason to perform additional studies 
beyond those specified in the protocol to discover new lesions.  
 
 
Target lesions and target lymph nodes should be selected on the basis of 
their size, be representative of all involved sites of disease, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion (or 
malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be 
selected.  
 
 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the baseline sum of dimensions 
(BSD). The BSD will be used as reference to further characterize any 
objective tumor response in the measurable dimension of the disease.  
 
 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes will be calculated and reported as the post-baseline 
sum of dimensions (PBSD). If the radiologist is able to provide an actual 
measure for the target lesion (or target lymph node), that should be 
recorded, even if it is below 0.5 cm. If the target lesion (or target lymph 
node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion 
of the radiologist that the target lesion or target lymph node has likely 
disappeared, the measurement should be recorded as 0 cm. 
 
 
The minimum sum of the dimensions (MSD) is the minimum of the 
BSD and the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline. 
These lesions and lymph nodes should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI must be measured on re-evaluation at evaluation times 
specified in Section 11.1. Specifically, a change in objective status 
to either a PR or CR cannot be done without re-measuring target 
lesions and target lymph nodes.  
 
 

 
 
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Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first 
response or confirmation of response. In selected circumstances, 
certain non-target organs may be evaluated less frequently. For 
example, bone scans may need to be repeated only when complete 
response is identified in target disease or when progression in bone 
is suspected. 
 
11.432 Evaluation of Target Lesions 
 
 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have reduction in 
short axis to <1.0 cm. 
 
 
Partial Response (PR): At least a 30% decrease in PBSD 
(sum of the longest diameter for all target lesions plus the 
sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the BSD (see Section 11.41). 
 
 
Progression (PD): At least one of the following must be 
true: 
 
a. At least one new malignant lesion, which also 
includes any lymph node that was normal at 
baseline (< 1.0 cm short axis) and increased to ≥ 1.0 
cm short axis during follow-up.  
 
b. At least a 20% increase in PBSD (sum of the 
longest diameter for all target lesions plus the sum 
of the short axis of all the target lymph nodes at 
current evaluation) taking as reference the MSD 
(Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in regards to the 
requirements for PD via FDG-PET imaging. 
  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify 
for PR, nor sufficient increase to qualify for PD taking as 
reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all non-target lesions.  
 

 
 
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b. Each non-target lymph node must have a reduction 
in short axis to <1.0 cm. 
 
 
Non-CR/Non-PD: Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
 
Progression (PD): At least one of the following must be 
true: 
 
a. At least one new malignant lesion, which also 
includes any lymph node that was normal at 
baseline (< 1.0 cm short axis) and increased to ≥ 1.0 
cm short axis during follow-up.  
 
b. Unequivocal progression of existing non-target 
lesions and non-target lymph nodes. (NOTE: 
Unequivocal progression should not normally trump 
target lesion and target lymph node status. It must 
be representative of overall disease status change.)  
 
c. See Section 11.32 for details in regards to the 
requirements for PD via FDG-PET imaging. 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables:  
 
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data 
collection and analysis purposes the objective status changed from SD to PR in the ACCRU 
protocol RECIST v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
12.0 
Descriptive Factors  
 
12.1 
ECOG PS: 0 vs. 1 vs. 2. 
 
12.2 
Disease characteristics: Unresectable vs. Metastatic. 
 
12.3 
Prior treatment: TAS-102 vs. regorafenib vs. neither. 
 
12.4 
Primary tumor location: cecum vs. ascending vs. hepatic flexure vs. transverse vs. 
splenic flexure vs. descending vs. sigmoid vs. rectosigmoid vs. rectum vs other. 
 
 
12.5 
Microsatellite instability or mismatch repair deficiency tested: Yes vs. no. 
 
 
12.51 If yes, MSI-High (MSI-H) vs. microsatellite stable/MSI-Low (MSS/MSI-
L); loss of mismatch repair protein (MMR deficient, dMMR) vs. mismatch 
repair proteins intact (MMR proficient, pMMR). 
 
12.6 
ERBB2 (HER2) amplification tested: Yes vs. no. 
 
 
12.61  If yes, ERBB2 amplified vs. ERBB2 equivocal vs. ERBB2 not amplified. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
 
13.1 
Patients who have CR, PR, or SD will continue treatment per protocol for a 
maximum of 24 cycles. Subsequent treatment is at the discretion of their attending 
physician. 
 
13.2 
Patients who develop PD while receiving therapy or choose an alternative therapy 
will go to the event-monitoring phase and be followed for survival (i.e. event-
monitoring phase) every 3 months (±7 days) for 3 years after randomization (per 
Section 18.0). Subsequent treatment is at the discretion of their attending physician. 
 
13.3 
Patients who go off protocol treatment for any reason will go to the event-
monitoring phase and be followed for survival (i.e. event monitoring phase) every 3 
months (±7 days) for 3 years after randomization (per Section 18.0). Subsequent 
treatment is at the discretion of their attending physician. 
 
 
 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study 
entry. The patient may continue treatment off-protocol at the discretion of the 

 
 
ACCRU-GI-1623 
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physician as long as there are no safety concerns, and the patient was properly 
registered. The patient will go directly to the event-monitoring phase of the study 
(or off study, if applicable).  
 
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 
18.0 of the protocol.  
 
 
If the patient never received treatment, on-study material must be submitted.  
The patient will not be followed for survival. 
 
 13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment 
in cycle 1 of the initial therapy are severely violated that evaluability for primary 
end point is questionable. All data up until the point of confirmation of a major 
violation must be submitted. The patient will go directly to the event-monitoring 
phase of the study. The patient may continue treatment off-protocol at the discretion 
of the physician as long as there are no safety concerns, and the patient was 
properly registered. Event monitoring will be required per Section 18.0 of the 
protocol. 
 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason 
before any study treatment is given. On-study material and the Off Treatment Form 
must be submitted. The patient will not be followed for survival.  
 
13.7 
Patients have the option to complete cfDNA testing at study completion and are 
encouraged to re-register with protocol ACCRU-GI-1611 (COLOMATE). The 
results of the cfDNA test will be used in protocol ACCRU-GI-1611 (COLOMATE) 
to identify genomic alterations and facilitate enrollment on COLOMATE 
companion clinical trials. Sites will access results by creating an account at 
Sites will be notified by Guardant Health via 
email when results are available in the portal.  See detailed instructions on the 
ACCRU website under Manuals and Forms.  
 
14.0 
Body Fluid Biospecimens  
 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This 
Protocol  
 
 
Indicate if 
specimen 
is 
mandatory 
or optional 
Collection 
tube 
descriptio
n and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number 
of tubes to 
be 
collected) 
Blood 
product 
being 
processed 
and 
submitted 
by 
participating 
site 
Baseline1 
 
 
Prior to 
dosing 
on Day 
1 of 
Cycle 2 
Restaging2 
End of 
Treatment3 
Additional 
processing 
required at 
site after 
blood 
draw? 
Storage 
/shipping 
conditions4 
Mandatory EDTA K2 
(Purple) 
10 mL (1) 
Whole 
Blood 
X 
 
 
 
No 
Freeze /dry 
ice 
Mandatory EDTA K2 
(Purple) 
10 mL (4) 
Platelet Poor 
Plasma and 
X 
X 
X 
X 
Yes 
Freeze /dry 
ice 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
1. May occur prior to treatment on Cycle 1 Day 1. 
2. At time of radiographic assessments (i.e., every other cycle beginning on cycle 3) which 
may occur ≤14 days prior to day 1 of new cycle (estimated 4 restagings per patient). 
3. Discontinuation of study treatment. 
4. After all samples have been processed according to kit instructions, ship all specimens 
according to shipping instructions (see Section 14.3 for detailed shipping instructions.) 
Patients have the option to complete cfDNA testing at study completion and are 
encouraged to re-register with protocol ACCRU-GI-1611. See section 13.7.  
14.2 
Kits are required for this study. 
 
NOTE: You will be ordering and receiving kits from two different locations.  
 
14.21 EDTA K2 
 
 
14.211 Each kit will contain supplies and instructions for collecting, 
processing, and shipping specimens. 
 
14.212 Participating institutions may obtain kits for EDTA K2 by 
completing and faxing the Supply Order Form (found in the Forms 
Packet) to the number listed on the form. Fill out the site address to 
where the kits will be shipped on the Fax Supply form. A small but 
sufficient supply of the specimen collection kits should be ordered 
prior to patient entry. Unused/expired kits should be disposed of 
per institution policy. Do not send unused kits back to BAP. 
Supply Order Forms must be filled in completely and legibly 
for quick processing. 
 
14.213 Kits will be sent via FedEx Ground at no cost to the participating 
institutions. Allow up to two weeks to receive the kits.  
 
14.214 Kits will not be sent via rush delivery service unless the 
participating institution provides their own FedEx account number 
or for express service. ACCRU will not cover the cost for rush 
delivery of kits. 
 
14.22 Guardant 360 (Streck Tube) 
 
14.221 In order to receive kits and access to the Guardant portal, fill out 
the Guardant Site Setup form for each treating location and email to 
 
 
14.222 Sites will create an account at 
 
Once account is created, Guardant Health will ship the sites their 
kits and their own pre-printed Test Requisition Form(TRFs). Once 
that happens, kits and TRFs can be refreshed/replaced by 
contacting Guardant Health Client Services Team at 
 
or 
 
 
14.3 
Shipping and Handling 
White blood 
cells 
Optional 
Streck 
tube5 
10 mL (2) 
Whole 
blood 
 
 
 
X 
No 
Room 
temperature 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
NOTE: You will be shipping kits to two different locations.  
 
14.31 EDTA K2 
 
14.311 Verify ALL sections of the Blood Specimen Submission Form (see 
Forms Packet), BAP Requisition Form (provided in kit) and 
specimen collection labels are completed and filled in correctly. 
Tube labels MUST match requisition form. 
 
14.312 Specimens must be shipped the same day they are drawn. 
 
14.313 Ship the EDTA tube in a combo shipper with the EDTA going into 
the side with a properly prepared cold pack. Place the frozen 
aliquots in the side for dry ice. Completely fill the box with dry ice 
pellets and be sure to label the weight of the dry ice on the shipping 
label. See kit instructions for specific details.  
 
14.314 Ship specimens via Priority Overnight service, Monday – Friday, to 
BAP Freezer according to kit instructions. Do not send samples on 
weekends or just prior to federal holidays.  
 
14.315 The BAP kits will include a smart shipper label (3x5 white 
barcoded label) affixed to the shipping boxes. The smart shipper 
label is a pre-addressed return label, which replaces the need for an 
air bill. Shipping costs will be covered by ACCRU if the shipping 
box provided with the BAP kit is used for shipping specimens to 
BAP Freezer. 
 
14.316 BAP Freezer will receive the samples and immediately forward 
specimens to the ACCRU Research Base BAP Shared Resource, 
Stabile SL-16. At study completion, specimens will be forwarded 
to the Duke Phase I Biomarker Laboratory located at Duke 
University for future processing. 
 
14.32 Guardant 360 (Streck Tube) 
 
 
14.321 Complete the Test Requisition Form and barcode labels (provided 
in kit). 
 
14.322 Ship tubes the same day as collection with properly prepared gel 
pack. Do not freeze gel packs. Use as is.  
 
14.323 Place the kit into the preprinted FedEx Clinical Pak and call FedEx 
for a pickup to be shipped to Guardant Health.  
 
14.324 Detailed Blood Draw and Shipping Instructions are located on the 
ACCRU website under Manuals and Forms.  
 
14.4 
Study Methodology and Storage Information 
 
14.41 Blood/blood product samples will be collected for the following research 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
14.411 Whole blood for pharmacogenomics 
 
Whole blood will be stored for future pharmacogenetic assays (e.g., 
genetic polymorphisms such as those known to regulate 
angiogenesis, inflammation, immunity, auto-immunity, and antibody 
or drug action of clearance) that may correlate with efficacy and 
tolerability. The Duke Phase I Biomarker Laboratory located at 
Duke University may analyze the DNA for the presence of markers 
of interest using standard laboratory protocols. 
 
14.412 Soluble protein (blood-based) biomarkers 
 
Blood (platelet poor plasma, and white blood cells (buffy coat)) will 
be collected at baseline, every restaging, and progression for future 
analysis. The Duke Phase I Biomarker Laboratory located at Duke 
University may analyze for the following, but are not limited to 
soluble HGF, c-MET, EGF, HBEGF, HER1-3, FGFa, FGFb, 
VEGFA-D, PlGF, VEGFR2, GAS6, AXL, SDF1, Ang2, and TIE-2. 
Additional biomarkers may also be explored using multiplex array 
technology. Final biomarker selection will reflect the best science at 
the time of analysis. 
 
14.413 Plasma for mutational analysis 
 
Blood (platelet poor plasma) will be stored for future analysis of cell 
free DNA (cfDNA) and will be collected at baseline, every 
restaging, and at the 30-day post-treatment visit. The Duke Phase I 
Biomarker Laboratory located at Duke University may analyze for 
the following, but are not limited to HER2 amplification, EGFR 
amplification, BRAF mutations, and extended KRAS/NRAS testing 
(exons 2, 3, and 4). Final biomarker selection will reflect the best 
science at the time of analysis. 
 
14.414 Future use of patient samples 
 
Any remaining biological materials (platelet poor plasma, and buffy 
coats) at the end of the study will be retained for possible use in 
future biomarker research. 
 
14.5 
Return of Genetic Testing Research Results 
 
Results of CLIA-certified assays (e.g., Guardant360) are permitted to be shared 
with patients and their treating physicians. Because the results generated by other 
genetic testing included in this section are not currently anticipated to have clinical 
relevance to the patient or their family members, the genetic results will not be 
disclosed to the patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB 
review and approval will be sought regarding the most appropriate manner of 
disclosure and whether or not validation in a CLIA-certified setting will be 
required. Sharing of research data with individual patients should only occur when 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
data have been validated by multiple studies and testing has been done in CLIA-
approved laboratories. 
 
15.0 
Drug Information 
 
 
IND exempt 
 
Investigator brochure 
Will be sent hard copy to sites by ACCRU. Sites will email Research 
Protocol Specialist with shipping address.   
 
15.1 
Panitumumab (Vectibix®) 
 
15.11 Background: Panitumumab is a recombinant human IgG2 monoclonal 
antibody which binds specifically to the epidermal growth factor receptor 
(EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of 
epidermal growth factor (EGF) and other ligands. Binding to the EGFR 
blocks phosphorylation and activation of intracellular tyrosine kinases, 
resulting in inhibition of cell survival, growth, proliferation and 
transformation. EGFR signal transduction results in KRAS wild-type 
activation; cells with KRAS mutations appear to be unaffected by EGFR 
inhibition. 
 
15.12 Formulation: Panitumumab is supplied as a sterile, colorless, preservative-
free solution in a single-dose vial. The vial is designed to deliver 20 mg/mL 
(5 mL, 20 mL). 
 
15.13 Preparation, storage, and stability: Store unopened vials at 
refrigerated temperature 2 to 8ºC (36º to 46ºF), do not freeze or 
shake, protect from light. Dilute in 100-150 mL of 0.9% sodium 
chloride injection, USP to a final concentration of less than or equal 
to 10 mg/mL. Doses higher than 1000 mg should be diluted to 150 
mL with 0.9% sodium chloride injection, USP. Do not shake, invert 
gently to mix. Preparations in infusion containers are stable for 24 
hours under refrigeration (2º to 8ºC or 36º to 46ºF) or for 6 hours at 
room temperature. Do not freeze the diluted solution. 
 
 
15.14 Administration: Doses less than or equal to 1000 mg, infuse over 1 hour: 
doses > 1000 mg, infuse over 90 minutes. For doses that are less than or 
equal to 1000 mg, if the first infusion is well tolerated, subsequent infusions 
may be administered over 30 to 60 minutes. Reduce infusion rate by 50% 
for mild-to-moderate infusion reactions (grades 1 and 2); discontinue for 
severe infusion reactions (grades 3 and 4). Administer through a low 
protein-binding 0.2 or 0.22 micrometer in-line filter. Flush with 0.9% 
sodium chloride injection, USP before and after infusion. 
 
 
15.15 Pharmacokinetic information: 
Half-life elimination: ~7.5 days (range: 3.6 to 10.9 days) 
 
 
15.16 Potential Drug Interactions:  
Increased Effect/Toxicity: There are no known interactions where it 
is recommended to avoid concomitant use. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
15.17 Known potential adverse events:  
Most common known potential toxicities, > 10%:  
General disorders: Fatigue/asthenia, pyrexia, mucosal inflammation, 
peripheral edema, weight loss, decreased appetite 
Dermatologic: Skin toxicity, erythema, pruritus, dry skin, dermatitis 
acneiform, paronychia, rash, skin fissure, acne, conjunctivitis, 
alopecia 
Endocrine & metabolic: Hypomagnesemia, hypokalemia 
Gastrointestinal: Nausea, diarrhea, constipation, vomiting, abdominal 
pain, stomatitis 
Respiratory: Dyspnea, cough 
Musculoskeletal: Back pain 
Nervous system disorder: Paresthesia 
Psychiatric: Insomnia 
 
Common known potential toxicities, 1% - 10%:  
Cardiovascular: Pulmonary embolism, epistaxis, deep vein 
thrombosis, flushing 
Central nervous system: Chills, headache, dizziness 
Dermatologic: Exfoliative rash, nail disorder, skin exfoliation, 
palmar-plantar erythrodysesthesia syndrome, hyperhidrosis, macular 
rash, hypertrichosis, maculopapular rash, skin toxicity, onychoclasis 
pruritic rash, abnormal hair growth, pain of the skin, skin lesion, 
dermatitis, generalized rash  
Endocrine & metabolic: Dehydration, decreased blood magnesium, 
hypocalcemia, hyperglycemia, hyperphosphatemia 
Gastrointestinal: Dyspepsia, dry mouth, rectal hemorrhage, 
gastroesophageal reflux disease, lower abdominal pain, apthous 
ulcer, oral pain, cheilitis  
Immunologic: Hypersensitivity 
Ocular: Increased lacrimation, dry eye, abnormal eyelash growth, 
blepharitis, ocular hyperemia, eye irritation, eye pruritus 
Hematologic: Leukopenia 
Infections and infestations: Urinary tract infection, pustular rash, 
folliculitis, cellulitis, localized infection 
Musculoskeletal: Pain in extremity 
Psychiatric: Anxiety 
 
 
Uncommon known potential toxicities, <1%  
Eye disorders: Eyelid irritation, keratitis, ulcerative colitis 
Gastrointestinal: Chapped lips, dry lip 
Infections and infestations: Eye infection, nail infection, eyelid 
infection 
Procedural complication: Infusion related reaction 
Nervous system disorder: Cholinergic syndrome 
Respiratory, thoracic and mediastinal disorders: Nasal dryness 
Skin and subcutaneous tissue: Ingrowing nail, onycholysis, 
hirsutism, angioedema, skin necrosis, Stevens-Johnson syndrome/ 
toxic epidermal necrolysis,  
Immunologic: Hypersensitivity reaction 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
Respiratory: Interstitial lung disease 
 
15.18 Drug procurement: Each participating ACCRU treating location will fill 
out the pharmacy contact sheet posted in ARMS. ACCRU will send sites a 
site specific Drug Order Form. Sites will then send completed Drug Order 
Form to email address listed on the form.   
 
Each participating ACCRU treating location with be responsible for 
monitoring the supply of panitumumab and will use the Drug Order 
Request Form to order additional supplies as needed.  
 
Outdated or remaining drug is to be destroyed on-site as per procedures in 
place at each institution.  
 
15.19a Temperature excursions that occur at the site should be reported by the site 
using the Temperature Excursion Form found on the ACCRU web site for 
this study and emailed to ‘send to’ address on the form.  
 
 
15.19b Nursing Guidelines:  
 
15.19b1  Patient may experience typical EGFR inhibitor related rash, which 
is generally acneiform in nature and may be associated with 
pruitis and erythema. Treat symptomatically and monitor for 
effectiveness. 
 
15.19b2  Premedication is generally not required with panitumumab 
administrations as infusion related reactions are rare. If patients 
do experience a transfusion related reaction, stop the infusion, 
inform the MD and treat as necessary. Patient then may need 
premedication prior to future infusions. 
 
15.19b3  Panitumumab must be infused via infusion pump through a 0.2 or 
0.22 micron in-line filter infusion set up. Flush with 0.9% sodium 
chloride injection, USP before and after infusion. 
 
15.19b4  Hypomagnesmia is seen with this agent. Monitor magnesium level 
prior to each infusion. If level is below normal, inform the MD.  
 
15.19b5  Patients may experience nail related changes, including 
discoloration, ridging, paronychias, and/or loss of the nail itself. 
Instruct patients to report nail changes to the study team, as 
intervention may be indicated. 
 
15.19b6  Gastrointestinal side effects including nausea, diarrhea, 
constipation and vomiting have been seen. Treat symptomatically 
and monitor for effectiveness.  
 
15.19b7  Monitor patients closely and instruct them to report any side 
effects to the study team as all side effects of panitumumab in 
combination with chemotherapy are not known at this time. 
 
15.19b8  Panitumumab is a protein and should be handled carefully to 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
avoid break down of the product. This includes both when 
mixing from the vial and when administering the product via IV 
infusion. 
 
15.2 
Regorafenib (BAY 73-4506, Stivarga®)   
 
 
Refer to package insert for complete, up-to-date information. 
 
15.21 Background 
 
Regorafenib is a novel oral multi-kinase inhibitor that targets tumor cells 
and the tumor microenvironment. It inhibits tumor growth, progression and 
metastasis by inhibiting the proliferation of tumor cells, the formation of 
new tumor vasculature and stromal signaling in the microenvironment of 
the tumor. 
 
 
15.22 Formulation  
 
Commercially available as light pink, oval-shaped 40 mg tablets. Tablets 
are supplied in packages containing three bottles, with each bottle 
containing 28 tablets. 
 
 
15.23 Preparation and storage 
 
Once the drug has been received it must be kept in a secure, dry 
location. Study drug must be stored in its original bottle at a 
temperature not above 25°C (77°F).  
 
15.24 Administration 
 
Regorafenib tablets should be taken in the morning with approximately 8 
fluid ounces (240 mL) of water after a low-fat (<30% fat) breakfast. 
Regorafenib should not be taken with grapefruit juice. 
 
 
15.25 Pharmacokinetic information 
 
a) Absorption – Following a single 160 mg dose of Regorafenib in 
patients with advanced solid tumors, regorafenib reaches a 
geometric mean peak plasma level (Cmax) of 2.5µg/mL at a 
median time of 4 hours and a geometric mean area under the 
plasma concentration vs time curve (AUC) of 70.4µg*h/mL. A 
high-fat meal increased the mean AUC of the parent drug by 
48% compared to the fasted state and decreased the mean AUC 
of the M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) active 
metabolites by 20% and 51%, respectively. A low-fat meal 
increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 
40% and 23%, respectively (as compared to the fasted state). 
 
b) Distribution – Regorafenib undergoes enterohepatic circulation 
with multiple plasma concentration peaks observed across the 
24-hour dosing interval. Regorafenib is highly bound (99.5%) to 
human plasma proteins. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
c) Metabolism – Regorafenib is metabolized by CYP3A4 and 
UGT1A9. The main circulating metabolites measured at steady 
state are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), 
both of them having similar in vitro pharmacological activity and 
steady-state concentrations as regorafenib. M-2 and M-5 are 
highly protein bound (99.8% and 99.95%, respectively). 
 
d) Elimination – Elimination half-lives for regorafenib and the M-2 
metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours 
(14 to 32 hours), respectively. M-5 has a longer mean (range) 
elimination half-life of 51 hours (32 to 70 hours). 
 
e) Excretion – Approximately 71% of radiolabeled dose was 
excreted in feces (47% as parent compound; 24% as 
metabolites); and 19% of the dose was excreted in urine (17% as 
glucuronides). 
 
 
15.26 Potential Drug Interactions  
 
Avoid concomitant use of strong CYP3A4 inducers (i.e. rifampin, 
phenytoin, carbamazepine, phenobarbital and St. John’s Wort) and 
strong CYP3A4 inhibitors (i.e. clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin 
and voriconazole). 
 
Co-administration of Regorafenib with a Breast Cancer Resistance 
Protein (BCRP) substrate increased the plasma concentrations of the 
BCRP substrate. Monitor patients closely for signs and symptoms of 
exposure related toxicity to the BCRP substrate (e.g. methotrexate, 
fluvastatin, atorvastatin). 
 
 
15.27 Known potential toxicities  
Consult the package insert for the most current and complete 
information.  
 
Serious Adverse Effects 
 
Hepatotoxicity: [U.S. Boxed Warning]: Severe liver toxicity and 
hepatic failure (sometimes resulting in death) have been observed in 
clinical trials; hepatocyte necrosis with lymphocyte infiltration has 
been demonstrated with liver biopsy. Monitor hepatic function at 
baseline and during treatment. Interrupt therapy for hepatotoxicity; 
dose reductions or discontinuation are necessary depending on the 
severity and persistence. 
 
Most Common Adverse Events, >10%: 
Cardiovascular: Hypertension, hemorrhage 
Central nervous system: Fatigue, dysphonia, pain, fever, headache. 
Dermatologic: Skin toxicity, Palmar-plantar erythrodysesthesia, rash 
Endocrine & metabolic: Hypocalcemia, hypophosphatemia, 
hyponatremia, hypokalemia 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
Gastrointestinal: Appetite decreased, lipase increased, diarrhea, 
mucositis, weight loss, amylase increased 
Hematologic: Anemia, lymphopenia, thrombocytopenia, INR 
increased, neutropenia 
Hepatic: AST increased, ALT increased, hyperbilirubinemia 
Renal: Proteinuria 
Miscellaneous: Infection, pain (including gastrointestinal and 
abdominal pain) 
 
Less Common Adverse Events, 1% - 10%: 
Hepatic: Hepatic failure 
 
Rare Adverse Events (Important or life-threatening), <1%: 
Gastrointestinal: Gastrointestinal perforation, gastrointestinal fistula,  
Cardiovascular: Cardiac ischemia or infarction 
Neurologic: Reversible posterior leukoencephalopathy syndrome 
(RPLS) 
Dermatologic: Stevens-Johnson syndrome, toxic epidermal 
necrolysis 
 
Additional risks: 
Hypersensitivity reactions: Hypersensitivity reactions have been 
reported during post-approval use of regorafenib. Because these 
reactions are reported voluntarily from a population of uncertain size, 
it is not always possible to reliably estimate their frequency or 
establish a causal relationship to drug exposure 
 
Wound Healing Complications: No formal studies of the effect of 
regorafenib on wound healing have been conducted. Since vascular 
endothelial growth factor receptor (VEGFR) inhibitors such as 
regorafenib can impair wound healing, discontinue treatment with 
regorafenib at least 2 weeks prior to scheduled surgery. The decision 
to resume regorafenib after surgery should be based on clinical 
judgment of adequate wound healing. Discontinue regorafenib in 
patients with wound dehiscence. 
 
Embryo-Fetal Toxicity: Based on animal studies and its mechanism 
of action, regorafenib can cause fetal harm when administered to a 
pregnant woman. There are no available data on regorafenib use in 
pregnant women. Regorafenib was embryolethal and teratogenic in 
rats and rabbits at exposures lower than human exposures at the 
recommended dose, with increased incidences of cardiovascular, 
genitourinary, and skeletal malformations. Advise pregnant women 
of the potential risk to a fetus. Advise females of reproductive 
potential to use effective contraception during treatment with 
regorafenib and for 2 months after the final dose. Advise males with 
female partners of reproductive potential to use effective 
contraception during treatment with regorafenib and for 2 months 
after the final dose. 
 
 
 

 
 
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15.28 Drug procurement: Commercial supplies. Each participating ACCRU 
treating location shall obtain supplies from normal commercial supply 
chain or wholesaler.   
 
Outdated or remaining drug is to be destroyed on-site as per procedures in 
place at each institution.  
 
15.29 Nursing Guidelines  
 
15.291 Liver toxicity and liver failure have resulted from this agent. 
Monitor LFT’s closely and instruct patients to report any 
abdominal pain, jaundice or significant fatigue to the study team. 
Dose reduce or interrupt treatment as per protocol. 
 
15.292 Hypertension has been seen. Monitor blood pressure as outlined in 
protocol. 
 
15.293 Instruct patient to report a rash, or signs and symptoms of palmar-
plantar erythrodysesthesia to the study team. Rarely SJS and TENS 
have been seen with this agent. Instruct patients to seek immediate 
medical attention if they experience rash with fever, blisters, 
sloughing of tissue (especially in the mouth and vaginal, anal 
regions). Treat symptomatically and monitor for effectiveness. 
 
15.294 Inform patients of possibility of alopecia. 
 
15.295 Gastrointestinal side effects can include, diarrhea, nausea, 
vomiting, decreased appetite, weight loss, mucositis and less 
commonly taste changes, dry mouth, and reflux. Treat 
symptomatically and monitor for effectiveness.  
 
15.296 Cytopenias are seen with agent. Monitor CBC w/diff and instruct 
patient to report signs, symptoms of infection or any unusual 
bruising or bleeding to the study team.  
 
15.297 Secondary skin cancers have been reported. Instruct patients to 
report new or changing lesions to study team. 
 
15.298 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a 
rare (<1%) but serious condition. Presenting symptoms may 
include changes in mental status, visual disturbance, seizure, or 
other CNS changes. Patients with this syndrome generally had 
HTN as well, therefore BP monitoring is important. Instruct patient 
to report any mental status changes, visual changes, seizures, or 
other CNS changes to the MD immediately. These may be a sign of 
RPLS or more serious condition, such as hemorrhagic event in the 
CNS. 
 
15.3 
TAS-102 Trifluridine (FTD)/Tipiracil (TPI) (TAS-102, Lonsurf®) 
 
 
 
Refer to package insert for complete, up-to-date information. 
 

 
 
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15.31 Background 
 
TAS-102 is a combination of trifluridine, a nucleoside metabolic inhibitor, 
and tipiracil, a thymidine phosphorylase inhibitor, indicated for the 
treatment of patients with metastatic colorectal cancer who have been 
previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based 
chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an 
anti-EGFR therapy 
 
15.32 Formulation 
 
 
FTD/TPI (TAS-102) tablet (15 mg) contains 15 mg trifluridine and 
6.14 mg tipiracil as active ingredients. The appearance is white 
round tablet.  
 
FTD/TPI (TAS-102) tablet (20 mg) contains 20 mg trifluridine and 
8.19 mg tipiracil as active ingredients. The appearance is pale red 
round tablet.  
 
15.33 Preparation and storage  
 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C 
to 30°C (59°F to 86°F). If stored outside of original bottle, discard after 30 
days.  TAS-102 is a cytotoxic drug. Follow applicable special handling and 
disposal procedures.  
 
15.34 Administration  
 
Recommended to take within 1 hour after completion of the morning and 
evening meals. Anyone other than the patient who handles their medication 
should wear gloves. 
 
 
15.35 Pharmacokinetic information 
 
After twice daily dosing of TAS-102, systemic exposure (AUC) of 
trifluridine increased more than dose-proportionally over the dose 
range of 15 to 35 mg/m2. After administration of TAS-102 35 mg/m2 
twice daily, the mean elimination of half-life (t1/2) of trifluirdine was 
1.4 hours and of tipiracil was 2.1 hours after a single dose. The mean 
elimination half-life at steady state of trifluridine was 2.1 hours and 
of tipiracil was 2.4 hours. 
 
Protein Binding 
Trifluridine: >96% (primarily to albumin); Tipiracil: <8% 
 
Metabolism 
Trifluridine and tipiracil are not metabolized by cytochrome P450 
(CYP) enzymes. Trifluridine is mainly eliminated by metabolism via 
thymidine phosphorylase to form an inactive metabolite, 5-
(trifluoromethyl) uracil (FTY)  
 
 
Excretion 
Following a single dose of TAS-102, the mean 48-hour cumulative urinary 

 
 
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excretion was 1/5% for unchanged trifluridine, 19.2% for FTY, and 29.3% 
for unchanged tipiracil.   
 
15.36 Potential Drug Interactions  
 
Trifluridine is a substrate of thymidine phosphorylase, and is not 
metabolized by cytochrome P450 (CYP) enzyme. Tipiracil is not 
metabolized in either human liver or hepatocytes. 
 
In vitro studies indicated that trifluridine, tipiracil, and FTY did not 
inhibit the CYP enzymes and had no inductive effect on CYP1A2, 
CYP2B6, or CYP3A4/5. 
 
In vitro studies indicated that trifluridine was not an inhibitor of or 
substrate for human uptake and efflux transporters.  
 
 
15.37 Known potential toxicities 
Consult the package insert for the most current and complete information.  
 
 
Most common known potential toxicities, >/= 10%: 
 
Blood and lymphatic: Anemia, neutropenia, thrombocytopenia 
 
Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain 
 
General: Fatigue, pyrexia, infection 
 
Metabolism and nutrition: Decreased appetite 
 
 
Common known potential toxicities, >/=1% - <10%: 
 
Cardiovascular: Pulmonary emboli 
 
Gastrointestinal: Stomatitis 
 
 
Nervous System: Dysgeusia 
 
 
Uncommon known potential toxicities, <1% (Limited to important or 
life-threatening):  
 
 
Blood and lymphatic: Severe myelosuppression  
 
Respiratory: Interstitial lung disease 
 
15.38 Drug procurement: Commercial supplies. Each participating ACCRU 
treating location shall obtain supplies from normal commercial supply 
chain or wholesaler.  
 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in 
place at each institution.  
 
 
15.39 Nursing Guidelines 
  
15.391 Instruct patients that agent should be taken within 1 hour after 
completion of morning and evening meal. 
15.392 Patients may experience fatigue. Instruct patients in energy 
conserving lifestyle. 
15.393 GI side effects are common, including nausea, decreased appetite, 

 
 
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diarrhea, vomiting, and abdominal pain. 
15.394 Cytopenias are common. Monitor CBC w/diff and instruct patients 
to report any signs or symptoms of infection and/or unusual 
bruising or bleeding to the study team.  
15.395 Rarely Pulmonary embolism has been reported with this agent. 
Instruct patient to report any shortness of breath or chest pain to 
study team and/or seek out emergency medical attention. 
15.396 Although uncommon, inform patients of the possibility of alopecia.  
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Overview and Study Design  
 
This is a randomized Phase II study which is designed to compare the overall 
survival (OS) in patients with EGFR refractory RAS wild-type metastatic CRC, who 
are randomized to panitumumab or standard therapy (TAS-102 or regorafenib). 
Prior studies have shown that the median OS is around 6.5 months for patients in 
this disease population receiving TAS-102 or regorafenib and PFS is around 1.9 
months for patients receiving TAS-102 or regorafenib in this disease population 
[40, 41]. It is hypothesized that panitumumab can increase the median OS to at least 
10 months. In addition to OS, this trial will also compare the overall response rate, 
PFS, adverse event rates, and self-reported quality of life outcomes (measured by 
LASA) between the panitumumab arm and standard therapy (TAS-102 or 
regorafenib). 
 
16.11 Primary Endpoint 
 
The primary endpoint for this study is overall survival (OS) which is 
defined as the time from randomization to death from any cause. Patients 
who are alive will be censored at the last known alive date.  
 
16.12 Interim Analysis 
 
 
One interim analysis for futility will be conducted when at least 42 patients 
across both arms combined have provided documentation of death. Overall 
survival will be used as the endpoint for the interim analysis. The interim 
futility boundary was selected using EAST software. Un-stratified log-rank 
p-value will be used for decision making .  The trial will continue accrual 
while the interim analysis is being conducted. If the 1-sided p-value > 0.529 
for panitumumab compared to standard therapy (TAS-102 or regorafenib), 
which corresponds to a hazard ratio (HR) > 1.022, the panitumumab will be 
considered as futile and the accrual will be suspended. Otherwise, if the 1-
sided p-value ≤ 0.529 (HR ≤ 1.022), the study will continue to full accrual 
and the final analysis will be conducted as described below. 
 
 
 
16.13 Final Analysis 
 
Efficacy analysis will be conducted when at least 83 death events, across 

 
 
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both arms combined, have been observed. The stratified log-rank test will 
be used for decision making except when there are 0 events in any of the 
strata; in that case, the un-stratified log-rank will be used for decision 
making. If the 1-sided p-value is > 0.15 for panitumumab compared to 
standard therapy (TAS-102 or regorafenib), which corresponds to a hazard 
ratio (HR) > 0.797, panitumumab will be considered as inefficacious; if the 
1-sided p-value ≤0.15 (equivalently, HR ≤0.797), panitumumab will be 
considered as promising for future study. All eligible patients who sign the 
consent form, are randomized, and received any protocol treatment are 
considered evaluable for this endpoint.  
  
16.14 Decision Rules 
 
Analysis 
time point 
Number of 
events1 
Critical p-value  
Hazard Ratio 
Futility 
Efficacy 
Futility 
Efficacy 
50% 
42 
> 0.529 
N/A 
> 1.022 
N/A 
100% 
83 
> 0.15 
≤0.15 
> 0.797 
≤ 0.797 
 
 
1 Documentation of death 
 
 
16.15 Power and Sample Size  
 
The primary goal is to compare the OS between patients who are 
randomized to panitumumab and those randomized to standard therapy 
(TAS-102 or regorafenib). The null hypothesis is that the panitumumab arm 
does not show a superior OS outcome compared to standard therapy (TAS-
102 or regorafenib). The alternative hypothesis is that the panitumumab 
arm has improvement in OS compared to standard therapy (TAS-102 or 
regorafenib).  
 
We will enter 53 evaluable patients to each arm of the study using a 1:1 
randomization scheme (106 evaluable patients in total); unless the study is 
stopped early. Stratification factors are defined in section 5.0. With 53 
evaluable patients per arm, we have 80% power to detect an improvement 
in the median OS from 6.5 to 10 months (HR=0.65), assuming a 1-sided 
significance level of 0.15 and an accrual rate of 8 patients per month. The 
trial has a single interim analysis for futility, adopting the Rho family 
(Rho=1.5) beta spending function for controlling the overall type II error 
rate and will be considered non-binding. 
 
 
 
 
16.151 Operating Characteristics 
 
The table below shows the operating characteristics assuming the 
OS follows the exponential survival function along with a one-
sided significance level of 0.15.  
 
The table below includes the operating characteristics according to 
the monitoring plan outlined above. The proportion of times that 1) 
the study would stop early at the interim analysis due to futility of 
panitumumab, and 2) the study would conclude panitumumab is 
superior to TAS-102 or regorafenib at the final analysis, are 
tabulated by true OS median survival times and equivalent true 

 
 
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hazard ratios for OS by treatment groups.  
 
 
 
 
 
 
True median overall 
survival (months)1 
 
 
True 
Hazard 
Ratio  
 
% of times the 
study will be 
stopped for 
futility at the 
interim 
analysis 2 
 
% of times that 
panitumumab 
is deemed 
superior at the 
final analysis 2 
TAS-102 or 
regorafenib 
 
panitumumab 
6.5 
6.5 
1 
47.7 
14.1 
6.5 
7.2 
0.90 
34.3 
26.8 
6.5 
7.9 
0.82 
24.3 
41.9 
6.5 
8.6 
0.76 
16.5 
56.7 
6.5 
9.3 
0.70 
11.2 
69.9 
6.5 
10 
0.65 
7.5 
79.4 
 
1 Although we use the median OS to illustrate each scenario, the 
hypothesis testing is based on the entire survival curve. 
  
2 Proportions are based on 50,000 replicates in a simulation study 
 
16.2 
Sample Size  
 
We plan to randomize at least 106 eligible patients (53 to panitumumab; 53 to 
standard therapy (TAS-102 or regorafenib). We anticipate randomizing an 
additional 14 patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Therefore, maximum accrual is projected to be 120 
patients.  
 
16.3 
Accrual Time and Study Duration  
 
The anticipated accrual rate is approximately 8 patients per month. Therefore, the 
accrual period for this randomized Phase II study is expected to be around 15 
months. The final analysis can begin as soon as the 83rd OS event has occurred; 
approximately 25 months after the study begins under the alternative hypothesis. 
 
16.4  
Data & Safety Monitoring  
 
16.41 The principal investigator(s) and the study statistician will review the study 
at least twice a year to identify accrual, adverse event, and any endpoint 
problems that might be developing. The trial is monitored continually by 
the study team. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety 
data for this trial at least twice a year, based on reports provided by the 
study statistician. Any safety issues requiring protocol changes are 
communicated through protocol amendments.  
 
16.42 Adverse Event Monitoring and Stopping Rules  
 

 
 
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The monitoring rule specified below is based on the knowledge available at 
study development. We note that the Adverse Event Monitoring Rule may 
be adjusted in the event of either (1) the study re-opening to accrual after 
any temporary suspension or (2) at any time during the conduct of the trial 
and in consideration of newly acquired information regarding the adverse 
event profile of the treatment(s) under investigation. The study team may 
also choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual may be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e., 
an adverse event with attribute specified as "possible", "probable", or 
"definite") that satisfy any of the following criteria for each arm 
separately: 
 
 
If at any time, 4 of the initial 10 treated patients, or 33% or more of all 
patients (when accrual is greater than 10 patients) have experienced a 
grade 4+ adverse event at least possibly related to treatment. 
 
16.43 Data Safety Monitoring 
 
This trial will be monitored by the Mayo Clinic Cancer Center Data and 
Safety Monitoring Board (MCCC DSMB) every 6 months. 
 
16.5 
Definitions and Analyses of Secondary Endpoints  
 
All these endpoints will be assessed individually and will also be compared between 
the 2 arms. Descriptive statistics will be provided. P-values will be reported but will 
be considered descriptive.  
 
16.51 Progression Free Survival (PFS)  
 
Progression free survival is defined as the time from randomization to 
documentation of disease progression or death due to any cause, whichever 
is first. For patients who are progression-free and alive, PFS will be 
censored at the last disease evaluation. If the patient did not have any 
disease evaluation post randomization, PFS will be censored at one day 
after randomization. The distribution of progression free survival will be 
estimated using the method of Kaplan-Meier (Kaplan 1958). Progression 
free survival will be compared between the 2 treatment arms using the log-
rank test.  
 
16.52 Overall Response Rate (ORR)  
 
Overall response rate is defined as the number of patients with a complete 
response (CR) or partial response (PR) (as defined by the RECIST 1.1) 
divided by the number of evaluable patients in each arm at 12 months post 
registration. ORR will be compared between the 2 treatment arms. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Clopper and Pearson. 
 

 
 
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16.53 Clinical Benefit Rate 
 
 
 
Clinical benefit rate is defined as the number of patients with a complete 
response (CR), partial response (PR), or stable disease for ≥ 6 months (as 
defined by the RECIST 1.1) divided by the number of evaluable patients in 
each arm. Confidence intervals for the true success proportion will be 
calculated according to the approach of Clopper and Pearson. 
 
16.54 Adverse Events  
 
All eligible patients who have initiated treatment will be considered 
evaluable for adverse event analyses. The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will be 
reviewed to determine adverse event patterns. The overall adverse event 
rates for grade 3 or higher adverse events will be compared using Chi-
Square or Fisher’s Exact tests.  
 
 
 
16.55 Patient-reported Outcomes 
 
 
 
 
Patients reported quality of life (QOL) outcomes will be collected using the 
Linear Analog Self-Assessment (LASA) Questionnaire. Data will be 
collected each cycle. Mean values of the first question (regarding overall 
QOL) at each cycle will be plotted, and stratified by arm. Additional 
analyses using data collected from the LASA questionnaire may be 
performed.   
  
16.56 Over Accrual:  
 
If more than the target number of patients are accrued, the additional 
patients will be used to evaluate the stopping rule or used in any decision 
making processes. They will also be included in final point estimates and 
confidence intervals. 
 
 
16.6 
Correlative Research 
 
 
 
16.61 Blood-based Biomarker Studies 
 
 
 
 
16.611 Cell free tumor DNA (cfDNA) 
 
Cell free DNA will be analyzed at baseline, each restaging and at 
progression. A report will be generated for each clinical specimen, 
which may include (but not limited to) the presence or absence of 
relevant gene mutations or amplifications, along with the allele 
frequency. Mutations of interest include KRAS and NRAS exons 2, 
3, and 4, BRAF, PIK3CA, EGFR, AKT, PTEN, MAP2K1, and MET. 
Amplifications of interest include MET, EGFR, KRAS, and ERBB2. 
Genes and alterations analyzed will be based on best available 
science at the time of analysis. We will also explore the association 
between genetic alterations and clinical outcomes.  
 
 
 
 
16.612 Circulating protein studies 
 

 
 
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Plasma samples will be analyzed for multiple soluble protein 
analytes, which may include (but not limited to) HGF, c-MET, 
EGF, HBEGF, TGF-α, EGFR, HER2, and CD73. Additional 
biomarkers may also be explored using multiplex array technology. 
We will explore the association between soluble protein expression 
and clinical outcomes.  
 
 
 
16.62 Tumor Tissue Studies 
 
Comprehensive mutational analysis will be performed on archived formalin 
fixed paraffin embedded (FFPE) tumor samples. This analysis may include, 
but is not limited to Next Generation Sequencing (NGS) and IHC where 
appropriate. We will explore the association between genetic alterations and 
gene expression and clinical outcomes.  
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Type of tissue 
biospecimen to submit 
Mandatory 
or optional 
When to submit 
Reason for 
submission 
(background/me
thodology 
section) 
Where to find 
specific 
details for 
biospecimen 
submission 
FFPE tissue block with 
corresponding H&E 
slide or up to twenty-
five (25) 4-micron, 
unstained slides and up 
to three (3) 
corresponding H&E 
slides from primary 
tumors present prior 
to study entry (if 
available) 
Mandatory 
Baseline 
Correlative 
studies (Section 
17.3) 
Section 17.2 
 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides 
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block 
with largest amount of invasive tumor (at least 1 cm of tumor for cases of 
surgical resection) from original surgery at the time of diagnosis. Biopsy 
material obtained at the time of metastatic diagnosis may be submitted, if 
blocks from the surgical resection are inadequate or unavailable. A 
corresponding H&E slide for each submitted block must be provided./ 
The H&E slide for each block should be reviewed by the institution’s 
pathologist to assess tissue quality prior to submission. 
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut up to 25 (twenty-five) 4-micron sections and 

 
 
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mount on charged glass slides. Label the slides with ACCRU patient ID 
number, accession number, and order of sections, and thickness of 
sections. NOTE: do NOT place “sticky” labels directly on slides, the 
institution label needs to be visible. H&E stain every tenth slide (i.e., 
slides labeled 1, 11, 21, etc.). The H&E slides should be reviewed by the 
institution’s pathologist to assess tissue quality prior to submission. For 
samples containing less than 7 square millimeters of tumor tissue, multiple 
sections should be mounted onto each slide to ensure that the appropriate 
amount of tumor tissue is available. Ideally, each slide should have a 
minimum of 75% tumor tissue on the slide to be deemed adequate for 
study. Do not bake or place covers slips on the slides. 
 
17.23 The following materials below are mandatory (unless indicated otherwise) 
and required for shipment: 
 
 
Paraffin embedded tissue blocks with corresponding H&E slide(s) 
(OR up to 25 (twenty-five) unstained slides with corresponding 
H&E slide(s)).  
 
Specimen Submission: Tissue form 
 
Surgical Pathology Report 
 
Operative Report (optional) 
 
NOTE: Please include the ACCRU patient ID number on all materials 
listed above. 
 
17.24 The block/slides must be appropriately packed to prevent damage (e.g., 
slides should be placed in appropriate slide container) and placed in an 
individual plastic bag. Label the bag with the protocol number, ACCRU 
patient ID number, and patient initials. 
 
17.25 Tissue specimens must be shipped ≤90 days from date of randomization. 
 
17.26 Verify that the appropriate sections of the Specimen Submission: Tissue 
form are completed and filled in correctly. Enter information from the 
Specimen Submission: Tissue form into the remote data entry system on the 
same day the specimen is submitted (see Forms Packet). 
 
17.27 Ship all block/slide tissue specimens and accompanying materials to the 
ACCRU Research Base: 
 
 
 
 
 
 
 
17.28 When an appropriate request is submitted, the ACCRU Operations Office 
will forward the block(s) to the 
 
At study 
completion specimens will be sent to the Duke Phase I Biomarker 
Laboratory located at Duke University for processing as outlined in Section 
17.3. 

 
 
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17. 3 
Study Methodology and Storage Information 
 
Submitted tissue samples will be analyzed as follows: 
 
17.31 At the completion of the study, any unused/remaining material will be 
stored in the Duke Phase I Biomarker Laboratory located at Duke 
University for future research according to the patient consent permission 
(see Section 6. 5). Potential future research may include 
immunohistochemistry (IHC) analyses to analyze predictive biomarkers, 
changes in expression pattern with therapy, and correlation with response 
and/or adverse events. When a protocol is developed, it will be presented 
for IRB review and approval. 
 
17.32 Banking of tumor tissue, according to the patient consent permission (see 
Section 6. 5), is for future research. As protocols are developed, they will 
be presented for ACCRU and IRB review and approval. (This collection is 
part of a general strategy of investigation for ACCRU studies). 
 
17.33 The institutional pathologist will be notified by the Pathology Coordinator 
if the block may be depleted. 
 
17.34 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.35 Return of Genetic Testing Research Results: No genetic specimens will be 
collected from tissue biospecimens for this study. If future genetic testing is 
being requested for stored tissue, patient reconsent is required. 
 
18.0 
Records and Data Collection Procedures  
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and 
authorized personnel. Access the RAVE RDE system through the iMedidata portal at 
. All data on the CRF must reflect the corresponding source 
document. Please refer to the ACCRU website for instructions (
.  
 
18.1 
Submission Timetable 
 
 
Initial Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
≤2 weeks after registration 
On-Study  
On-Study: Prior Systemic Therapy 
Adverse Events: Baseline  
RECIST Measurements: Baseline 
Laboratory Tests & Results: Baseline 
Supporting Documentation: Baseline2 
Specimen Submission: Blood (Baseline) (see 

 
 
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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Section 14.0) 
Specimen Submission: Tissue (Baseline) (see 
Section 17.0) 
Patient Status: Baseline  
Notice of New Primary1 
OP and Path Reports (see Section 17.0)2 
Off Treatment 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet-PRO/QOL: 
Linear Analogue Self Assessment (LASA) 
 2 weeks after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
PRO/QOL : Booklet Compliance3 
 2 weeks after registration - This form must be completed 
only if the (name of booklet/s – or whatever verbiage you 
want to use to describe the booklet/s) contains absolutely NO 
patient provided assessment information. 
ACCRU Deviation Form1 
Submit only if applicable during all phases of the study  
(initial, active and observation) 
1. Submit only if applicable. 
2. Upload via the Supporting Documentation: Baseline form. COLOMATE Companion Trial 
Recommendation Form. This is in addition to the pathology material requirements for tissue 
submission (Section 17.0). 
3.    This form must be completed only if the Linear Analogue Self Assessment (LASA) contains 
absolutely NO patient provided assessment information. 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
(within 30 days after last 
dose of study drug) 
 
Treatment (Intervention) 
X 
X 
Treatment (Intervention): Dose 
Modifications, Omissions and Delays1 
X 
 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other1 
X 
X 
RECIST Measurements2 
X 
X 
Supporting Documentation2 
X 
X 
Laboratory Tests and Results 
X 
X 
Specimen Submission: Blood (see Section 
14.0) 
X  
 
Patient Status: Treatment (Intervention) 
X 
X 
Notice of New Primary1 
X 
X 
Consent Withdrawal (choose appropriate 
form)1 
 
Consent Withdrawal: Specimen Only 
X 
X 

 
 
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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
(within 30 days after last 
dose of study drug) 
 
Off Treatment 
 
X 
ACCRU Deviation1 
X 
X 
Patient Questionnaire Booklet3 – PRO/QOL: 
Linear Analogue Self Assessment (LASA) 
(if applicable) 
X 
X 
PRO/QOL : Booklet Compliance4 (if 
applicable) 
X 
X 
1. Submit only if applicable. 
2. Upload documentation of response or progression on the Supporting Documentation form. 
3. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
4. This form must be completed only if the Linear Analogue Self Assessment (LASA) contains 
absolutely NO patient provided assessment information. 
 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
q. 3 
months 
until PD 
or 
alternative 
therapy 
 
 
 
At PD 
After 
PD or 
alternati
ve 
therapy 
q. 3 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Patient Status: Survival and Disease 
Status Follow-Up/Event Monitoring  
X2 
X2 
X 
X 
At each occurrence 
Adverse Events: Late3 
 
 
 
 
X 
Supporting Documentation2, 3 
 
 
 
 
 
Notice of New Primary3 
 
 
 
 
X 
Consent Withdrawal (choose 
appropriate form)3 
• Consent Withdrawal: Specimen 
Only 
• Consent Withdrawal: All Follow-Up 
 
 
 
 
X 
Lost to Follow-Up3, 4 
 
 
 
 
 
ACCRU Deviation Form3 
X3 
X3 
X3 
X3 
 
1. If a patient is still alive 3 years after randomization, no further follow-up is required. 
2. Upload a copy of documentation of progression in RAVE on the Supporting Documentation 
Form. 
3. Submit only if applicable. 
4. Patients are eligible to be confirmed lost to follow-up after 2 years of unsuccessful contact with 
the patient.  

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
19.0 
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local 
and regional coverage policies, to determine which items are standard of care and 
which are research at their site. Refer to the payment synopsis for funding provided 
per accrual for covering study costs, as well as any additional invoiceables that may 
be allowed. 
 
19.2 
Tests to be research funded:  
 
 
Pharmacogenomic collection 
 
Mutational collection 
 
cfDNA Guardant360 
 
Tumor tissue collection 
 
19.3 
Other budget concerns: 
 
 
19.31 Panitumumab will be supplied by Amgen. TAS-102 and regorafenib will 
not be supplied, but is commercially available. 
 
 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
 
20.0 
References 
 
1. 
Jemal, A., et al., Cancer statistics, 2010. CA: A Cancer Journal for Clinicians, 2010. 
60(5): p. 277-300. 
2. 
Grothey, A., et al., Regorafenib monotherapy for previously treated metastatic 
colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-
controlled, phase 3 trial. Lancet, 2013. 381(9863): p. 303-12. 
3. 
Mayer, R.J., et al., Randomized trial of TAS-102 for refractory metastatic colorectal 
cancer. N Engl J Med, 2015. 372(20): p. 1909-19. 
4. 
Douillard, J.Y., et al., Overall survival (OS) analysis from PRIME: Randomized 
phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic 
colorectal cancer (mCRC). J Clin Oncol, 2013. 31(suppl; abstr 3620). 
5. 
Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for 
metastatic colorectal cancer. N Engl J Med, 2009. 360(14): p. 1408-17. 
6. 
Heinemann, V., et al., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab 
as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a 
randomised, open-label, phase 3 trial. Lancet Oncol, 2014. 15(10): p. 1065-75. 
7. 
Peeters, M., et al., Randomized phase III study of panitumumab with fluorouracil, 
leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line 
treatment in patients with metastatic colorectal cancer. J Clin Oncol, 2010. 28(31): 
p. 4706-13. 
8. 
Sobrero, A.F., et al., EPIC: phase III trial of cetuximab plus irinotecan after 
fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal 
cancer. J Clin Oncol, 2008. 26(14): p. 2311-9. 
9. 
Van Cutsem, E., et al., Open-label phase III trial of panitumumab plus best 
supportive care compared with best supportive care alone in patients with 
chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol, 2007. 25(13): 
p. 1658-64. 
10. 
Cunningham, D., et al., Cetuximab monotherapy and cetuximab plus irinotecan in 
irinotecan-refractory metastatic colorectal cancer. N Engl J Med, 2004. 351(4): p. 
337-45. 
11. 
Jonker, D.J., et al., Cetuximab for the treatment of colorectal cancer. N Engl J Med, 
2007. 357(20): p. 2040-8. 
12. 
Siravegna, G., et al., Clonal evolution and resistance to EGFR blockade in the blood 
of colorectal cancer patients. Nat Med, 2015. 21(7): p. 827. 
13. 
Liu, X., et al., Retreatment with anti-EGFR based therapies in metastatic colorectal 
cancer: impact of intervening time interval and prior anti-EGFR response. BMC 
Cancer, 2015. 15: p. 713. 
14. 
Pietrantonio, F., et al., Single agent panitumumab in KRAS wild-type metastatic 
colorectal cancer patients following cetuximab-based regimens: Clinical outcome 
and biomarkers of efficacy. Cancer Biol Ther, 2013. 14(12): p. 1098-103. 
15. 
Santini, D., et al., Cetuximab rechallenge in metastatic colorectal cancer patients: 
how to come away from acquired resistance? Ann Oncol, 2012. 23(9): p. 2313-8. 
16. 
Douillard, J.Y., et al., Panitumumab-FOLFOX4 treatment and RAS mutations in 
colorectal cancer. N Engl J Med, 2013. 369(11): p. 1023-34. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
17. 
Van Cutsem, E., et al., Fluorouracil, leucovorin, and irinotecan plus cetuximab 
treatment and RAS mutations in colorectal cancer. J Clin Oncol, 2015. 33(7): p. 
692-700. 
18. 
Di Nicolantonio, F., et al., Wild-type BRAF is required for response to panitumumab 
or cetuximab in metastatic colorectal cancer. J Clin Oncol, 2008. 26(35): p. 5705-
12. 
19. 
Laurent-Puig, P., et al., Analysis of PTEN, BRAF, and EGFR status in determining 
benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin 
Oncol, 2009. 27(35): p. 5924-30. 
20. 
Loupakis, F., et al., KRAS codon 61, 146 and BRAF mutations predict resistance to 
cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal 
cancer. Br J Cancer, 2009. 101(4): p. 715-21. 
21. 
Vlacich, G. and R.J. Coffey, Resistance to EGFR-targeted therapy: a family affair. 
Cancer Cell, 2011. 20(4): p. 423-5. 
22. 
Bertotti, A., et al., The genomic landscape of response to EGFR blockade in 
colorectal cancer. Nature, 2015. 526(7572): p. 263-7. 
23. 
Yonesaka, K., et al., Activation of ERBB2 signaling causes resistance to the EGFR-
directed therapeutic antibody cetuximab. Sci Transl Med, 2011. 3(99): p. 99ra86. 
24. 
Bardelli, A., et al., Amplification of the MET receptor drives resistance to anti-
EGFR therapies in colorectal cancer. Cancer Discov, 2013. 3(6): p. 658-73. 
25. 
Strickler, J.H., et al., Cell free DNA (cfDNA) to monitor clonal evolution in patients 
(pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary 
results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor 
cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P). Mol 
Cancer Ther, 2015. 14(12 Suppl 2: Abstract nr A52). 
26. 
Hong, D.S., et al., First-in-human study of AMG 337, a highly selective oral 
inhibitor of MET, in adult patients (pts) with advanced solid tumors. J Clin Oncol, 
2014. 32(5s suppl; abstr 2508). 
27. 
Strickler, J.H., et al., Phase 1, open-label, dose-escalation, and expansion study of 
ABT-700, an anti-C-met antibody, in patients (pts) with advanced solid tumors. J 
Clin Oncol, 2014. 32 (5s suppl; abstr 2507)(5s suppl; abstr 2507). 
28. 
Raghav, K., et al., MET amplification in metastatic colorectal cancer: An acquired 
response to EGFR inhibition, not a de novo phenomenon. Oncotarget, 2016. 
29. 
Arena, S., et al., MM-151 overcomes acquired resistance to cetuximab and 
panitumumab in colorectal cancers harboring EGFR extracellular domain 
mutations. Sci Transl Med, 2016. 8(324): p. 324ra14. 
30. 
Sanchez-Martin, F.J., et al., The first-in-class anti-EGFR antibody mixture Sym004 
overcomes cetuximab-resistance mediated by EGFR extracellular domain mutations 
in colorectal cancer. Clin Cancer Res, 2016. 
31. 
Bettegowda, C., et al., Detection of circulating tumor DNA in early- and late-stage 
human malignancies. Sci Transl Med, 2014. 6(224): p. 224ra24. 
32. 
Diaz, L.A., Jr., et al., The molecular evolution of acquired resistance to targeted 
EGFR blockade in colorectal cancers. Nature, 2012. 486(7404): p. 537-40. 
33. 
Misale, S., et al., Emergence of KRAS mutations and acquired resistance to anti-
EGFR therapy in colorectal cancer. Nature, 2012. 486(7404): p. 532-6. 
34. 
Parseghian, C.M., et al., Anti-EGFR-resistant clones decay exponentially after 
progression: implications for anti-EGFR re-challenge. Ann Oncol, 2019. 30(2): p. 
243-249. 

 
 
ACCRU-GI-1623 
                                                                                                                                     Amendment 1 
 
 
35. 
Jia, J., et al., A phase I/II trial of cabozantinib (C) with or without panitumumab (P) 
in patients (pts) with RAS wild-type (WT) metastatic colorectal cancer (mCRC): 
Clinical outcomes in pts with MET amplification (amp) detected in blood. J Clin 
Oncol, 2018. 36(suppl; abstr 3555). 
36. 
Rossini, D., et al., Liquid biopsy to predict benefit from rechallenge with cetuximab 
(cet) + irinotecan (iri) in RAS/BRAF wild-type metastatic colorectal cancer patients 
(pts) with acquired resistance to first-line cet+iri: Final results and translational 
analyses of the CRICKET study by GONO. J Clin Oncol, 2018. 36(suppl; abstr 
12007). 
37. 
Montagut, C., et al., Efficacy of Sym004 in Patients With Metastatic Colorectal 
Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected 
by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial. JAMA 
Oncol, 2018: p. e175245. 
38. 
Basilico, C., et al., Tivantinib (ARQ197) Displays Cytotoxic Activity That Is 
Independent of Its Ability to Bind MET. Clin Cancer Res, 2013. 19(9): p. 2381-92. 
[38] 

ACCRU-GI-1623 
Appendix I 
Page 1 of 1 
 
 
Appendix I: ACCRU-GI-1623 PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet 
(Baseline and Each Cycle) 
________________________________________________________________________ 
 
You will be given booklets to complete for this study. This booklet contains some 
questions about your ‘quality-of-life’ as a patient receiving treatment for cancer. Your 
answers will help us to better understand how the treatment you are receiving is 
affecting the way you feel. 
 
1. You are being asked to complete a questionnaire booklet for this study. This booklet 
must be completed prior to dosing at each cycle and at the end of treatment (within 
30 days after your last dose).   
 
2. This booklet contains the following questionnaire: 
a. Linear Analogue Self Assessment (LASA) 
 
3. Directions on how to complete each set of questions are written on the top of the 
page. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. 
You can call anytime with any concerns or questions. 
 
5. Please complete the booklet and return it to your study staff. It is very important that 
you return the booklet to us. 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix II 
 
Page 1 of 2 
 
 
 
 
Appendix II: ACCRU-GI-1623 LINEAR ANALOGUE SELF ASSESSMENT 
 
Patient Name: ________________________________ 
Date: _____________________ 
Patient Number:  ______________________________ 
  
Directions: Please circle the number (0-10) best reflecting your response to the following 
 
 
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
7. the frequency of your pain? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Constant pain 
 
8. the severity of your pain, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Pain as bad as  
 
 
 
 
 
 
 
 
 
 
 
you can imagine 
9. your level of fatigue, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No fatigue 
 
 
 
 
 
 
 
 
 
Constant  

 
 
  
ACCRU-GI-1623 
 
Appendix II 
 
Page 2 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiredness 
 
 
 
10. your level of support from friends and family? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No support 
 
 
 
 
 
 
 
 
 
Highest level of  
 
 
 
 
 
 
 
 
 
 
 
 
support 
 
11. your financial concerns? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns  
 
 
 
 
 
 
 
No concerns 
 
12. your legal concerns (will, advanced directives, etc.)? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns  
 
 
 
 
 
 
 
No concerns 
 
© 1996  Mayo Foundation for Medical Research 
 

 
 
  
ACCRU-GI-1623 
 
Appendix III 
 
Page 1 of 2 
 
 
 
 
Appendix III: ACCRU-GI-1623 (PULSE) Examples of CYP3A4 Inducers and Inhibitors 
 
Please see 
 for examples of CYP3A4 
therapies. This list is not comprehensive. Contact your investigational/central pharmacy for 
any questions. 
 
(Strong and moderate classifications may be referenced on Lexi-Comp Online, drug 
information reference 
 
 
CYP3A4 INHIBITORS 
GENERIC NAME 
TRADE NAME 
Indinavir 
Crixivan 
Nelfinavir 
Viracept 
Ritonavir 
Norvir 
clarithromycin 
Biaxin 
itraconazole 
Sporanox 
ketoconazole 
Nizoral 
Nefazodone 
Serzone 
Saquinavir 
Invirase 
telithromycin 
Ketek 
Aprepitant 
Emend 
erythromycin 
Ery-Tab 
Fluconazole 
Diflucan 
grapefruit juice 
 
Verapamil 
Calan 
Diltiazem 
Cardizem 
Cimetidine 
Tagamet 
Amiodarone 
Cordarone 
chloramphenicol 
Chloroptic 
Delavirdine 
Rescriptor 
diethyldithiocarbamate 
Imuthiol 
fluvoxamine 
Luvox 
gestodene 
Minesse 
mibefradil* 
Posicor 
mifepristone 
Mifeprex 
norfloxacin 
Noroxin 
norfluoxetine 
N/A 
star fruit 
 
voriconazole 
VFEND 
amprenavir1 
Agenerase 
atazanavir1 
Reyataz 
fosamprenavir1 
Lexiva 
seville oranges 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix III 
 
Page 2 of 2 
 
 
 
 
 
CYP3A4 INDUCERS 
GENERIC NAME 
TRADE NAME 
efavirenz 
Sustiva 
nevirapine 
Viramune 
barbiturates 
Luminal 
carbamazepine 
Tegretol 
glucocorticoids 
 
modafinil 
Provigil 
nevirapine 
Viramune 
oxcarbazepine 
Trileptal 
phenobarbital 
Luminal 
phenytoin 
Dilantin 
pioglitazone 
Actos 
rifabutin 
Mycobutin 
rifampin 
Rifadin 
St. John's wort 
 
troglitazone* 
Rezulin 
 

 
 
  
ACCRU-GI-1623 
 
Appendix IV(A) 
 
Page 1 of 2 
 
 
 
 
Appendix IV(A): ACCRU-GI-1623 (PULSE) PATIENT MEDICATION DIARY: 
Regorafenib 
 
Name: 
Patient ID Number: 
Cycle:  
You will take:  
 
ORAL MEDICATION DIARY 
Patient Instructions 
 
Please bring your Medication Diary and any empty or unused medication container(s) with 
you to every appointment 
 
Please use an ink pen when completing the Medication Diary as these will be retained in our 
research record. 
 
Please contact your physician and study coordinator any time you go into the hospital. Your 
physician can advise if you should stop taking your medication or continue it.  
 
To correct an error or mistake, please make a single line through that entry and write your 
initials and date next to the error or mistake. 
 
Please record each dose as soon as you take it and fill in the date as directed. 
 
Please indicate on the calendar below every day that you take your study medication by 
placing the dose taken on the line under the date. 
 
If you miss a dose, place a  “0” under the date, but remember to take your prescribed dose at 
the next regularly scheduled time. 
 
If you accidentally take more than you are instructed to, contact your doctor or the 
emergency room immediately. 
 
If you miss a dose, do not make up the dose or double up the next dose. 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix IV(A) 
 
Page 2 of 2 
 
 
 
 
ACCRU-GI-1623 (PULSE) PATIENT MEDICATION DIARY – Regorafenib 
 
 
 
 
 
 
Date:__________________ 
Participants Signature___________________________________ 
 
Area Below Only To Be Completed only by Coordinator 
  
Week 
1 
2 
3 
4 
Discrepancy (Yes or No) 
Date of Pill Count 
 
 
 
 
 
Number of Pills 
Returned 
 
 
 
 
 
Study Coordinator 
Initials 
 
 
 
 
 
 
Study Drug/Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Regorafenib/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Regorafenib/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Regorafenib/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Regorafenib/__mg    
 
 
 
 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix IV(B) 
 
Page 1 of 2 
 
 
 
 
Appendix IV(B): ACCRU-GI-1623 (PULSE) PATIENT MEDICATION DIARY:TAS-102 
 
Name: 
Patient ID Number: 
Cycle:  
You will take:  
 
ORAL MEDICATION DIARY 
Patient Instructions 
 
Please bring your Medication Diary and any empty or unused medication container(s) with 
you to every appointment 
 
Please use an ink pen when completing the Medication Diary as these will be retained in our 
research record. 
 
Please contact your physician and study coordinator any time you go into the hospital. Your 
physician can advise if you should stop taking your medication or continue it.  
 
To correct an error or mistake, please make a single line through that entry and write your 
initials and date next to the error or mistake. 
 
Please record each dose as soon as you take it and fill in the date as directed. 
 
Please indicate on the calendar below every day that you take your study medication by 
placing the time dose taken on the line under the date. 
 
If you miss a dose, place a  “0” under the date, but remember to take your prescribed dose at 
the next regularly scheduled time. 
 
If you accidentally take more than you are instructed to, contact your doctor or the 
emergency room immediately. 
 
If you miss a dose, do not make up the dose or double up the next dose. 
 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix IV(B) 
 
Page 2 of 2 
 
 
 
 
ACCRU-GI-1623 (PULSE) PATIENT MEDICATION DIARY – TAS-102 
 
 
 
 
 
 
 
 
 
Date:__________________ 
Participants Signature___________________________________ 
 
Area Below Only To Be Completed only by Coordinator 
  
Week 
1 
2 
3 
4 
Discrepancy (Yes or No) 
Date of Pill Count 
 
 
 
 
 
Number of Pills 
Returned 
 
 
 
 
 
Study Coordinator 
Initials 
 
 
 
 
 
 
Study Drug/Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
TAS-102/___mg AM 
 
 
 
 
 
 
 
TAS-102/___mg PM 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
TAS-102/___mg AM 
 
 
 
 
 
 
 
TAS-102/___mg PM 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
TAS-102/___mg 
 
 
 
 
 
 
 
TAS-102/___mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
TAS-102/___mg       
 
 
 
 
 
 
TAS-102/___mg 
 
 
 
 
 
 
 

 
 
  
ACCRU-GI-1623 
 
Appendix V 
 
Page 1 of 1 
 
 
 
 
Appendix V: Submission of Safety Data Regarding the Study Drug Panitumumab 
 
NOTE: For ACCRU personnel only 
For Interventional studies with IMP*: 
 
Safety Data 
Timeframe for Submission to the 
Funding Sponsor 
Suspected Unexpected Serious Adverse 
Reaction (SUSARs) 
Sent to funding sponsor at time of 
regulatory submission 
Serious Adverse Events (SAEs) 
Not required, unless contractually 
specified per study 
Adverse Events not meeting serious 
criteria 
Not required, unless contractually 
specified per study 
Events of Interest 
Not required, unless contractually 
specified per study 
Pregnancy/Lactation 
Within 10 calendar days of Sponsor 
awareness 
Event listing for reconciliation 
As specified per contract 
*Specific requirements are to be outlined in the Research Agreement 
 
 
For all studies – aggregate reports*(as applicable): 
 
Safety Data 
Timeframe for submission to the 
Funding Sponsor 
Annual Safety Report 
(eg, EU Clinical Trial Directive [CTD] 
DSUR, and US IND Annual Report) 
Annually 
Other Aggregate Analyses 
(any report containing safety data 
generated during the course of a study) 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) 
Final (End of Study Report, 
including): 
 Unblinding data for blinded 
studies 
 Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) but not later than 1 
calendar year of study completion 
*Specific requirements are to be outlined in the Research Agreement