A Randomized Phase II Study of Regorafenib Followed by Anti-EGFR Monoclonal Antibody Therapy Versus the Reverse Sequencing for Metastatic Colorectal Cancer Patients Previously Treated With Fluoropyrimidine, Oxaliplatin and Irinotecan (REVERCE II)
Phase: PHASE2
Conditions: BRAF V600E Negative, KRAS Gene Mutation Negative, Locally Advanced Unresectable Colorectal Adenocarcinoma, Metastatic Colorectal Adenocarcinoma, NRAS Gene Mutation Negative, Stage III Colorectal Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8
Sponsor: Academic and Community Cancer Research United

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Academic and Community Cancer Research United (ACCRU) 
 
A Randomized Phase II Study of Regorafenib Followed by Anti-EGFR monoclonal antibody therapy 
Versus the Reverse Sequencing for metastatic colorectal cancer patients previously treated with 
fluoropyrimidine, oxaliplatin and irinotecan (REVERCE II) 
 
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: 
 
 
 
 
 
 
Study Co-Chair: 
 
 
 
 
 
Correlative Science Co-Chair: 
(Duke Cancer Institute) 
Statistician: 
 
 
 
 
 
 
 
 
Drug Availability 
Commercial Agents: Cetuximab, Panitumumab, Irinotecan 
Drug Company Supplied: Regorafenib- IND exempt 
 
 Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document History 
(effective date) 
Initial Version  
Amendment 1 
August 21, 2019 
June 22, 2020 
Amendment 2 
June 30, 2023 

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Index 
 
Schema 
1.0 
Background 
2.0 
Goals 
3.0 
Patient Eligibility 
4.0 
Test Schedule 
5.0 
Stratification Factors 
6.0 
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 Medication Diary 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
Arm A1 
 
 
Initial 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
Sequential 
Treatment 
Arm B2 
 
 
 
 
 
 
 
 
 
Generic name: Regorafenib 
Brand name(s): Stivarga® 
Availability: McKesson 
Generic name: Cetuximab 
Brand name(s): Erbitux® 
Availability: Commercial 
Generic name: Panitumumab 
Brand name(s): Vectibix® 
Availability: Commercial 
Generic name: Irinotecan 
Brand name(s): Camptosar®, CPT11 
Availability: Commercial 
Randomization 1:1 
Metastatic colorectal cancer 
Treatment failure or intolerance to any of the 
following: fluoropyrimidines, oxaliplatin and 
irinotecan 
Anti-EGFR mAb#, regorafenib naïve 
RAS wildtype 
Regorafenib* 
Disease progression (PD1) or 
unacceptable adverse event 
Sequential Registration 
Anti –EGFR mAb (cetuximab or 
panitumumab) ± irinotecan* 
Disease progression (PD2) or 
unacceptable adverse event 
Anti –EGFR mAb (cetuximab or 
panitumumab) ± irinotecan* 
Disease progression (PD1) or 
unacceptable adverse event 
Sequential Registration 
Regorafenib* 
Disease progression (PD2) or 
unacceptable adverse event 
1. Arm A: regorafenib followed by 
anti-EGFR mAb 
2. Arm B: anti-EGFR mAb 
followed by regorafenib 
*Cycle length=28 days 
#mAb= monoclonal antibody 
Needs to discontinue 
treatment (section 8.45) 
EM** 
Patient refusal 
Treating physician’s decision 
 
** EM= Event Monitoring (on either treatment arm) 

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1.0 
Background 
 
Worldwide, nearly 1.3 million patients are diagnosed with and more than 600 000 patients die 
from colorectal cancer every year 1. In patients with advanced (metastatic or recurrent disease), 
systemic chemotherapy has been established as the standard treatment and associated with a poor 
prognosis, with a median overall survival of approximated 30 months 2. Unresectable colorectal 
cancer (CRC) is treated with systemic chemotherapy as the first choice, but is difficult to cure as 
shown by the fact that the progression-free survival is approximately 10-12 months with initial 
chemotherapy and approximately 4-6 months with second-line chemotherapy, requiring third- 
and fourth-line treatment in most patients 3,4. 
 
1.1 
Efficacy of cytotoxic agents, anti-EGFR therapies in CRC 
 
Antibodies that target the epidermal growth factor receptor (EGFR) have been studied in 
clinical studies primarily involving previously treated patients since the beginning of 
development. In a US phase II study, IMCL CP02-9923, patients with metastatic CRC 
unresponsive to chemotherapy including irinotecan, the response rate of combination 
therapy with irinotecan and cetuximab (Cmab) was 15.2%. BOND-1, a European phase II 
randomized study evaluated Cmab alone or in combination with irinotecan in patients 
with colorectal cancer unresponsive to chemotherapy including irinotecan, where the 
response rate was 22.9% and significantly higher in the combination group than 10.8% in 
the monotherapy group5. The progression-free survival was also improved in the 
combination group (4.1 vs. 1.5 months, respectively), despite the apparent resistance to 
irinotecan 5. These findings suggest that anti-EGFR therapy can potentially re-induce 
irinotecan sensitivity in irinotecan resistant colon cancer. In the CO-17 study, Cmab 
monotherapy significantly prolonged survival time in patients with irinotecan-, 
fluoropyrimidine-, and oxaliplatin-resistant colorectal cancer, compared with best 
supportive care (BSC) 6. Based on these findings, Cmab was approved for monotherapy 
or combination therapy with irinotecan for the treatment of irinotecan-resistant, EGFR- 
positive metastatic colorectal cancer in the US and Europe. 
 
EPIC, a phase III study that consisted of 1298 patients with treatment refractory advanced 
CRC, investigated irinotecan monotherapy in comparison to the combination of 
irinotecan with Cmab as second-line treatment 7. The combination group demonstrated a 
significant improvement in response rate (4.2% vs. 16.4%) and progression-free survival 
(2.6 vs. 4.0 months), but no difference in overall survival (10.9 months vs 10.0 months, 
combination versus monotherapy respectively). The lack of survival benefit may be 
attributed to the 46.9% of patients randomized to irinotecan monotherapy that received 
Cmab as post-study therapy. In the CRYSTAL trial, Cmab in combination with FOLFIRI 
demonstrated a significant improvement in response rate and progression-free survival 
compared to FOLFIRI 8. 
 
Similarly, panitumumab (Pmab), a full humanized anti-EGFR monoclonal antibody, was 
approved for the treatment of advanced CRC based on the results of a comparative study 
that showed it significantly prolonged progression-free survival in patients previously 
treated with fluoropyrimidine, oxaliplatin, and irinotecan when given alone as the third- 
line treatment compared with placebo 9. In addition, a randomized phase III study (Study 
20050181) was conducted to compare FOLFIRI and FOLFIRI + Pmab as the second-line 

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treatment10. The concomitant use of Pmab resulted in a significant improvement in 
progression-free survival in wild-type KRAS, with a median of 5.9 months in the 
combination group versus 3.9 months in the non-combination group (hazard ratio: 0.73, 
95% CI: 0.59-0.90, p=0.004). The overall survival trended towards an improvement 
favoring the combination group, but was not statistically significant (median OS 14.5 vs. 
12.5 months, HR: 0.85, 95% CI: 0.70-1.04, p=0.12). In the PRIME study 11, the addition 
of Pmab to FOLFOX therapy resulted in significant improvement in progression-free 
survival in wild-type KRAS (9.6 vs. 8.0 months, hazard ratio: 0.80, 95% CI: 0.66-0.97, 
p=0.02) tumors. The results from these clinical trials have shown that anti-EGFR 
antibodies improve progression-free survival in patients with advanced CRC, regardless 
of treatment line. 
 
1.2 
Efficacy of anti-EGFR antibodies and RAS mutation 
 
After anti-EGFR antibodies were approved for the treatment of colorectal cancer, several 
reports have suggested that these antibodies are not effective in patients with mutations in 
KRAS, a downstream effector of EGFR 12,13. In the CRYSTAL study, post hoc analysis 
revealed an additive effect from Cmab in patients without KRAS mutation, which was 
absent in patients whose tumors exhibited KRAS mutations 8. Similarly in the CO-17 
study for third-line treatment in CRC, a significant clinical benefit from Cmab was 
observed in patients without KRAS mutation, (median survival time: 9.5 vs. 4.8 months, 
hazard ratio: 0.55, p<0.001, median progression-free survival: 3.7 vs. 1.9 months, HR 
0.40, p<0.001) but was absent in those with a KRAS mutation 14. In a randomized study of 
Pmab in third-line treatment, KRAS analysis was performed in 427 patients, showing that 
PFS was significantly prolonged from 7.3 weeks to 12.3 weeks in patients with tumors 
that were wild-type KRAS (HR 0.45, p<0.001), but not in those with KRAS mutation 9. 
Furthermore, in the 181 trial, Pmab did not improve patient outcomes in those with KRAS 
mutated tumors. In the PRIME study, which evaluated the addition of Pmab to FOLFOX 
chemotherapy, the presence of RAS mutations predicted a lack of response to Pmab- 
FOLFOX, while patients whose tumors were without RAS mutations experienced an 
improvement in overall survival to the addition of Pmab to FOLFOX. Furthermore, RAS 
mutations were associated with inferior progression-free survival and overall survival 
from the addition of Pmab15. Based on these findings, a consensus has been achieved that 
anti-EGFR antibodies should be used only in patients whose tumors are RAS wildtype 2. 
 
1.3 
Anti-EGFR antibody-related adverse events 
 
EGFR may control proliferation and differentiation of keratinocytes in normal skin. 
Inhibition of EGFR results in cessation of proliferation and migration of keratinocytes, 
leading to apoptosis. In addition, inflammatory cytokines are released, and the entire 
epidermis may become thin, fragile, vulnerable, and unable to retain moisture 16. Rash 
acneiform is the most common skin disorder, and usually occurs within 1 to 3 weeks after 
administration of an anti-EGFR antibody. The most commonly affected area is the upper 
trunk, including the face, anterior chest, back, and forearm. The severe rash acneiform is 
often associated with itching and pain. It is replaced by skin dryness and cracking 
approximately 4 weeks after administration. Paronychia characterized by impaired nail 
growth and periungual pain may occur 8 weeks or later and be complicated by 
granulation or abscess in serious cases 16,17. Grade 3 or higher skin toxicity has been 
reported in 9.4% to 16.7% of patients treated with cetuximab 5-8, partly contributing to 

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premature discontinuation of treatment. Another significant adverse drug reaction is 
severe infusion reaction, with an incidence of less than 5% and interstitial pneumonia (1- 
2%). In addition, hypomagnesemia, hypokalemia, and hypocalcemia have been reported, 
requiring monitoring of serum electrolytes before, during, and after treatment and 
appropriate supplementation as needed. 
 
1.4 
Efficacy of regorafenib for colorectal cancer 
 
Regorafenib is an oral multi-kinase inhibitor and inhibits receptor tyrosine kinases 
involved in neovascularization (VEGFR 1-3, TIE2), tumor microenvironment (PDGFR- 
β, FGFR), and oncogenesis (KIT, PDGFR, RET, BRAF) 18. Regorafenib was recently 
shown to provide a survival benefit in metastatic colorectal cancer patients who have 
progressed after all standard therapies in the CORRECT trial 19. This led to its approval in 
September 2012 by the FDA for use in the United States. Despite the observed benefits in 
a patient population with no current standard, toxicities such as Palmar-planter 
erythrodysesthesia syndrome (PPES) (which occurs early in the first 1-2 weeks) and 
fatigue have widely limited its use in the US 19. ReDOS (Regorafenib dose optimization 
study), a randomized phase II trial, evaluated a dose escalation strategy compared to the 
standard dosing evaluated in the CORRECT study. The study demonstrated superiority in 
the proportion of patients who initiated the third cycle in the weekly dose escalation arm 
compared to patients who received standard dosing of 160mg per daily (43% vs 25%) 20. 
A survival benefit was also observed favoring the dose escalation arm (9.0 versus 5.9 
months; p=0.094) 20. Based off these results, the NCCN has recommended the weekly 
dose-escalation strategy for regorafenib. 
 
1.5 
Regorafenib-related adverse events 
 
In the CORRECT study, the common grade 3 or higher adverse events related to 
regorafenib were hand- foot-skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), 
diarrhea (7.2%), and rash/exfoliation (5.8%). Drug-related adverse events led to 
discontinuation of treatment in 8.2% in the regorafenib group and 1.2% in the placebo 
group 19. It has been reported that adverse events, primarily hand- -foot-skin-reaction, 
occurred the most frequently in the first course, and the incidence decreased thereafter 
due to appropriate dose reduction 21. 
 
1.6 
Position of molecularly targeted drugs in guidelines and standard treatment 
 
In the National Comprehensive Cancer Network (NCCN) treatment guidelines (2013 
version 3), which serve as the guidelines for standard cancer therapy in the US, the 
following standard treatment options are presented for first- to fourth-line treatment of 
colorectal cancer based on the results of the abovementioned clinical studies, and 
selection of an appropriate option according to the patient’s condition and previous 
chemotherapy is advised 22. 
 
• First-line treatment: FOLFOX (XELOX)/FOLFIRI ± bevacizumab (BV) or 
Cmab*/Pmab*, 5-FU + l-LV (capecitabine) ± BV 
• Second-line treatment: FOLFOX (XELOX) ± BV, FOLFIRI ± BV, FOLFIRI ± 
Cmab*/Pmab*, irinotecan ± Cmab*/Pmab*, Cmab*/Pmab* alone 
• Third-line treatment: Cmab*/Pmab* ± irinotecan, FOLFOX 

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• Fourth-line treatment: regorafenib 
* For patients with no KRAS mutation (codon 12, codon 13) 
 
Treatment flow in patients with wild-type KRAS is shown in the following schematic 
diagram: 
 
Chemotherapy flow in wild-type KRAS colorectal carcinoma 
 
 
The results from CALBG 80405 failed to show any significant survival 
difference between the addition of cetuximab or bevacizumab with chemotherapy 
(physician’s choice) for treatment naïve metastatic colorectal cancer, suggesting 
either biologic therapy with FOLFOX or FOLFIRI chemotherapy are appropriate 
therapeutic options 23. 
 
As second-line treatment options following first-line treatment using BV, 
backbone chemotherapy is changed (oxaliplatin to irinotecan or vice versa), and 
BV may be continued or replaced by an anti-EGFR antibody (wild-type KRAS). 
Since the TML study showed that continued BV treatment resulted in 
significantly prolonged survival time24, and it was shown that anti-EGFR 
antibodies were useful in third-line treatment 5,6,9, sequential treatment with BV 
in first- and second-line treatment followed by an anti-EGFR antibody in third- 
line treatment is widely used. For patients unresponsive or intolerable to all of 
these drugs, regorafenib is used as the standard treatment based on the results of 
the CORRECT study 19. 
 
1.7 
Background for Investigation of Biomarkers 
 
1.71 
Biomarkers related to treatment efficacy of or resistance to anti-EGFR antibodies 
 
It is established that the presence or absence of RAS mutation is a predictive 
factor for the efficacy of anti-EGFR antibodies for colorectal câncer 2,8,15. In the 
CO-17 study, however, the response rate of Cmab was as low as 12.8% in 
patients with wild-type KRAS, and approximately 40% of patients treated with 
Cmab had disease progression within 2 months after the start of treatment 14, 
suggesting that there may be non-KRAS factors involved in resistance to anti- 

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EGFR antibodies in colorectal cancer. As the biomarker related to the efficacy of 
or resistance to anti-EGFR antibodies, BRAF, PIK3CA, NRAS, and KRAS 
(mutations other than codon 12 and codon 13: codon 61, codon 146, etc.), which 
are downstream of EGFR, have been studied and are suggested to be related to 
resistance to anti-EGFR antibodies 25. However, none have been established as 
biomarkers, warranting further studies. 
 
One recent research topic is an attempt to detect genetic mutations in tumors by a 
highly sensitive measurement technique using tumor cell-derived DNA (cell-free 
DNA or circulating free DNA) in blood specimens. It was reported that this 
technique was successfully used to detect KRAS mutations in tumor cell-derived 
DNA in blood specimens from patients with wild-type KRAS under anti-EGFR 
antibody treatment 26,27. This may have resulted from proliferation of KRAS 
mutant clones following anti-EGFR antibody therapy and is thus of interest as a 
mechanism of resistance to anti-EGFR antibodies. In addition, KRAS mutations 
were examined by BEAMing using tumor tissue DNA and plasma DNA from 
colorectal carcinoma patients enrolled in the CORRECT study, a phase III study 
of regorafenib, showing that the agreement rate of KRAS mutations was 76%, 
and disagreement of KRAS mutations was mostly wild type in the tumor tissue 
and mutation in the plasma specimen 19. This may have resulted from 
proliferation of KRAS mutant clones following anti-EGFR antibody therapy, and 
is thus of interest as a possible mechanism of resistance to anti-EGFR antibodies. 
BEAMing is a digital PCR technique with an estimated sensitivity of 0.01% (one 
mutant DNA among 10,000 wild-type DNA can be detected). It is thus expected 
that plasma DNA can be used to detect genetic mutations in tumors by improving 
the sensitivity. 
 
Another potential mechanism of resistance to anti-EGFR antibodies, through a 
different signaling pathway, is also suggested. Heregulin is a ligand for HER3, a 
tyrosine kinase on the cell membrane. It is suggested that heregulin, which is 
overexpressed in the established Cmab-resistant cell lines, may not only activate 
HER3, but also dimerize to activate HER2 and thereby activate cell proliferation 
signaling pathways originating from these molecules 28. In a clinical study, it was 
reported that among 70 colorectal cancer patients treated with Cmab, those with 
no response to Cmab had significantly higher plasma heregulin concentrations. In 
addition, both progression-free survival and overall survival were significantly 
shorter in patients with high heregulin expression (>1,600 pg/mL) than in those 
with low expression (<1,600 pg/mL) 28. Other possible mechanisms of resistance 
to anti-EGFR antibodies are cell proliferation resulting from abnormal ligand 
expression for HER2, HGF-cMET pathway, and VEGF 29. The present study is 
designed to detect mutations using circulating free DNA at each point of 
sequential treatment and comprehensively examine multiple serum proteins, 
including these EGFR ligands, with an aim of producing findings that may be 
useful in elucidating the mechanism of resistance to anti-EGFR antibodies and 
contribute to future individualized therapy. 
 
1.72 
Biomarkers related to treatment efficacy of or resistance to regorafenib 
 
No biomarker predictive of the efficacy of or related to resistance to regorafenib 
has been established, raising important issues. In the CORRECT study, 

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regorafenib significantly prolonged survival time and progression-free survival. 
The progression-free survival curve greatly improved in the regorafenib group 
compared with that in the placebo group after the two curves overlapped until 
50% of patients had an event, suggesting that more responsive patients can be 
selected19. Regorafenib has various effects, including inhibition of 
neovascularization (VEGFR 1-3, TIE2), effect on tumor microenvironment 
(PDGFR-β, FGFR), and direct effect on oncogenesis (KIT, PDGFR, RET, 
BRAF). Since it is suggested that the efficacy of BV, an anti-VEGF-A antibody, 
is correlated with the blood VEGF-A level, it may be valuable to assess VEGF- 
related biomarkers for regorafenib. 
 
In the CORRECT study, blood samples from 611 (80%) of 760 enrolled patients 
were examined30. In the assessment of OS, regorafenib was more effective in 
patients with high expression of Tie-1 protein (regorafenib vs. placebo: hazard 
ratio: 0.56 in patients with high expression, 0.87 in those with low expression, P 
for interaction 0.035). In the assessment of PFS, regorafenib tended to be more 
effective in patients with low expression of von Willebrand factor (VWF) protein 
(regorafenib vs. placebo: hazard ratio: 0.39 in patients with low expression, 0.67 
in those with high expression, P for interaction 0.02). OS tended to be poor in 
patients with high levels of IL-8 and placental growth factor (PlGF) (high vs. low 
IL-8, HR 3.48, p<0.001; high vs. low PIGF: HR 1.81, p=0.002). Patients with 
high IL-8 levels also tended to have a poor outcome in terms of PFS. It is 
suggested that these biomarkers may be related to the efficacy of regorafenib or 
prognosis, but further validation is required in other cohorts. 
 
Stanniocalcin-1 (STC1), a glycoprotein hormone that plays an integral role in 
stromal and angiogenic tumor microenvironment and has been identified as a 
potential plasmatic biomarker. 
 
1.8 
Reason for Including Bevacizumab-naive Patients in the Study 
 
Bevacizumab (BV) is widely used as the standard first- and second-line treatment. 
However, since BV is not recommended for patients with a history of serious arterial 
thromboembolism (within approximately 6 months), uncontrolled hypertension, a risk of 
hemorrhage, severe protein urine, or delayed postoperative wound healing, it is assumed 
that some patients have received chemotherapy alone or in combination with an anti- 
EGFR antibody rather than BV in first- and second-line treatment. Therefore, previous 
treatment with BV is not a requisite for participation in the study. 
 
1.9 
Significance of the Study 
 
As mentioned above, the current standard treatment is sequential treatment with an anti- 
EGFR antibody followed by regorafenib 22. However, regorafenib, which is orally 
administered once daily, may be more convenient and thus preferable for patients than 
anti-EGFR antibodies, which require intravenous infusion every week or every other 
week. In addition, since anti-EGFR antibodies and regorafenib have different toxicity 
profiles as described in, sequential treatment with regorafenib followed by an anti-EGFR 
antibody is expected to provide a new treatment option with different convenience and 
toxicity profile if it is as effective as standard sequential treatment in terms of survival. 

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REVERCE, a Japanese randomized phase II trial, demonstrated a significant 5.8 month 
survival benefit from the sequencing of regorafenib prior to cetuximab therapy (17.4 
versus 11.6 months, HR 0.61, 95% CI 0.39-0.96, p=0.0293) compared to patients that 
received the reverse therapeutic sequence 31. Recently, the PARADIGM study (presented 
at the ASCO Annual Meeting 2022) demonstrated a survival benefit in patients that 
received the combination of anti-EGFR antibody with chemotherapy as first-line 
treatment for metastatic colorectal cancer. In the subgroup analysis, patients with right 
sided colon cancer did not derive a benefit from first-line anti-EGFR antibody with a 
numerically worse median OS. Based off the recent results from the PARADIGM study, 
patients with left sided metastatic colorectal cancer will likely receive anti-EGFR 
antibody therapy as first line treatment, whereas in those with right-sided disease, the 
potential sequencing of regorafenib prior to anti-EGFR antibody therapy remains of 
interest. 
 
The proposed phase II trial is to confirm the observed survival benefit from regorafenib 
sequencing prior to anti-EGFR monoclonal antibody therapy in REVERCE in a US 
patient population in patients with right sided colon cancer. In addition, biomarkers will 
be assessed as described in Section 2-3 to investigate whether biomarkers can be used to 
select subjects for a phase III study on an exploratory basis. 
 
2.0 
Goals 
 
2.1 
Primary 
 
2.11 
To compare the overall survival between patients with right sided (primary 
tumor) metastatic colon cancer who were randomized to receive regorafenib 
followed by anti-EGFR monoclonal antibody therapy compared to those 
that receive anti-EGFR monoclonal antibody followed by regorafenib. 
 
2.2 
Secondary 
 
2.21 
To compare the first progression free survival (PFS1) between patients with right 
sided (primary tumor) metastatic colon cancer who were randomized to receive 
regorafenib followed by anti-EGFR monoclonal antibody therapy compared to 
those that receive anti-EGFR monoclonal antibody followed by regorafenib. 
 
2.22 
To compare the second progression free survival (PFS2) between patients with 
right sided (primary tumor) metastatic colon cancer who were randomized to 
receive regorafenib followed by anti-EGFR monoclonal antibody therapy 
compared to those that receive anti-EGFR monoclonal antibody followed by 
regorafenib. 
 
2.23 
To compare the sequential treatment progression free survival (stPFS) between 
patients with right sided (primary tumor) metastatic colon cancer who were 
randomized to receive regorafenib followed by anti-EGFR monoclonal antibody 
therapy compared to those that receive anti-EGFR monoclonal antibody followed 
by regorafenib. 
 
2.24 
To assess the frequency and severity of adverse events between patients withright 
sided (primary tumor) metastatic colon cancer who were randomized to receive 
regorafenib followed by anti-EGFR monoclonal antibody therapy compared to 
those that receive anti-EGFR monoclonal antibody followed by regorafenib. 
 
2.25 
To compare the objective response rate (ORR), while on initial treatment, 
between patients with right sided (primary tumor) metastatic colon cancer who 

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were randomized to receive regorafenib followed by anti-EGFR monoclonal 
antibody therapy compared to those that receive anti-EGFR monoclonal antibody 
followed by regorafenib. 
 
2.26 
To compare the objective response rate (ORR), while on sequential treatment, 
between patients with right sided (primary tumor) metastatic colon cancer who 
were randomized to receive regorafenib followed by anti-EGFR monoclonal 
antibody therapy compared to those that receive anti-EGFR monoclonal antibody 
prior to regorafenib. 
 
2.3 
Correlative Research 
 
2.31 
To assess plasma pharmacodynamics biomarkers of response and resistance to 
therapy. 
 
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 
Inclusion Criteria 
 
3.11 
Age ≥18 years. 
 
3.12 
Histologically proven, unresectable distant metastatic or locally advanced 
Colorectal adenocarcinoma with primary tumor site from right-sided disease only 
(cecum, ascending colon, hepatic flexure, and transverse colon). 
 
3.13 
KRAS, NRAS wild type. 
 
3.14 
BRAF v600E wildtype. 
 
3.15 
Measurable disease as defined in Section 11.0. 
 
3.16 
ECOG Performance Status (PS) 0, 1, or 2. (Form is available on the ACCRU 
web site: 
 
 
3.17 
Life expectancy of ≥ 3 months per estimation of treating physician. 
 
3.18 
The following laboratory values obtained 7 days prior to randomization. 

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• 
Absolute neutrophil count (ANC) ≥1200/mm3 
• 
Platelet count ≥75,000/mm3 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 
2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
• 
Serum creatinine ≤1.5 x ULN 
• 
INR/PTT ≤ 1.5 x ULN 
NOTE: Patients who are therapeutically treated with an agent such as 
warfarin or heparin will be allowed to participate provided that no prior 
evidence of underlying abnormality in coagulation parameters exists. Close 
monitoring of at least weekly evaluations will be performed until INR/PTT is 
stable based on a measurement that is pre-dose as defined by the local 
standard of care. 
• 
Alkaline phosphatase limit ≤2.5 x ULN (≤5 x ULN for patients with liver 
involvement of their cancer) 
 
3.19 a 
Negative serum pregnancy test done ≤7 days prior to randomization for women 
of childbearing potential only. NOTE: Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not required to 
undergo a pregnancy test. The definition of adequate contraception will be based 
on the judgment of the treating physician. 
 
3.19b 
Provide informed written consent. 
 
3.19c 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19d 
Disease progression on or intolerable to any of the following: fluoropyrimidine, 
oxaliplatin and irinotecan. 
 
3.19e 
Able to swallow and retain oral medication. 
 
3.19f 
Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6.0, 14.0 and 17.0). 
 
3.19g 
Willing to allow transfer of tissue and blood samples, clinical information, and 
outcome data collected from this trial for future research. (see Sections 6.0, 14.0, 
and 17.0). 
 
3.2 
Exclusion Criteria 
 
3.21 
Prior treatment with regorafenib, cetuximab or panitumumab. 
 
3.22 
Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days 
prior to randomization. 
 
3.23 
Congestive heart failure > New York Heart Association (NYHA) class 2. 

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NOTE: Class 3 is defined as marked limitation in activity due to symptoms, even 
during less-than-ordinary activity, e.g., walking short distances (20-100m). They 
are comfortable at rest. Class 4 is defined as patients with severe limitations. 
Experiences symptoms even while at rest. Mostly bed bound. 
 
3.24 
Unstable angina (angina symptoms at rest), new-onset angina (begun ≤3 months 
prior to randomization) or myocardial infarction ≤ 6 months prior to 
randomization. 
 
3.25 
Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: Pacemakers, beta 
blockers or digoxin are permitted. 
 
3.26 
Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic 
pressure > 90 mmHg despite optimal medical management). 
 
3.27 
History of or current pheochromocytoma. 
 
3.28 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism ≤6 months prior to randomization. 
 
3.29 a 
Ongoing infection > grade 2 NCI-CTCAE v5.0. 
 
3.29b 
Known history of chronic hepatitis B or C. 
 
3.29c 
Patients with seizure disorder requiring medication. 
 
3.29d 
Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 
months from definitive therapy, has a negative imaging study within 4 weeks of 
randomization and is clinically stable with respect to the tumor at the time of 
randomization. Note: Patient must not be undergoing acute steroid therapy or 
taper (chronic steroid therapy is acceptable provided that the dose is stable for 
one month prior to and following screening radiographic studies). 
 
3.29e 
History of organ allograft (including corneal transplant). 
 
3.29f 
Evidence or history of bleeding diathesis or any hemorrhage or bleeding event 
>CTCAE v5.0 grade 3 ≤4 weeks prior to randomization. 
 
3.29g 
Non-healing wound, ulcer, or bone fracture. 
 
3.29h 
Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results. 
 
3.29i 
MSI-H patients who have not received prior PD-1 mAb therapy. 
 
3.29j 
Concurrent anti-cancer therapy ≤3 weeks from randomization (chemotherapy, 
radiation therapy, surgery, immunotherapy, biologic therapy, or tumor 
embolization).3.29k Known hypersensitivity to any of the study drugs, study 
drug classes, or excipients in the formulation. 
 
3.29l 
Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent. 
 

14 
ACCRU-GI-1809 
Amendment 2 
 
3.29m History of known persistent proteinuria of CTCAE v5.0 Grade 3 or higher (≥ 3.5 
g/24 hrs). 
 
3.29n 
Any malabsorption condition. 
 
3.29o 
Unresolved toxicity greater than CTCAE v5.0 Grade 1 attributed to any prior 
therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity 
≤Grade 2. 
 
3.29p 
Albumin levels <2.5 g/dl. 
 
3.29q 
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 
 
NOTE: Men and women of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after 
the last dose of study drug. The definition of adequate contraception will be 
based on the judgment of the principal investigator or a designated associate. 
 
3.29r 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the treating physician, 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. 
 
3.29s 
Known history of human immunodeficiency virus (HIV) infection or active 
hepatitis B or C infection requiring treatment with antiviral therapy. 
 
3.29t 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.29u 
Previous or concurrent cancer that is distinct in primary site or histology from 
colorectal cancer ≤ 3 years prior to randomization EXCEPT for cervical cancer 
in-situ, treated ductal carcinoma in situ of the breast, curatively treated 
nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or 
superficial bladder tumor [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and 
T1 (Tumor invades lamina propria)]. Note: All cancer treatments for cancers that 
were distinct in a primary site other than colorectal must be completed at least 
3years prior to randomization (i.e., signature date of the informed consent form). 
 
3.29v 
Pleural effusion or ascites that causes respiratory compromise (≥CTCAE v5.0 
Grade 2 dyspnea). 
 
3.29w Any condition which, in the treating physician’s opinion, makes the subject 
unsuitable for trial participation. 

15 
ACCRU-GI-1809 
Amendment 2 
 
4.0 
Test Schedule 
 
4.1 
Treatment with regorafenib 
 
NOTE: Subjects should follow this test table while taking regorafenib regardless of treatment arm. 
 
 
 
 
 
Tests and procedures 
Active Monitoring Phase 
≤7 days prior 
to 
randomization 
Cycle 1 
Cycle 2 
Prior to dosing 
each cycle 
beginning 
cycle 3+ (+/- 7 
days) 
Prior to dosing 
at restaging 
(C3 and every 
other cycle 
after) until 
progression 
(+/- 7 days) 
End of Initial 
Treatment Mandatory 
Sequential Registration 
(if regorafenib is initial 
treatment)12 
End of 
All 
Treatment 
(within 30 
days after 
last dose) 
Week1 
(Day 
1) 
Week 
2 
(Day 
8) 
Week 3 
(Day 15) 
Week 
4 
(Day 
22) 
Week 
1 
(Day 
1) 
Week 
2 
(Day 
8) 
Week 
3 
(Day 
15) 
Week 
4 
(Day 
22) 
History and exam, 
weight, ECOG PS, 
blood pressure 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Adverse event 
assessment 
X 
X 
X 
X 
X 
X 
Hematology5 
CBC/ differential, 
ANC, INR/PTT13 
X 
X9 
X 
X 
Chemistry5 SGOT 
(AST), alk phos, T. 
bili, serum 
creatinine, calcium, 
glucose, Na, K, 
SGPT (ALT), Mg 
X 
X9 
X 
X 
X 
X 
Albumin5 
X 
X9 
X 
X 
Tumor Blood Bio- 
Markers (CEA) 
X 
X 
X 
Tumor 
measurement1 (CT 
scan of chest, 
abdomen and 
pelvis), CT 
X 
X 
X6 

16 
ACCRU-GI-1809 
Amendment 2 
 
 
component of a 
PET/CT, (MRI if CT 
is not feasible) 
ECG4 
X 
Serum pregnancy 
test2 
X 
X9 
Mandatory blood 
sample-plasma10,R 
X 
X 
STC1 biomarker 
blood collectionR 
X 
X 
Mandatory tissue 
sample-archival 
tumor paraffin(see 
Section 17.0)8, R 
X 
Patient Medication 
Diary (Appendix I)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Blood 
sample –cfDNA 
Guardant 36010, 11, R 
X 
 
1. CT scans preferred (MRI if CT is not feasible), CT component of a PET/CT, of the chest, abdomen and pelvis. Use same imaging throughout the 
study. Tumor measurements at baseline (≤28 days prior to randomization) and every 8 weeks beginning on cycle 3 day 1 prior to treatment until 
progression. 
2. For women of childbearing potential only. 
3. The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution during 
each scheduled visit. 
4. Performed at screening and then as needed. 
5. Hematology and chemistry tests to be done prior to each cycle. 
6. If patient goes off study during Cycle 1 and last CT scan was done >28 days prior, the CT scan must be done. 
7. If baseline history, exam, weight, ECOG PS, and blood pressure were performed ≤3 days of C1D1, they do not need to be repeated for C1D1. 
8. Receipt of archival tumor tissue is not required for study randomization and initiation of therapy. However, it is mandatory to receive the required 
tissue ≤ 90 days from randomization. See section 17.0. 
9. If screening tests occur  7 days prior to C1D1, they do not have to be repeated prior to dosing. 
10. Kits are required for this collection. Refer to Section 14.0. 

17 
ACCRU-GI-1809 
Amendment 2 
 
11. Patients have the option to complete cfDNA testing at study completion and will be allowed to register with protocol ACCRU-GI-1611. Site will 
access results through the Guardant Health portal: 
. 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. 
12. At the time of disease progression or intolerance from initial treatment, patients will be re-registered (See 6.3) to Sequential Treatment Phase. Tests 
should be completed after re-registration and prior to dosing of sequential treatment. Patients will then move to the cetuximab or panitumumab ± 
irinotecan test table (4.2). 
13. If the INR/PTT is normal at screening (and subject is not on warfarin) this test will not need to be repeated unless indicated per investigator 
assessment. If a subject is on warfarin with stable INR/PT at baseline, the INR/PT should be assessed on Day 5 (+/- 3 days). If value is above the 
therapeutic range, the dose should be modified and the assessment should be repeated weekly until it is stable. 
R Research funded. 
 
4.2 
Treatment with anti-EGFR mAb (cetuximab or panitumumab) ± irinotecan 
 
NOTE: Subjects should follow this test table while taking anti-EGFR mAb (cetuximab or panitumumab) ± irinotecan regardless of 
treatment arm. 
 
 
 
 
Tests and 
procedures 
Active Monitoring Phase 
≤7 days prior 
to 
randomization 
Cycle 1 
Cycle 2 
Prior to dosing each 
cycle beginning cycle 
3+ (+/- 7 days) 
Prior to dosing at 
restaging (C3 and 
every other cycle 
after) until 
progression (+/- 7 
days) 
Day 15 (While 
on anti-EGFR 
mAb +/- 
irinotecan) 
End of Initial 
Treatment Mandatory 
Sequential 
Registration (if anti- 
EGFR mAb +/- 
irinotecan is initial 
treatment)11 
End of ALL 
Treatment 
(within 30 
days after 
last dose) 
Week1 
(Day 1) 
Week 3 
(Day 15) 
Week 1 
(Day 1) 
Week 3 
(Day 15) 
History and exam, 
weight, ECOG 
PS, blood pressure 
X 
X6 
X 
X 
X 
X 
X 
X 
Height 
X 
Adverse event 
assessment 
X 
X 
X 
X 
X 
X 
Hematology4: 
CBC/ differential, 
ANC, INR/PTT12 
X 
X8 
X 
X 
X 
X 
X 

18 
ACCRU-GI-1809 
Amendment 2 
 
 
 
1. CT scans preferred (MRI if CT is not feasible), CT component of a PET/CT, of the chest, abdomen and pelvis. Use same imaging throughout the 
study. Tumor measurements at baseline (≤28 days prior to randomization) and every 8 weeks beginning on cycle 3 day 1 prior to treatment until 
progression. 
2. For women of childbearing potential only. 
Chemistry4: 
SGOT (AST), alk 
phos, T. bili, 
serum creatinine, 
calcium, glucose, 
Na, K, SGPT 
(ALT), Mg 
X 
X8 
X 
X 
X 
X 
X 
Albumin4 
X 
X8 
X 
X 
Tumor Blood Bio- 
Markers (CEA) 
X 
X 
X 
Tumor 
measurement1 (CT 
scan of chest, 
abdomen and 
pelvis ), CT 
component of a 
PET/CT, (MRI if 
CT is not feasible) 
X 
X 
X5 
ECG3 
X 
Serum pregnancy 
test2 
X 
X8 
 
Mandatory blood 
sample-plasma9, R 
X 
X 
 
 
STC1 Biomarker 
blood collection 
 
X 
X 
 
 
 
 
 
 
 
Mandatory tissue 
sample-archival 
tumor paraffin(see 
Section 17.0)7, R 
X 
X 
Optional Blood 
sample –cfDNA 
Guardant 3609,10, R 
X 

19 
ACCRU-GI-1809 
Amendment 2 
 
3. Performed at screening and then as needed. 
4. Hematology and chemistry tests to be done prior to each cycle. 
5. If patient goes off study during Cycle 1 and last CT scan was done >28 days prior, the CT scan must be done. 
6. If baseline history, exam, weight, ECOG PS, and blood pressure were performed ≤3 days of C1D1, they do not need to be repeated for C1D1. 
7. Receipt of archival tumor tissue is not required for study randomization and initiation of therapy. However, it is mandatory to receive the required 
tissue ≤ 90 days from randomization. See section 17.0. 
8. If screening tests occur  7 days prior to C1D1, they do not have to be repeated prior to dosing. 
9. Kits are required for this collection. Refer to Section 14.0. 
10. Patients have the option to complete cfDNA testing at study completion and will be allowed to 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. 
11. At the time of disease progression or intolerance from initial treatment, patients will be re-registered (See 6.3) to Sequential Treatment Phase. Tests 
should be completed after re-registration and prior to dosing of sequential treatment. Patients will then move to the regorafenib test table (4.1). 
12. If the INR/PTT is normal at screening (and subject is not on warfarin) this test will not need to be repeated unless indicated per investigator 
assessment. If a subject is on warfarin with stable INR/PT at baseline, the INR/PT should be assessed on Day 5 (+/- 3 days). If value is above the 
therapeutic range, the dose should be modified and the assessment should be repeated weekly until it is stable. 
R Research funded. 

20 
ACCRU-GI-1809 
Amendment 2 
 
 
5.0 
Stratification and Grouping Factors: 
 
5.1 
Stratification Factors 
 
5.11 
Prior bevacizumab treatment in the metastatic setting: yes vs no. 
 
5.13 
Treating physician decision on using Irinotecan with anti-EGFR mAb for 
this study: yes vs no. 
 
5.2 
Grouping Factors 
 
5.21 
Initial Treatment Received: Regorafenib vs. Anti-EGFR 
 
6.0 
Randomization Procedures 
 
6.1 
Site Procedures 
 
6.11 
Study staff will need to complete the required training prior to gaining access 
to the registration application. This is located on the ACCRU webpage at 
 Refer to Study Resources→ Applications. Near the bottom of 
the page there will be a link to the “Research Registration Application 
Training.” After training is complete, study staff must complete the 
“Attestation of Training” and send to the ACCRU Registration Office at 
 
 
6.12 
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. 
 
 
6.2 
Randomization Procedures 
 
6.21 To register a patient, access the ACCRU web page at 
 go to the 
Study Resources → Application section and click on “Registration” and enter 
the registration/randomization application. The registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system 
support contact information is available on the Web site. If unable to access the 
Web site, call the Academic and Community Cancer Research United 
(ACCRU) Registration Office at email 
between the 
hours of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 

21 
ACCRU-GI-1809 
Amendment 2 
 
 
Instructions for the registration/randomization application are available on the 
above web page under the Study Resources section → Application section. 
Please refer to the “Research Registration Application Training” or Quick 
Reference Guide for instructions. 
 
Prior to initiation of protocol study intervention, this process must be completed 
in its entirety and an ACCRU subject ID number must be available as noted in 
the instructions. It is the responsibility of the individual and institution 
registering the patient to confirm the process has been successfully completed 
prior to release of the study agent. Patient registration via the 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the ACCRU Registration Office at 
 If the 
patient was fully registered, the ACCRU Registration Office staff can 
access the information from the centralized database and confirm the 
registration. 
• 
Refer to the Research Registration Application training on the 
ACCRU website under Study Resources → Applications. 
 
6.22 
Prior to accepting the registration, the registration 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 
 
6.23 
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. 
 
6.24 
At the time of randomization, 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, 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 

22 
ACCRU-GI-1809 
Amendment 2 
 
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. 
 
6.25 
Treatment cannot begin prior to randomization and must begin ≤14 days 
after randomization. 
 
6.26 
Pretreatment tests/procedures (see Section 4.0) must be completed within 
the guidelines specified on the test schedule. 
 
6.27 
All required baseline symptoms (see Section 10.52) must be documented 
and graded. 
 
6.28 
Treatment on this protocol must commence at an ACCRU institution under 
the supervision of a medical oncologist. 
 
6.29 a 
Study drug is available on site. 
 
6.29b 
Blood draw kit is available on site. 
 
 
6.3 
Randomization Procedures 
 
6.31 
The factors, defined in Section 5.0, together with the registering 
membership, will be used as stratification factors. 
 
6.32 
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 
one of the two treatment groups using the Pocock and Simon [39] dynamic 
allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups. At entry, physicians 
must declare whether each patient will receive irinotecan in protocol 
treatment (ie, irinotecan+anti-EGFR therapy versus anti-EGFR therapy 
alone). The stratification factors is defined as 6.21. 
 
6.4 
Sequential Treatment Phase 
 
NOTE: Re-registration must occur ≤28 days from documentation of progression or 
intolerance. 
 
6.41 
Upon local confirmation of progression or intolerance, patients will be 
allowed to re-registered to receive the sequential treatment in the treatment 
arm. 
 
6.42 
To re-register a patient, email 
 a completed sequential 
treatment phase eligibility checklist to the Academic and Community 
Cancer Research United (ACCRU) Registration Office between 8 a.m. 
and4:30 p.m. central time Monday through Friday. 
 
 
 

23 
ACCRU-GI-1809 
Amendment 2 
 
6.43 
Treatment cannot begin prior to re-registering to the sequential treatment 
phase and must begin ≤7 days after registration for the sequential treatment 
phase. 
 
7.0 
Protocol Treatment 
 
Drugs will be administered in accordance with the information on the respective package 
inserts. Treatment will be given according to the schedule specified in the protocol. The 
terms “delay,” “modification,” and omission” are defined as follows: 
 
Delay: A delay indicates dose was postponed or not received when expected. 
Modification: Indicates a change in dose level during the current cycle. However, if a 
modification was issued after the last dose was received in the current cycle, the 
modification should be reported on the subsequent cycle. 
Omission: Indicates a dose was skipped and not made up, or that the drug was discontinued. 
 
Arm A, treatment with regorafenib followed by anti-EGFR therapy (± irinotecan). 
Arm B, treatment with anti-EGFR therapy (± irinotecan) followed by regorafenib. 
 
Treatment on regorafenib will be continued in accordance with Section7.11 “Planned 
treatment with regorafenib” until any of the “Criteria for discontinuing treatment with 
regorafenib” (Section 8.34) is met. 
 
Treatment on Anti-EGFR therapy (± irinotecan) will be continued in accordance with 
Section 8.4, “Combination therapy of Anti-EGFR therapy (cetuximab (Cmab) OR 
panitumumab (Pmab) and irinotecan” until any of the “Criteria for discontinuing treatment 
including Cmab or Pmab” (Section 8.44) is met. 
 
Patients assigned to Anti-EGFR therapy will receive either cetuximab or panitumumab per 
treating physician discretion and will be dosed per prescribing guidelines. Patients cannot 
switch between cetuximab and panitumumab during the course of the study. The use of 
irinotecan is per treating physician discretion and will be dosed per prescribing guidelines. 
If treating physician chooses to add irinotecan, irinotecan must be included in treatment 
starting at cycle 1. 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
 
Agent 
Dose 
Route 
Frequency 
ReRx 
Regorafenib 
80mg daily 
(Starting 
dose) See 
table 7.11 
PO 
Daily for 
Days1-21 of 
28 day cycle 
Every 28 
days 
Cetuximab* 
500mg/m2 
IV 
Days 1, 15 
Every 28 
days 
Panitumumab* 
6mg/kg 
IV 
Days 1, 15 
Every 28 
Days 
Irinotecan 
180mg/m2 
IV 
Days 1, 15 
Every 28 
days 
* Patients assigned to Anti-EGFR therapy will receive EITHER cetuximab OR 
panitumumab, not both 
 
 
7.11 
Planned treatment with regorafenib 
Regorafenib Dose Escalation 

24 
ACCRU-GI-1809 
Amendment 2 
 
Cycle 1: 
Week 
Dose1 
1 
Starting Dose 
80 mg* 
2 
120 mg 
3 
160 mg 
4 
Off 
*starting dose level 
1 Dose escalation/reduction should follow section 8.1 
Cycle 2 and beyond: 
Week 
Dose 
1 
Remain at 
2 
highest 
3 
tolerated dose 
from Cycle 1 
(up to 160 mg) 
4 
Off 
 
 
Regorafenib tablets should be taken once a day with approximately 8 fluid ounces (240 mL) 
of water after a low-fat (<30% fat) meal. Regorafenib should be taken with a meal at the 
same time every day. Some examples of low fat meals are: 
 
• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of 
fat). 
• One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of 
toast with jam (no butter or marmalade), apple juice, and one cup of coffee or tea (2 
g fat, 17 g protein, 93 g of carbohydrate, 520 calories. 
 
If vomiting occurs shortly after regorafenib are swallowed, the dose should only be replaced 
if all of the intact tablets can be seen and counted. Should any patient enrolled on the study 
miss a scheduled dose for whatever reason (e.g. as a result of forgetting to take the tablets or 
vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 2 
hours after that scheduled dose time. If greater than 2 hours after the scheduled dose time, 
the missed dose is not to be taken and the patient should take their allotted dose at the next 
scheduled time. 
 
7.2 
Planned treatment with Anti-EGFR therapy (cetuximab (Cmab) or panitumumab 
(Pmab)) and irinotecan. Refer to 8.4 for treatment initiation requirements.\ 
 
 
7.21 
Dose levels of panitumumab and cetuximab 
Dose reduction 
level 
Dose of panitumumab 
Dose of cetuximab 
Initial dose level 
6 mg/kg 
500 mg/m2 
-1 
4.8 mg/kg 
400 mg/m2 
-2 
3.6 mg/kg 
300 mg/m2 
-3 
2.4 mg/kg 
200mg/m2 

25 
ACCRU-GI-1809 
Amendment 2 
 
 
 
7.22 Dose levels of irinotecan 
 
Dose reduction 
level 
Dose of irinotecan 
Initial dose level 
180 mg/m2 
-1 
150 mg/m2 
-2 
120 mg/m2 
-3 
100 mg/m2 
7.3 
Study treatment with regorafenib, cetuximab, panitumumab, and Irinotecan may be 
administered up to 3 days before or after the scheduled Day 1, Day 15 of each cycle 
due to administrative reasons. 
 
NOTE: Future treatment dates may need to be adjusted as a result of the ±3 days. 
 
8.0 
Dosage Modification Based on Adverse Events 
 
Strictly follow the modifications in the following tables for the first two cycles, until 
individual treatment tolerance can be ascertained. Thereafter, these modifications should be 
regarded as guidelines to produce mild-to-moderate, but not debilitating, side effects. 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. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
 
 
 
 
 
8.1 
Regorafenib Dose Escalation/Reduction 
 
Dose level 
If No SDRT 
If + SDRT** 
80 mg* 
Proceed to 
next dose 
level 
- 
120 mg 
Proceed to 
next dose 
Decrease to 
80 mg 
level 
160 mg 
- 
Decrease to 
120 mg 
*starting dose level 
**SDRT = Significant Drug Related Toxicities 
 
8.11 
After week 8, if toxicities have resolved to ≤ Grade 0-1, re-escalation is 
allowed 40 mg at a time every 4 weeks to a maximum of 160 mg and at the 
discretion of the treating physician. 
 
8.12 
Patients with dose reductions below 80 mg should go off treatment and go 
to event monitoring. 
 
8.13 
Any patients with toxicities requiring >4 week delay should go off 
treatment and then to event monitoring. 
 

26 
ACCRU-GI-1809 
Amendment 2 
 
8.2 
Regorafenib Dose Modifications 
 
8.21 
Regorafenib may be dose reduced per the table 8.21 in case of 
intolerable toxicity such as weight loss, fatigue, rash or anorexia. 
 
Table 8.21 Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/AST/bilirubin 
NCI-CTCAE v5.0a 
Dose Delay 
Dose Modification b 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
No change 
Grade 3 
Delay until ≤ Grade 2c 
Reduce by 1 dose level 
If toxicity remains < 
Grade 2, dose re- 
escalation can be 
considered at the 
discretion of the treating 
physician. If dose is re- 
escalated and toxicity (≥ 
Grade 3) recurs, institute 
permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 1 dose level. 
Permanent 
discontinuation can be 
considered at treating 
physician’s discretion. 
a. 
NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, version 
5.0 
b. Excludes alopecia, non-refractory nausea/vomiting, lymphocyte count decreased, non-refractory 
hypersensitivity and nonclinical and asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless subject is 
deriving clinical benefit. 
* 
Modify according to study specific cycle length 
 
If greater than 2 dose level reductions are required, regorafenib will be discontinued and the rest of 
the study follow up may be continued. The following tables outline dose adjustments for toxicities 
related to regorafenib except hand-foot skin reaction, hypertension and liver function test 
abnormalities. 
 
The table above outlines dose adjustments for hematologic and non-hematologic toxicities related to 
regorafenib except PPES and hypertension. In addition to these recommended dose modifications, 
subjects who develop diarrhea, mucositis, anorexia or other events predisposing to fluid loss or 
inadequate fluid intake should be carefully monitored and rehydrated as clinically necessary. This is 
in order to minimize the risk of postural hypotension and renal failure. 
 
8.22 
Regorafenib may be dose reduced per Table 8.22b in case of Palmar-plantar 
erythrodysesthesia using Table 8.22a for grading guidelines. 
 
 
Table 8.22a: Grading for Palmar-plantar erythrodysesthesia syndrome 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v5.0 
Minimal skin changes 
Skin changes 
Severe skin changes 
Palmar-plantar 
or dermatitis 
(e.g., peeling, 
(e.g., peeling, 
erythrodysesthesia 
(e.g., erythema, edema, 
blisters bleeding, 
blisters, bleeding, 
syndrome 
or hyperkeratosis) 
edema, or 
edema, or 
without pain 
hyperkeratosis) with 
hyperkeratosis) with 
pain 
pain 

27 
ACCRU-GI-1809 
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Further description / 
examples of skin 
changes 
Numbness, dysesthesia 
/ paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema 
and swelling of the 
hands and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt 
Limiting 
Limiting self-care 
normal activities 
instrumental 
activities of daily life 
activities of daily life 
(e.g., bathing, 
(e.g., preparing 
dressing and 
meals, shopping for 
undressing, feeding 
groceries or clothes, 
self, using the toilet, 
using the telephone, 
taking medications) 
managing money) 
and not bedridden 
a. 
Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
 
Grade of event 
(NCI-CTCAE v5.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute supportive 
measures for symptomatic relief 
Grade 2 
1st occurrence 
Consider decreasing dose by one dose level and 
immediately institute supportive measures. If no 
improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to Grade 0-1b,d 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. 
When resuming treatment, treat at reduced dose level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease dose by one dose 
level.b,d 
4th occurrence 
Discontinue therapy 
Grade 3 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1.c When resuming treatment, decrease dose 
by one dose level.b,d 
2nd occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1.c When resuming treatment, decrease dose 
by one additional dose levelb,d 
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the treating physician. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is not permitted. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued 
permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
f. Refer to Section 9.0 for management strategies for Palmer-plantar erythrodysesthesia syndrome 
reactions. 
 
8.23 
Hypertension 
 
Hypertension is a known AE associated with regorafenib treatment. Subject 
will have their blood pressure measured at least weekly during the first 5 
weeks of treatment. If additional blood pressure measurements are done 
outside the study site, and the blood pressure is >140 mm Hg systolic or 
>90 mm Hg diastolic (NCI CTCAE v5.0), then the subject must contact 
Table 8.22bRecommended dose modification for Palmar-plantar erythrodysesthesia syndrome 
reactiona 

28 
ACCRU-GI-1809 
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study personnel. The management of hypertension, including the choice of 
antihypertensive medication, will be performed according to local standards 
and to the usual practice of the treating physician. Every effort should be 
made to control blood pressure by medical means other than study drug 
dose modification. If necessary, Tables Section 8.1 and 8.2 outline 
suggested dose reductions. 
 
 
Table 8.23: Management of Treatment-Emergent Hypertension 
Grade 
(CTCAE v5.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
Prehypertension 
(systolic BP120 - 139 mmHg 
None 
Continue regorafenib 
Consider increasing blood pressure (BP) 
monitoring 
or 
diastolic BP 80 - 89 mmHg) 
2 
Systolic BP 140 - 159 mmHg 
or 
diastolic BP 90 - 99 mmHg, 
OR 
Symptomatic increase by >20 
mmHg (diastolic) if 
previously within normal 
limits 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
If BP previously within 
normal limits, start anti- 
hypertensive monotherapy 
If patient already on anti- 
hypertensive medication, 
titrate up the dose. 
Continue regorafenib 
If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤90 
mm Hga. When regorafenib is restarted, 
continue at the same dose level. 
3 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
OR 
More than one drug or more 
intensive therapy than 
previously used indicated 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive 
medication 
AND/OR 
Increase current anti- 
hypertensive medication 
AND/OR 
Add additional anti- 
hypertensive medications. 
Hold regorafenib until diastolic BP ≤ 90 
mm Hg, and if symptomatic, until 
symptoms resolvea 
When regorafenib is restarted, continue 
at the same dose level. 
If BP is not controlled with the addition 
of new or more intensive therapy, reduce 
by 1 dose level. 
If Grade 3 hypertension recurs despite 
dose reduction and antihypertensive 
therapy, reduce another dose level. 
4 
Life-threatening 
consequences 
(e.g., malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
If BP remains controlled for at least one cycle. Patients requiring >2 dose reductions should go off 
protocol therapy. 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per treating physician’s 
discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 
 
 
 
 

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8.24 
Liver Function Abnormalities 
 
For patients with observed worsening of serum liver tests considered related 
to regorafenib (i.e. where no alternative cause is evident, such as post- 
hepatic cholestasis or disease progression), the dose modification and 
monitoring advice in Table below should be followed. 
 
 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) 
hyperbilirubinemia may occur in patients with Gilbert’s syndrome. 
 
 
Increases in AST/ALT 
(per NCI-CTCAE v 5.0) 
1st Occurrence 
Restart 
Re-occurrence 
AST and/or ALT ≤5 X 
ULN (< Grade 3) 
Continue dosing, with 
weekly monitoring of 
liver function until 
transaminases return 
to <3 X ULN (≤ Grade 
1) or baseline. 
ALT and/or AST >5 X 
ULN (≥ Grade 3) 
Interrupt dosing, with 
weekly monitoring 
until transaminases 
return to <3 X ULN or 
baseline. 
If the potential benefit 
for reinitiating 
regorafenib/ placebo is 
considered to outweigh 
the risk of 
hepatotoxicity: Reduce 
one dose level and 
measure serum liver tests 
weekly for at least 4 
weeks. 
Discontinue 
ALT and/or AST >20 X 
ULN (≥ Grade 4) 
Discontinue 
ALT and/or AST >3 X 
Discontinue treatment 
ULN (≥ Grade 2) with 
and measure serum 
concurrent bilirubin >2 X 
liver tests weekly until 
ULN 
resolution. Exception: 
patients with Gilbert’s 
syndrome who 
develop elevated 
transaminases should 
be managed as per the 
recommendations 
outlined above for 
ALT/AST elevations. 
During the first 2 cycles of treatment, ALT, AST and bilirubin must be monitored every 2 weeks. 
 
8.3 Criteria for discontinuing treatment with regorafenib 
 
Treatment with regorafenib will be discontinued if any of the following 
criteria for discontinuation is met: 
1. When regorafenib is considered to be ineffective 
• 
Radiographically confirmed disease progression. 
• 
Significant worsening of symptoms or physical findings 
(disease progression should be radiographically confirmed 
whenever possible). 
Table 8.24: Dose delay/modifications for ALT and/or AST and/or bilirubin increases related to 
study drug 

30 
ACCRU-GI-1809 
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2. When treatment with regorafenib cannot be continued 
• 
It is necessary to reduce the dose of regorafenib to less than 
dose level -2 according to the criteria for dose 
reduction/modification of treatment. 
• 
Treatment cannot be resumed within 28 days after modification 
of treatment due to an adverse event. 
• 
A 3rd episode of grade 3 hand-and-foot syndrome occurs 
despite symptomatic treatment and dose reduction of 
regorafenib. 
• 
Grade 4 hypertension. 
• 
Grade 4 or higher increase in AST/ALT, 2nd episode of grade 3 
increase in AST/ALT or bilirubin > upper limit of normal x 2 
and AST or ALT > upper limit of normal x 3. 
• 
Other grade 4 non-hematological toxicity. 
• 
The treating physician decides that treatment with regorafenib 
cannot be continued due to safety concerns. 
3. Patient’s request for discontinuation of treatment with regorafenib. 
4. After enrollment, the patient is found to be ineligible for the study, and 
it is concluded that further treatment with regorafenib is detrimental to 
him/her. 
5. Transfer to another institution for any reason during treatment with 
regorafenib. 
 
8.4 
Combination therapy of Anti-EGFR therapy (cetuximab (Cmab) OR panitumumab 
(Pmab)) and irinotecan 
 
Treatment with cetuximab/panitumumab or irinotecan will be started if it is 
confirmed that all criteria for treatment are met prior to treatment initiation. If all 
criteria for starting treatment with Cmab/Pmab are met, but any of the criteria for 
starting treatment with irinotecan is not met, only Cmab/Pmab can be administered. 
If the case is reversed, however, irinotecan should not be administered alone 
(without Cmab/Pmab). 
 
8.41 
Criteria for starting treatment with Cmab or Pmab 
Event 
Criteria for starting treatment with Cmab / Pmab 
Skin symptom (rash 
acneiform, dry skin, 
paronychia, etc.) 
Grade 2 or lower (Local infection is considered grade 3 if oral 
antimicrobial treatment is required, but not if oral antibiotic 
treatment is given based on the anti-inflammatory effect.) 
Infusion-related reaction 
Grade 1 or lower 
Other 
At the discretion of the treating physician, treatment can be 
delayed due to an adverse event not listed above if necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.42 
Criteria for starting treatment with irinotecan 
Event 
Criteria for starting treatment with irinotecan 
Neutrophil count 
≥ 1200/mm3 
Platelet count 
≥ 7.5 104/mm3 
AST, ALT 
≤ upper limit of normal x 3 
(≤ upper limit of normal x 5 in subjects with liver 
metastasis) 
T-bil 
≤ upper limit of normal x 1.5 
Pyrexia 
Absence of pyrexia (≥ 38℃) 
Diarrhea, oral mucositis 
Grade 1 or lower 
Other 
At the discretion of the treating physician, 
treatment can be delayed due to an adverse event 
not listed above if necessary. 
 
 
 
8.43 
Criteria for changing the dose level at the second and subsequent doses for Cmab or  
Pmab and Irinotecan 
 
If any of the events listed below occurs after the previous dose, the next 
dose will be reduced or discontinued. Dose reduction will be performed one 
level at a time. When treatment with irinotecan is discontinued in 
accordance with the criteria for dose reduction/discontinuation during 
combination therapy with Cmab/Pmab and irinotecan, treatment with 
Cmab/Pmab will be continued as protocol treatment if none of the criteria 
for discontinuing protocol treatment are met. Treatment with irinotecan 
alone should not be continued. The dose should not be increased once 
reduced. 
 
 
8.431 
Criteria for changing the dose level of Cmab or Pmab at the second 
and subsequent doses and the dose level 
 
Event 
Cmab \ Pmab 
1st episode of grade 3 or higher skin symptom 
No dose reduction 
2nd and subsequent episodes of grade 3 or higher 
skin symptom 
1-level dose reduction 
The treating physician concludes that the dose should 
be reduced due to an adverse event not listed above. 
1-level dose reduction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.432 
Criteria for changing the dose level of irinotecan at the second and 
subsequent doses and the dose level 
 
Event 
Grade 
Irinotecan 
Neutropenia, thrombocytopenia 
4 
1-level 
dose 
reduction 
Grade 3 neutropenia or grade 3 thrombocytopenia for more 
than 7 days 
3 
Febrile neutropenia, infection, nausea, vomiting, diarrhea, 
fatigue, oral mucositis 
3 
The treating physician concludes that the dose should be 
reduced due to an adverse event not listed above. (Specify the 
reason on the case report form.) 
3 
Irinotecan should be discontinued if dose reduction is necessary more than -2 level. 
 
8.44 
Criteria for discontinuing treatment including Cmab or Pmab 
 
Treatment with Cmab/Pmab plus irinotecan or Cmab/Pmab alone will be 
discontinued if any of the criteria for discontinuation listed below is met. 
When treatment with irinotecan is discontinued due to an irinotecan-related 
adverse event, treatment with Cmab/Pmab alone will be continued if none 
of the following criteria are met: 
 
1. 
When treatment including Cmab/Pmab is considered to be 
ineffective 
• 
Radiographically confirmed disease progression per RECIST 
1.1. 
• 
Significant worsening of symptoms or physical findings 
(disease progression should be radiographically confirmed 
wherever possible). 
2. 
When treatment with Cmab/Pmab cannot be continued 
• 
It is necessary to reduce the dose of Cmab/Pmab to less than 
dose level -3 according to the criteria for dose 
reduction/modification of treatment. 
• 
Treatment cannot be resumed within 28 days after modification 
of treatment due to an adverse event. 
• 
The 3rd episode of grade 3 skin toxicity occurs despite 
symptomatic treatment and dose reduction of Cmab/Pmab. 
• 
Grade 3 or higher infusion-related reaction related to 
Cmab/Pmab. 
• 
Grade 4 non-hematological toxicity. 
• 
The treating physician concludes that treatment with 
Cmab/Pmab cannot be continued due to safety concerns. 
3. 
Patient’s request for discontinuation of treatment with Cmab/Pmab. 
4. 
After entry, the patient is found to be ineligible for the study, and it 
is concluded that further treatment including Cmab/Pmab is 
detrimental to him/her. 
5. 
Transfer to another hospital for any reason during treatment 
including Cmab/Pmab. 
 
 
 
 
 
 

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8.5 
Management of neutropenia, leukopenia and thrombocytopenia 
 
Adverse event of neutropenia and leukopenia should be managed as deemed 
appropriate by the treating physician with close follow up and modification of 
study drug if required. 
 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment 
should be stopped and appropriate management including G-CSF should be given 
according to local hospital guidelines. Please note that G-CSF should not be used 
within at least 24 h (7 days for PEGylated G-CSF) of the last dose of study 
treatment unless absolutely necessary. Platelet transfusions, if indicated, should 
be done according to local hospital guidelines. Study treatment can be interrupted 
for CTCAE grade 1 /2 neutropenia or thrombocytopenia as per treating 
physician’s judgement. In case of CTCAE grade 3/4 neutropenia, leukopenia or 
thrombocytopenia, study treatment should be interrupted for a maximum of 4 
weeks. Study treatment can be restarted at the same dose if an adverse event of 
neutropenia, leukopenia or thrombocytopenia has been recovered up to CTCAE 
grade 1 or less. 
 
8.6  
Criteria for Discontinuing Protocol Treatment  
Protocol treatment will be continued until any of the criteria for discontinuing 
protocol treatment is met, and the study will be completed when it is decided to 
discontinue treatment. 
 
1. Any of the criteria for discontinuing initial treatment (regorafenib for patients in 
Arm A and anti-EGFR±irinotecan for patients in Arm B) is met, and sequential 
treatment cannot be resumed within 28 days 
2. Any of the criteria for discontinuing sequential treatment (anti-EGFR±irinotecan 
for patients in Arm A and regorafenib for patients in Arm B) is met. 
3. Patient’s request for discontinuation of protocol treatment. 
4. Treating physician’s decision 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetic’s 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 
(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 

34 
ACCRU-GI-1809 
Amendment 2 
 
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 
Prevention and treatment of hand-foot skin reaction 
• 
Use of creams (urea-based or non-ureabased), avoid pressure points, use 
insole cushions, steroid cream, analgesics, keep rest, etc 
• 
Symptomatic treatment, including drugs for complications (e.g., ointment 
and Minomycin for skin symptoms), bisphosphonates, and morphine, can 
be given simultaneously if there are no interactions with anticancer drugs 
used. 
9.6 
Unacceptable concomitant therapies/supportive therapies 
During the treatment period, chemotherapy other than protocol treatment, radiation 
therapy, immunotherapy, or surgical therapy should not be given, because protocol 
treatment may be affected. In addition, no investigational product that may affect 
protocol treatment is allowed. Avoid to use of strong inhibitors and inducers of 
CYPA34. For any other medications that must be carefully administered in 
combination with protocol treatment, see the package insert. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
 
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. 
 
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). 
 
 
 

35 
ACCRU-GI-1809 
Amendment 2 
 
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 Sections 
10.53 and 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. 
 
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)/treatment. 

36 
ACCRU-GI-1809 
Amendment 2 
 
Probable - The adverse event is likely related to the agent(s)/treatment. 
Possible - The adverse event may be related to the agent(s)/treatment. 
Unlikely - The adverse event is doubtfully related to the 
agent(s)/treatment. 
Unrelated - The adverse event is clearly NOT related to the agent(s) 
treatment. 
 
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. 
 
10.31 
EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
 
 
For this protocol only, the following Adverse Events/Grades are expected to occur within 
this population and do not require Expedited Reporting. These events must still be reported 
via Routine Reporting (see Section 10.53). * 
 
Note: These exceptions only apply if the adverse event does not result in hospitalization. 
 
If the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the 
event will not be expeditedly 
reported. 
Gastrointestinal 
Disorders 
Diarrhea 
Any Grade 
Dyspepsia 
Nausea 
Vomiting 
Colitis 
Pancreatitis 
Grades 1-3 
General disorders and 
administrations site 
conditions 
Anorexia 
Any Grade 
 General disorders and 
administrations site conditions- 
Other (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 

37 
ACCRU-GI-1809 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

38 
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Amendment 2 
 
*Report any clinically important increase in the rate of a serious suspected adverse 
reaction (at your study) site over that which is listed in the protocol or investigator 
brochure as an expedited event. 
*Report an expected event that is greater in severity or specificity than expected as 
an expedited event 
*An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is required. 
A list of known/expected AEs is reported in the investigator brochure, package 
insert or the literature, including AEs resulting from a drug overdose. 
 
10.312 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. 
 
• 
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 should be 
reported as Grade 5 “Disease Progression” under 
the (SOC) 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. 
 
 
 
 
 
 
 

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10.313 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]) 
 
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. 
 
10.314 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. 
 
10.315 Pregnancy 
 
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. The funding sponsor will be 
notified by ACCRU within 24 hours of notification. 
 
 
 
 
 
 

40 
ACCRU-GI-1809 
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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 
 
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 via MedWatch 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 

41 
ACCRU-GI-1809 
Amendment 2 
 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site. A list of known/expected AE’s are reported in the 
package insert or the literature, including AE’s resulting from a drug overdose. 
 
2. Follow site-specific reporting guidelines. 
 
3. All SAEs occurring after start of administration of regorafenib, regardless of their causal 
relationship to the study drug shall immediately, within 24 hours at the latest, be 
reported. Submit a complete FDA 3500A MedWatch form and all deidentified 
supporting documents to Bayer by fax: 
 
The FDA 3500A MedWatch form can be found at 
 
or on the ACCRU web site along with the MedWatch Fax Cover Sheet (found on the ACCRU 
website). 
 
 
Also submit the MedWatch form 3500A to the ACCRU SAE Coordinator by email at 
 
 
 
3. 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 

42 
ACCRU-GI-1809 
Amendment 2 
 
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 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v5.0 
grading unless otherwise stated in the table below: 
 
System Organ Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each evaluation 
Gastrointestinal 
disorders 
Diarrhea 
# stools per 
day 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
General Disorders 
Fatigue 
X 
X 
Palmar-plantar erythrodysesthesia 
syndrome 
X 
X 
Skin and 
Subcutaneous Tissue 
Disorders 
Rash maculo-papular 
X 
X 
Vascular disorders 
Hypertension 
X 
X 
Investigations 
Blood bilirubin increased 
X 
X 
Alanine aminotransferase increased 
X 
X 
Asparatate aminotransferase 
increased 
X 
X 
 
10.53 Submit via appropriate Academic and Community Cancer Research United 
(ACCRU) Case Report Forms (i.e., paper or electronic, as applicable) the 
following AEs experienced by a patient and 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. 
 
10.5332Any 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. 
 
 
 

43 
ACCRU-GI-1809 
Amendment 2 
 
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 measurable 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)33. 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. 
 
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 ≥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). 
 
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 

44 
ACCRU-GI-1809 
Amendment 2 
 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to 
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. 
 
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 
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 

45 
ACCRU-GI-1809 
Amendment 2 
 
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. 
 
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). 
 
 

46 
ACCRU-GI-1809 
Amendment 2 
 
• 
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. 
 
• 
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. 
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.) 
 
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: 
 
 
 
 
 
 
 
 
 
 
 
 
 

47 
ACCRU-GI-1809 
Amendment 2 
 
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 
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. 
 
For Patients with Non-Measurable Disease Only: 
 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New 
Sites of Disease 
Overall 
Objective Status 
CR 
No 
CR 
Non-CR/Non-PD 
Non-Target Lesions & 
Non-Target Lymph Nodes 
Not All Evaluated* 
Unequivocal PD 
Any 
No 
Non-CR/Non-PD 
 
*See Section 11.431 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health 
status requiring discontinuation of treatment without objective evidence of 
disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment due to symptomatic 
deterioration. A patient is classified as having PD due to “symptomatic 
deterioration” if any of the following occur that are not either related to 
study treatment or other medical conditions: 
 

48 
ACCRU-GI-1809 
Amendment 2 
 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
 
12.0 
Descriptive Factors 
 
12.1 
ECOG Performance Status: 0 vs. 1 vs. 2 
 
12.2 
Primary tumor location: cecum vs. ascending vs. hepatic flexure vs. transverse vs. 
splenic flexure vs. descending vs. sigmoid vs. rectosigmoid vs. rectum. vs other 
 
12.3 
Microsatellite instability or mismatch repair deficiency tested: yes vs. no. 
 
12.31 
If yes, 
MSI-High (MSI-H/dMMR) vs. MSS/MSI-L/pMMR 
 
12.4 
ERBB2 (HER2) amplification tested: yes vs. no. 
 
12.41 If yes, ERBB2 amplified vs. ERBB2 equivocal vs. ERBB2 not amplified. 
 
12.5 
BRAF analysis done: yes vs. no. 
 
12.51 
If yes, wild-type vs. mutated. 
12.511 If mutated, V600E mutation: yes vs. no. 
 
12.6 
KRAS analysis done: yes vs. no. 
 
12.61 
If yes, wild-type vs. mutated. 
 
12.6 
NRAS analysis done: yes vs. no. 
 
12.61 
If yes, wild-type vs. mutated. 

49 
ACCRU-GI-1809 
Amendment 2 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
A patient is deemed ineligible if after randomization, it is determined that at the 
time of randomization, 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 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. 
 
13.2 
A patient is deemed a major violation, if protocol requirements regarding treatment 
in cycle 1 of the initial therapy are so severely violated that evaluability for the 
primary endpoint 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. 
 
13.3 
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 End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
 
13.4 
Patients who are CR, PR, or SD will continue treatment per protocol with 
evaluation every 8 weeks, until disease progression or intolerance. 
 
13.5 
Patients who develop PD while receiving therapy on the initial treatment may be 
re-registered to the sequential treatment phase, or may go to event-monitoring, per 
physician discretion. If a patient develops PD while receiving sequential treatment, 
they will be followed for survival (i.e. event monitoring phase) every 3 months (±7 
days) for 3 years after randomization (per Section 18.0). 
 
13.6 
Patients who go off protocol treatment on the initial treatment for reasons other than 
PD may be re-registered to the sequential treatment phase, or may go to event- 
monitoring, per physician discretion. If a patient goes off protocol treatment while 
receiving sequential treatment, they will be followed for survival (i.e. event 
monitoring phase) every 3 months (±7 days) for 3 years after randomization (per 
Section 18.0). 
 
13.7 
Patients have the option to complete cfDNA testing at study completion and are 
encouraged to 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. 

50 
ACCRU-GI-1809 
Amendment 2 
 
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 
Collectio
n 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 
Baseline
1 
Prior 
to 
dosing 
on 
Day 
15 of 
Cycle 
1 
Prior 
to 
dosing 
on day 
1 of 
cycle 2 
 
End of 
Treatment2 
Additiona
l 
processin
g 
required 
at site 
after 
blood 
draw? 
Storage 
/shipping 
conditions3 
Mandatory 
EDTA K2 
(Purple) 
10 mL (1) 
Platelet 
Poor 
Plasma and 
White 
blood cells 
X 
 
X 
 
 
Ye
s 
Freeze /dry ice 
Mandatory 
EDTA K2 
(Purple) 
10ml (1) 
Platelet 
Poor 
Plasma 
X 
X 
 
Yes 
Frozen 
Optional 
Strec
k 
tube4 
10 mL (2) 
Whole blood 
X 
No 
Room 
temperature 
1. May occur prior to treatment on Cycle 1 Day 1. 
2. Discontinuation of study treatment. 
3. 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.) 
4. 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 
Specimen collection kits can be ordered through Mayo Clinic 
Research Client Request Portal (MCRPCRP). A small but 
sufficient supply of the specimen collection kits should be ordered 
prior to patient entry. Unused/expired kits should be disposed per 
institution policy. Do not send unused kits back to BAP. Kit 
requests must be filled in completely and accurately for quick 
processing. For questions regarding your kit order contact 
 
Please prepare to submit your kit order by reviewing educational 
material in the following order 
 
 
 
 

51 
ACCRU-GI-1809 
Amendment 2 
 
 
 
 
 
 
Once you have reviewed all material, proceed by creating your 
account, submitting your access request(s) and submitting your kit 
request through the portal. 
 
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. Kits will 
arrive inside the shipping boxes. 
 
14.214 Kits will not be sent via rush delivery service unless the 
participating institution provides their own FedEx account number 
or alternate billing number 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 an initial kit shipment and access to the 
Guardant portal, fill out the Guardant Site Setup form for each 
treating location and email it to ACCRU at 
 
 
14.222 ACCRU will notify Guardant Health once each site is activated and 
will help facilitate portal access requests and the initial kit 
shipment. Guardant Health will provide portal access to 
 will ship the initial supply of 
kits to each site. Following the initial shipment, each site can 
request that kits be refreshed/replaced by completing the “Kit 
Reorder Form” and emailing it to Guardant Health Client Services 
Team at 
 
 
14.3 
Shipping and Handling 
 
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. 
 
 
14.312 Processing the EDTA tubes 
 
Gently invert the EDTA 10 times to mix the blood. Process the 
blood within 2 hours after collection. 
Centrifuge EDTA tubes at 2000 x g x 5 minutes to separate the 
blood components. Using a graduated pipette, carefully transfer the 
plasma into a 15mL conical tube being careful to not disturb the 

52 
ACCRU-GI-1809 
Amendment 2 
 
 
cell pellet of buffy coat. Centrifuge the conical tube at 2000 x g x 5 
minutes. Use a new graduated pipette to aliquot the platelet poor 
plasma into 1 mL platelet poor plasma into (4) 2mL cryovials, 
labeled with study ID, Subject ID, collection date and time and 
(PPP) and freeze at -80°C, Using a new graduated pipette, 
carefully transfer the white blood cells and place them into (1) 
2mL cryovial labeled with study ID, Subject ID, collection date and 
time and with (B)and freeze at -80°C. 
14.313 Specimens must be shipped the same day they are drawn 
 
Place the frozen aliquots in the frozen shipper. 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 – 
Thursday, to BAP Freezer according to kit instructions. Do not 
send samples on weekends or just prior to federal holidays. If a 
patient can only be seen on Fridays, email the Biospecimen 
Manager (found on resource page) with the sample information and 
FedEx tracking number. 
 
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. 
 
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. 
 
 
 
 
 
 
 
 

53 
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14.4 
Study Methodology and Storage Information 
14.41 
Blood/blood product samples will be collected for the following research 
 
 
14.411 Soluble protein (blood-based) biomarkers 
 
Blood (platelet poor plasma, and white blood cells (buffy coat)) will 
be collected at baseline and C2D1 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. 
 
14.412 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, and C2D1. 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. 
 
14.413 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 
data have been validated by multiple studies and testing has been done in CLIA- 
approved laboratories. 
 
15.0 
Drug Information 
 
15.1 
Regorafenib (BAY73-4506, Stivarga®) 
 
• 
Refer to package insert for complete, up-to-date information. 

54 
ACCRU-GI-1809 
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15.11 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. 
 
15.12 Formulation 
 
Commercially available in 40 mg tablets. 
 
15.13 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). 
 
15.14 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. 
 
15.15 Pharmacokinetic information 
 
a) Absorption – 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. 
 
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) Excretion – 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 

55 
ACCRU-GI-1809 
Amendment 2 
 
longer mean (range) elimination half-life of 51 hours (32 
to 70 hours). 
 
e) Feces (71%; 47% as parent compound; 24% as parent 
compound; 24% as metabolites); Urine (19%). 
 
15.16 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, 
posaconazole, telithromycin and voriconazole). 
 
15.17 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 
Central nervous system: Fatigue, dysphonia, pain, fever, 
headache. 
Dermatologic: Palmar-plantar erythrodysesthesia, rash, 
alopecia 
Endocrine & metabolic: Hypocalcemia, hypophosphatemia, 
hyponatremia, hypokalemia, hypothyroidism 
Gastrointestinal: Appetite decreased, lipase increased, 
diarrhea, mucositis, weight loss, amylase increased, nausea, 
vomiting 
Hematologic: Anemia, lymphopenia, thrombocytopenia, INR 
increased, hemorrhage, neutropenia 
Hepatic: AST increased, ALT increased, hyperbilirubinemia 
Neuromuscular & skeletal: Stiffness 
Renal: Proteinuria 
Miscellaneous: Infection 
 
Less Common Adverse Events, 1% - 10%: 
Cardiovascular: Myocardial ischemia and infarction 
Gastrointestinal: Taste disturbance, xerostomia, 
gastroesophageal reflux 

56 
ACCRU-GI-1809 
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Neuromuscular & skeletal: Tremor 
Respiratory: Dyspnea 
 
Rare Adverse Events (Important or life-threatening), 
<1%: 
Bradycardia, erythema multiforme, gastrointestinal fistula, 
hypertensive crisis, liver injury (severe), liver failure, 
reversible posterior encephalopathy syndrome (RPLS), skin 
cancer (keratoacanthoma, squamous cell carcinoma), 
Stevens-Johnson syndrome, toxic epidermal necrolysis 
 
15.18 Drug procurement: Bayer will supply the drug to Clinical 
Research Services, a division of Rx Crossroads by McKesson. Each 
participating ACCRU treating location will order regorafenib from 
Clinical Research Services by submitting the Drug Order Request 
Form (found on the ACCRU web site) to: 
 
 
 
 
 
 
Each participating ACCRU treating location will be responsible for 
monitoring the supply of regorafenib 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. 
 
15.19 Nursing Guidelines 
 
15.191 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. 
 
15.192 Hypertension has been seen. Monitor blood pressure as 
outlined in protocol. 
 
15.193 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. 
 
15.194 Warn patients of possibility of alopecia. 
 
15.195 Gastrointestinal side effects can include, diarrhea, nausea, 

57 
ACCRU-GI-1809 
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vomiting, decreased appetite, weight loss, mucositis and 
less commonly taste changes, dry mouth, and reflux. Treat 
symptomatically and monitor for effectiveness. 
 
15.196 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. 
 
15.197 Secondary skin cancers have been reported. Instruct 
patients to report new or changing lesions to study team. 
 
15.198 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. 
 
15.2 
Cetuximab (Erbitux®) 
 
• 
Refer to package insert for complete, up-to-date information. 
 
15.21 Background: Cetuximab is a recombinant human/mouse chimeric 
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 receptor-associated 
kinases, resulting in inhibition of cell growth, induction of apoptosis, and 
decreased matrix metalloproteinase and vascular endothelial growth factor 
production. EGFR signal transduction results in KRAS wild-type 
activation; cells with KRAS mutations appear to be unaffected by EGFR 
inhibition. 
 
15.22 Formulation: Commercially available for injection 2 mg/mL (50 mL, 100 
mL). 
 
15.23 Preparation, storage, and stability: Refer to package insert for 
complete preparation and dispensing instructions. Store intact vials at 
refrigeration temperature (2 to 8ºC 38 to 46ºF), do not freeze or 
shake. Reconstitution is not required. Appropriate dose should be 
added to empty sterile container; do not shake or dilute. Preparations 
in infusion containers are stable for up to 12 hours under 
refrigeration (2 to 8ºC 38 to 46ºF) and up to 8 hours at room 
temperature (20 to 36ºC or 68 to 77ºF). 
 
15.24 Administration: Administer via I.V. infusion; loading dose over 2 hours, 
weekly maintenance dose over 1 hour. Do not administer as I.V. push or 
bolus. Do not shake or dilute. Premedication with antihistamines is 

58 
ACCRU-GI-1809 
Amendment 2 
 
 
recommended. The maximum infusion rate is 10 mg/minute. Administer 
through a low protein-binding 0.22 micrometer in-line filter. Use 0.9% 
NaCl to flush line at the end of infusion. For biweekly administration 
(unlabeled frequency and dose), the initial dose was infused over 120 
minutes and subsequent doses infused over 60 minutes. 
 
15.25 Pharmacokinetic information: 
Distribution: Vd: ~2-3 L/m2 
Half-life elimination: ~112 hours (range: 63-230 hours) 
 
15.26 Potential Drug Interactions: 
There are no known interactions where it is recommended to avoid 
concomitant use. 
 
15.27 Known potential adverse events: Consult the package insert for the 
most current and complete information. Refer to the package insert 
pertaining to the following boxed warnings: Severe infusion 
reactions and cardiopulmonary arrest. Cetuximab is contraindicated 
in patients with known sever reactions to cetuximab. 
Common known potential toxicities, > 10%: 
Central nervous system: Fatigue, pain, peripheral sensory 
neuropathy, headache, insomnia, fever, confusion, anxiety, chills, 
depression 
Dermatologic: Skin rash, acneiform eruption, xeroderma, pruritus, 
nail disease 
Endocrine & metabolic: Hypomagnesemia, dehydration 
Gastrointestinal: Nausea, abdominal pain, constipation, diarrhea, 
vomiting, stomatitis, xerostomia 
Neuromuscular & skeletal: Ostealgia, arthralgia 
Respiratory: Dyspnea, cough 
Miscellaneous: Fever, infusion related reactions 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Cardiopulmonary arrest 
Central nervous system: Taste disorder 
Immunologic: Antibody development 
Infection: Sepsis 
Renal: Renal failure 
 
Rare known potential toxicities, <1% (Limited to important or 
life-threatening): 
Abscess, aseptic meningitis, blepharitis, cardiac arrest, cardiac 
arrhythmia, cellulitis, cheilitis, conjunctivitis, corneal ulcer, 
hypertrichosis, hypotension, interstitial pulmonary disease, keratitis, 
leukopenia, loss of consciousness, MI, pulmonary embolism, 
radiation dermatitis, shock, skin fissure, skin infection, stridor 
 
15.28 Drug procurement: Commercial supplies. Pharmacies or clinics shall 
obtain supplies from normal commercial supply chain or wholesaler. 
 
 
 
 
 
 

59 
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15.29 Nursing guidelines 
15.291 Patients should be closely monitored during the infusion for signs 
of anaphylaxis and standard resuscitative medications should be 
available during and for one hour following the cetuximab infusion. 
 
CAUTION: Infusion reactions may occur during or following 
cetuximab administration. Most infusion reactions occur with the 
first infusion of cetuximab, but some patients’ first infusion 
reactions have been reported following subsequent doses (as far out 
as the 8th dose). The infusion reaction may occur during the 
infusion, or be delayed until any time after the infusion. A nurse 
should be present in the immediate treatment area throughout the 
infusion and observation period. A physician should be in close 
proximity to the patient treatment area. Should an infusion reaction 
occur, the patient should be treated according to institutional 
guidelines. Patient should be instructed to report any delayed 
reactions to the investigator immediately. Patients who have had 
severe reactions should not receive further doses of cetuximab. 
 
15.292 Vital signs should be taken prior to, during, post and 1 hour post 
infusion. 
 
15.293 Patient should be observed for 1 hour following the loading dose 
and each maintenance dose. 
 
15.294 Premedicate with 50 mg of IV diphenhydramine, or other specific 
premedications called for in the protocol, prior to each dose. 
 
15.295 Patients should be taught to wear sunscreen and hats and limit sun 
exposure while receiving treatment. 
 
15.296 Recommend that all infusions be run on a volumetric pump. 
Infusion rate MUST NEVER EXCEED 10MG/MINUTE (5 
ML/MINUTE). 
 
15.297 Monitor CBC and instruct patient to report any signs or symptoms 
of infection, unusual bruising, or bleeding to the health care team. 
 
15.298 Monitor LFTs. 
 
15.299 aFever and chills may occur. Discuss with MD about premedication 
with an antipyretic. 
 
15.299bMonitor for signs and symptoms of gastrointestinal side effects, 
including nausea, constipation, diarrhea, and vomiting. Administer 
antiemetics and antidiarrheals and/or stool softeners as indicated 
and evaluate their effectiveness. 
 
15.299c Instruct patient to report rash. 
 
15.299dHypomagnesemia is a complication of cetuximab therapy. Instruct 
patients to report any of the following signs or symptoms as these 
may be signs of the disorder. Neuromuscular: muscle weakness, 

60 
ACCRU-GI-1809 
Amendment 2 
 
 
muscle cramps, painful swallowing; CNS: Irritability, 
combativeness, disorientation, psychosis, vertigo, seizures; 
Cardiac: irregular and/or fast heartbeat. Any or all of the symptoms 
may or may not be present in the patient with this condition. If 
patients present with any of these symptoms, inform MD and a 
magnesium level should be checked. 
 
15.299e Sensory neuropathy has been seen. Assess for this and inform MD 
if this develops. 
 
 
15.3 
Panitumumab (Vectibix®) 
 
• Refer to package insert for complete, up-to-date information. 
 
15.31 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. 
 
15.32 Formulation: Commercially available for injection 20 mg/mL (5 mL, 20 
mL). 
 
15.33 Preparation, storage, and stability: Refer to package insert for 
complete preparation and dispensing instructions. Store unopened 
vials at refrigeration temperature, do not freeze or shake, protect 
from light. Dilute in 100-150 mL of normal saline to a final 
concentration of less than or equal to 10 mg/mL. Do not shake, invert 
gently to mix. Preparations in infusion containers are stable for 24 
hours under refrigeration or for 6 hours at room temperature. 
 
15.34 Administration: Doses less than or equal to 100 mg, infuse over 1 hour: 
doses > 1000 mg, infuse over 90 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 NS before and after 
infusion. 
 
15.35 Pharmacokinetic information: 
Half-life elimination: ~7.5 days (range: 4-11 days) 
 
15.36 Potential Drug Interactions: 
Increased Effect/Toxicity: There are no known interactions where it 
is recommended to avoid concomitant use. 
 
15.37 Known potential adverse events: Consult the package insert for the 
most current and complete information. Refer to the package insert 

61 
ACCRU-GI-1809 
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pertaining to the following boxed warnings: Dermatologic toxicities 
and severe infusion reactions. 
Common known potential toxicities, > 10%: 
Cardiovascular: Peripheral edema 
Central nervous system: Fatigue 
Dermatologic: Skin toxicity, erythema, Acneiform rash, pruritus, 
exfoliation, paronychial, rash, fissures, acne 
Endocrine & metabolic: Hypomagnesemia 
Gastrointestinal: Abdominal pain, nausea, diarrhea, constipation, 
vomiting 
Respiratory: Cough 
Less common known potential toxicities, 1% - 10%: 
Dermatologic: Dry skin, nail disorder 
Endocrine& metabolic: Dehydration 
Gastrointestinal: Stomatitis, mucositis 
Ocular: Eyelash growth, conjunctivitis, ocular hyperemia, 
lacrimation increased, eye/eye lid irritation 
Miscellaneous: Antibody formation, infusion reactions 
 
Rare known potential toxicities, <1% (Limited to important or 
life-threatening): 
Abscess formation, allergic reaction, anaphylactoid reaction, 
angioedema, chills, dyspnea, fever, hypocalcemia, hypoxia, 
pulmonary embolism, pulmonary fibrosis, pulmonary infiltrate, 
sepsis, septic death 
 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall 
obtain supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines: 
 
15.391 
Patient may experience typical EGFR inhibitor related rash, 
which is generally acneiform in nature and may be associated 
with pruritus and erythema. Treat symptomatically and monitor 
for effectiveness. 
 
15.392 
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. 
 
15.393 
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. 
 
15.394 
Hypomagnesmia is seen with this agent. Monitor magnesium 
level prior to each infusion. If level is below normal, inform the 
MD. 
 
15.395 
Patients may experience nail related changes, including 
discoloration, ridging, paronychias, and/or loss of the nail itself. 

62 
ACCRU-GI-1809 
Amendment 2 
 
 
Instruct patients to report nail changes to the study team, as 
intervention may be indicated. 
 
15.396 
Gastrointestinal side effects including nausea, diarrhea, 
constipation and vomiting have been seen. Treat symptomatically 
and monitor for effectiveness. 
 
15.397 
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. 
 
15.398 
Panitumumab is a protein and should be handled carefully to 
avoid break down of the product. This includes both when 
mixing from the vial and when administering the product via IV 
infusion. 
 
15.4 
Irinotecan (Camptosar®, CPT11) 
 
• Refer to package insert for complete, up-to-date information. 
 
15.41 Background: Irinotecan and its active metabolite (SN-38) bind reversibly 
to topoisomerase I-DNA complex preventing relegation of the cleaved 
DNA strand. This results in the accumulation of cleavable complexes and 
double-strand DNA breaks. As mammalian cells cannot efficiently repair 
these breaks, cell death consistent with S-phase cell cycle specificity 
occurs, leading to termination of cellular replication. 
 
15.42 Formulation: Commercially available for injection 20 mg/mL (2 mL, 5 
mL, 25 mL) [contains sorbitol 45 mg/mL; do not use in patients with 
hereditary fructose intolerance]. 
 
15.43 Preparation, storage, and stability: Store intact vials at room 
temperature (15 to 30ºC or 59 to 86ºF) and protect from light. Doses 
should be diluted in 250-500 mL D5W or 0.9% NaCl to a final 
concentration of 0.12-2.8 mg/mL. Solutions diluted in D5W are 
stable for 24 hours at room temperature or 48 hours under 
refrigeration at 2ºC to 8ºC. Solutions diluted in 0.9% NaCl may 
precipitate if refrigerated. Do not freeze. 
 
15.44 Administration: Administer by I.V. infusion, usually over 90 minutes. 
 
15.45 Pharmacokinetic information: 
Distribution: Vd: 33-150 L/m2 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% 
to 68%, SN-38 (active metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by 
carboxylesterase enzymes; SN-38 undergoes conjugation by UDP- 
glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide 
metabolite. Conversion of Irinotecan to SN-38 is decreased and 
glucoronidation of SN-38 is increased in patients who smoke 
cigarettes, resulting in lower levels of the metabolite and overall 
decreased systemic exposure. SN-38 is increased by UGT1A1*28 

63 
ACCRU-GI-1809 
Amendment 2 
 
 
polymorphism (10% of North Americans are homozygous for 
UGT1A1*28 allele). Patients homozygous for the UGT1A1*28 
allele are at increased risk of neutropenia; initial one-level dose 
reduction should be considered for both single-agent and 
combination regimens. The lactones of both Irinotecan and SN-38 
undergo hydrolysis to inactive hydroxyl acid forms. 
Half-life elimination: SN-38: Mean terminal: 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion: ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), 
metabolites (SN-38 <1%, SN-38 glucuronide, 3%) 
 
15.46 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4, P- 
glycoprotein, SLCO1B1 and UGT1A1 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may 
increase the levels/effects of irinotecan. Bevacizumab may increase 
the adverse effects of Irinotecan (e.g., diarrhea, neutropenia). 
Ketoconazole increases the levels/effects of Irinotecan and active 
metabolite; discontinue ketoconazole 1 week prior to Irinotecan 
therapy; concurrent use is contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the 
levels/effects of irinotecan. 
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St John’s 
wort decreases therapeutic effect of irinotecan; discontinue ≥ weeks 
prior to irinotecan therapy; concurrent use is contraindicated. 
 
15.47 Known potential adverse events: Consult the package insert for the 
most current and complete information including U.S. Boxed 
Warnings pertaining to severe diarrhea and severe myelosuppression. 
 
Common known potential toxicities, > 10%: 
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, 
increased salivation, miosis, lacrimation, diaphoresis, flushing and 
intestinal hyperperistalsis); fever, pain, dizziness, insomnia, 
headache, chills 
Dermatologic: Alopecia, rash 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, nausea, 
abdominal pain, vomiting, cramps, anorexia, constipation, mucositis, 
weight loss, flatulence, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic infection 

64 
ACCRU-GI-1809 
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Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
 
Rare known potential toxicities, <1% (Limited to important or 
life-threatening): 
ALT increased, amylase increased, anaphylactic like reaction, 
anaphylaxis, angina, arterial thrombosis, bleeding, bradycardia, 
cardiac arrest, cerebral infarct, cerebrovascular accident, circulatory 
failure, colitis, dysrhythmia, embolus, gastrointestinal bleeding, 
gastrointestinal obstruction, hepatomegaly, hyperglycemia, 
hypersensitivity, hyponatremia, ileus, interstitial pulmonary disease 
(IPD), intestinal perforation, ischemic colitis, lipase increased, 
lymphocytopenia, megacolon, MI, myocardial ischemia, neutropenic 
typhlitis, pancreatitis, paresthesia, peripheral vascular disorder, 
pulmonary embolus, pulmonary toxicity (dyspnea, fever, reticulo- 
nodular infiltrates on chest x-ray), renal failure (acute), renal 
impairment, syncope, thrombophlebitis, thrombosis, typhlitis, 
ulceration, ulcerative colitis 
 
15.48 Drug procurement: Commercial supplies. Pharmacies or clinics shall 
obtain supplies from normal commercial supply chain or wholesaler. 
 
15.19 
Nursing Guidelines: 
 
15.191 Early diarrhea (occurring during or shortly after infusion of 
CAMPTOSAR) is usually transient and infrequently severe. It may 
be accompanied by cholinergic symptoms of rhinitis, increased 
salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal 
hyperperistalsis that can cause abdominal cramping. Bradycardia 
may also occur. Early diarrhea and other cholinergic symptoms may 
be prevented or treated. Consider prophylactic or therapeutic 
administration of 0.25 mg to 1 mg of intravenous or subcutaneous 
atropine (unless clinically contraindicated). These symptoms are 
expected to occur more frequently with higher irinotecan doses. 
Begin loperamide at the first episode of poorly formed or loose stools 
or the earliest onset of bowel movements more frequent than normal. 
One dosage regimen for loperamide is 4 mg at the first onset of late 
diarrhea and then 2 mg every 2 hours until the patient is diarrhea- 
free for at least 12 hours. Loperamide is not recommended to be used 
for more than 48 consecutive hours at these doses, because of the risk 
of paralytic ileus. During the night, the patient may take 4 mg of 
loperamide every 4 hours. Patients should contact their physician if 
any of the following occur: diarrhea for the first time during 
treatment; black or bloody stools; symptoms of dehydration such as 
lightheadedness, dizziness, or faintness; inability to take fluids by 
mouth due to nausea or vomiting; or inability to get diarrhea under 
control within 24 hours. 
 
15.192 Late diarrhea (generally occurring more than 24 hours after 
administration of CAMPTOSAR) can be life threatening since it 
may be prolonged and may lead to dehydration, electrolyte 
imbalance, or sepsis. 

65 
ACCRU-GI-1809 
Amendment 2 
 
 
 
15.193 Hypersensitivity reactions including severe anaphylactic or 
anaphylactoid 
reactions 
have 
been 
observed. 
Discontinue 
CAMPTOSAR if anaphylactic reaction occurs. 
 
15.194 Interstitial Pulmonary Disease (IPD)-like events, including fatalities, 
have occurred in patients receiving irinotecan (in combination and as 
monotherapy). Risk factors include pre-existing lung disease, use of 
pneumotoxic drugs, radiation therapy, and colony stimulating 
factors. Patients with risk factors should be closely monitored for 
respiratory symptoms before and during CAMPTOSAR therapy. 
 
15.195 Hold CAMPTOSAR if neutropenic fever occurs or if the absolute 
neutrophil count drops 
 
15.196 Patients should be warned about the potential for dizziness or visual 
disturbances which may occur within 24 hours following the 
administration of CAMPTOSAR. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Overview 
 
This randomized phase II trial is designed to compare the overall survival (OS) in 
patients with metastatic colorectal cancer, who randomized to regorafenib followed 
by anti-EGFR therapy (either cetuximab or panitumumab) ±irinotecan (arm A, R+E) 
vs. anti-EGFR therapy ±irinotecan followed by regorafenib (arm B, E+R). Prior 
studies have shown that the median OS of patients in this disease population who 
received anti-EGFR follow by regorafenib is around 7.5 months 20,32. It is 
hypothesized that the sequence of regorafenib followed by anti-EGFR can increase 
the median OS to 14.5 months. In addition to OS, this trial will also compare the first 
progression-free survival 1 (PFS1), the second progression-free survival (PFS2), 
sequential treatment progression-free survival (stPFS), objective response rates 
(ORR) and adverse event rates between two arms. 
 
This study’s original design had no restriction on tumor sidedness. Due to the results 
of the PARADIGM trial, this study has been amended to reflect treatment patterns 
where patients will likely receive anti-EGFR therapy as first line therapy. In 
PARADIGM, the study aimed to test the superiority of panitumumab versus 
bevacizumab in combination with standard double first-line chemotherapy for 
patients with newly diagnosed metastatic colon cancer with RAS WT mCRC and left 
sided tumors. The addition of panitumumab significantly improved overall survival 
compared to patients who received bevacizumab amongst those with left sided tumors 
(HR, 0.82; 95.798% CI, 0.68-0.99, p = .031) and the full analysis of all patients (HR, 
0.84; 95% CI, 0.72-0.98; p = .030). However, in patients with right sided disease, no 
improvement in overall survival was observed in patients who received panitumumab 
(HR 1.09). Given the absence of survival benefit observed in patients with right sided 
colon cancer, the potential clinical benefit from sequencing therapy remains of 
interest. 

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The study has been amended to enrollment of patients with right-sided tumors in 
Amendment 2. Patients with left-sided tumors who were enrolled prior to 
Amendment 2 will continue being followed per protocol but their data will not be 
utilized for the primary endpoint analysis. 
 
Evaluable Population: The Evaluable Population comprises all patients who are 
eligible, consented, randomized, received any protocol treatment, and have right- 
sided tumors. 
 
Safety Population: The Safety Population comprises all patients who received any 
protocol treatment. 
 
16.11 Primary Endpoint: The primary endpoint is overall survival. The primary 
objective for this trial is to compare the overall survival (OS) between 
evaluable patients who were randomized to arm A and arm B. Overall 
survival is defined as the time from randomization to death from any cause. 
Patients who are alive at the time of statistical analysis will be censored at 
the last known alive date. 
 
16.12 Secondary Endpoints: Each secondary endpoint will be compared between 
arms. These include first progression free survival (PFS1), second 
progression free survival two (PFS2), sequential treatment progression free 
survival (stPFS), objective response rate of initial treatment and sequential 
treatment, and incidence of adverse events from initial treatment, sequential 
treatment and whole period. 
 
16.2 
Statistical Design 
 
6.21  The primary goal is to compare the OS between evaluable patients who were 
randomized to R+E (arm A) and E+R (arm B). The null hypothesis is that 
R+E (arm A) does not show a significantly superior OS outcome compared 
to E+R (arm B). The alternative hypothesis is that R+E has improvement in 
OS compared to E+R. 
 
16.22 Power and Sample Size 
 
We will enter 26 evaluable patients to each arm of the study using a 1:1 
randomization scheme (52 evaluable patients in total), unless the study is 
stopped early. Stratification factors are defined in section 5.0. With 26 
evaluable patients per arm, we have 80% power to detect an improvement in 
median OS from 7.5 months to 14.5 months, assuming a 1-sided significance 
level of 0.1, and exponential survival. 
 
An additional 8 patients (4 in each arm) will be enrolled to account for 
ineligibility, major violation, loss of follow-up, etc. The total expected 
accrual for primary analysis (i.e. patients with right-sided tumor) is 60. 
Including the 12 patients with left-sided tumors who enrolled prior to 
Amendment 2, the total expected accrual is 72 patients. 
 
 
 
 
 
 
 

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16.23 Final Analysis and Decision Rules 
Efficacy analysis will be conducted when at least 42 death events, across both 
arms combined, have been observed. If the 1-sided p-value from stratified 
log-rank test is > 0.1 (hazard ratio > 0.673) for arm A vs. B, (R+E) treatment 
regimen will be considered inefficacious. Conversely, if the 1-sided p-value 
from stratified log-rank test is ≤ 0.1 (hazard ratio ≤ 0.673) for Arm A vs. B, 
the (R+E) treatment regimen will be considered promising for future study. 
Evaluable patients will be used for this analysis (see 16.1 for evaluable 
definition). 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. 
 
 
Analysis 
time point 
Number 
of events1 
Critical p-value 
Hazard Ratio 
Futility 
Efficacy 
Futility 
Efficacy 
100% 
42 
> 0.1 
≤0.1 
> 0.673 
≤ 0.673 
 
 
16.24 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 
0.1. The proportion of times that regorafenib followed by anti-EGFR (R+E) 
would be concluded to be superior at the final analysis are tabulated by true 
median OS times and equivalent true hazard ratios for OS by treatment 
groups. 
 
 
True median overall 
survival (months)3 
True 
Hazard 
Ratio 
(Arm A 
vs. B) 
% of times that 
R+ E is 
deemed 
superior at the 
final analysis 4 
R + E1 
(Arm A) 
E + R2 
(Arm B) 
7.5 
7.5 
1 
10.3 
9.5 
7.5 
0.789 
30.0 
11 
7.5 
0.682 
47.8 
12.5 
7.5 
0.6 
63.7 
14.5 
7.5 
0.517 
79.4 
 
1 R + E: regorafenib followed by anti-EGFR ±irinotecan 
 
2 E + R: anti-EGFR ±irinotecan followed by regorafenib 
 
3 Although we use the median OS to illustrate each scenario, the 
hypothesis testing is based on the entire survival curve. 
 
4 Proportions are based on 50,000 replicates in a simulation study 
 
 
 
 

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16.25 Accrual Time and Study Duration 
 
We plan to accrue a total of 72 patients (approximately 30 patients per arm 
with right-sided tumor + 12 patients enrolled with left-sided tumor) in 51 
months with a minimum follow-up of 7.5 months to achieve 42 OS events. 
The length of accrual time is based on an accrual rate of 0.2 patients per 
month for the first 33 months and 3 patients per month for the remaining 
accrual period. 
 
 
16.26 Other Considerations 
 
Adverse events, quality/duration of response, and patterns of treatment 
failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the 
study. 
 
16.3 
Analysis Plan 
 
The analysis for this trial will commence when the sufficient number of OS events 
has been observed (see 16.23). Such a decision will be made by the Statistician and 
Study Chair, in accordance with CCS Standard Operating Procedures, availability 
of data for secondary endpoints (eg, laboratory correlates), and the level of data 
maturity. 
 
16.31 Primary Endpoint 
 
16.311 Definition 
 
The primary endpoint for this trial is to compare the overall survival 
(OS) between evaluable patients who were randomized to arm A and 
arm B. Overall survival is defined as the time from study entry to 
death from any cause. OS will be estimated using the Kaplan-Meier 
method and compared between treatment groups using the stratified 
log-rank test. The median OS and 95% confidence interval will be 
reported. Patients will be censored at the date patient was last known 
to be alive. 
 
16.312 Over Accrual 
 
If more than the target number of patients are accrued, the 
additional evaluable patients will be used for decision making. 
 
16.32 Secondary Endpoints 
 
16.321 First Progression-Free Survival (PFS1) 
 
Progression-free survival one (PFS1) is defined as the time interval 
between randomization date and the date of first progression while 
on initial treatment or until death whichever is first, where disease 
progression will be determined based on RECIST 1.1 criteria. PFS 
will be estimated using the Kaplan-Meier method and compared 
between groups using the log-rank test. The median PFS and 95% 

69 
ACCRU-GI-1809 
Amendment 2 
 
 
confidence interval will be reported. Patients with no defined events 
observed during the follow-up period will be censored at the last 
disease assessment date prior to the initiation of sequential treatment, 
if applicable. 
 
16.322 Second Progression-Free survival (PFS2) 
 
Second progression-free survival (PFS2) is defined as the time 
interval from re-registration to the sequential treatment phase until 
the date of progression while on sequential treatment or until death, 
whichever occurred first. Disease progression will be determined 
based on RECIST 1.1 criteria. PFS2 will be estimated using the 
Kaplan-Meier method and compared between groups using the log- 
rank test. The median PFS2 and 95% confidence interval will be 
reported. Patients will be censored at the last disease assessment date 
while on sequential treatment . 
 
16.323 Sequential Treatment Progression-Free Survival (stPFS) 
 
Sequential treatment progression-free survival is defined as the time 
from randomization until progression while on the sequential 
treatment or until death, whichever occurred first. Patients who did 
not experience an event during follow-up will be censored at the last 
disease assessment date. 
 
Patients who completed initial treatment but did not begin sequential 
treatment will be censored at the date of last disease evaluation prior 
to discontinuation of initial treatment. Patients who began sequential 
treatment but discontinued protocol treatment prior to progression 
will be censored at the last disease assessment date while on 
sequential treatment. Analysis methods will mirror those of the other 
PFS endpoints. 
 
 
16.324 Objective Response Rate 
 
The objective response rate to initial treatment will be estimated by 
the number of patients who achieve a best response to initial 
treatment of complete response or partial response (CR or PR) 
divided by the total number of evaluable patients. Point estimates 
and the corresponding 95% confidence intervals for the true 
success proportions will be calculated. 
 
16.325 Sequential Treatment Objective Response Rate 
 
The objective response rate to sequential treatment is defined as the 
number of patients who achieve a best response to sequential 
treatment of complete response or partial response (CR or PR) 
while on sequential treatment divided by the total number of 
evaluable patients who initiated sequential treatment. Point 
estimates and the corresponding 95% confidence intervals for the 
true success proportions will be calculated. 

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Amendment 2 
 
16.326 Adverse Events 
 
Adverse events by patient will be summarized by frequencies and 
severity using CTCAE version 5.0. We will also closely monitor 
adverse events throughout the study. 
 
16.327 Correlative Research 
Serial blood collections – prior to cycle 1, every 8 weeks at the time 
of restaging scans and disease progression will be collected to post- 
hoc evaluate for plasma biomarkers prognostic or predictive to 
response and acquired treatment resistance 
 
16.4 
Data & Safety Monitoring 
 
16.41 Review 
 
The study chair(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 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 MCCC Statistical Office. 
 
16.42 Adverse Event Stopping Rules 
 
The stopping rules specified below are based on the knowledge available at 
study development. We note that the Adverse Event Stopping Rule may be 
adjusted in the event of either (1) the study re-opening to accrual 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 choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the specified rule 
below. 
 
Accrual will be temporarily suspended to this study if at any time, in either 
arm, we observe events considered to be at least possibly related to study 
treatment (i.e., an adverse event with attribute specified as “possible”, 
“probable”, or “definite”) that satisfy the following: 
 
If at any time, 3 of the initial 15 treated patients or 20% or more of all 
patients (i.e. when accrual is greater than 30 patients) have experienced a 
grade 4+ adverse event. 
 
We note that we will review Grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
 
 
 
 
 
 
 
 
 
 

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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 
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 

72 
ACCRU-GI-1809 
Amendment 2 
 
• 
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 Duke Phase I Biomarker Laboratory located 
at Duke University for processing as outlined in Section 17.3. 
 
 
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 
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, 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. 

73 
ACCRU-GI-1809 
Amendment 2 
 
 
 
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 
 
Access the RAVE system through the iMedidata portal at 
All 
data must be entered by Remote Date Entry (RDE) and completed by qualified and 
authorized personnel. All data on the CRF must reflect the corresponding source document. 
 
18.1 
Submission Timetable 
 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
2 weeks after randomization 
On-Study 
On-Study: Prior Surgery2 
On-Study: Prior Radiation2 
On-Study: Prior Systemic Therapy2 
Adverse Events: Baseline 
RECIST Measurements: Initial Treatment 
(Baseline) 
Laboratory Tests & Results: Baseline 
Op and Pathology Reports1 
Supporting Documentation: Baseline3 
Patient Status: Baseline 
Specimen Submission: Blood -Baseline (see 
Section 14.0) 
Specimen Submission: Tissue-Baseline (see 
Section 17) 
2 weeks after randomization 
Notice of New Primary2 
Off Treatment 
Submit 2 weeks after randomization if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
ACCRU Deviation Form2 
Submit only if applicable during all phases of the 
study 
1. Submit Op and Path Reports via the Supporting Documentation: Baseline form. 
2. Submit only if applicable. 
3. Submit copy of imaging report 

74 
ACCRU-GI-1809 
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Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Treatment (Intervention) 
X2 
X 
Treatment (Intervention): Dose 
Modifications, Omissions and Delays3 
X 
X 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other3 
X 
X 
RECIST Measurements: Initial Treatment3 
X1 
X1 
RECIST Measurements: Sequential 
Treatment (Baseline)3 
X 
X 
RECIST Measurements: Sequential 
Treatment3 
X 
X 
Supporting Documentation3 
X1 
X 
Laboratory Tests and Results 
X 
X 
Specimen Submission: Blood 
X (see Section 14.0) 
X (see Section 14.0) 
Patient Status: Treatment (Intervention) 
X 
X 
End of Initial Treatment 
X 
Off Treatment 
X 
Notice of New Primary3 
X 
Consent Withdrawal (choose appropriate 
form)3 
• 
Consent Withdrawal: Optional 
Specimens 
• 
Consent Withdrawal: All Follow-Up 
X 
X 
Lost to Follow-Up3 
X 
ACCRU Deviation Form3 
X 
1. Attach a copy of imaging report for each restaging scan and documentation of 
response or progression in RAVE on the Supporting Documentation Form. 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
3. Submit only if applicable. 

75 
ACCRU-GI-1809 
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Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q. 3 
months 
until PD 
At PD 
After 
PD q.3 
mos. 
Death 
At Each Event 
Occurrence 
Patient Status: Survival and 
Disease Status Follow-Up/Event 
Monitoring 
X2 
X2 
X 
X 
At each 
occurrence 
Adverse Events: Late3 
At each 
occurrence 
Supporting Documentation3 
At each 
occurrence 
Lost to Follow-Up3 
At each 
occurrence 
Notice of New Primary3 
At each 
occurrence 
Consent Withdrawal (choose 
appropriate form)3 
• 
Consent Withdrawal: 
Optional Specimens 
• 
Consent Withdrawal: All 
Follow-Up 
At each 
occurrence 
ACCRU Deviation Form3 
1. If a patient is still alive 3 years after randomization, no further follow-up is 
required. 
2. Attach a copy of documentation of response or progression in RAVE on the 
Supporting Documentation Form. 
3. Submit only if applicable. 
4. Please use the “Add Event” function to record the first instance of non-protocol 
treatment received. If the patient has never had any non-protocol treatment, 
record as “no” at the end of the Event Monitoring Phase. 
 
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 
Regorafenib will be supplied by Bayer Pharmaceuticals. Cetuximab, 
pantiumumab, and irinotecan will not be supplied, but is commercially 
available. 

76 
ACCRU-GI-1809 
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26. 
Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance 
to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532-536. 
27. 
Diaz LA, Jr., Williams RT, Wu J, et al. The molecular evolution of acquired resistance to 
targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537-540. 
28. 
Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance 
to the EGFR-directed therapeutic antibody cetuximab. Science translational medicine. 
2011;3(99):99ra86. 
29. 
Laurent-Puig P, Manceau G, Zucman-Rossi J, Blons H. Dual Blockade of Epidermal Growth 
Factor Receptor–Induced Pathways: A New Avenue to Treat Metastatic Colorectal Cancer. 
Journal of Clinical Oncology. 2012;30(13):1550-1552. 
30. 
Tabernero J, Lenz HJ, Siena S, et al. Analysis of circulating DNA and protein biomarkers to 
predict the clinical activity of regorafenib and assess prognosis in patients with metastatic 
colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. The lancet 
oncology. 2015;16(8):937-948. 
31. 
Shitara K, Yamanaka T, Denda T, et al. Reverce: Randomized phase II study of regorafenib 
followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients 
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32. 
Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan 
alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer 

78 
ACCRU-GI-1809 
Amendment 2 
 
 
(PICCOLO): 
a 
prospectively 
stratified 
randomised 
trial. The 
lancet 
oncology. 
2013;14(8):749-759. 
33. 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). 
Eur J Cancer 45(2): 228-247, 2009. 

ACCRU-GI-1809 
Appendix I 
Amendment 2 
Page 1 of 2 
 
 
 
 
Appendix I: ACCRU-GI-1809 SUBJECT MEDICATION DIARY: Regorafenib 
 
Name: 
Patient ID Number: 
Cycle: 
You will take: 
ORAL MEDICATION DIARY 
Subject 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 check “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-1809 
Appendix I 
Amendment 2 
Page 2 of 2 
 
 
 
ACCRU-GI-1809 SUBJECT MEDICATION DIARY – Regorafenib 
Cycle # 
 
 
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 
 
Date: 
 
Subject’s 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 
 
 
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