A Randomized Phase II Study of Hepatic Arterial Infusion With Intravenous Irinotecan, 5FU and Leucovorin With or Without Panitumumab, in Patients With Wild Type RAS Who Have Resected Hepatic Metastases From Colorectal Cancer
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 1 of 47 
 
 
 
 
A Randomized Phase II Study of Hepatic Arterial Infusion with FUDR and 
Dexamethasone and Intravenous Irinotecan, 5FU and Leucovorin with or without 
Panitumumab, in Patients with Wild Type RAS who have Resected Hepatic 
Metastases from Colorectal Cancer 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal 
Investigator/Department: 
Nancy Kemeny, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Michael D‘Angelica, MD 
Surgery 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
David Ilson, MD 
David Kelsen, MD 
Eileen O‘Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard B. Saltz, MD 
Zsofia Stadler, MD 
Neil Segal, MD 
Yelena Janjigian, MD 
Andrea Cercek, MD 
Anna Varghese, MD 
James Harding, MD 
Geoffrey Ku, MD 
Andrew Epstein, MD 
Kenneth Yu, MD 
Rona Yaeger, MD 
Armin Shahrokni, MD 
Nitya Raj, MD 
Louise Connell, MD 
Luis Diaz, MD 
Karuna Ganesh, MD, PhD 
Danny Khalil, MD, PhD 
Juan Manuel Schvartzman, MD 
Imane El Dika, MD 
Ping Gu, MD 
Wungki Park, MD 
Steven Maron, MD 
William Jarnagin, MD 
Philip Paty, MD 
Peter Kingham, MD 
Vinod Balachandran, MD 
Mario Lacouture, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Irina Konzelmann, APN 
Janet Cogswell, RN 
Lisa Sarmasti, RN 
Daniel Danila, MD 
Anuja Kriplani, MD 
Louise Ligresti, MD 
Isabel Preeshagul, DO 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Surgery 
Surgery 
Surgery 
Surgery 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 2 of 47 
 
 
 
Rui Wang, MD PhD 
Kristen O‘Hagan, APN 
Geri Arnell, RN 
Medicine 
Nursing 
Nursing 
Stuart Lichtman, MD 
Avni Desai, MD 
Jahan Aghalar, MD 
Jia Li, MD, PhD 
Deaglan McHugh, MD 
Megan Stasi, RN 
Ofer Maimran, RN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Arl yn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Oscar Lahoud, MD 
Irene Kelly, RN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Elizabeth Won, MD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Melanie Albano, NP 
Gloria Wasilewski, RN 
Sherie Mar-Chaim, RN 
Maureen Kennedy, RN 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Marina Shcherba, DO 
Loren Michel, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Catherine Pires, APN 
Jacintha (O‘Flaherty) Ballingall, APN 
Raylene Langish, RN 
Nicole Heinz, RN 
Jessica Marchisotto, RN 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Claudy Aime, NP 
Patricia Gabriel, NP 
Vanessa Grant, RN 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Jaclyn Norris, NP 
Natasha Pinheiro, NP 
Pamela Vaiskauskas , RN 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
David Solit, MD 
Kinh Gian Do, MD 
Marinela Capanu, PhD 
Pathology 
Radiology 
Epidemiology-Biostatistics 
Consenting 
Professional(s)/Department: 
Nancy Kemeny, MD 
Michael D‘Angelica, MD 
Ghassan Abou-Alfa, MD 
Medicine 
Surgery 
Medicine 
David Ilson, MD 
Medicine 
David Kelsen, MD 
Medicine 
Eileen O‘Reilly, MD 
Medicine 
Diane Reidy-Lagunes, MD 
Medicine 
Leonard B. Saltz, MD 
Medicine 
Zsofia Stadler, MD 
Medicine 
Neil Segal, MD 
Medicine 
Yelena Janjigian, MD 
Medicine 
Andrea Cercek, MD 
Medicine 
Anna Varghese, MD 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 3 of 47 
 
 
 
James Harding, MD 
Geoffrey Ku, MD 
Andrew Epstein, MD 
Kenneth Yu, MD 
Rona Yaeger, MD 
Luis Diaz, MD 
Karuna Ganesh, MD, PhD 
Danny Khalil, MD, PhD 
Juan Manuel Schvartzman, MD 
Imane El Dika, MD 
Ping Gu, MD 
Wungki Park, MD 
Armin Shahrokni, MD 
Elizabeth Won, MD 
Sree Chalasani, MD 
Nitya Raj, MD 
Louise Connell, MD 
Steven Maron, MD 
William Jarnagin, MD 
Philip Paty, MD 
Peter Kingham, MD 
Vinod Balachandran, MD 
Claudy Aime, NP 
Patricia Gabriel, NP 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Jaclyn Norris, NP 
Natasha Pinheiro, NP 
Leticia Smith, NP 
Han Xiao, MD 
Afsheen Iqbal, MD 
Daniel Danila, MD 
Anuja Kriplani, MD 
Louise Ligresti, MD 
Isabel Preeshagul, DO 
Rui Wang, MD PhD 
Stuart Lichtman, MD 
Avni Desai, MD 
Jahan Aghalar, MD 
Jia Li, MD, PhD 
Deaglan McHugh, MD 
Arl yn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Oscar Lahoud, MD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Elizabeth Won, MD 
Marina Shcherba, DO 
Loren Michel, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Surgery 
Surgery 
Surgery 
Surgery 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 4 of 47 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
All Protocol Activities 
Basking Ridge 
All Protocol Activities 
Bergen 
All Protocol Activities 
Commack 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Rock ville Centre 
All Protocol Activities 
Westchester 
All Protocol Activities 
Nassau 
All Protocol Activities 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 5 of 47 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 6 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 15 
4.1 
Design ........................................................................................................................... 15 
4.2 
Intervention .................................................................................................................... 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.......................................................................... 16 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 19 
6.1 
Subject Inclusion Criteria ............................................................................................... 19 
6.2 
Subject Exclusion Criteria .............................................................................................. 20 
7.0 
RECRUITMENT PLAN ..................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION..................................................................................... 21 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 22 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION................................................... 24 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 25 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 33 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 33 
14.0 
BIOSTATISTICS ............................................................................................................... 34 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES35 
15.1 
Research Participant Registration .................................................................................. 35 
15.2 
Randomization............................................................................................................... 35 
16.0 
DAT A M ANAGEMENT ISSUES ....................................................................................... 35 
16.1 
Quality Assurance ......................................................................................................... 35 
16.2 
Data and Safety Monitoring ........................................................................................... 36 
17.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................... 36 
17.1 
Privacy .......................................................................................................................... 36 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 36 
17.2.1 
 38 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 40 
18.1 
Research Authorization ................................................................................................. 40 
19.0 
REFERENCES ................................................................................................................. 40 
20.0 
APPENDICES ................................................................................................................... 47 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 6 of 47 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Study Objective 
• 
The primary objective of the study is to determine if panitumumab with hepatic arterial infusion 
(HAI) in combination with systemic chemotherapy can increase the recurrence free survival 
(RFS) for colorectal cancer patients with resected liver metastases. 
Study Population 
• 
Eligible patients (metastatic colorectal cancer with no extra-hepatic disease immediately prior 
to protocol enrollment) who have liver resection and are all-RAS wild type. 
Number of Patients 
• 
78 
Study Design 
• 
Randomized phase II trial 
Therapeutic Intervention 
• 
All patients receive HAI FUDR (0.12 mg/kg/day X kg X pump volume) / pump flow rate and 
Dexamethasone flat dose of 25 mg on days 1. 
• 
All patients receive CPT-11 (150 mg/m2 IV over 30 min to an hour), Leucovorin (400 mg/m2 
IV over 30 min to an hour) and 5FU (1000 mg/m2/day continuous infusion over two days) on 
days 15 and 29 
• 
Randomization to panitumumab 6 mg/kg day 15 and 29 (or no panitumumab) 
• 
Each cycle repeats every 36 days for a total of 6 cycles. 
This phase II study aims to assess the efficacy of panitumumab with HAI in combination with systemic 
chemotherapy in patients with completely resected hepatic metastases from colorectal cancer. The 
protocol includes biological correlative studies. The primary objective of this study is to determine if 
the RFS increases with the addition of concurrent intravenous Panitumumab to HAI plus systemic 
chemotherapy after hepatic resection. This study will 1:1 randomize 78 patients who are all-RAS wild 
type after liver resection to HAI FUDR and dexamethasone with systemic chemotherapy, +/- systemic 
Panitumumab. The primary endpoint is 15 month RFS. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
• 
The primary objective of the study is to determine if panitumumab with HAI in combination with 
systemic chemotherapy can increase the 15 month RFS for colorectal cancer patients with 
resected liver metastases. 
• 
The secondary objectives are (1) to assess toxicity, (2) to determine survival, (3) to analyze 
tumor tissue for predictive biomarkers (such as NRAS, BRAF, PIK3CA, AKT1 and MEK1), and 
correlate with patient progression and survival following therapy. Most patients will have had 
RAS testing performed prior to protocol treatment; RAS will be analyzed at surgery if not 
performed previously. Frozen and paraffin-fixed tissue from the liver metastases will be 
available at surgery to measure these values. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 7 of 47 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
There are almost 150,000 new cases of colorectal cancer each year in the United States. 
Approximately 60% of patients develop hepatic metastases, and 15% are suitable for surgical 
resection. Of those who are able to undergo resection, 5-year survival is approximately 30% to 
50%. About 200 patients each year undergo surgery at MSKCC for treatment of hepatic 
metastases, and approximately 100 undergo resection. Our older single institution experience with 
liver resection documents the efficacy of this aggressive approach with an actuarial two-year 
survival of 75%, but a two-year disease-free survival of only 21.2% in the subset of patients who 
underwent complete resection of colorectal liver metastases. Combined multi-institutional data 
from the registry of hepatic metastases was similar, with two-year actuarial survival and disease- 
free survivals of 65% and 35% respectively. These studies were conducted without standardized 
adjuvant chemotherapy post-surgical resection. Those least likely to be cured by resection of 
hepatic metastases are patients with node-positive primary, disease free interval ≤ 12 months, > 1 
tumor, tumor size ≥ 5 cm, CEA > 200 ng/ml. Giving one point to each risk factor produces a Clinical 
Risk Score (CRS) between 0-5. Those with a risk score of 0 have a 60 percent five-year survival 
and those with a score of 5 have a 14 percent five-year survival. Therefore, we will use CRS to 
stratify patients. 
 
Patients who do not undergo resection do not have favorable outcomes. Scheele et al reported 
no patient surviving 5 years if complete resection was not performed. 
 
3.1 Rationale for Treatment after Hepatic Resection 
3.1.1 Recurrence-Free Survival 
RFS greatly depends on patient characteristics such as used in the Fong and Nordlinger scores, 
and can therefore vary from one study to another. 
In data from our institution and in review of the surgical literature, patients who underwent complete 
resection of hepatic metastases from colorectal cancer were only afforded a 5-year actuarial 
overall survival of 33-50%, with a 5-year disease-free survival of only 22%. Therefore, 
approximately 75% of resected patients will recur, with 50% recurring in the liver and 50% recurring 
elsewhere. Of those patients who do recur, approximately 80% will do so in the first two years. 
Our definition of recurrence will be any lesion growing in the liver or extrahepatic sites that is felt 
by the reference radiologist to be new disease. RFS or disease-free survival (DFS) as seen most 
recently in studies using systemic therapy or no therapy are listed below. 
 
 
 
Publications 
DFS/RFS at 
15 months 
Characteristics 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 8 of 47 
 
 
 
Kornprat 
(Annals of Surgical Oncology; 
Vol. 14, No. 3, 2007) 
35% 
All patients had greater than 4 
metastases; largest median size 4.3 
cm; 69% of patients were 
synchronous 
Choti 
(Annals of Surgery; Vol. 235, 
No. 6, 2002) 
40% 
Patients with ≤ 3 and > 3 metastases 
had a median DFS of 16 vs 8 months; 
Synchronous disease had a median 
DFS of 13 months 
Nordlinger 
(Cancer; Vol. 77, No. 7, 1996) 
40% 
40% of patients were synchronous; 
86% had 1-3 metastases; 12% had > 
4 metastases 
 
3.1.2 
Systemic Chemotherapy 
Perioperative chemotherapy has shown to increase disease free survival. The EORTC 
randomized 364 patients with resectable liver metastases (1-4 metastases) to 6 cycles of FOLFOX4 
pre-surgery and had 6 cycles post versus surgery alone. The endpoint was an improvement in 
disease free survival (DFS) which was not significant when all patients were included (7.3%, 
p=0.058). In eligible patients the DFS increased from 28% to 36% at 3 years with perioperative 
chemotherapy (p=0.041) which increased further to a 9.2% difference (p=0.025) when only resected 
patients were analyzed. Median followup time was 39 months. 
Recurrence after liver resection is a significant problem with nearly 70% of patients developing 
recurrence, and the majority of recurrences occur in the first 2-years post resection. A Canadian 
and European Intergroup (EORTC-NCICTG-GIVO) compared bolus FU/LV to surgery alone in 107 
patients after liver resection and showed no increase in overall survival or DFS. The Fédération 
Francophone de Cancérologie Digestive (FFCD) trial randomized 173 patients after liver resection 
to bolus FU/FA or no further therapy. The end-point of the study was DFS which was 33.5% and 
26.7% at 5 years in the treated and control arms, respectively. After adjusting for negative 
prognostic factors, there was a significant DFS advantage for the chemotherapy group (p=0.028). 
Sixty-nine percent of patients in this study had only one metastasis, and 72% had a 
>12 month time interval from primary to metastases. With a median follow-up of 84.7 months, the 
median survival was 62 and 46 months for the treated and control patients, respectively (p=0.13). 
A meta-analysis of these two studies with a total of 278 patients reported a median PFS of 
27.9 and 18.8 months for chemotherapy versus control groups, respectively (p=0.058) and a median 
survival of 62.2 and 47.3 months, respectively (p=0.95). Patients in this study had very good risk 
factors; 69 % had only 1 metastasis, 66 % had Duke‘s B carcinoma and 67 % had liver recurrence 
documented one year after the primary. In their multivariate analysis, adjuvant chemotherapy was 
independently associated with improved PFS (p=0.026) and overall survival (p=0.046). The number 
of metastases (≥2) was also associated with decreased PFS (p=0.022) and survival (p=0.023). 
A European study randomized 151 patients to bolus/infusional 5FU/LV or FOLFIRI after liver 
resection. With a median follow-up of 42 months, the median DFS was 21.6 and 24.7 months for 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 9 of 47 
 
 
the 5FU/LV and FOLFIRI groups, respectively (p=0.47). On multivariate analysis, adverse factors 
associated with DFS included prior adjuvant chemotherapy for the primary tumor, diagnosis of liver 
metastases ≤ 1 year after the primary cancer, and >1 liver lesion. There are currently no 
randomized trials to support adjuvant FOLFOX after liver resection. A Japanese trial of adjuvant 
FOLFOX started accrual in 2004 and enrolled only 60 patients, since 62 were excluded because of 
extrahepatic disease and 20 refused randomization, demonstrating some of the difficulty doing 
randomized trials in this setting. A newer study is accruing patients to hepatectomy followed by 
FOLFOX versus no further therapy. 
Several retrospective series have shown a benefit for adjuvant treatment after liver resection. 
Parks and colleagues reported on 792 patients who had liver resections between 1991 and 1998. 
Multivariate analysis showed that positive margins (HR=1.59), bilateral liver tumors (HR=1.39) and 
adjuvant chemotherapy (HR=0.75) were independent predictors of outcome. Patients who received 
adjuvant chemotherapy with a higher CRS had increased chances of surviving (1.3-2 times higher) 
compared with those patients who did not receive adjuvant treatment. Wang et al using the Seers-
Medicare data base found 923 patients >65 years of age who had liver metastases. The 5 year 
survival was 22%, which was increased with both systemic and HAI + SYS therapy after resection. 
A retrospective study from Korea compared of 156 patients who were treated after liver resection 
with FOLFOX, FOLFIRI or fluoropyrimidines alone. After median follow-up of 3.7 years, there was 
a non-significant difference among the three adjuvant regimens with respect to DFS (p=0.088). 
[35% (FOLFOX), 25% (FOLFIRI) and 25% (fluoropyrimidines alone).] After adjusting for adverse 
prognostic variables there was a trend towards a greater benefit with FOLFOX (p=0.068). 
In summary, the administration of chemotherapy, with 5FU/LV after resection of liver 
metastases tends to improve prognosis and DFS. Irinotecan added to FU/LV did not improve 
results. Newer studies with post-op FOLFOX or XELOX with or without Cetuximab are ongoing 
by NSABP and European groups. 
3.1.3 
HAI Therapy after Hepatic Resection 
Ackerman has demonstrated that microscopic metastases less than 1mm in size derive their 
blood supply from the portal circulation. As tumors begin to grow they induce the development of 
new vessels. Tumors measuring 1 to 2mm are encircled by new vessels derived from both the 
arterial and portal circulation, which mix freely. Tumors greater than 3mm have a well-developed 
arterial circulation. Metastases that remain after hepatic resection are probably in the range of 2 
to 3mm and are therefore not detectable by the ultrasound scanning technique, which has a 
resolution of 5mm. Presumably, these metastases derive most of the their blood supply from the 
arterial circulation. Therefore, adjuvant chemotherapy to the liver for resected hepatic metastases 
should be given via arterial circulation. 
A number of studies randomized patients after liver resection to HAI plus systemic therapy 
versus no further therapy, or systemic chemotherapy alone. The Eastern Cooperative Oncology 
Group (ECOG) randomized 109 patients to HAI plus systemic versus no further therapy. The arms 
were well matched, and all patients had 1-3 resectable liver metastases. This study achieved its 
primary endpoint of an increase in DFS. The DFS at 4 years was 46% for the HAI group and 25% 
for surgery alone (p=0.04). 
A randomized study at MSKCC compared hepatic arterial infusion (HAI) and systemic therapy 
versus systemic chemotherapy alone. The study revealed a significant increase in hepatic disease-
free survival in those patients who received HAI therapy in addition to systemic. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 10 of 47 
 
 
At 2 years, hepatic progression-free survival was 89% and 37% for the HAI + SYS vs. SYS alone 
groups. Median PFS was 31 and 17 months, respectively. Updated survival analysis reveals a 
median survival of 5.6 years for the HAI and 4.7 years for systemic alone. For patients with a poor 
clinical risk score of 3-5, the 10 year survival was 40% for the HAI + SYS group versus 18% for 
SYS group. 
A study from Greece on 122 patients reported a significant improvement in 5 year DFS, 58% 
versus 34% (p=0.002), and 5 year survival, 73% versus 60% (p=0.05) for adjuvant HAI plus 
systemic chemo-immunotherapy versus systemic alone groups, respectively. A randomized study 
from Germany showed no improvement in DFS. 
Modern chemotherapy such as irinotecan in combination with HAI FUDR/ Dexamethasone 
(Dex) in a phase I/II trial after resection of liver metastases yielded a 5 year survival of 59%. In a 
phase I trial with oxaliplatin + FU/LV added to HAI FUDR/Dex after liver resection, the 4 year 
overall survival was 88%. Alberts and colleagues reported results from the NSABP study of 
systemic capecitabine and oxaliplatin alternating with HAI FUDR after resection of liver 
metastases. The 2 year survival rate was 88% (95% CI 82-98%) with a median follow-up of 4.8 
years. The 2 year overall recurrence was 59.7 %. 
In a retrospective review, House et al evaluated patients who underwent liver resection 
between 2001-2005 and compared 125 patients who were treated with HAI plus modern systemic 
chemotherapy with those who received modern chemotherapy alone. They reported a 
5 year survival of 72% and 52% (p=0.004) for the 2 groups, respectively. In a larger retrospective 
review at MSKCC of over 1,000 patients who underwent liver resection, a multivariate analysis 
demonstrated that one of the most significant factors leading to improved survival was 
postoperative HAI therapy. Those who received HAI therapy after hepatic resection had a median 
survival of 68 months versus 50 months for those who did not (p<0.001). 
In our last four adjuvant studies, the patient population has been changing. Our surgeons are 
resecting patients with more disease. As we accrue patients with worse prognostic factors, the 
recurrence-free survival is decreasing. The table below reflects these characteristics. 
 
Variables 
HAI + 5FU/LV 
(n = 74) 
% 
HAI + CPT-11 
(n = 96) 
% 
HAI + FOLFOX 
(n = 37) 
% 
HAI + FOLFOX or 
FOLFIRI, +/- BEV 
(n = 73) 
% 
# lesions 
(Pathology) 
1 
36 
40 
32 
23 
2-4 
45 
47 
57 
43 
>4 
19 
13 
11 
33 
Lesion Size 
> 5cm 
30 
25 
22 
18 
DFI 
< 12 mos 
77 
74 
62 
79 
Margins 
< 1 mm 
23 
11 
11 
16 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
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Page 11 of 47 
 
 
 
+ Margins 
0 mm 
15 
4 
5 
10 
Post-op CEA 
> 5 ng/ml 
26 
33 
16 
21 
 
Because of the increase in poor patient characteristics, the recurrence-free survival in our most 
recent study with HAI depicted above by the red line appeared to be inferior to previous adjuvant 
studies conducted at MSKCC with HAI (RFS was 59 % at 15 months). This is compared with a RFS 
of approximately 40 % at 15 months from recent studies evaluating systemic therapy (as reflected in 
the chart in section 2.1.1). 
To fairly evaluate our next trial, we feel we should use as historical control a recurrence-free 
survival that reflects both what is in literature and our most recent trial. Therefore an RFS at 15 months 
of 50% (which is an average between the estimates in our study and in the other studies), will be 
considered as an appropriate historical control for the 15 months RFS. 
This year at ASCO the N0147 trial (adjuvant cetuximab after stage III colon resection) was 
presented. Results will show no benefit for patients receiving cetuximab. Our proposed trial is for 
adjuvant therapy after liver resection. This patient population has a much higher rate of recurrence 
(especially outside the liver). Because of the good protection of the liver with HAI therapy, one of the 
common places for recurrence is lung and nodal disease. In my experience, both these areas benefit 
from anti-EGFR therapy. Therefore, we feel the addition of anti-EGFR agents to systemic therapy and 
HAI therapy may improve RFS after liver resection. 
This trial will evaluate HAI therapy with systemic CPT-11+ 5FU/LV plus or minus panitumumab. 
Patients will be stratified by clinical risk score (1-3 vs 3 or greater) and previous chemotherapy 
(oxaliplatin vs irinotecan or no previous therapy). 
3.2 
Panitumumab 
 
Panitumumab is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to the 
human epidermal growth factor receptor (EGFR). EGFR is a member of the ErbB receptors, a grouping 
of four closely related receptor tyrosine kinases, namely EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 
(ErbB-3) and Her 4 (ErbB-4). Panitumumab, a human monoclonal antibody, works 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 12 of 47 
 
 
by selectively binding to the EGFR‘s extracellular domain, thus preventing its activation. Panitumumab 
arrests the cascade of intracellular signals activated by this receptor, thereby inhibiting tumor cell 
proliferation. The clinical efficacy of panitumumab appears to be limited to patients with non-mutated 
(wild type) KRAS tumors. Approximately 65 percent of patients express the non-mutated tumor. 
 
Recent results from Phase II and Phase III clinical trials of metastatic colorectal cancer demonstrate 
that patients with RAS mutations are unlikely to benefit from monoclonal antibodies (Allegra et al, 
2015). Limitation of use: Panitmumab (Vectibix) is not indicated for the treatment of patients with RAS-
mutant mCRC or for whom RAS mutation status is unknown. 
3.2.1 
Phase I/II Efficacy Results 
 
Analyses by KRAS status demonstrated a statistically significant larger panitumumab treatment effect 
on PFS in the wild-type KRAS stratum versus the mutant KRAS stratum (quantitative interaction test 
p-value < 0.0001) (Amado et al, 2008). Within the KRAS wild-type group, a 55% reduction in relative 
risk of disease progression or death was observed between subjects treated with panitumumab 
compared with those who received BSC alone (hazard ratio = 0.45, 95% CI: 0.34, 0.59) (Amado et al, 
2008). In contrast, the hazard ratio for the mutant KRAS analysis set was 0.99 (95% CI: 0.73, 1.36), 
suggesting no meaningful effect of panitumumab treatment on PFS among subjects with mutant KRAS 
tumor type (Amado et al, 2008). 
 
A number of studies showed a significant increase in survival and response rate for anti-EGFR agents. 
A Phase III trial of panitumumab plus best supportive care (BSC) compared with BSC alone showed 
a significant increase in RFS for patients receiving panitumumab (hazard ratio [HR], 0.54; 95% CI, 
0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for 
panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. 
 
A phase III study randomized patients to second-line therapy with FOLFIRI +/- panitumumab. The 
study showed a significant increase in RFS when adding panitumumab to FOLFIRI compared with 
FOLFIRI alone in patients with wild-type KRAS. Median PFS in KRAS wild-type patients was 5.9 
months for the FOLFIRI + panitumumab group and 3.9 months for the FOLFIRI alone group (p = 
0.004); Median overall survival was 14.5 months versus 12.5 months in the FOLFIRI + panitumumab 
and FOLFIRI arms, respectively (p = 0.12). 
The CRYSTAL trial randomized patients either to FOLFIRI alone or FOLFIRI plus cetuximab. 
Response rates were significantly increased by the addition of cetuximab (38.7 % for FOLFIRI alone 
and 46.9 % for cetuximab, FOLFIRI, p= 0.0038). A statistically significant difference in favor of 
cetuximab was seen in RFS (p=0.0167; hazard ratio [HR] estimate 0.68 [95% CI: 0.051-0.934]) for 
wild type KRAS patients. 
Independent analyses have consistently shown a high positive predictive value (range 80% to 100%) 
for lack of objective tumor response associated with mutant KRAS status (Benvenuti et al, 2007; De 
Roock et al, 2007; Di Fiore et al, 2007; Freeman et al, 2008; Liévre et al, 2006). 
Additionally, at the 2011 ASCO meeting, a small randomized comparison showed trends for improved 
DFS and OS with the addition of Cetuximab to FOLFIRI in patients with resected stage III colon cancer 
patients. Trends were seen regardless of KRAS status. 

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The PRIME trial, a randomized phase III study of panitumumab with FOLFOX compared to FOLFOX 
alone as first-line treatment for metastatic colorectal cancer, also showed a significant increase in RFS. 
In the KRAS wild-type patient group, the median PFS was 9.6 months versus 8.0 months for the 
FOLFOX + panitumumab group versus FOLFOX only, respectively (p = 0.02). A prospective- 
retrospective analysis done by Douillard et al on patients treated on the PRIME trial (FOLFOX4- 
panitumumab versus FOLFOX4 alone) found that in using patients without any RAS mutations, the 
PFS with panitumumab-FOLFOX4 versus FOLFOX4 alone was 10.1 versus 7.9 months, respectively 
(p=0.04). There was a slight improvement in PFS when they used all RAS wild type versus KRAS wild 
type (10.1 versus 9.6 months respectively) (Douillard et al.2013), 
 
3.2.2 
Safety of Panitumumab 
 
The below referenced studies reflect the reported adverse events at the time of the last Panitumumab 
Investigator‘s Brochure (Version 7.0, 10 June 2008). Please refer to the current version of the 
Panitumumab Investigator‘s Brochure as well as the updated safety information contained in the 
Investigational New Drug safety letters for further updates. 
Safety analyses from 16 clinical studies in subjects with a variety of solid tumors (n = 1599 receiving 
panitumumab) indicated that panitumumab is generally well tolerated. Among these studies, 11 
enrolled subjects with mCRC (n = 1052 receiving panitumumab as a single agent). In these subjects, 
dermatologic-related toxicities were the most frequently reported adverse events (91% of subjects), 
with most events being mild to moderate. Relatively few subjects (2%) permanently discontinued 
panitumumab due to dermatologic adverse events. Infusion reactions to panitumumab (defined as 
any reported allergic reaction, anaphylactoid reaction, chills, fever, or dyspnea, occurring within 24 
hours of the first dose that were not otherwise designated as either anaphylactoid or allergic reaction) 
were infrequent (3% of subjects; < 1% severe) Panitumumab antigenicity, as measured by enzyme-
linked immunosorbent assay (ELISA) and Biacore assay, was very low and was not associated with 
clinical sequelae. 
3.2.3 Panitumumab Monotherapy Studies 
An integrated analysis of the safety of panitumumab has been conducted for 1052 subjects with mCRC 
receiving panitumumab monotherapy (mCRC Monotherapy Set). Subjects primarily received 
panitumumab doses of 2.5 mg/kg once weekly (15%) or 6.0 mg/kg every 2 weeks (82%). 
Consistent with the published data on subjects treated with EGFr inhibitors (i.e., class/target effect) 
(Perez-Soler and Saltz, 2005), the most commonly reported treatment-related adverse events in 
subjects treated with panitumumab were associated with the skin, including pruritus (52%), acneiform 
dermatitis (51%), erythema (50%), and rash (38%). Most subjects (833 of 1052 subjects, 79%) with 
any dermatologic toxicity had events that were considered to be mild or moderate. Only 3% of subjects 
permanently discontinued panitumumab administration for dermatologic toxicities. Dermatologic 
toxicities typically were observed after initiation of panitumumab, with a median time to first integument 
toxicity (of any severity) of 10 days (95% CI: 8, 11). 
Other common treatment-related adverse events (i.e., subject incidence ≥ 10%) included fatigue 
(15%) and diarrhea (13%). 
Infusion reactions to panitumumab were infrequent even though premedication was not mandated in 
the panitumumab clinical program. Overall, 1% of subjects had an infusion reaction reported by the 

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Approval date: 15-Apr-2019 
Page 14 of 47 
 
 
investigator as an adverse event. Using a definition consistent with the Vectibix USPI (2007), 3% of 
panitumumab-treated subjects had a potential infusion reaction; < 1% of subjects had a potential 
infusion reaction by this definition ≥ grade 3. 
Please refer to the current Panitumumab Investigator‘s Brochure for further details. 
To date, panitumumab has been evaluated in combination with chemotherapy in subjects with CRC, 
NSCLC, and SCCHN. 
In the mCRC setting in combination with IFL (Study 20025409), the incidence of grade 3 or 4 diarrhea 
(58%) was notably higher than that historically expected for this already highly GI-toxic chemotherapy 
regimen, and 1 subject had an episode of grade 4 diarrhea that was also considered serious. Of note, 
panitumumab in combination with the FOLFIRI regimen using the same agents but different 
doses/infusion times was better tolerated with an incidence of grade 3 or 4 diarrhea similar to that 
expected from the literature for this chemotherapy regimen alone (25%) (Andre et al, 1999; Saltz et al, 
2000). These data suggest that the potential for additive toxicities in the gastrointestinal tract exists 
when panitumumab is administered in combination with GI-toxic chemotherapy. 
Acute renal failure has been observed in patients who develop severe diarrhea and dehydration. 
Infusion reactions, including anaphylactic reactions, bronchospasm, and hypotension, have been 
reported in the clinical trials and post-marketing experience (including fatal outcomes). Fatal reactions 
have also been observed in patients with a history of prior hypersensitivity reaction to panitumumab 
including a case of fatal angioedema occurring more than 24 hours following the administration of 
panitumumab. 
3.2.4 Rationale for HAI FUDR + Dex and Systemic Chemotherapy, +/- Panitumumab 
 
In studies analyzing patients with wild-type KRAS, a statistically significant improvement in PFS was 
observed for the panitumumab group. By combining Panitumumab with HAI and systemic treatment, 
we seek to obtain better control of hepatic and extrahepatic progression, thereby enhancing patient 
survival. 
 
This study is based on the hypothesis that the growth and progression of metastatic liver lesions 
may be associated with mutations affecting the epidermal growth factor receptor (EGFR) pathway. 
EGFR is a member of the ErbB receptors, a grouping of four closely related receptor tyrosine kinases, 
namely EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). The clinical efficacy 
of panitumumab appears to be limited to patients with non-mutated (wild type) KRAS tumors. When 
Panitumumab binds to EGFR it competitively inhibits the binding of ligands for EGFR. This results in 
inhibition of cell growth, stimulation of apoptosis, decreased pro-inflammatory cytokine and vascular 
growth factor production. Panitumumab arrests the cascade of intracellular signals activated by this 
receptor, thereby inhibiting tumor cell proliferation. 
 
3.2.5 
Evaluation of Molecular Markers and Tumor Specimens 
Permission from patients entering the study will be obtained for liver biopsy of normal and tumor liver 
tissue at the time of surgery to be sent to Dr. Solit‘s lab at Memorial Sloan Kettering. All tumor samples 
will be reviewed by board certified Gastrointestinal Pathologies for >70% tumor content and for 
histologic verification. For specimens in which less than 70% of the collected tissue comprises 

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Page 15 of 47 
 
 
viable tumor, macrodissection will be performed. Genomic DNA will be obtained by using the DNeasy 
Tissue Kit (Qiagen, Valencia, CA). For studies using the Sequenom platform, mutations are detected 
using the iPLEX assay (Sequenom, Inc., San Diego, CA), which is based on a single-base primer 
extension assay. Briefly, multiplexed PCR and extension primers are designed for a panel of known 
mutations. After PCR and extension reactions, the resulting extension products are analyzed using a 
MALDI-TOF mass spectrometer. Our current sequenom assay is an 8 well assay which detects 
mutations in the KRAS, NRAS, BRAF, PIK3CA, AKT1 and MEK1 genes. This assay has been 
optimized for use with formalin fixed paraffin embedded tissues and validated using a set of 626 
colorectal tumors. Mutations detected by Sequenom are further validated by Sanger sequencing. For 
mutation detection by the Sanger method, intron-based PCR primer sequences are used for exon 
amplification by PCR. PCR products are sequenced using the Applied Biosystems PRISM dye 
terminator cycle sequencing method. For detection of the copy number alterations in PTEN, we will 
use a custom Agilent aCGH array which detects copy number alterations in over 100 genes commonly 
altered in human cancer. For detection of PTEN methylation, we will use a Sequenom-based assay 
which has been validated using a retrospective set of human tumors. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
A total of 78 patients whose liver metastases have been completely resected will be randomized 1:1 
to two arms: patients in Arm A will receive Panitumumab in addition to HAI FUDR/Dexamethasone 
plus systemic CPT-11/5FU/LV, and patients randomized to Arm B will receive HAI FUDR/Dex plus 
systemic CPT-11/5FU/LV alone. Patients in both arms will be treated for a total of 6 cycles (7.5 
months). 
 
Cycle Schema q5 weeks 
Day 1 
Day 15 
Day 29 
Day 36 (Day 1 of next 
cycle) 
Pump Therapy 
FUDR* + 
Dexamethasone (14 
day infusion) 
Systemic ** +/- 
Panitumumab*** 
Systemic ** +/- 
Panitumumab*** 
Pump Therapy 
FUDR + 
Dexamethasone (14 
day infusion) 
Pump Emptied 
Saline‡ 
Pump Emptied 
Saline 
*The following pump dose will be used: 
FUDR 0.12 mg/kg * kg * 30 / pump flow rate 
Dexamethasone flat dose of 25 mg 
** The following systemic doses will be used (at PI’s discretion, lower dose of CPT-11 (150 
mg/m2) can be used if clinically appropriate and can be escalated to 150 mg/m2): 
CPT-11 150 mg/m2 IV over 30 min to an hour 
5FU 1000 mg/m2/day cont. infusion over two days (no bolus FU) 
Leucovorin 400 mg/m2 IV over 30 min to an hour 
***For patients randomized to receive Panitumumab, the dose will be: 6 mg/kg IV, over 60 
minutes. Panitumumab will be given on Days 15 and 29 only. 

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‡ If clinically appropriate, patients will have pump emptied and filled with glycerol instead of 
heparin saline. Glycerol will last for 6 to 8 weeks; within that time, patient does not have to have 
pump filled with heparin and saline. If patients are allergic to heparin, they will receive 
Fondaparinux in the pump instead along with saline. 
4.2 
Intervention 
• 
All patients receive HAI FUDR (0.12 mg/kg/day X kg X pump volume) / pump flow rate and 
Dexamethasone flat dose of 25 mg on days 1. 
• 
All patients receive CPT-11 (150 mg/m2 IV over 30 min to an hour), Leucovorin (400 mg/m2 
IV over 30 min to an hour) and 5FU (1000 mg/m2/day continuous infusion over two days) on 
days 15 and 29 
• 
Randomization to panitumumab 6 mg/kg day 15 and 29 (or no panitumumab) 
• 
Each cycle repeats every 36 days for a total of 6 cycles 
• 
CT C/A/P every 2 cycles during treatment 
4.3 
Correlative Studies 
4.3.1 
Liver Biopsy 
Permission from patients entering the study will be obtained to take normal and tumor liver biopsies 
at the time of surgery. These will be sent to and stored at Dr. David Solit‘s lab at Memorial Sloan 
Kettering, Genitourinary Oncology Service. 
4.3.2 
Planned Experiments 
 
 
We will evaluate the genomic profiles of the tumors in an effort to identify markers of 
sensitivity or resistance to therapy. Primary or liver biopsy tissue will be evaluated for all 
RAS testing in order to determine eligibility for study. We will test the tumor tissue for all 
patients for mutations in the RAS/BRAF pathway, among others using a next-generation 
sequencing platform. Ad dit i onal ly, genomic DNA will be extracted by standard 
techniques and analyzed using MSK-IMPACT (Wagle et al). This assay uses targeted, 
massively parallel sequencing to analyze all exons of over 400 genes selected for their 
known roles in cancer initiation or progression (examples include APC, all RAS, BRAF, 
TP53, NF1, etc.).. Genomic DNA will be subjected to solution-phase hybrid capture using 
the RNA baits, followed by massively parallel sequencing. To exclude germline single 
nucleotide polymorphisms, concurrent analysis of normal tissue DNA will be performed. 
Somatic alterations, including mutations, insertions and deletions, and copy number 
changes, detected by this assay will be correlated with clinical parameters. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
FUDR 
 
5.1.1 
Floxuridine (FUDR) is an antimetabolite that blocks the methylation of deoxyuridylic 
acid interfering with the synthesis of DNA. It is also incorporated into RNA and 
interferes with its function. The drug is metabolized in the liver. 

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5.1.2 
FUDR is commercially available from Roche and Adria Laboratories in 500 
mg/10 cc ampules. It is stable (protected from light) and is a colorless aqueous 
solution. Store at room temperature. 
 
5.1.3 
Toxicities associated with the intrahepatic administration of FUDR include biliary 
sclerosis, hepatic enzyme elevation, gastric ulcers. 
 
5.2 
IRINOTECAN 
 
5.2.1 
Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin that possesses 
greater aqueous solubility, greater in vitro and in vivo activity, and is associated with 
less severe and more predictable toxicity than camptothecin. Both camptothecin and 
CPT-11 are potent inhibitors of topoisomerase I, a nuclear enzyme that plays a critical 
role in DNA replication and transcription. 
 
5.2.2 
CPT-11 will be diluted with 250 ml of 5% Dextrose (D5W ) and infused intravenously 
over 30 min to an hour. Nothing else should be added to the infusate. No other 
diluent is to be used. 
 
5.2.3 
CPT-11 vials must be stored in a cool, dry place, protected from light in a locked 
cabinet accessible only to authorized individuals. CPT-11 is relatively stable against 
heat and light but becomes slightly unstable against light in aqueous solution. It is 
stable for at least three years at room temperature. CPT-11 is stable for at least 24 
hours in glass bottles or plastic bags when mixed with D5W. 
 
5.2.4 
Phase I and II studies of CPT-11 have reported neutropenia and diarrhea as the 
dose-limiting toxicities. It is expected that these toxicities will also be encountered in 
this trial. Other Grade 2-3 toxicities seen in phase I trials include nausea and 
vomiting, anorexia, abdominal cramping, cumulative asthenia, thrombocytopenia, 
renal insufficiency, increase in transaminase level and hair loss. 
5.3 
FLUOROURACIL 
 
5.3.1 
Antimetabolite that will be administered by MSKCC guidelines. 
 
5.3.2 
Toxicity: Nausea, vomiting, stomatitis, diarrhea, dermatitis, alopecia, leukopenia, 
and thrombocytopenia. 
5.4 
LEUCOVORIN CALCIUM (FOLINIC ACID) 
5.4.1 
Leucovorin calcium is a stable reduced formyl derivative and the active form of folic 
acid. 
 
5.4.2 
The only adverse reaction reported for Leucovorin has been rare cases of allergic 
sensitization. 
5.5 
DEXAMETHASONE 
 
5.5.1 
Dexamethasone is an adrenocortical steroid, used for chronic inflammation, 
neoplastic and autoimmune diseases; used in HAI treatment as an agent to prevent 
liver damage. 

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5.5.2 
Common potential side effects include anxiety, mood alteration/lability, 
hyperglycemia, insomnia, peripheral edema, myopathy (with chronic use), acne, and 
hirsutism. 
5.6 
PANITUMUMAB 
5.6.1 
Panitumumab is a recombinant, human IgG2 kappa monoclonal antibody that 
binds specifically to the human Epidermal Growth Factor Receptor (EGFR). When 
Panitumumab binds to EGFR it competitively inhibits the binding of ligands for EGFR. 
This results in inhibition of cell growth, induction of apoptosis, decreased pro- 
inflammatory cytokine and vascular growth factor production. Panitumumab is 
specifically indicated for the treatment of EGFR-expressing, metastatic colorectal 
carcinoma with disease progression on or following fluoropyrimidin e-, oxaliplatin-, and 
irinotecan- containing chemotherapy regimens. For further details and molecule 
characterization, see the Panitumumab Investigator Brochure. The panitumumab 
administered in this study is not a commercially marketed product. Although it is 
expected to be very similar in safety and activity to the commercially marketed drug, it 
is possible that some differences may exist. Because this is not a commercially 
marketed drug, panitumumab can only be administered to patients enrolled in this 
clinical trial and may only be administered under the direction of physicians who are 
investigators in this clinical trial. 
5.6.2 
Panitumumab is supplied as a sterile, colorless, preservative-free solution containing 
20 mg/mL designed for intravenous infusion. Each vial of panitumumab will contain 
10 mL of a sterile, colorless, preservative-free protein solution containing a 20-mg/mL 
solution of panitumumab. The vial will contain approximately 200 mg of 
panitumumab and is for single dose use only. Boxes of panitumumab will contain 12 
vials of panitumumab. Each vial of panitumumab will be labeled in accordance with 
current ICH GCP, FDA and specific national requirements. 
5.6.3 
Panitumumab must be stored at 2-8 °C (36° to 46°F) in a secured area upon receipt. 
Vials are to be stored in the original carton under refrigeration at 2-8 °C (36° to 46°F) 
until time of use. The product should be protected from direct sunlight and should not 
be frozen or shaken excessively. Exposure of the material to excessive temperature 
above or below this range should be avoided. Do not allow panitumumab to freeze 
and do not use if contents freeze in transit or in storage. If vials fall out of specified 
temperature requirement, please contact Amgen for instructions. 
As panitumumab contains no preservative, vials are designed for single use only. 
Any unused portion of panitumumab remaining in the vial must not be used. The 
diluted solution should be used ≤ 6 hours after dilution, if stored at room temperature, 
or ≤ 24 hours after dilution if stored refrigerated at 2° to 8°C (36° to 46°F). 
Records of the actual storage condition during the period of the study should be 
maintained. 
5.6.4 
Preparation 
NOTE: Panitumumab is a protein and should be handled gently to avoid foaming, 
which may lead to denaturation of the protein product. This precaution applies not 
only to panitumumab stored in the vial, but also for diluted panitumumab prepared in 
the IV bag. It is, therefore, essential to avoid medication delivery methods, 
particularly pneumatic tube systems that could potentially lead to excessive shaking 
or vibration that would lead to particulate formation in the protein product. 

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The pharmacist, using aseptic techniques, will prepare panitumumab infusion. The 
dose of panitumumab will be 6 mg/kg and will be based upon the subject‘s baseline 
weight. The dose will not be recalculated unless the weight changes at least + 10% 
from the baseline weight. It is recommended that the calculated amount of 
panitumumab (may be rounded to the nearest tenth milligram [e.g., 456 mg rounded 
to 460 mg or 312 mg rounded to 310 mg]) to be removed from the vials and added to 
a total volume of 100 mL of pyrogen-free 0.9% sodium chloride solution USP. 
The maximum concentration of the diluted solution to be infused should not exceed 
10 mg/mL. 
Doses higher than 1000 mg should be diluted to 150 ml with 0.9% sodium chloride 
injection USP. The diluted solution should be mixed by gentle inversion, do not 
shake. Once diluted, panitumumab should be used ≤ 6 hours after dilution if stored at 
room temperature, or ≤ 24 hours after dilution if stored refrigerated at 2° to 8°C (36° 
to 46°F). The bag should be labeled per site pharmacy standard operating 
procedures and promptly forwarded to the clinic center for infusion. 
No incompatibilities have been observed between panitumumab and sodium chloride 
injection in polyvinyl chloride bags, polyolefin bags, or glass bottles (study specific per 
EU label). 
5.6.5 
Administration 
The total dose may be rounded up or down by no greater than 10 mg. The 
panitumumab dose will be calculated based on the subject‘s actual body weight at 
baseline and will not be re-calculated unless the actual body weight changes by at 
least 10%. It is recommended that panitumumab is diluted in to a total volume of 100 
mL in pyrogen-free 0.9% sodium chloride solution USP/PhEur (normal saline solution, 
supplied by the site). The maximum concentration of the diluted solution to be 
infused should not exceed 10 mg/mL. The volume of normal saline should be 
increased as needed to ensure the maximum concentration of the diluted solution 
does not exceed 10 mg/mL. Panitumumab will be administered IV by an infusion 
pump through a peripheral line or indwelling catheter using a non-pyrogenic, low 
protein binding filter with a 0.2 or 0.22-micron in-line filter infusion set-up over 1 hour 
±15 minutes by a trained healthcare professional. 
If the first infusion is well tolerated (i.e. without any serious infusion-related reactions) 
all subsequent infusions may be administered over 30 ±10 minutes. In the event a 
subject‘s actual weight requires greater than 150 mL volume infusion, panitumumab 
will be administered over 60 minutes ±15 minutes, as tolerated. Doses higher than 
1000mg should be diluted to 150ml in 0.9% sodium chloride solution, USP (saline 
solution) and infused over 60+/- 15 minutes. 
Strict adherence to aseptic technique should be used during panitumumab 
preparation and administration. The bag should be labeled per site pharmacy 
Standard Operating Procedures and promptly forwarded to the clinical research 
center for infusion. 
The effects of overdose of panitumumab are not known. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 

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• 
History of histologically confirmed colorectal adenocarcinoma metastatic to the liver with no 
clinical or radiographic evidence of extrahepatic disease. Confirmation of diagnosis must be 
performed at MSKCC. 
• 
Completely resected hepatic metastases without current evidence of other metastatic 
disease. 
• 
Lab values ≤ 14 days prior to treatment start: 
o WBC > 3.0 K/uL 
o ANC > 1.5 K/uL 
o Platelets > 100,000/uL 
o Creatinine <1.5 mg/dL 
o HGB > 9 gm/dL 
• 
Renal function (≤ 14 days prior to treatment start). 
o Creatinine ≤1.5 mg/dL or creatinine clearance ≥ 50 mL/min calculated by the 
Cockcroft-Gault method as follows: 
o Male creatinine clearance = (140 –age in years) x (weight in Kg) / (serum Cr in mg/dl 
x 72) 
o Female creatinine clearance = (140 – age in years) x (weight in Kg) x 0.85 / (serum 
Cr in mg/dl x 72) (use of creatinine clearance per protocol based on chemotherapy 
regimen) 
• 
Hepatic function, as follows: (≤ 14 days prior to treatment start) 
o Aspartate aminotransferase (AST) (≤ 5 x ULN) 
o Alanine aminotransferase (ALT) (≤ 5 x ULN) 
o Total Bilirubin ≤ 1.5 mg/dl 
• 
Magnesium ≥ lower limit of normal (≤ 48 hours prior to treatment start) 
• 
Calcium ≥ lower limit of normal (≤ 48 hours prior to treatment start) 
• 
Prior chemotherapy is acceptable if last dose given > 3 weeks prior to registration to this 
study. [Note: no chemotherapy to be given after resection of liver lesions prior to treatment 
on this study.] 
• 
Any investigational agent is acceptable if administered ≥ 30 days before registration 
• 
KPS > 60% (ECOG (or Karnofsky) performance status (preferably 0 or 1/≥ 60% for 
Karnofsky) 
• 
Histologically confirmed all-RAS wild type . Paraffin-embedded tumor tissue obtained from 
the primary tumor or metastasis (Prior to 
 
6.2 
Subject Exclusion Criteria 
• 
Patients < 18 years of age. 
• 
Prior radiation to the liver (Prior radiation therapy to the pelvis is acceptable if completed at 
least 4 weeks prior to registration.) 
• 
Active infection, ascites, hepatic encephalopathy. 
• 
Prior treatment with HAI FUDR. 
• 
Patients who have had prior anti-EGFR antibody therapy and who have not responded to this 
treatment will be excluded. However, patients who have responded to prior anti-EGFR 
therapy are eligible. 
• 
Female patients who are pregnant or lactating – or planning to become pregnant within 6 
months after the end of the treatment (female patients of child-bearing potential must have 
negative pregnancy test ≤ 72 hours before registration). 

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• 
If a patient has any serious medical problems which may preclude receiving this type of 
treatment. 
• 
Patients with current evidence of hepatitis A, B, C (ie, active hepatitis) 
• 
Patients with history or known presence of primary CNS tumors, seizures not well-controlled 
with standard medical therapy, or history of stroke will also be excluded. 
• 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Panitumumab. 
• 
Serious or non-healing active wound, ulcer, or bone fracture. 
• 
History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of 
interstitial lung disease on baseline chest CT scan. 
• 
Patients who have a diagnosis of Gilbert‘s disease. 
• 
History of other malignancy, except: 
1. Malignancy treated with curative intent and with no known active disease present for ≥ 3 
years prior to registration and felt to be at low risk for recurrence by the treating physician 
2. Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of 
disease 
3. Adequately treated cervical carcinoma in situ without evidence of disease 
 
7.0 
RECRUITMENT PLAN 
We will make every effort to include women and minorities. Patients will be recruited from medical and 
surgical oncology clinics based on their eligibility criteria. The consenting professional will explain in 
detail the study to the patient and will review the informed consent with the patient. Patients will be 
made aware of the protocol, its specific aims and objectives, and the potential risks and benefits the 
patient may incur. Upon signing the requisite three copies of the informed consent, the patient will be 
registered to Step One of the protocol. This will ―pend‖ the patient to the study, allowing for liver 
tissue procurement at surgery. If the patient remains eligible for study participation after surgery, 
he/she will be registered to Step Two, and then will be randomized to Arm A or Arm B. There will be 
no financial compensation for patients enrolling on this protocol. 
 
8.0 
PRETREATMENT EVALUATION 
Prior to treatment start, patients will undergo the following procedures: 
 
• 
CT Angiogram or liver triphasic to determine arterial structures: any time prior to surgery 
• 
Perfusion flow scan (TcMAA): any time prior to treatment start 
• 
RAS Testing: any time prior to surgery; if not done previously, adequate tissue will be 
obtained at surgery 
• 
CT scan of chest, abdomen*, pelvis: within 6 weeks prior to treatment start 
• 
Surgery, pump placement: within 6 weeks prior to treatment start 
• 
Post-surgery CT chest, abdomen*, pelvis: within 3 weeks prior to treatment start 
• 
EKG: within 3 weeks prior to treatment start 
• 
MediPort placement: any time prior to treatment start 
• 
HX, PE, BP; Ht / Wt: within 2 weeks prior to treatment start 
• 
Pregnancy test (females of child-bearing potential): 72 hours prior to treatment start 
• 
Magnesium and Calcium: within 48 hours prior to treatment start 
• 
KPS, CBC with diff/plts, albumin, LDH, BUN, creatinine, alk phos, SGOT, SGPT, bilirubin, 
CEA, serum electrolytes: within 14 days prior to treatment start. 
* 
MRI may be obtained instead of CT if patient’s disease is not visible on CT 

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IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 22 of 47 
 
 
 
8.1 
Patients will have full resection of liver metastases along with pump placement within 
6 weeks prior to treatment. Surgeons will report whether the resection is R0 or R1 
and whether patients have positive or negative lymph nodes. 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Chemotherapy will be administered on a 5-week cycle basis. Pump therapy with 
FUDR and Dex will be administered on Day 1 of each cycle. The pump will be 
emptied and filled with heparin and normal saline on Days 15 and 29. Systemic 
chemotherapy will be administered on Days 15 and Day 29 of each cycle. Treatment 
recycles on Day 36. 
On Days 15 and 29, patients will receive systemic chemotherapy. Patients on the 
panitumumab arm will receive the drug over a 60 minute infusion first. CPT-11/LV will 
be administered subsequently via a Y-line over a 30 to 60 minute infusion, and 5FU 
will follow by a 48-hour infusion. 
9.2 
For the first cycle, the dose of FUDR will be calculated based on the predetermined 
flow rate provided by the pump manufacturer. Thereafter, doses will be adjusted 
(lowered, if necessary, but never increased) based on actual observed flow rate. The 
pump will be filled with FUDR, Dexamethasone, heparin and saline. 
Dose calculation: 
FUDR:  0.12 mg/kg X kg (patient weight) X pump volume 
pump flow rate 
Dexamethasone: flat dose of 25 mg 
Overweight patients: 
If a patient is 35% above ideal weight, dose of FUDR chemotherapy will be calculated as 
follows: 
To calculate Ideal Body weight (kg): 
Males: 50kg + (2.3 x height in inches above 5 ft) 
(i.e.: for a patient who is 5‘10‖, use 10) 
Females: 45.5 kg + (2.3 x height in inches above 5 ft) 
 
Example: An overweight male is 106 kg and 5‘11‖ 
50kg + (2.3 x 11) = 50kg + 25.3 = 75.3 is the Ideal Body Weight 
To calculate Ideal Average weight (kg): 
Actual weight + Ideal Body Weight 
2 
 
Using the male example from above: 
106 + 75.3 = 181.3 ÷ 2 = 90.65 is the Ideal Average Weight 

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Use the Ideal Average Weight to calculate the FUDR dose in patients who are overweight*. 
 
* If PI feels the patient is an appropriate weight, the ideal average weight equation should not be 
used and patients can have the regular dose calculation of FUDR. 
Heparin: 30,000 units total dose 
Normal saline: quantity sufficient to make total reservoir volume of 30 ml. 
If no dose modification due to toxicity is required, the dosages given above (adjusted for 
changes in weight and pump flow rate) will be repeated on Day 1 of Cycle 2 and all 
subsequent cycles. 
 
Pump Flow Rate: The first total dose of FUDR should be calculated using the precalculated 
flow rate provided by the pump manufacturer. The pump will be filled with FUDR, 
Dexamethasone, heparin and saline. Thereafter, the flow rate should be recalculated each 
cycle. If a significant (> 20%) discrepancy is seen, notify the Principal Investigator. 
To recalculate flow rate, the amount of any residual infusate removed from the pump at the 
end of the 14-day infusion is subtracted from the total pump volume. This result is divided by the 
number of days in the infusion period (usually 14). See example below: 
 
Example: Pump is filled with 30.0 ml infusate on Day 1. At pump emptying on 
Day 15, pump yields 12 ml residual. 
 
Total infusion over the 14-day period was 30 – 12 = 18 ml 
Flow rate = 18 ml ÷ 14 days = 1.3 ml/day 
9.3 
On Days 15 and 29 of each cycle, the pump will be emptied and then filled with 
30,000 units of heparin in normal saline (q.s. 30cc) for 14 days. 
9.4 
Patients must meet all hematologic and blood chemistry criteria outlined in 
Section 6.0 before beginning the first cycle of therapy. For subsequent cycles, 
patients must meet the following criteria: 
WBC 
> 2.5 K/uL 
ANC 
≥ 1.0 K/uL 
Platelet count 
> 75 K/uL 
Creatinine 
< 1.8 mg/dL 
Bilirubin 
< 1.5 mg/dL 
 
If counts are outside these levels on date of schedule treatment, therapy will be 
delayed one to two weeks or at the discretion of the treating physician. 
Parameters for treatment with FUDR via intrahepatic pump are outlined in Section 
11.4.2. 
9.5 
The starting panitumumab dose is 6 mg/kg. The total dose may be rounded up or 
down by no greater than 10 mg. The panitumumab dose will be calculated based on 
the subject‘s actual body weight at baseline and will not be re-calculated unless the 
actual body weight changes by at least 10%. 

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9.6 
All reasonable efforts will be made to adhere to treatment and evaluation schedules, 
however minor infrequent variations to accommodate holidays, transportation issues, 
or patient‘s personal schedule will be permitted if these do not, in the opinion of the 
investigator, constitute a major safety or compliance issue. Such variations, assuming 
they do not occur with unreasonable frequency or regularity, will not be considered 
protocol violations. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Day 1* each 
cycle 
Days of 
systemic 
chemotherapy** 
Q10 weeks 
approximately 
after treatment 
start 
HX, PE, MD or NP visit 
X 
HX, Nurse visit 
X 
Tox assessment 
X 
Weight 
X 
KPS 
X 
CBC, Plts 
X 
X 
BUN, Creat 
X 
X 
Bili, SGOT, SGPT 
X 
X 
Alk phos, LDH 
X 
X 
Electrolytes 
X 
X 
CEA 
X 
X 
Magnesium (for patients randomized to 
Panitumumab arm) 
X 
X 
Calcium 
X 
X 
CT Chest/abdomen/pelvis*** 
X 
* Or within 48 hours prior to Day 1 
* Or within 72 hours prior to Day 15 and Day 29 
*** MRI may be obtained instead of CT if patient’s disease is not visible on CT. Allowances of 
+/-3 weeks will be acceptable. 
 
10.1 
While being treated with protocol therapy, patients will be seen at or prior to the first day of 
each cycle by their medical oncologist. 

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Page 25 of 47 
 
 
 
 
In cases approved by the Principal Investigator, patients randomized to Arm B (no panitumumab) 
can see local oncologists for systemic treatments. 
10.2 Patients will be assessed for adverse events prior to administration of systemic chemotherapy, 
panitumumab, or HAI. 
 
10.3 Patients will have an end of study assessment for toxicity. 
11.0 
TOXICITIES/SIDE EFFECTS 
All toxicities will be rated as per the NCI Common Toxicity Criteria, with the exception of skin or 
nail related toxicities, which will be graded using CTC version 3.0 with modifications (see 
appendix B). Hepatic enzyme toxicities will also be captured according to the schema on page 
30 as well (see FUDR Dose Modifications and Table I). 
11.1 
Toxicity Related to Chemotherapy 
11.1.1 
FUDR: gastritis, gastroduodenal ulcers, chemical hepatitis, sclerosing cholangitis 
with jaundice, pruritus, diarrhea. 
11.1.2 
Dexamethasone: sodium retention, fluid retention, hypertension, development of 
cushingoid state, secondary adrenocortical and pituitary hypo-responsiveness, 
decreased carbohydrate tolerance, manifestations of latent diabetes. 
 
11.1.3 
Systemic Chemotherapy (CPT-11, 5FU/LV): diarrhea, myelosuppression, nausea, 
vomiting, stomatitis, neurotoxicity; neutropenia, thrombocytopenia, cumulative 
asthenia (CPT-11). 
11.2 
Toxicity Related to Panitumumab 
Toxicities will be recorded as adverse events on the Adverse Event case report form and 
must be graded using The National Cancer Institute‘s Common Toxicity Criteria (CTC) 
version 4.0. 
Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe 
(NCI-CTC grade 3 and higher) in 12% of patients receiving Panitumumab monotherapy. The 
clinical symptoms include, but are not limited to, dermatitis acneiform, pruritus, erythema, 
rash, skin exfoliation, paronychia, dry skin, and skin fissures. In some cases, it may cause 
infected sores requiring medical and/or surgical treatment, or cause severe skin infections 
that could be fatal. Subsequent to the development of severe dermatologic toxicities, 
infectious complications, including sepsis, septic death, and abscesses requiring incisions 
and drainage were reported. 
Infusion Reactions: Severe infusion reactions included anaphylactic reactions, 
bronchospasm, and hypotension, which occurred in approximately 1% of patients. 
Pulmonary fibrosis: In patients enrolled in clinical studies of Panitumumab, pulmonary 
fibrosis occurred in less than 1% (2/1467). Patients with a history of interstitial pneumonitis, 
pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded 
from clinical studies. Therefore, the probability of risk in a general population is uncertain. 

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Approval date: 15-Apr-2019 
Page 26 of 47 
 
 
Electrolyte Depletion/Monitoring: In patients enrolled in a clinical trial, 2% experienced 
hypomagnesemia (NCI-CTC grade 3 or 4), which required oral or IV electrolyte repletion. 
Hypomagnesemia occurred 6 weeks or longer after the initiation of Panitumumab. In some 
patients, both hypomagnesemia and hypocalcemia occurred. 
Photosensitivity: Exposure to sunlight can worsen dermatologic toxicity. It is recommended 
that patients wear sunscreen and hats and limit sun exposure while receiving Panitumumab. 
Dermatologic, Mucosal, and Ocular Toxicity: Ocular toxicities occurred in 15% of patients 
and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased 
lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were 
reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The 
incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders were 
observed in 9% of patients. 
Other adverse effects include: nausea, vomiting, mouth irritation, fever, headache, cough, 
shortness of breath, diarrhea (sometimes causing severe dehydration), abdominal pain, 
constipation, swelling of the hands and feet, and fatigue/weakness, hair loss, a decrease in 
magnesium, calcium and potassium levels in the blood, nose dryness or bleeding, increased 
growth of eyelashes and excessive hair growth. 
The following adverse are rare but serious: blood clots in legs and lungs, stroke, acute 
kidney failure, lung complications, heart attack, shortness of breath, and septic death. 
Pregnancy: Adequate contraception in both males and females must be used while receiving 
Panitumumab and for 6 months after the last dose of Panitumumab therapy. 
Pre-medication for Panitumumab: Panitumumab specific pre-medication is not required for 
routine panitumumab infusions. If, during or after any infusion, a reaction occurs, pre- 
medication may be used for subsequent panitumumab infusions (e.g., 
acetaminophen/paracetemol and/or an H1 blocker, e.g., diphenhydramine). 
Interruption of Panitumumab Infusion: Subjects who experience any serious infusion reaction 
during panitumumab administration will have the infusion stopped. Continuation of dosing 
will be based on the severity and resolution of the event. Suspected infusion reactions 
should be reported as an adverse event. All subjects who experience such an event will be 
followed for safety. 
Pre-emptive Management of Panitumumab Associated Skin Toxicities: Clinical trial data 
indicate that integument and eye toxicities associated with panitumumab therapy are 
consistent with what has been observed for other EGFr inhibitors. Most integument- and eye- 
related toxicity events were mild or moderate in intensity. 
Pre-emptive treatment for skin toxicity includes (recommended): 
• 
Sunscreen SPF>30 when going outside 
• 
Topical steroid (0.05% alclometasone cream) twice daily on face, chest and upper back 
• 
Prophylactic use of alcohol-free emollient creams or ointments to combat dryness 
• 
Doxycycline 100mg twice daily or Minocycline 100 mg tabs 1 tab daily 
The optimal duration of pre-emptive skin treatment is 6 weeks from panitumumab initiation. 
Subjects who subsequently experience skin toxicities ≥ grade 2 may discontinue the pre- 

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Page 27 of 47 
 
 
emptive skin treatment, and their symptoms should be managed appropriately according to 
the institution‘s standard procedures. 
11.3 
Toxicity Related to the Pump and Catheters 
 
Infection, hepatic artery thrombosis, pump malfunction, catheter occlusion, intra-abdominal 
bleed. The rate of pump failure is less than 1 percent. Patients will receive standard systemic 
therapy if the pump is unusable. 
11.4 
Dose Modifications 
 
11.4.1 Irinotecan, 5FU, Leucovorin Dose Modifications 
• 
If patients have delays in treatments due to hospitalization or other reasons, they should 
proceed with treatment as scheduled. 
• 
Patients who experience grade 3 or 4 toxicity may continue treatment at a lower dosage 
level once toxicities have fully resolved (refer to tables below). Toxicity should resolve 
within two weeks. If the physician feels the patient cannot tolerate systemic therapy, they 
can hold therapy for one week. If the patient has elevated liver function tests in the PI‘s 
discretion, systemic therapy can be held and Decadron can be placed in the pump with 
heparin saline. 
• 
Guidelines for re-starting medication are listed in table below: 
Dose Reduction for Hematologic Toxicities: Irinotecan + 5FU + LV (mg/m2/day) 
 
Grade 
Toxicity 
Irinotecan 
5FU Infusion 
Leucovorin 
3 
Neutropenia 
20% decrease 
20% decrease 
20% decrease 
4 
Neutropenia 
30% decrease 
30% decrease 
30% decrease 
3 
Febrile neutropeniaa 
20% decrease 
20% decrease 
20% decrease 
4 
Febrile neutropeniaa 
30% decrease 
30% decrease 
30% decrease 
3 
Thrombocytopenia 
20% decrease 
20% decrease 
20% decrease 
4 
Thrombocytopenia 
30% decrease 
30% decrease 
30% decrease 
aFebrile Neutropenia = ANC < 1.0 x 109/L with fever > 38.5◦ C 
Dose Reductions for Non-Hematologic Toxicities: Irinotecan + 5FU + LV (mg/m2/day) 
 
Grade 
Toxicity 
Irinotecan 
5FU Infusion 
Leucovorin 
3 
Nausea and/or vomiting 
despite premedication with an 
effective antiemetic therapy 
20% decrease 
20% 
decrease 
20% 
decrease 
3 
Diarrhea despite 
premedication with an 
effective antidiarrheal therapy 
20% decrease 
20% 
decrease 
20% 
decrease 
4 
Nausea and/or vomiting 
despite premedication with an 
effective antiemetic therapy 
30% decrease 
30% 
decrease 
30% 
decrease 
4 
Diarrhea despite 
premedication with an 
effective antidiarrheal therapy 
30% decrease 
30% 
decrease 
30% 
decrease 

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3 
Stomatitis 
No dose reduction 
20% 
decrease 
20% 
decrease 
4 
Stomatitis 
No dose reduction 
30% 
decrease 
30% 
decrease 
> 2 
Cardiac toxicity 
No dose reduction 
Stop 
treatment 
Stop 
treatment 
3 or 4 
Hand/Foot Skin reaction 
No dose reduction 
20% 
decrease 
20% 
decrease 
 
11.4.2 
FUDR Dose Modifications 
―Reference value‖ is defined as the value obtained on the first day of the most recent 
FUDR dose. 
 
To determine if a FUDR dose modification is necessary, compare reference value to the 
either the value obtained on the day pump was emptied (e.g. day 14) or the value 
obtained on the day of planned pump filling (e.g. day 28), whichever is higher. 
Percentages listed under ―FUDR Dose‖ refer to percentage of last dose of FUDR 
administered. 
TABLE I: FUDR DOSE MODIFICATION SCHEMA: 
 
Reference Value* 
% FUDR dose 
SGOT (at pump emptying or 
day of planned retreatment, 
whichever is higher) 
0 to < 2 x reference value 
100% 
2 to < 3 x reference value 
80% 
3 to < 4 x reference value 
50% 
> 4 x reference value 
HoldA 
ALK PHOS (at pump 
emptying or day of planned 
retreatment, whichever is 
higher) 
0 to < 1.2 x reference value 
100% 
1.2 to < 1.5 x reference value 
50% 
> 1.5 x reference value 
HoldB 
TOT BILI (at pump emptying 
or day of planned retreatment, 
whichever is higher) 
0 to < 1.2 x reference value 
100% 
1.2 to < 1.5 x reference value 
50% 
> 1.5 x reference value 
HoldC 
If SGOT > 4X reference value, alkaline phosphatase > 1.5X reference value, total bilirubin > 
1.5X reference value, then treatment will be held and will not be reinstituted until values come 
down to more normal levels, as indicated in section ―Recommencing FUDR Treatment After 
Hold‖. 
ASGOT elevation, BAlkaline Phosphatase elevation, CTotal bilirubin elevation 
* If patient’s Alkaline Phosphatase or T Bili shows a continual rise from Day 1 of treatment, then 
the Day 1 value will be used as the reference value for that patient when determining whether to 
hold treatment, and time of re-treatment after hold. 
RECOMMENCING TREATMENT AFTER HOLD 
 
Reason for treatment delay 
Chemotherapy resumed 
when value has returned to: 
% FUDR dose 

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SGOT elevation 
3 X reference value 
25% of last dose 
Alkaline Phosphatase 
elevation 
1.2 X reference value 
25% of last dose 
Total bilirubin elevation 
1.2 X reference value 
25% of last dose 
• 
If patient develops a total bilirubin > 3.0 mg/dl, the pump should be emptied and Dex 25 mg 
plus heparin 30,000 u and saline 30 cc placed in the pump q 14 days. Once there is no 
longer evidence of toxicity, Dex dose should be tapered in increments of 5 mg every 14 days. 
Tapering will continue unless enzymes increase. FUDR should be permanently discontinued 
unless there is evidence of disease progression (increasing CEA, worsening CT scan, 
worsening clinical status) AND bilirubin has returned to < 1.5 mg/dl. In this case, FUDR can 
be restarted as follows: Use 25% of the last FUDR dose given with Dex, heparin and saline 
in the pump for 7 days. Pump should be emptied after 7 days, and patients given a 3-week 
rest period. This treatment and treatment schedule should continue as long as bilirubin 
remains < 1.5 mg/dl and liver enzyme values do not increase. 
• 
If a patient presents with abdominal pain, HAI FUDR should not be given and, if the pump is 
already filled with FUDR, then the FUDR should be emptied immediately. Epigastric pain 
unresponsive to oral H2 blocker use is suggestive of gastroduodenal irritation or ulcer. 
Severe pain should prompt workup with an upper gastrointestinal endoscopy. Serum 
amylase should be checked along with the routine blood (screening profile, creatinine, and 
CBC) in patients with abdominal pain. If an ulcer or gastroduodenitis is documented, therapy 
should be held for one month to allow healing. If abdominal pain is severe, the pump should 
be emptied of FUDR until results of workup are available. 
 
If patients have delays in FUDR treatment, the cycle numbering will go as follows: 
 
• 
2 systemic treatments = 1 cycle 
• 
If patients return for FUDR and the liver function tests (SGOT, alkaline phosphatase and/or 
bilirubin) are too elevated (as in table 1) patients will wait one to two weeks. If they are still 
elevated, patients will start the next cycle with systemic and not with FUDR. During that cycle 
if the liver function tests come down enough (according to Table Recommencing Treatment 
After Hold), patients will be able to receive FUDR again at a lower dose. In that case they 
can receive the FUDR, then two weeks later they will receive systemic once afterwards and 
then move onto the next cycle. 
• 
If liver function tests are too high for a patient to receive FUDR, they may continue on study 
treatment with systemic chemotherapy for a total of 12 systemic treatments. In this case, the 
patient will be treated with systemic treatment on Day 1 and on Day 15, then move onto the 
next cycle starting with Day 1. 
11.4.3 
Panitumumab Dose Modifications 

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• 
Infusion-Related Adverse Events: If a patient experiences an infusion-associated adverse 
event, premedication will be given for the next infusion; however, the infusion time may not 
be decreased. If the next infusion is well-tolerated with premedication, the subsequent 
infusion time may then be decreased by 30 + 10 minutes as long as the patient continues to 
be premedicated. If a patient experiences an infusion-associated adverse event with the 60- 
minute infusion, all subsequent doses should be given over 90 + 15 minutes. Similarly, if a 
patient experiences an infusion-associated adverse event with the 30-minute infusion, all 
subsequent doses should be given over 60 + 10 minutes. 
 
• 
For subjects who experience toxicities while on study, one or more doses of panitumumab 
may need to be withheld, reduced, or delayed. On resolution of toxicity, a limited number of 
attempts to re-escalate reduced panitumumab doses will be allowed. Dose escalations 
above 6 mg/kg starting dose are not allowed. Panitumumab dose reductions are listed in 
Table 1. 
Symptomatic skin- or nail-related toxicity felt to be intolerable by the subject can have a reduction in 
dose according to Table 1. 
 
Table 1. Panitumumab Dose Reductions 
 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
Percentage (%) 
100 
80 
60 
mg/kg 
6 
4.8 
3.6 
 
11.4.4 
Criteria for Withholding a Dose of Panitumumab 
Skin- or nail-related toxicities: 
• 
Skin or nail infection requiring IV antibiotic or IV antifungal treatment 
• 
Any skin- or nail-related serious adverse event 
Non-skin- or nail-related toxicities: 
Any grade 3 or 4 toxicity with the following exceptions: 
• 
Panitumumab will only be withheld for symptomatic hypomagnesemia and/or hypocalcemia 
that persists despite aggressive magnesium and/or calcium replacement 
• 
Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that 
persists despite maximum supportive care 
• 
Panitumumab will only be withheld for grade ≥ 3 anemia or grade 4 thrombocytopenia that 
cannot be managed by transfusion(s) or cytokine therapy 
11.4.5 Criteria for Re-treatment with Panitumumab 
Skin- or nail-related toxicities: 
Panitumumab administration may recommence once: 
• 
The adverse event has improved to ≤ Grade 2 or returned to baseline, or; 
• 
The subject has recovered to the point where symptomatic skin- or nail-related toxicity is 
felt to be tolerable; or, 

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• 
Systemic steroids are no longer required, or 
• 
IV antibiotic or IV antifungal treatment is no longer required 
Non-skin- or nail-related toxicities: 
Panitumumab administration may recommence once the adverse event has improved to ≤ Grade 
1 or returned to baseline. 
11.4.6 Dose Modification Schedule 
• 
Subjects should be assessed for toxicity before each dose. Dose modification should be 
performed according to the schedule described below. 
• 
Subjects who develop a toxicity that does not meet the criteria for withholding a dose of 
panitumumab (Section 11.4.4) should continue to receive panitumumab and their 
symptoms should be treated. 
• 
Panitumumab-related toxicity will be considered resolved if it improves to a degree that 
allows for re-treatment with panitumumab (Section 11.4.5). 
For subjects who experience a toxicity that meets the criteria for withholding a dose of 
panitumumab: 
• 
Subjects receiving either 100% or 80% of the starting dose of panitumumab are allowed 
to have up to 2 subsequent doses withheld for toxicity. However a second dose should 
only be withheld if the toxicity has not resolved by the time that the subsequent dose is 
due. 
• 
Subjects treated at the 100% dose level whose toxicity resolves after 1 dose of 
panitumumab is withheld should be re-started at the 100% dose level (recommended but 
not required, reduction to the 80% dose is allowed as an alternative to re-challenge with 
the 100% dose). 
• 
If toxicity recurs, subjects treated at the 100% dose or 80% dose should be re-started at 
the 80% dose or 60% dose, respectively, when the toxicity resolves after withholding 1 or 
2 doses of panitumumab. 
• 
Subjects treated at the 100% dose level whose toxicity resolves only after 2 subsequent 
doses of panitumumab are withheld should be re-started at the 80% dose level. 
• 
Subjects treated at the 80% dose level whose toxicity resolves after withholding 1 or 2 
doses of panitumumab should be re-started at the 60% dose level. 
• 
Subjects who experience toxicity at the 60% dose level will not be re-treated with 
panitumumab. 
It is recommended that panitumumab doses will be escalated in subjects whose toxicity resolves 
to the degree that meets the criteria for re-starting a dose of panitumumab (Section 11.4.5). 
Dose escalations are recommended but not required. Dose escalations should occur in the 
following manner: 
• 
Subjects treated at the 80% dose level whose toxicity does not recur should receive the 
100% dose level at the next dose unless a previous attempt to re-escalate to the 100% 
dose level was not tolerated (re-initiation of the 80% dose is allowed as an alternative to 
dose escalation). 
• 
Subjects treated at the 60% dose level whose toxicity does not recur should receive the 
80% dose at the next dose unless a previous attempt to re-escalate to the 80% dose 
level was not tolerated (re-initiation of the 60% dose is allowed as an alternative to dose 
escalation). 

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• 
Subjects who miss more than 2 consecutive scheduled doses due to toxicity or are 
unable to receive a dose of panitumumab within 6 weeks of having received their 
previous dose of panitumumab due to toxicity will be considered unable to tolerate 
panitumumab and will not be retreated with panitumumab. 
• 
If a subject demonstrates a clinical benefit with a documented response of stable 
disease, partial response or complete response and there are reasons that the dose 
modification rules above cannot be implemented, the investigator should contact and 
discuss these reasons with Amgen. The investigator must obtain written agreement from 
Amgen before any changes in the dose modification rules can be implemented. 
11.4.7 Panitumumab Delayed- or Missed-Doses 
• 
Delays of panitumumab administration beyond 6 weeks from the previous dose of 
panitumumab are not allowed. 
• 
Reasons to withhold a dose of panitumumab are described in Section 11.4.4. More than 
2 consecutively missed doses (i.e. 4 weeks without panitumumab) are not allowed. 
Missed panitumumab doses will not be made up. 
11.4.8 Discontinuation of Panitumumab 
Panitumumab will be administered until subjects develop disease progression or are unable 
to tolerate panitumumab. 
11.4.9 Guidelines for Diarrhea Management 
• 
Symptoms of diarrhea and/or abdominal cramping may occur at any time and should be 
managed according to standard institutional practice. 
• 
Subjects should also be instructed to notify the investigator or nurse for the occurrence of 
bloody or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, 
inability to control diarrhea (return to baseline) within 24 hours. Subjects with diarrhea 
should be evaluated frequently by a nurse or physician until resolution of diarrhea. 
• 
Changes in electrolytes, even without BUN/urea and/or creatinine elevation, may reflect 
early physiologic consequences of treatment-induced gastrointestinal toxicity. Subjects 
with clinically significant electrolyte changes should be evaluated for dehydration and 
receive aggressive fluid and electrolyte replacement, if indicated. 
11.4.10 Electrolyte Management 
• 
Subjects should be evaluated as outlined in Section 11 and managed as per local 
medical practice. If hypomagnesemia is present, replacement should be managed with 
either oral or parental replacement, or both, according to institutional practice and to the 
degree of hypomagnesemia present. It is recommended that subject‘s serum 
magnesium level should be maintained within the normal range during study treatment. 
• 
It is important to assess and manage serum potassium and calcium (adjusted for 
albumin) in subjects who have concomitant hypomagnesemia. Subject‘s serum 
potassium and calcium parameters are recommended to be maintained, as per local 
medical practice, within the normal ranges during study treatment. 
11.4.11 Proscribed Therapy During Study Period 
• 
Subjects must be withdrawn from the study if they receive any other investigational 
agents, anti-EGFr targeting agents other than panitumumab, experimental or approved 
anti-tumor therapies (e.g., bevacizumab), chemotherapy or radiotherapy (with the 
exception of use for pain control). 

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• 
Subjects should not schedule any elective surgeries (excluding central venous catheter 
placement) during their participation in the study, or until 7 days after their last 
administration of study treatment. If a subject undergoes any unexpected surgery during 
the course of the study, that subject must discontinue all study treatment immediately, 
and the sponsor should be notified as soon as possible. A subject may be allowed to 
resume study treatment after each surgical case is reviewed by the sponsor study team 
in conjunction with the investigator to determine the appropriateness of treatment 
resumption. 
• 
Patients will be prophylactically administered minocycline and a topical steroid. If toxicity 
cannot be managed, Dr. Mario Lacouture will see the patients for evaluation. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Assessments of tumor response to treatment while on treatment are not appropriate 
since tumor is resected. 
12.2 
Patients will receive 3 CT scans of the chest, abdomen and pelvis during treatment 
(every 2 cycles). Scans will be assessed closely for disease status and possible 
recurrence. Our definition of recurrence will be any lesion growing in the liver or 
extrahepatic sites that is felt by the reference radiologist to be new disease. 
 
12.3 
CT scan of the chest, abdomen and pelvis and CEA every 12 weeks for the first 2 
years after the completion of treatment. A CT scan will coincide with 15 months after 
treatment start, which will allow us to determine 15 month RFS. 
 
 
Baseline CT scan 
0 weeks 
CT # 2 
10 weeks after treatment start 
CT # 3 
20 weeks 
CT # 4 
30 weeks 
End treatment 
CT # 5 
42 weeks 
CT # 6 
54 weeks 
CT # 7 
66 weeks (+/- 3 weeks) 
 
12.3 
Colonoscopy within the first 2 years after completion of treatment; this test will enable 
us to determine whether the patients are NED. 
 
12.4 
CT scan of the chest, abdomen and pelvis and CEA every 4 months between 2 and 4 
years after completion of the treatment. CT scan of the chest, abdomen and pelvis 
and CEA every 6 months for five years, and yearly thereafter until patient expires. 
The follow-up scans are necessary to determine the RFS of this patient population. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1 
Development of clear-cut evidence of recurrent colorectal cancer in the liver 
compared to the baseline postoperative CT scan, via clinical exam or imaging 
studies. These patients will still be followed for recurrence and survival. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 34 of 47 
 
 
13.2 
Development of clear-cut evidence of extrahepatic recurrence via clinical exam or 
imaging studies. These patients will still be followed for recurrence and survival. 
13.3 
Patient is unable to resume hepatic arterial FUDR due to hepatic toxicity. These 
patients will still be followed for recurrence and survival. 
 
13.4 
Unacceptable toxicity that does not respond to the dosage modification. Even if 
patients cannot tolerate treatment they will be continued to be followed for survival 
and recurrence. 
 
13.5 
Patient elects to discontinue treatment. 
 
13.6 
Changes in a patient‘s condition which render the patient unacceptable for further 
treatment in the judgment of the investigator. These patients will still be followed for 
recurrence and survival. 
14.0 
BIOSTATISTICS 
 
This study will 1:1 randomize 78 patients to two treatment arms: HAI FUDR and 
dexamethasone with systemic chemotherapy, +/- systemic Panitumumab. Randomization 
procedures will be discussed in section 15.2. 
The primary endpoint is 15 month recurrence free survival (RFS). Based on an exact binomial 
single stage design, with 39 patients in each arm we are able to differentiate between 
unacceptable 15 month RFS of 50% and acceptable 15 month RFS of 70% with type I error 
(falsely accepting a non-promising therapy) and II error (falsely rejecting a promising therapy) 
rates of 10 % each. For a particular arm, if 24 or more patients are alive and disease free at 15 
months the regimen in that arm will be considered worthy of further investigation. We will use the 
―pick the winner‖ format based on the randomized phase II clinical trials approach proposed by 
Simon et al. (1985) to differentiate between 15 month RFS of 50% and 70%. The pick the winner 
role only occurs if both regimens are efficacious. If the number of patients who are disease free 
and alive at 15 months in one arm is at least 24 and it exceeds by at least 3 patients the number 
of alive and disease free patients at 15 months in the other arm, then the arm with the higher 15 
months RFS would be declared the winner. If neither arm had at least 24 patients alive and 
disease free at 15 months, the regimens in both arms would be considered unworthy of further 
evaluation. The probability of selecting the better regimen is 85%; the probability that no regimen 
is selected is approximately 9%, while the probability of a tie is 6 % (Simon R, Wittes RE, Ellenberg 
SS. (1985). Randomized phase II clinical trials. Cancer Treat Rep 69, 1375-1381.) 
RFS will also be estimated using the Kaplan Meier method. As secondary endpoint, overall 
survival will be estimated by the Kaplan Meier method. Associations between biomarkers 
and RFS and overall survival will be assessed using the log-rank test. In each arm, safety and 
tolerability will be summarized using descriptive statistics. 
The prevalence of RAS mutations is about 40%; therefore we would have to approach about 
120 patients in order to accrue 78 patients. On average, we see about 40 eligible patients per 
year; therefore we would need three years to reach 120. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 35 of 47 
 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
 
15.2 
Randomization 
 
Patients from the GI medical oncology clinic at MSKCC who meet the inclusion criteria are eligible 
for enrollment and randomization. We plan to consecutively recruit 78 patients. Patients will be 
randomized with a 1:1 ratio to the HAI FUDR + systemic chemotherapy, + Panitumumab arm or the 
HAI FUDR + systemic chemotherapy, - Panitumumab arm. After eligibility is established and 
immediately after consent is obtained, patients will be registered in the Protocol Participant 
Registration (PPR) system and randomized using the Clinical Research Database (CRDB), by calling 
the MSKCC PPR Office at 646-735-8000 between the hours of 8:30 am and 5:30 pm, Monday – 
Friday. Two stratification variables will be used: prior chemotherapy status and clinical risk score (0-2 
vs. 3 or more) [See Appendix A, Fong Score]. Patients will be randomized after surgery and 
immediately prior to study enrollment. 
16.0 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. 
The data collected for this study will be entered into a secure database. Source documentation will 
be available to support the computerized patient record. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 36 of 47 
 
 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study team, at 
a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled ―Policy of the National Cancer Institute for Data and 
Safety 
Monitoring 
of 
Clinical 
Trials‖ 
which  
can 
be 
 found 
 at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
 The DSM Plans  at 
MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/indexx.htm. 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e. g. protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center‘s 
Research Council and Institution Review Board. 
During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g. NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
17.1 
Privacy 
 
MSKCC‘s Privacy Office may allow the use and disclosure of protected health information pursuant to 
a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A Research 
Authorization form must be completed by the Principal Investigator and approved by the IRB and 
Privacy Board. 
 
17.1.1 Study Costs 
 
The cost of the study drug, Panitumumab, will be supplied by Amgen. All other costs will be billed to 
the patient. 
 
17.2 
Serious Adverse Event (SAE) Reporting 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 37 of 47 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
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 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 30- 
days after the participant‘s last investigational treatment or intervention. Any events that occur after 
the 30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‗Reporting of Serious Adverse 
Events‘, the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB 
requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE 
Office as follows: 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other reports 
should be sent to saemskind@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‘s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 38 of 47 
 
 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI‘s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the SAE staff through the IND Office. 
17.2.1 Reporting of Serious Treatment Emergent Adverse Events to Amgen 
Investigators are required to report to Amgen Drug Safety ANY serious treatment emergent 
adverse event (STEAE) as soon as possible. 
A STEAE is any sign, symptom or medical condition that emerges during Panitumumab 
treatment or during a post-treatment follow-up period that (1) was not present at the start of 
Panitumumab treatment and is not a chronic condition that is part of the patient‘s medical history 
OR (2) was present at the start of Panitumumab treatment or as part of the patient‘s medical 
history but worsened in severity and/or frequency during therapy, AND that meets any of the 
following regulatory serious criteria: 
• 
Is fatal 
• 
Is life threatening (places the subject at immediate risk of death) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Other significant medical hazard 
A hospitalization meeting the regulatory definition for ―serious‖ is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any adverse event 
that does not meet one of the definitions of serious (e.g., emergency room visit, outpatient surgery, 
or requires urgent investigation) may be considered by the investigator to meet the 
―other significant medical hazard‖ criterion for classification as a serious adverse event. 
Examples include allergic bronchospasm, convulsions, and blood dyscrasias. 
Hospitalization for the performing of protocol-required procedures or administration of study 
treatment is not classified as an SAE. 
Serious adverse events will be collected and recorded at least throughout the study period, 
beginning with the signing of the informed consent through 30 days after the end of the treatment 
phase or through the safety follow-up visit, whichever is longer. 
The investigator should notify the Sponsor of all serious adverse events occurring at the site(s) 
in accordance with FDA Regulations. The Sponsor will medically review all SAEs. The Sponsor 
will ensure the notification of the appropriate Ethics Committees/Institutional Review Boards, of all 
serious adverse events occurring at the site(s) in accordance with FDA regulations. 
The study sponsor is responsible for providing all suspected serious adverse drug reactions 
(SADRs) related or possibly related to panitumumab to Amgen within 1 month of the event. It is 
possible that Amgen may request follow-up information from the sponsor. 
All suspected unexpected serious adverse reactions (SUSARs) related or possibly related to 
panitumumab and their follow-up reports must be reported to Amgen within 1 working day of 

Memorial Sloan Kettering Cancer Center 
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Approval date: 15-Apr-2019 
Page 39 of 47 
 
 
submission to the FDA, IRB or IEC. A copy of any safety report submitted to the FDA, IRB or IEC 
should be faxed to Amgen, within 24 hours of such submission. All reporting to the FDA must go 
through MSKCC‘s IND Office. The sponsor is responsible to ensure that the latest investigator's 
brochure is used as the source document for determining the expectedness of an SAE. 
A copy of any safety report submitted to the FDA, or any other regulatory agency, IRB or IEC, 
should be faxed with the Amgen Adverse Event fax coversheet to Amgen, within 24 hours of such 
submission, at: 
Amgen Global Safety 
Fax: 888-814-8653 
 
REPORTING 
FREQUENCY 
SADRs 
Within 1 month of the event 
SUSARs 
Within 1 business day of FDA submission 
Investigators should not wait to receive additional information to fully document the event 
before notifying the sponsor of the SAE. Any SAE, if brought to the attention of the investigator at 
any time after cessation of study drug, and considered by the investigator to be possibly related 
to study drug, should be reported. 
17.2.2 Reporting Procedures for All Adverse Events to Amgen 
 
All AEs occurring after informed consent signing observed by the investigator or reported by 
the subject (whether or not attributed to investigational product) will be reported. The investigator 
is responsible for ensuring that all adverse events observed by the investigator or reported by 
subjects are properly captured in the subjects‘ medical records. 
 
An adverse event is defined in the International Conference on Harmonization (ICH) Guideline 
for Good Clinical Practice as ―any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.‖ (ICH E6:1.2). The ongoing review of safety data will 
include review of clinical AEs and SAEs including skin-related toxicity assessment and laboratory 
studies. The CTCAE version 4.0 will be used to grade all AEs, except Panitumumab related toxicity 
which will be graded by modified CTCAE version 3.0 Dermatology Skin Assessment (Appendix B). 
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a change from values before the study. 
In general, abnormal laboratory or clinical findings without clinical significance (Grades 1 and 2 or 
based on the investigator's judgment) should not be recorded as adverse events; however, 
laboratory value changes requiring therapy or adjustment in prior therapy are considered adverse 
events. All Grade 3 and Grade 4 or clinically significant toxicities will be recorded. 
 
The following adverse event attributes must be assigned by the investigator: 
• 
Adverse event diagnosis or syndrome(s) (if known, signs or symptoms if not known) 
• 
Event description (with detail appropriate to the event) 
• 
Dates of onset and resolution 
• 
Severity 
• 
Assessment of relatedness to study treatment 
• 
Action taken. 
 
Amgen may request follow-up information. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 10-137 A(15) 
Approval date: 15-Apr-2019 
Page 40 of 47 
 
 
Medically significant adverse events considered related to the investigational product by the 
investigator or the sponsor will be followed until resolved or considered stable. 
 
It will be left to the investigator‘s clinical judgment to determine whether an adverse event is 
related and of sufficient severity to require the subject‘s removal from treatment or from the 
study. A subject may also voluntarily withdraw from treatment due to what he or she 
perceives as an intolerable adverse event. If either of these situations arises, the subject 
should be strongly encouraged to undergo an end-of-study assessment and be under 
medical supervision until symptoms cease or the condition becomes stable. 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In addition 
to signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
Click here to enter text. 
 
 
19.0 
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Approval date: 15-Apr-2019 
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Approval date: 15-Apr-2019 
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20.0 
APPENDICES 
 
20.1 APPENDIX A: Clinical Risk Score for Tumor Recurrence 
20.2 APPENDIX B: Dermatology/Skin/Nail Assessment (from CTCAE version 3.0 with modifications)