Clinical trial NCT01814501
Conditions: Mucinous Adenocarcinoma of the Colon Mucinous Adenocarcinoma of the Rectum Recurrent Colon Cancer Recurrent Rectal Cancer Signet Ring Adenocarcinoma of the Colon Signet Ring Adenocarcinoma of the Rectum Stage IV Colon Cancer Stage IV Rectal Cancer
Keywords: Metastatic colon cancer
Sponsor: John Hays
Start date: 2013-02-01; Completion date: 2018-08-06
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well panitumumab and combination chemotherapy works in treating patients with metastatic colorectal cancer previously treated with combination chemotherapy and bevacizumab. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving panitumumab and combination chemotherapy together may kill more tumor cells

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the median progression-free survival in patients treated with leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) and panitumumab for K-ras and NRAS wild-type, metastatic colorectal carcinoma who have already progressed on FOLFIRI + Bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of toxicities of the regimens. II. To determine overall response rate. III. To determine the median overall survival and the overall survival rate at 1 year.

OUTLINE:

Patients receive panitumumab intravenously (IV) over 60-90 minutes, leucovorin calcium IV over 90 minutes, fluorouracil IV continuously over 46 hours, and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms: arm 1: 5-Fluorouracil, irinotecan, and panitumumab
Interventions: intervention 1: panitumumab intervention 2: irinotecan hydrochloride intervention 3: fluorouracil intervention 4: leucovorin calcium
Intervention descriptions: intervention 1: Each vial of panitumumab will contain 20 mL of a sterile protein solution containing a 20-mg/mL solution of panitumumab. The vial will contain approximately 400mg of panitumumab and is for single dose use only. intervention 2: Diluted with 5% dextrose (D5W) to a total volume of 500 mL and infused intravenously over 90 minutes. Nothing else should be added to the bag. Patients will be given a dose of 180 mg/M2 by intravenous infusion. intervention 3: Administered intravenously. A bolus of 400 mg/m2 to be followed by a continuous infusion over 46 hrs at a dose of 2400mg/m2. intervention 4: Leucovorin will be administered at a dose of 200 mg/m2 over 120 minutes prior to the 5-FU bolus. Leucovorin may be run simultaneously with irinotecan infusion via y-site connection.

Protocol documents:
Prot_SAP_000.pdf: 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 9.19.2017 
IRB Approved:  10.21.2017 
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A PHASE II STUDY OF PANITUMUMAB IN COMBINATION 
WITH FOLFIRI AFTER PROGRESSION ON FOLFIRI PLUS 
BEVACIZUMAB IN KRAS AND NRAS WILD TYPE METASTATIC 
COLORECTAL CANCER. 
 
September 19 2017 
 
 
 
Principal Investigator: 
John Hays, MD, PhD 
 
 
                         Multi-Center Trial Program 
Clinical Trials Office 
The Ohio State University 
Comprehensive Cancer Center 
Fax: 614-366-6652 
                                         E: OSUCCC-CTO-MCTP@osumc.edu 
 
Institution: The Ohio State University 
Address: 320 W. 10th Ave, Columbus 
OH 43210 
Telephone: 614-293-94248 
Email: John.Hays@osumc.edu 


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ABBREVIATIONS 
 
Abbreviation 
Term 
5-FU 
5-Fluorouracil 
ALT 
alanine transaminase (also referred to as SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also referred to as SGOT) 
BEV 
Bevacizumab 
BUN 
blood urea nitrogen 
CO2 
total carbon dioxide 
CBC 
complete blood count 
IRINOTECAN 
Irinotecan 
CR 
complete response 
CRF 
case report form 
(CR+PR) 
objective complete and partial responses 
CTC 
Common Toxicity Criteria 
ECOG PS 
Eastern Cooperative Oncology Group Performance Score 
FOLFIRI 
Chemotherapy regimen as outlined with 5-FU, LV, and 
irinotecan 
G-CSF 
granulocyte-colony stimulating factor 
IRB 
Institutional Review Board 
LV 
Leucovorin 
pa 
Posteroanterior 
Pan 
Panitumumab 
pCR 
pathologic complete response rate 
PD 
progressive disease 
PI 
Principal Investigator 
PR 
partial response 
SD 
stable disease 
TS 
thymidylate synthase (spelling error) 
ULN 
upper limits of normal 
UPC 
Urine Protein Creatinine Ratio 
WNL 
within normal limits 
dThdPase 
thymidine phosphorylase 


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TABLE OF CONTENTS – PHASE II STUDY OF PANITUMUMAB IN COMBINATION WITH 
FOLFIRI AFTER PROGRESSION ON FOLFIRI PLUS BEVACIZUMAB IN KRAS WILD TYPE 
METASTATIC COLORECTAL CANCER ............................................................................... 3 
ABBREVIATIONS ....................................................................................................................... 2 
SCHEMA     …………………………………………………………………...………………5 
1. 
BACKGROUND AND RATIONALE .............................................................. 6 
1.1. 
Disease Background ............................................................................................... 6 
1.2. 
Drug Background ................................................................................................... 6 
1.2.1. 
Panitumumab.......................................................................................................... 6 
1.2.1.1. 
Panitumumab Pharmacology ................................................................................ 6 
1.2.1.2. 
Preclinical Antitumor Activity of Panitumumab ..................................................... 6 
1.2.1.3. 
Clinical Studies With Panitumumab ........................................................................ 7 
1.2.1.4. 
Toxicities .................................................................................................................. 8 
1.2.1.5. 
Panitumumab Clinical Safety Experience ............................................................ 8 
1.2.1.6. 
Panitumumab Safety Monotherapy Studies ............................................................. 9 
1.2.1.7. 
Safety of Panitumumab in Combination with Chemotherapy ............................... 10 
1.2.2 
5-Fluorouracil ....................................................................................................... 11 
1.2.2.1 
Pharmacology of 5-Fluorouracil ............................................................................ 11 
1.2.2.2 
Clinical Studies With 5FU  …………………………………………………….11 
1.2.2.3. 
Clinical Studies With 5-FU ...................................................................................... 11 
1.2.3 
Irinotecan .............................................................................................................. 12 
1.2.3.1 
Pharmacology of Irinotecan ................................................................................... 12 
1.2.3.2 
Toxicities………………………………………………………………………..12 
1.2.3.3. 
Clinical Studies with Irinotecan ............................................................................. 12 
1.3. 
Rationale for Performing the Study…………………………………………. 12 
1.4.1 
Rationale for Correlative Study ………………………………………..  14 
2. 
STUDY OBJECTIVES ..................................................................................... 14 
2.1. 
Primary Objective  ………………………………………………………….  14 
2.2 
Secondary Objectives…………………………………………………….14 
3. 
STUDY DESIGN ............................................................................................... 15 
3.1. 
Study design and Sample Size ............................................................................. 15 
4. 
SELECTION CRITERIA ................................................................................ 15 
4.1. 
Inclusion Criteria ................................................................................................. 15 
4.2. 
Exclusion Criteria ................................................................................................ 16 
5. 
REGISTRATION PROCEDURES………………………………………...17 
6. 
DETAILED STUDY ASSESSMENTS ........................................................... 18 
6.1. 
Informed Consent ................................................................................................. 18 
6.2. 
Screening Procedures ........................................................................................... 18 
6.3. 
Pre-Study Assessment .......................................................................................... 18 
6.4. 
Assessment during Treatment ............................................................................ 19 
6.4.1 
On-Study Follow-Up Assessment …………………………………………….19 
6.4.2. 
After Study Assessment ....................................................................................... 20 
6.5. 
Schedule of Assessments and Procedures .......................................................... 20 
6.6. 
Efficacy Parameters ............................................................................................. 20 
6.7. 
Safety Parameters ................................................................................................. 21 


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6.7.1. 
Laboratory Tests .................................................................................................. 21 
6.7.2. 
Physical Exam, Vital Signs and Physical Measurements ................................. 22 
6.8. 
Premature Withdrawal ……………………………………………………….22 
7. 
STUDY MEDICATION ................................................................................... 22 
7.1. 
Drug Formulation, Packaging, and Storage ...................................................... 22 
7.2. 
Protocol Dosage Regimen and Administration ................................................. 23 
7.3. 
Duration of treatment .......................................................................................... 25 
7.4. 
Dose Adjustment for 5FU and Irinotecan Toxicities ........................................ 25 
7.5. 
Panitumumab Dose Modification for Toxicity- (Please refer to Table 4) ...... 27 
Pre-medication for Panitumumab ...................................................................... 28 
Toxicity Assessment ............................................................................................. 28 
Panitumumab Dosage Adjustments ................................................................... 28 
Criteria for Withholding a Dose of Panitumumab ........................................... 29 
Criteria for Re-treatment with Panitumumab .................................................. 29 
Dose Modification Schedule ................................................................................ 29 
Panitumumab Delayed- or Missed-Doses .......................................................... 30 
Discontinuation of Panitumumab ....................................................................... 31 
Electrolyte Management ...................................................................................... 31 
7.6. 
Special Instructions Regarding Treatment of Toxicity .................................... 33 
7.7. 
Supportive Therapy ............................................................................................. 34 
7.8. 
Concomitant Medications and Treatments ....................................................... 35 
7.9. 
Warnings/Precautions regarding specific agents used in this protocol .......... 35 
8. 
STUDY OUTCOME MEASURES ................................................................. 36 
9. 
SAFETY PARAMETERS ................................................................................ 37 
Adverse Events ..................................................................................................... 37 
Serious Adverse Events ........................................................................................ 37 
Reporting Procedures for All Adverse Events .................................................. 38 
Serious Adverse Events Reporting Procedures ................................................. 38 
Subsite SAE Reporting Requirements ............................................................... 39 
10. 
STATISTICAL CONSIDERATIONS ............................................................ 40 
10.1. 
Hypothesis and Endpoints ................................................................................... 40 
10.2. 
Study design and Sample Size Calculation ........................................................ 40 
10.3. 
Analysis of Primary and Secondary Efficacy Parameters ............................... 40 
11. 
Tissue collection and correlative analysis …………………………….41 12.
 
REFERENCES .................................................................................................. 42 
13. 
APPENDICES ................................................................................................... 47 
Appendix 1: 
ECOG Performance Status Scale .................................................................... 47 
Appendix 2: 
BSA Nomogram ................................................................................................. 48 
Appendix 3: 
CTC - Common Toxicity Criteria 4.0 ............................................................ 49 
Appendix 4: 
Panitumumab Pharmacy Guide ...................................................................... 50 
 


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SCHEMA 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Disease Background 
Colorectal cancer is the second leading cause of cancer mortality in the United States (1). Recent 
advances in the treatment of this deadly cancer have almost doubled the median survival time of those 
patients. The introduction of Irinotecan and Oxaliplatin along with 5FU has enabled patients to live 
longer (2-4). Those drugs represent the conventional chemotherapeutic armamentarium for treating 
metastatic colorectal cancer (MCRC). More recently, added to that armamentarium, came targeted 
biologic therapies, cetuximab, panitumumab, and bevacizumab with the potential to improve survival 
even further (5-6). With these molecularly targeted agents, the survival of patients with metastatic 
disease is now approximating 24 months. 
 
1.2. 
Drug Background 
 
1.2.1. Panitumumab 
 
1.2.1.1. Panitumumab Pharmacology 
Panitumumab is a high affinity (Kd = 5 x 10-11 M) fully human IgG2 monoclonal antibody that is 
directed against the human EGFR. This fully human antibody was engineered using XenoMouse® 
technology developed by Abgenix Inc. In this proprietary strain of mice, murine heavy and light chain 
immunoglobulin genes were inactivated and most of the human heavy and light chain immunoglobulin 
genes (both kappa and lambda) were inserted. When this strain of engineered mice was immunized with 
EGFr over- expressing A431 cells, fully human anti-EGFr antibodies were produced, from which 
panitumumab was selected for further development. (7) 
Through the high-affinity interaction of panitumumab with the active site of the EGFr, binding of the 
ligands EGF, TGFα, amphiregulin, betacellulin, epiregulin, and heparin- EGF is blocked. This inhibition 
may in turn arrest tumor cell proliferation, inhibit metastasis, and trigger apoptosis (programmed cell 
death). (7) 
 
1.2.1.2. Preclinical Antitumor Activity of Panitumumab 
In murine xenograft tumor models, panitumumab has demonstrated tumor growth inhibition, eliciting 
both tumor regression and eradication of established tumors (8). When panitumumab was combined 
with chemotherapeutic agents, eradication and inhibition of the growth of human epidermoid, ovarian, 
breast, and pancreatic carcinoma cells in vitro and A431 epidermoid, DU145 prostrate, and A549 lung 
xenografts in vivo were observed. In addition, the administration of panitumumab combined with a 
multikinase inhibitor, AMG 706, in mice resulted in significantly greater tumor growth inhibition of 
A431 epidermoid, HT29 colon, and Calu6 non-small cell lung xenografts than with either agent alone. 
The antineoplastic effects of panitumumab have been demonstrated in multiple human xenograft tumor 
models. Panitumumab, at a dose of 1.0 mg/injection administered intraperitoneally (IP) twice weekly 
for 3 weeks, inhibited the growth of human A431 epidermoid carcinoma xenografts in athymic mice 
versus the control treatment group, resulting in the complete regression of established (≤ 1.2 cm3) 
tumors. Lower doses of panitumumab administered twice weekly for 3 weeks inhibited established 
xenografts  more effectively than similar doses of the m225 anti-EGFr antibody. 
Non-clinical pharmacology studies indicate that panitumumab antitumor activity is not solely correlated 
with the total number of EGFr molecules on the tumor cell surface, but are also dependent on the 
functional activity of this signaling pathway in different tumor cell types (9).   A lack of antitumor 


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activity was observed with panitumumab treatment in a subset of EGFr-expressing human tumor 
xenografts in vivo. EGFr levels in these tumor cell types may not absolutely correlate with EGFr 
functional activity, and therefore, tumor cell dependency on this signaling pathway for proliferation, 
survival, and/or angiogenesis may be more important. The data indicate that expression of EGFr on 
tumors is frequently accompanied by growth dependency on the EGFr pathway and that blocking the 
pathway with neutralizing anti-EGFr antibodies, such as panitumumab, may lead to growth arrest and 
regression (9). 
 
The effects of panitumumab in combination with chemotherapeutic agents (doxorubicin, cisplatin, and 
docetaxel) have been evaluated in in-vivo models and have indicated additive growth inhibition of tumor 
xenografts. Panitumumab also has been evaluated in combination with AMG 706, a  multikinase inhibitor 
including VEGF receptor, resulted in significantly greater inhibition of tumor xenografts than either 
agent alone. 
 
1.2.1.3. 
Clinical Studies with Panitumumab 
The clinical development program for panitumumab is extensive and includes a wide range of studies. 
Fifteen studies have been initiated and over 1467 patients have been treated with panitumumab at 
multiple dose levels and 1 of 3 dosing schedules (2.5 mg/kg weekly, 6 mg/kg every 2 weeks or 9 mg/kg 
every 3 weeks). Subjects with a variety of solid tumors (CRC, renal cell, prostate, NSCLC, pancreatic, 
esophageal) have been treated with panitumumab in either a monotherapy setting or in combination with 
chemotherapy. 
 
Initially in MCRC, panitumumab, as a single agent, had been shown to have antitumor activity in 
refractory MCRC in both EGFR-positive and –negative tumors (10,11). However subsequent follow up 
has shown a significant difference in response comparing patients with mutated KRAS oncogene 
compared to those without a mutation on this oncogene (12,43). The patients with patients a wild-type 
or unmutated KRAS oncogene have a significantly better response to monoclonal antibody targeted 
therapies against EGFR. As such, panitumumab has been FDA approved for the treatment of EGFR- 
expressing mCRC after progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan- 
containing chemotherapy regimens. 
 
In addition, a recent phase 3, multicenter, randomized controlled trial (RCT) of panitumumab plus best 
supportive care (BSC) vs BSC alone in patients (pts) with metastatic colorectal cancer (mCRC). In this 
study, patients receiving panitumumab had a 46% lower relative progression rate than those receiving 
BSC alone (hazard ratio=0.54, 95% CI: 0.44, 0.66). By the first scheduled assessment (week 8), a higher 
percentage of patients alive without progression was observed in the panitumumab versus BSC group 
(49% versus 30%, respectively); a difference in the percentage of patients alive favoring panitumumab 
continued through week 32 (AACR abs CP-1,12). In combination with IFL (Amgen 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%) (median 
PFS=10.9 months) (13,14).. These data suggest that the potential for additive toxicities in the 
gastrointestinal tract exists when panitumumab is administered in combination with GI-toxic 
chemotherapy. However, these toxicities could be managed by appropriate selection of the concomitant 


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chemotherapy regimen. 
 
1.2.1.4. 
Toxicities 
 
Nonclinical toxicology studies were conducted to support the use of panitumumab for intravenous 
administration in the oncology setting. All toxicology studies were conducted in cynomolgus monkeys, 
the only pharmacologically relevant nonhuman species. Panitumumab was administered IV at doses 
ranging from 0.3 to 30 mg/kg once weekly for 4 weeks and ≤ 15 mg/kg once weekly for 12 weeks. 
Additionally, a study is ongoing in which panitumumab was administered weekly to monkeys at doses 
of ≤ 30 mg/kg for 26 weeks. The 30-mg/kg/week dose used in the toxicology studies provides a 6-fold 
safety margin (AUC-based) to the clinical dose of 2.5 mg/kg once weekly and an approximately 4.5-fold 
safety margin (AUC-based) to a clinical dose of 6.0 mg/kg once every 2 weeks or 9.0 mg/kg once every 
3 weeks. The principal treatment-related findings observed in these studies were diarrhea and skin rash, 
which were considered to be related to the pharmacologic action of panitumumab. Dehydration and 
electrolyte disturbances were observed in early studies and were considered likely to be associated with 
severe diarrhea.  Therefore, fluid support was administered in subsequent studies to prevent dehydration. 
 
Reproductive toxicity studies evaluating the effects of panitumumab on embryofetal development and 
female fertility are ongoing (in-life complete). In the embryofetal development study, panitumumab 
was administered once weekly at doses of 7.5, 15, or 30 mg/kg to pregnant cynomolgus monkeys during 
the period of organogenesis. A preliminary review of the data showed that fetal abortions occurred in all 
dose groups, and thus, panitumumab should not be administered to pregnant women, and women of 
childbearing potential as well as men should continue to use contraception during panitumumab therapy 
and for 6 months after the last dose is administered. In the fertility study, panitumumab (7.5, 15, or 30 
mg/kg) was administered once weekly to female cynomolgus monkeys before mating and through early 
pregnancy; based on an initial review of the draft data, minimal-to-severe skin rash and/or diarrhea, 
decreased food consumption, and body weight loss (sometimes resulting in amenorrhea) were observed 
in some animals in all dose groups (14). 
 
The mechanism of action of panitumumab is not expected to be mutagenic or carcinogenic, and no 
structural alerts regarding carcinogenicity have been identified for this drug class. Additionally, 
panitumumab is neither a growth hormone nor an immunosuppressant. Thus, mutagenicity or 
carcinogenicity studies are considered unnecessary. This approach is consistent with International 
Committee on Harmonization (ICH) guidelines. 
 
1.2.1.5 
Clinical Safety INFORMATION 
Panitumumab Clinical Safety Experience 
The below referenced studies reflect the reported adverse events at the time of the last Panitumumab 
Investigator’s Brochure (14). 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 


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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, hypersensitivity, 
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); particularly considering that premedication was not mandated in study protocols. 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, 
Panitumumab antigenicity, as measured by enzyme-linked immunosorbent assay (ELISA) and Biacore 
assay, was very low and was not associated with clinical sequelae. 
Acute renal failure has been observed in patients who develop severe diarrhea and dehydration. 
Please refer to the current Panitumumab Investigator’s Brochure for further details (14). 
1.2.1.6 
Panitumumab Safety 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 (ie, 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 (ie, subject incidence ≥ 10%) included fatigue (15%) 
and diarrhea (13%). 
Subjects in the wild-type KRAS subset received a higher number of panitumumab infusions compared 
with subjects in the mutant subset (mean [median] 10.0 [8.0] and 4.9 [4.0], respectively). More treatment-
related adverse events occurred in the wild-type KRAS subset compared with the mutant KRAS 
subset, presumably due to the greater number of panitumumab infusions received. These adverse events 
were mainly skin toxicities (erythema, pruritus, dermatitis acneiform) likely reflecting the increased 
duration of exposure to panitumumab. No qualitative differences in overall adverse events were 
observed between the wild-type KRAS subset, the mutant KRAS subset and the overall population, 
however, treatment related grade 3 adverse events were reported for 25% of subjects in the wild-type 
KRAS subset compared with 12% of subjects in the mutant KRAS subset. Two percent of wild-type 
KRAS subjects and 1% of mutant KRAS subjects withdrew for panitumumab-related events. 
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 
investigator as an adverse event.  Using a definition consistent with the Vectibix USPI (2007), 3% of 


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panitumumab-treated  subjects  had  a  potential  infusion  reaction;  <  1%  of  subjects  had  a  potential 
infusion reaction by this definition ≥ grade 3. 
 
 
1.2.1.7 
Safety of Panitumumab in Combination with Chemotherapy 
 
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%) (14). These data suggest that 
the potential for additive toxicities in the gastrointestinal tract exists when panitumumab is administered 
in combination with GI-toxic chemotherapy. However, these toxicities could be managed by 
appropriate selection of the concomitant chemotherapy regimen. 
No clear additive effects were observed in the NSCLC setting where panitumumab was combined with 
carboplatin/paclitaxel (Study 20025404). One case of pulmonary fibrosis was reported in a subject 
treated with this combination. Although subjects with evidence of interstitial pneumonitis or pulmonary 
fibrosis were excluded from clinical studies (from 2004 onward), this subject, who had a previous 
history of underlying idiopathic pulmonary fibrosis, was enrolled before the protocol exclusions were 
implemented. 
Amgen study 20040249 (PACCE) is an open-label, controlled study of bevacizumab and chemotherapy 
administered with and without panitumumab as first-line treatment of subjects with mCRC. 
Chemotherapy included oxaliplatin-or irinotecan-based regimens. Based on the results of a planned 
interim analysis (conducted after 257 progression or death events had occurred), adding panitumumab to 
bevacizumab and oxaliplatin-based chemotherapy did not prolong progression-free survival and 
contributed increased toxicity to the multi-agent regimens. Panitumumab treatment was discontinued 
from the study at that time (22 March 2007). 
A final analysis of on-treatment efficacy and safety was performed based on available data as of 31 May 
2007. The addition of panitumumab to bevacizumab and oxaliplatin-based chemotherapy showed an 
unfavorable benefit-to-risk profile with shorter progression-free survival time and increased toxicity. 
Although panitumumab treatment in the irinotecan-based chemotherapy stratum was also prematurely 
discontinued, there was no evidence of significant benefit with the addition of panitumumab to 
bevacizumab and irinotecan-based chemotherapy in first-line treatment of mCRC. Given the 
unfavorable benefit-to-risk outcome, the PACCE study as designed did not support the use of 
panitumumab with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy as first-line 
treatment of metastatic colorectal cancer. 
Please refer to the current Panitumumab Investigator’s Brochure for further details. 


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1.2.2    5-Fluorouracil 
 
1.2.2.1 
Pharmacology of 5-Fluorouracil 
5-FU, 5-fluoro-2,4(1H,3H)-pyrimidinedione, is an antineoplastic antimetabolite, is a colorless to 
faint yellow aqueous, sterile, nonpyrogenic injectable solution for intravenous administration. 
This antimetabolite has been used since its advent in the 1950s and has cell cycle specific 
activity in the S-phase. Its main target after conversion to the metabolite FdUMP is the enzyme 
thymidylate synthase (15). It can be incorporated into both DNA and RNA resulting in alteration 
and disruption of normal function and ultimately leading to cell death. With regard to colorectal 
cancer treatment, it has been long the standard of care in the adjuvant setting in combination with 
leucovorin (16). Given the paucity of active agents in this disease, it was also the mainstay in the 
metastatic setting. The drug is generally well tolerated with side effects most commonly related 
to the rate of infusion. 
 
1.2.2.2. 
Toxicities 
Please refer to the FDA approved package insert for more details about a comprehensive list of 
adverse events. Stomatitis and esophagopharyngitis (which may lead to sloughing and 
ulceration), diarrhea, anorexia, nausea and emesis are commonly seen during therapy. 
Leukopenia usually follows every course of adequate therapy with fluorouracil. The lowest white 
blood cell counts are commonly observed between the 9th and 14th days after the first course of 
treatment, although uncommonly the maximal depression may be delayed for as long as 20 days. 
By the 30th day the count has usually returned to the normal range. Alopecia and dermatitis may 
be seen in a substantial number of cases. The dermatitis most often seen is a pruritic 
maculopapular rash usually appearing on the extremities and less frequently on the trunk. It is 
generally reversible and usually responsive to symptomatic treatment. Other adverse reactions 
are: Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. Cardiovascular: 
myocardial ischemia, angina. Gastrointestinal: gastrointestinal ulceration and bleeding. Allergic 
reactions: anaphylaxis and generalized allergic reactions. Neurologic: acute cerebellar syndrome 
(which may persist following discontinuance of treatment), nystagmus, headache. Dermatologic: 
dry skin, fissuring, photosensitivity, as manifested by erythema or increased pigmentation of the 
skin; vein pigmentation; palmar-plantar erythrodysesthesia syndrome, as manifested by tingling 
of the hands and feet following by pain, erythema, and swelling. Ophthalmic: Lacrimal duct 
stenosis, visual changes, lacrimation, photophobia. Psychiatric: disorientation, confusion, 
euphoria. Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails). (17) 
 
 
1.2.2.3. 
Clinical Studies with 5-FU 
Many studies have been performed with 5-FU in the setting of colorectal cancer. Many of the 
early studies focused on the schedule of giving the 5-FU: bolus vs. infusional regimens (18, 19). 
More recently, the focus of studies with 5-FU have been in conjunction with oxaliplatin or 
irinotecan in regimens such as FOLFOX or FOLFIRI. These latter combinations when compared 
to a 5-FU/LV in Phase III studies proved to have superior response rates, progression free 
survival (20, 21) and survival (20). FOLFOX and FOLFIRI appear to be equivalent regimens 
in the metastatic setting (22, 23). 


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1.2.3. 
Irinotecan 
 
1.2.3.1. 
Pharmacology of Irinotecan 
Irinotecan is a water soluble camptothecin analog. Camptothecin is an alkaloid obtained from the  
Camptotheca acuminata tree. The subcellular target of camptothecin and camptothecin 
analogues in mammalian cells is the nuclear enzyme topoisomerase I (Topo I) which is encoded 
by a single copy gene mapped to human chromosome 20q11.2-13.1 (27). This enzyme, along 
with the nuclear enzyme topoisomerase II (Topo II) modulates the topological structure of DNA 
by inducing transient DNA breaks, thereby relieving the torsional strain that occurs during 
transcription. Topo I induces single-strand DNA breaks after covalently linking to the 3' terminus 
of DNA, and subsequently facilitates DNA religation. The camptothecins, along with Topo I 
and DNA, establish a reversible cleavable complex, inhibiting the religation of DNA. The DNA 
replication machinery then converts single-strand breaks to lethal double-strand breaks (27). 
In vivo, cellular carboxylesterases cleave the ester bond of irinotecan, which is inactive, thereby 
producing the active compound SN-38, (7-ethyl-10-hydroxycamptothecin). SN-38 is estimated 
to be 250-1000 fold more potent as a topoisomerase-I inhibitor than irinotecan (28,29). Mutations 
of the Topo I gene and stable decrements in Topo I activity are implied in tumor resistance 
to irinotecan (30,31). Exposure to irinotecan has also been shown to produce a rapid, transient 
decrease in Topo I concentration in vitro and in vivo, which in cell cultures correlates with a 
decrease in irinotecan cytotoxicity throughout the exposure period (30). 
 
1.2.3.2. 
Toxicities 
See section 6.9.2. Below. 
 
1.2.3.3. 
Clinical Studies with Irinotecan 
Significant clinical activity has been reported in phase II trials of irinotecan in patients with 
small-cell and non-small-cell lung cancer (NSCLC), colorectal cancer, squamous cell carcinoma 
of the cervix, ovarian cancer, stomach cancer and lymphoma (28). Irinotecan added to 5FU and 
leucovorin is one of the standards of care in the treatment of MCRC. While bolus irinotecan 
regimens when given with 5-FU and leucovorin, were found to have a significant effect on 
mortality (32), the continuous infusion regimens were found to be very effective in both the 
adjuvant and metastatic settings (33). Currently the preferred method to administer this 
combination is the bimonthly regimen with infusional 5FU (FOLFIRI). The bimonthly regimen 
tends to be very well tolerated by patients as well. 
 
1.3. 
Rationale for Performing the Study 
 
The rationale for this study stems out from the following: 1- FOLFIRI is an active combination 
in the first and second line treatment of MCRC with a high impact on survival. 2- EGFR is a well 
established target in colorectal cancer. 3- There is significant preclinical rationale to add 
panitumumab to irinotecan. Clinically, EGFR targeting monoclonal antibodies, such as 
panitumumab, enhance the activity of irinotecan in patients in first line therapy (13) as well in 
patients who are already refractory to irinotecan (34,35). The results of a phase 3 trial evaluating 
panitumumab in combination with FOLFIRI vs. FOLFIRI alone as a second-line treatment in 
1,186 patients with metastatic colorectal cancer (mCRC) showed that panitumumab significantly 


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VERSION: 09/19/2017 
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improved progression-free survival in combination with FOLFIRI (5.9 mos), compared to 
FOLFIRI alone (3.9 mos), in patients with KRAS wild-type mCRC(36). 
 
The proposed strategy of adding panitumumab to patients having progressed on first line 
FOLFIRI-Bevacizumab has many advantages. There is a high response rate (> 20%) with the 
combination of Irinotecan and cetuximab in patients who already failed irinotecan (34,35 ) 
equaling or surpassing all of the reported second line response rates (< 25%) from other studies 
(37,38). Irinotecan, unlike oxaliplatin has no known cumulative toxicity. Therefore this treatment 
strategy, to deliver second line therapy in a sequential fashion after the patient has progressed on 
first line FOLFIRI + bevacizumab, is feasible leaving the patients yet with an option for an 
active combination (FOLFOX) in the third line. 
 
As per the NCCN guidelines, irinotecan in combination with cetuximab is an acceptable second 
or third line of therapy after a patient has progressed on irinotecan based chemotherapy. This is 
based on the BOND 1 and BOND 2 study data showing that response rates and median TTP 
were superior when cetuximab was added to irinotecan vs. cetuximab alone in patients who 
already failed irinotecan (34,35). These efficacy parameters were comparable to salvage 
responses with oxaliplatin based regimen. This sets the stage for the rational for our study with 
panitumumab. 
 
Given the rationale stated above, we propose a phase II study looking at the addition of 
panitumumab to FOLFIRI upon disease progression with FOLFIRI plus bevacizumab. FOLFIRI 
is superior to irinotecan alone in patients who failed 5-FU in the first line (39). Thus,5-FU 
resistance is less relevant and the possible synergism/additivity of 5-FU with oxaliplatin and 
irinotecan justifies continuing its across lines of therapy. This study hypothesizes the possibility 
that a cancer becomes resistant to the FOLFIRI regimen, and that adding panitumumab will 
restore sensitivity to the regimen. This study will provide us with direct prospective data on the 
activity of FOLFIRI added to a novel targeted agent, panitumumab. The objective of the study is 
to determine the efficacy of this second line therapeutic regimen in patients with locally advanced, 
unresectable or metastatic colorectal carcinoma. The regimens consist of mFOLFIRI 
[5-
fluorouracil and irinotecan] and panitumumab. 
 
There is considerable variability of the metastatic colorectal cancer clinical response to anti- 
EGFR agents. Thus there is a pressing need to identify reliable markers with a predictive value 
to select the appropriate patients who can benefit from these treatments. There has  been reporting 
of the characterization of molecular markers predictive of anti-EGFR antibodies sensitivity in 
colorectal cancer. A study including 30 mCRC patients reported that KRAS mutation was 
highly predictive of tumor resistance to cetuximab (40). The 7 most common KRAS mutations 
in CRC occur in codons 12 and 13 of the KRAS gene. These mutations can be detected readily 
in paraffin-fixed tumor tissue by multiple technologies, including direct DNA sequencing or 
allele-specific PRC as well as with newer immunohistochemical staining. Based on a phase III 
study which looked at the impact of KRAS codon 12 and 13 mutation status on patients’ 
progression free survival with panitumumab compared to best supportive care, there was an 
increase from 7.4 to 12.3 weeks in those patients who were had no evidence of mutations (41). 
On July 17th , 2009, The U.S. Food and Drug Administration ( FDA) has recently approved the 
change in label for panitumumab indicating the utility of KRAS gene testing as a predictive 


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VERSION: 09/19/2017 
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biomarker in patients with mCRC . The Panitumumab Randomized Trial in Combination with 
Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was a 
randomized phase 3 study in which panitumumab was given in combination with oxaliplatin and 
5FU (FOLFOX4) vs FOLFOX4 alone, and patients were prospectively selected for KRAS exon 
2 (codon 12 and 13) wild-type tumors. There was an improvement in progression free survival 
from 8 to 9.6 months with the addition of panitumumab (HR 0.8; 95% CI 0.66-0.97, p= 0.02) but 
no statistically significant benefit in overall survival, 23.9 vs 19.7 months, respectively. (42) 
_Retrospective analysis of this study identified patients with additional RAS mutations such as 
KRAS exon 3 (codon 61) and exon 4 (codons 117 and 146) and NRAS exon 2 (codons 12 and 
13) and exon 3 (codon 61). Patients now identified without any RAS mutations had an 
improvement in their progression free survival with the addition of panitumumab to FOLFOX4, 
10.1 months vs 7.9 months with FOLFOX4 alone (HR 0.72; 95% CI 0.58-0.90 p=0.004) and 
overall survival from 26 vs 20.2 months (HR 0.78; 95% CI 0.62-0.99 p=0,04).(43) The FIRE-3 
trial, a phase III study comparing FOLFIRI and cetuximab or bevacizumab as first-line therapy 
has prospectively looked at these additional RAS mutations, and there was a greater benefit seen 
in patients treated with FOLFIRI and cetuximab if they wild-type for all RAS mutations. (44) 
 
Thus, enrollment to this trial requires that patient tumors are checked for RAS mutation (KRAS 
exon 3 (codon 61) and exon 4 (codons 117 and 146) and NRAS exon 2 (codons 12 and 13) and 
exon 3 (codon 61)). Only tumors that do not have these mutations will render patients eligible to 
receive panitumumab and enroll onto this study. 
 
1.4.1 
Rationale for correlative study 
Initially, our study selected only KRAS wild-type tumors for exon 2 (codon 12 and 13) but not 
for the additional RAS mutations [KRAS exon 3 (codon 61) and exon 4 (codons 117 and 146) 
and NRAS exon 2 (codons 12 and 13), exon 3 (codon 61), and exon 4 (codons 117 and 146)]. 
Thus, we proposed to collect patient tumor samples so that we could retrospectively analyze 
them for the additional RAS mutations to see if progression-free survival and overall survival are 
impacted by additional mutations. If patient tumors are analyzed for the additional RAS mutations 
prior to enrollment, then tissue collection is not necessary. 
 
 
2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
The primary objective for this phase II trial is to determine the median progression-free survival 
in patients treated with FOLFIRI and panitumumab who have RAS wild-type , metastatic 
colorectal carcinoma and have already progressed on FOLFIRI + Bevacizumab. 
 
2.2 
Secondary Objectives 
• To determine the frequency and severity of toxicities of the regimens. 
• To determine overall response rate 
• To determine the median overall survival and the overall survival rate at 1 year 


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VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
3. 
STUDY DESIGN 
 
3.1. 
Study design 
 
This is an open-label, prospective phase II clinical trial, with a primary endpoint of progression- 
free survival (PFS). Patients must fail a combination of FOLFIRI and bevacizumab prior to 
being considered for this study. At the time of consideration, all participants will be screened for 
RAS mutations and only patients who are considered RAS-wild type [KRAS exon 2 (codon 12 
and 13), KRAS exon 3 (codon 61) and exon 4 (codons 117 and 146) and NRAS exon 2 (codons 
12 and 13), exon 3 (codon 61), and exon 4 (codons 117 and 146)]will be enrolled on the study. 
Patients eligible for this study will receive a modified regimen of FOLFIRI as outlined in this 
study along with panitumumab as outlined in section 6.2. Each cycle will consist of days 1 and 
15 as outlined in section 6.2. Patients will be restaged after 2 cycles of therapy. If there is no 
evidence of progressive disease, patient will continue on study. They will be monitored at regular 
intervals with serial laboratory testing as well as periodic scans to assess response to treatment as 
outlined in section 5.5. 
 
3.2  Sample Size and Accrual Rate: 
A total of 25 patients will be required to test the null hypothesis that there is no difference in 
median PFS between the study regimen and the historical control. Please refer to Section 9 for 
details regarding the statistical methods. We anticipate a uniform accrual rate of 2 patients with 
KRAS wild type mCRC per month from the 2 participating institutions (The Ohio State 
University (lead) ), no lost to follow-up, and an additional 6 months of planned follow-up after 
accrual is completed. 
 
4. 
SELECTION CRITERIA 
 
4.1. 
Inclusion Criteria 
To be eligible for inclusion, each patient must fulfill each of the following criteria: 
 
1. Patients with advanced adenocarcinoma of the colon or rectum not curable with surgery or 
radiotherapy and have been previously treated for their disease with FOLFIRI plus 
bevacizumab in the first line metastatic setting. Patients will only be eligible if their last line 
of therapy prior to enrolling onto the study was FOLFIRI and bevacizumab received no 
more than 6 months prior to enrolling in this study. They should have been treated with 
FOLFIRI plus bevacizumab until disease progression is radiographically documented 
2. Patients’ tumors will need to be tested for the RAS mutation status.  Only those patients with 
wild-type or unmutated RAS oncogene are eligible to participate in this study. 
3. Provide written informed consent prior to study-specific screening procedures, with the 
understanding that the patient has the right to withdraw from the study at any time, without 
prejudice. 
4. Prior cetuximab is allowed in the adjuvant but not in the metastatic setting, but must have 
been completed at least 6 months before enrolling on this trial. 
5. Age > 18 years 
6. ECOG performance status < 1 
7. Life expectancy greater than 12 weeks 


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VERSION: 09/19/2017 
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8. No active brain metastasis. Previously surgically treated or irradiated lesions are allowed if 
not clinically active. 
9. Has a negative serum pregnancy test within 7 days of first dose of study treatment (female 
patients of childbearing potential). 
10. Ability to understand and willingness to sign a written informed consent 
11. No history of severe reactions to 5-FU, irinotecan, or a monoclonal antibody 
12. Adequate organ and marrow function as defined below: 
Leukocytes 
>3000/uL 
Absolute neutrophil count 
>1500/uL 
Platelets 
>100,000/uL 
Hemoglobin 
>9mg/dL 
Total Bilirubin 
<1.5 X ULN 
AST/ALT 
<3 X ULN (or < 5 x ULN with liver metastases). 
Creatinine Clearance 
( CrCl) > 30 ml/min (Cockroft-Gault Equation) 
Magnesium 
≥ lower limit of normal 
13. Measurable disease is required according to RECIST 1.1 criteria (45). 
14. The effects of Panitumumab on the developing human fetus are unknown. For this reason 
and because monoclonal antibodies as well as other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation and up to 6 months after completing 
therapy. Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
 
4.2. 
Exclusion Criteria 
Patients who fulfill any of the following criteria will be excluded: 
1. Pregnant or breast-feeding women. Women of childbearing potential with either a positive 
or no pregnancy test at baseline. Woman or men of childbearing potential not using a reliable 
and appropriate contraceptive method. (Postmenopausal woman must have been amenorrheic 
for at least 12 months to be considered of non-childbearing potential). 
2. Sexually active males unwilling to practice contraception during the study and 6 months 
beyond. 
3. History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of 
interstitial lung disease on baseline chest CT scan. 
4. KRAS  or NRAS mutant tumors. 
5. Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined 
as > CTC grade 2 (CTCAE version 4.0)) 
6. Clinically significant cardiovascular disease that is not well-controlled with medication 
(including myocardial infarction, unstable angina, symptomatic congestive heart failure, 
serious uncontrolled cardiac arrhythmia) or myocardial infarction within ≤ 1 year or serious 
concurrent infection. 
7. Bevacizumab within the last 3 weeks before enrollment on trial 
8. Patient is more than 6 months since the last dose of FOLFIRI. 
9. Patients who have required toxicity related dose reductions of greater than 50% of the 
original dose of infusional 5-FU and/or irinotecan during the administration of 
FOLFIRI/bevacizumab . 


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10. Prior exposure to panitumumab in any setting 
11. Prior exposure to cetuximab in the metastatic (Stage IV) setting. 
12. Radiotherapy  ≤  14  days  prior  to  enrollment. 
Patients  must  have  recovered  from  all 
radiotherapy-related toxicities. 
13. Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5- 
fluorouracil, leucovorin, irinotecan, or panitumumab. 
14. Treatment for other carcinomas within the last three years, except cured non-melanoma skin 
and treated in-situ cervical cancer. 
15. Concomitant use of strong CYP3A4 inducers are not permitted. 
16. Participation in any investigational drug study within 4 weeks preceding enrollment. 
17. Other serious uncontrolled medical conditions that the investigator feels might compromise 
study participation. 
18. Incomplete recovery from major surgery within 4 weeks of enrollment. 
19. Unwillingness to give written informed consent. 
20. Unwillingness to participate or inability to comply with the protocol for the duration of the 
study. 
21. Patients  with  HIV/AIDS  and  those  severely  immunocompromised  will  be  excluded. 
However, no patients will be tested for HIV. 
 
 
5. 
REGISTRATION PROCEDURES 
 
Subsite patients will have eligibility verified and will be centrally registered at The Ohio State 
University by the OSU Subsite Coordinator. Subsites should call or email the OSU Subsite 
Coordinator to verify enrollment availability prior to consenting patients. 
 
Following registration, patients should begin protocol treatment within 5 business days. Issues 
that may cause treatment delays should be discussed with the OSU Principal Investigator as soon 
as possible. If a patient does not receive protocol therapy following registration, the patient will 
be replaced. The OSU Subsite Coordinator must be notified immediately if a patient does not 
receive protocol therapy. 
 
Only patients deemed eligible by the subsite research team should be sent for eligibility 
verification and registration by the OSU Subsite Coordinator. 
 
To request patient registration, the documents below must be completed by the subsite research 
team and faxed or securely emailed to the OSU Subsite Coordinator. If secure email is the 
preferred method and the subsite does not have a confirmed secure email system, the OSU secure 
email system may be used. Contact the OSU Subsite Coordinator for more information. 
 
Required documents for registration: 
 
• Enrollment Form (Appendix 5) 
• Signed Eligibility Checklist (Appendix 6) 
• Source documents verifying every inclusion & exclusion criteria 
• Required screening items as listed in the Protocol Calendar. Screening tests must be 


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VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
within the specified window. 
• Emails and other signed forms used as source documentation 
 
The OSU Subsite Coordinator will confirm receipt of the registration documents with the subsite 
contact listed on the Enrollment Form (Appendix 5). If confirmation is not received within 2 
hours, it is strongly recommended that the subsite call the OSU Subsite Coordinator to confirm 
registration documents were received. 
 
Registration requests will be processed as soon as possible and no later than 1 business day after 
receipt of the registration documents, pending there is no additional information needed to 
complete eligibility verification. Patients will be registered immediately upon determining they 
meet eligibility criteria. 
 
The Subsite Coordinator will securely email the subsite contact listed on the Enrollment Form 
(Appendix 5) with the registration confirmation, and the patient’s assigned study number. 
 
 
6. 
DETAILED STUDY ASSESSMENTS 
 
6.1. 
Informed Consent 
The investigator must ensure written informed consent from each individual participating in this 
study after adequate explanation of the aims, methods, objectives and potential hazards of the 
study prior to undergoing any study-specific procedures. 
 
6.2. 
Screening Procedures 
This study will be conducted in patients with metastatic/unresectable advanced colorectal cancer. 
Patients may have been treated in the adjuvant setting with prior chemotherapy, but in the 
metastatic setting, should not have received more than one line of previous chemotherapy or 
biologic therapy. The patient’s tumor sample must be evaluated for RAS mutation status prior to 
enrollment and must be unmutated (wild-type). The patients will be included if upon pathologic 
confirmation of metastatic disease has been confirmed, radiographic assessment has been 
completed, and meet the above listed inclusion and exclusion criteria will be eligible. Patients 
will be evaluated by their treating physician, the study coordinator, and/or the protocol 
investigator prior to enrollment. The screening procedures will be performed within 28 days 
prior to the start of treatment. The patients should not have received and bevacizumab within 3 
weeks of starting treatment on this study. Pregnancy determination will occur within 7 days 
prior to study entry. 
 
6.3. 
Pre-Study Assessment 
6.3.1 To be completed within 28 days prior to treatment: 
 
a. Baseline measurements of tumor size based on CT scans and other relevant scanning 
to be used to document tumor status (includes full assessment of all known metastatic 
disease) 
b. Informed consent 
c. Adverse events 


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d. ECG 
e. Malignant Disease/Treatment History 
f. Demographic Data 
g. General Physical Exam 
h. Hematology 
i. Concomitant Diseases & Treatments 
 
6.3.2 To be completed within seven days prior to treatment: 
 
a. Medical History 
b. Physical examination, and weight 
c. Performance status 
d. CEA serum level 
e. Complete blood count with leukocyte differential 
f. Platelet count 
g. Serum  chemistries,  glucose and  electrolytes  (calcium,  inorganic phosphate), liver 
function tests, uric acid 
h. Urinalysis, 
i. PT (or INR), PTT. 
j. Medication history 
k. Pregnancy test (women of childbearing potential) on serum B-HCG 
 
6.3.3 To be completed prior to enrollment in the study: 
a. RAS mutation testing 
 
6.4. 
Assessment during Treatment 
The following will be obtained at regular intervals during treatment: 
a. History and physical examination Day 1 of each cycle 
b. Vital signs and weight assessment will be obtained prior to day 1 and day 15, (within 
2 days). 
c. Drug toxicity (Adverse Drug Events) will be assessed every two weeks (toxicities 
will be graded according to the NCI CTC version 4.0). 
d. Complete blood count and serum chemistries (electrolytes including magnesium, 
calcium, potassium, BUN, Creatinine, liver function tests) will be obtained within 48 
hours prior to each treatment, days 1 and 15. 
e. CEA serum level every as a baseline and once every cycle. 
f. Imaging studies including but not limited to CT scans prior to treatment as a baseline 
and every 8 weeks (+/- 5 days). 
 
6.4.1 
On-Study Follow-Up Assessment 
The following will be obtained at the end of the study 
a. Adverse events/toxicities 
b. Monitor for inflammatory or infectious sequela in patients with severe dermatologic 
toxicities. 
c. Performance status 
d. Weight 


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e. Vital signs (blood pressure, pulse rate, respiratory rate, temperature) 
f. Physical examination 
g. Reevaluation of extent of tumor (same imaging method) 
6.4.2 After Study Assessment. 
After  completion  of  the  study,  electrolytes  including  magnesium,  calcium,  potassium  will  be 
followed every two weeks for the duration of 8 weeks after completion of panitumumab therapy. 
 
6.5. 
Schedule of Assessments and Procedures 
 
Screening/Baseline 
Every Treatment 
Cycle
a
 
End of Study Visit 
Day of Cycle 
Within 28 
days 
prior to 
first dose 
Within 7 
days 
prior to 
first dose 
1 
15 
5-FU bolus then cont 
infusion (over 46 hours) 
X 
X 
Irinotecan 
X 
X 
Panitumumab* 
X 
X 
Informed Consent b 
X 
Medical History 
X 
Malignant Disease / 
Treatment History 
X 
Demographic Data 
X 
General Physical 
Examinatione 
X 
X 
X 
X 
Vital Signs, Height, Weight, 
ECOG Performance Status 
X 
X 
X 
X 
CBCg 
X 
X 
Xf 
X 
X 
Complete Metabolic Panel 
Creatinine Clearance # 
X 
Xf 
X 
Magnesium, potassiumg 
X 
Xf 
X 
X 
CEA 
X 
Xf 
X 
Urinalysis 
X 
––– as clinically 
indicated ––– 
PT (or INR) & PTT 
X 
––– as clinically 
indicated ––– 
Serum Β-HCG c 
X 
––– as clinically 
indicated ––– 
Tumor measurements 
(CT Scan ) 
X 
Tumor 
measurements 
to be done after 
every 8 weeks 
of  therapy 
X 
ECG 
X 
––– as clinically 
indicated ––– 
X 


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Adverse Events 
X 
––– recorded 
throughout 
study 
X 
Concomitant Diseases & 
Treatment 
X 
––– any 
changes noted 
throughout 
study –––––– 
X 
KRAS and NRAS mutation 
testing d 
X 
#Creatinine clearance is only required for baseline labs 
*Minocycline will be given prophylactically for all patients starting the day prior to starting 
panitumumab and continue throughout the treatment duration (Please refer to section 6.2 for more 
details) 
 
a   Each cycle is 28 Days, then repeated. Clinic visits can be performed +/- 2 days of treatment. 
b Informed consent must be obtained prior to any study-specific procedure 
c Only in women of childbearing potential 
d Archived tumor samples may be sent when they can be obtained at any time after screening process is 
started.  May already completed prior to 21 days of enrollment. 
e Day 1 Cycle 1 is a chemotherapy only appointment.  Clinic visit with physician is permitted but not 
mandatory 
f Day 1 Cycle 1 does not require labs to be repeated 
g Only CBC, magnesium and potassium to be obtained on day 15 
h MRI permitted with approval from PI 
i Survival data will be collected after the 8 week study assessment follow-up via chart review and/or 
phone follow-up every 3 months.  
 
6.6. 
Efficacy Parameters 
 
Patients will be assessed for tumor response according to the RECIST 1.1 criteria (43) after 8 
weeks of treatment, and every 8 weeks thereafter as well at the end of the study. Tumor 
assessments should also be made on each patient within 2 weeks of study completion, 
withdrawal or discontinuation, as appropriate, even if the patient demonstrates physical evidence 
of progressive disease and withdraws from the study before the first scheduled tumor assessment. 
 
6.7. 
Safety Parameters 
 
6.7.1. Laboratory Tests 
Laboratory tests during treatment will be performed according to the Schedule of 
Assessments and Procedures. 
The following laboratory tests during treatment will be performed according to the Schedule 
of Assessments and Procedures. 
– 
Complete Blood Count including differential, WBC, RBC, hemoglobin, hematocrit, platelet 
count 
– 
Total bilirubin, AST/ALT, alkaline phosphatase, albumin, and total protein 
– 
Conjugated (direct) bilirubin in the case of abnormal total bilirubin 
– 
Serum creatinine and uric acid 
– 
Glucose 
– 
Electrolytes (sodium, potassium, magnesium) 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
– 
Serum calcium and inorganic phosphate 
– 
Urinalysis (pH, protein, glucose and blood) (as clinically indicated) 
 
6.7.2. 
Physical Exam, Vital Signs and Physical Measurements 
A limited physical examination will be done at each visit as per standard clinical practice, which 
should include breast, lung, heart, abdomen and nodes (cervical, axillary, inguinal), with other 
areas examined as clinically indicated. 
The following vital signs and physical measurements will be measured at each patient visit: 
– 
Pulse 
– 
Blood pressure 
– 
Body temperature 
– 
Weight 
– 
ECOG Performance Status (Appendix 2) 
– 
Monitor  for  inflammatory  or  infectious  sequelae  in  patients  with  severe  dermatologic 
toxicities 
 
6.8. 
Premature Withdrawal** 
Should  a  patient  decide  to  withdraw,  all  efforts  will  be  made  to  complete  and  report  the 
observations as thoroughly as possible. 
1. Disease progression 
2. Patient is unable to tolerate the toxicity resulting from the study treatment, even with optimal 
supportive care, in the opinion of the Treating Physician. 
3. If retreatment must be held for > 6 weeks or at the discretion of the investigator (excluding 
the rest week). 
4. Intercurrent illness that would, in the judgment of the Investigator, affect assessment of 
clinical status to a significant degree or require discontinuation of study treatment 
5. Nonprotocol chemotherapy or immunotherapy is administered during the study 
6. Noncompliance with protocol treatment 
7. Patient becomes pregnant 
8. Patient is lost to follow-up 
9. Patient refuses to continue treatment (patient will continue to be followed for disease-free 
survival and overall survival) 
 
**Patients have the right to withdraw from the study at any time for any reason. The investigator 
also has the right to withdraw patients from the study in the event of intercurrent illness, adverse 
events, treatment failure, protocol violations, administrative reasons or other reasons. 
 
7. 
STUDY MEDICATION 
 
7.1. 
Drug Formulation, Packaging, and Storage 
 
7.1.1 
5-Fluorouracil: 
Storage and Stability- Although fluorouracil solution may discolor slightly during storage, the 
potency and safety are not adversely affected. Store at controlled room temperature 15° to 30°C 
(59°to 86°F). Protect from light. Retain in carton until time of use. 


23 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
Administration- 5FU should be administered only intravenously, using care to avoid 
extravasation. Extravasation should be handled according to hospital protocol. Patients will be 
given a bolus of 400 mg/m2 to be followed by a continuous infusion over 46 hrs at a dose of 
2400mg/m2. 
Leucovorin will be administered at a dose of 200 mg/m2 over 120 minutes prior to the 5-FU 
bolus. Leucovorin may be run simultaneously with irinotecan infusion via y-site connection. 
 
7.1.2 Irinotecan: 
 
Storage and stability- Irinotecan vials must be stored in a cool, dry place, protected from light in 
a locked cabinet accessible only to authorized individuals. It is stable for at least three years at 
room temperature. Irinotecan is stable for at least 24 hours in glass bottles or plastic bags after 
reconstitution with D5W. 
 
Administration- Irinotecan is diluted with 5% dextrose (D5W) to a total volume of 500 mL and 
infused intravenously over 90 minutes. Nothing else should be added to the bag. Patients will be 
given a dose of 180 mg/M2 by intravenous infusion. 
 
7.1.3 Panitumumab  (Refer to Appendix 4): 
Panitumumab will be manufactured and packaged by Amgen and distributed using Amgen’s 
clinical trial drug distribution procedures. Each vial of panitumumab will contain 20 mL of a 
sterile protein solution containing a 20-mg/mL solution of panitumumab. The vial will contain 
approximately 400mg of panitumumab and is for single dose use only. Each vial of 
panitumumab will be labeled in accordance with current ICH GCP, FDA and specific national 
requirements. 
The supplied investigational drug must be stored at 2-8° C in a secured area upon receipt. As 
panitumumab contains no preservatives, vials are designed for single use only. 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. 
Records of the actual storage condition during the period of the study must be maintained (ie, 
records of the date and time and initials of person checking, and the “working day” temperature 
of the refrigerator used for storage of trial supplies, continuous temperature recordings, or 
regularly maintained temperature alarm systems used in conjunction with  temperature recording). 
 
7.2. 
Protocol Dosage Regimen and Administration 
Prophylactic Skin Treatment: The day before treatment is initiated, patients will be given 
minocycline at a dose of 100 mg PO bid followed by daily minocycline at a dose of 100 mg PO 
qd for the duration of therapy. In the STEPP study (Piperdi et al, Abs 394, ASCO GI 2009), 
patients who received prophylactic therapy (doxycycline) had a significant reduction in the 
incidence and severity of rash. There was also an improvement in the risk of diarrhea when 
panitumumab was added to irinotecan in the presence of a prophylactic strategy. 


24 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
If patient experiences reaction to minocycline, it will be discontinued. The trial will proceed 
without modification. 
 
It is also recommended patients wear sunscreen and hats and limit sun exposure. 
 
On days one and 15 of a cycle the following drugs will be administered: Irinotecan 180 mg/m2, 
5-FU 400 mg/m2 bolus, leucovorin 200 mg/m2, panitumumab 6 mg/kg. Finally the patient will 
be given a pump to continue to receive their infusional 5-FU at a total dose of 2400mg/M2 over 
46 hours. Panitumumab will be administered first on each treatment day. A cycle of therapy is 
28 days and the regimen is repeated on Day 29. 
 
Of note: if a patient has required dose reduction of FOLFIRI chemotherapy with their previous 
administrations, then such dose reductions will continue at the time of enrollment in this protocol 
with the exceptions of sub-optimally controlled nausea, vomiting, diarrhea, neutropenia, and 
anemia. Patients with more than 50% reduction of the original dose of infusional 5FU and/or 
irinotecan will not be allowed on the study (see section 4.2.9). The aforementioned side effects 
should be attempted to be controlled with the appropriate supportive measures and the full dose 
of irinotecan should be given. 
Premedication for chemotherapy may be administered prior to, during, or after panitumumab 
administration (if given during panitumumab administration, pre-medications should be given 
through a separate IV line). Panitumumab will be administered until subjects develop disease 
progression or are unable to tolerate panitumumab. 
 
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 at least by + 10%. The total 
dose may be rounded up or down by no greater than 10 mg. The panitumumab dose will be 
diluted in a minimum of 100 mL of pyrogen-free 0.9% sodium chloride solution USP (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 0.22-micron in-line filter infusion set-up over 1 hour ± 15 minutes by 
a trained healthcare professional. In the event a subject’s actual weight requires greater than 150- 
mL volume infusion, panitumumab will be administered over 60 to 90 minutes ± 15 minutes, as 
tolerated. Strict adherence to aseptic technique will 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. 
 
The doses of irinotecan and 5-FU will be calculated on the basis of milligrams of drug per square 
meter of body surface area (BSA). As the weight of the patient may change throughout the 
study, the dose will be recalculated based on the new body surface area prior to the start of each 
cycle. Refer to Appendix 2:  BSA Nomogram for assessment of body surface area 


25 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
7.3. 
Duration of treatment 
Duration of individual patient treatment will depend on individual response and tolerance. Patients 
with clearly documented progressive disease must be taken off therapy with FOLFIRI + 
Panitumumab at time of progression. Patients who are responding (complete or partial), or 
whose disease is stable, will be treated until progression of disease, intolerable toxicity, patient 
refusal to continue with study, or investigator decision to remove patient from study in 
accordance with section 6.8.  Patients who have stable disease or better and have completed 6 
cycles of therapy, may at the treating physician’s discretion, continue with therapy or switch to 
single-agent panitumumab therapy, for improved tolerance.  They may not switch back to 
FOLFIRI + Panitumumab and will be taken off trial should they have disease progression. 
 
7.4. 
Dose Adjustment for 5FU and Irinotecan Toxicities 
 
A cycle is 4 weeks – with treatment on days 1 and 15. We do not make up day #15 treatments if 
a patient should require adjustment or omission based on outlined criteria below. 
 
 This study will take into consideration previous toxicities experienced with FOLFIRI 
prior to enrollment. The initial dose of FOLFIRI will determined by the investigator at 
time of trial initiation. Prior to enrollment, if the patient experienced significant toxicity 
with FOLFIRI and dose adjustments were required, these dose adjustments will continue 
upon initiation of this trial. 
 
 For toxicities which are considered by the investigator unlikely to develop into serious or 
life–threatening events (e.g. alopecia, altered taste etc.), treatment will be continued at the 
same dose without reduction or interruption. In addition, no dose reductions or 
interruptions will be required for anemia as it can be satisfactorily managed by 
transfusions. 
 
 For any event that is apparent at baseline, the dose modifications will apply according to 
the corresponding shift in toxicity grade, if the investigator feels it is appropriate.  (e.g. if 
a patient has grade 1 asthenia at baseline which increases to grade 2 during treatment, this 
will be considered as a shift of 1 grade and treated as a grade 1 toxicity for dose 
modification purposes). 
 
 If on the first day of chemotherapy treatment, the granulocyte count (ANC) is < 1,500 or 
the platelet count is < 75,000, treatment will be held for up to three weeks until ANC is ≥  
1200 and platelet count is ≥ 75,000. CBC should be obtained at least weekly when 
treatment is held. Chemotherapy doses will not be reduced based on nadir counts except 
in febrile neutropenia as defined below. 
 
 If the dose is modified to manage an adverse event, it is recommended that the patient be 
seen by the investigator prior to re-starting study drug. 
 
 If a rest period is extended due to toxicity, the “complete" cycle should be given afterwards 
with chemotherapy and panitumumab. If toxicity requires a dosing delay/interruption  
of  both  5-FU  and  irinotecan  of  more  than  six  weeks  or  at  the 


26 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
discretion of the investigator, the patient will be withdrawn from the study for toxicity 
reasons. 
 
Table 1: Dose modifications during a course of therapy (day #15 of each cycle). 
• Dose adjustments for hematological toxicity during a course of therapy are based on the 
blood counts obtained in preparation for that day of treatment. 
• All dose adjustments are relative to dose given at on day #1 of that cycle. 
 
FOLFIRI Regimen Dose Modification Guidelinea 
Dose Modifications for the Next Cycle Based on the 
Worst Toxicity Observedb,f 
Toxicity Gradeb (CTCAE v4.0) 
5-FU bolus and continuous 
infusion 
Irinotecan 
Neutropenia, Thrombocytopenia, and Leukopenia (since prior treatment) 
0 or 1 
Maintain dose level 
Maintain dose level 
2 
Discontinue 5-FU bolus 
Maintain dose level 
3 
Discontinue 5-FU bolus and 
↓ 1 dose level continuous 
infusion 
↓ 1 dose level 
4 
Discontinue 5-FU bolus and 
↓ 2 dose levels continuous 
infusion 
↓ 2 dose levels 
Neutropenic fever or infectionc 
Discontinue 5-FU bolus and 
↓ 2 dose levels continuous 
infusion 
↓ 2 dose levels 
Diarrhead  (since prior treatment) 
0 or 1 
Maintain dose level 
Maintain dose level 
2 
Discontinue 5-FU bolus and 
↓ 1 dose level continuous 
infusion 
Maintain dose level 
3 
Discontinue 5-FU bolus and 
↓ 1 dose level continuous 
infusion 
↓ 1 dose level 
4 
Discontinue 5-FU bolus and 
↓ 2 dose levels continuous 
infusion 
↓ 2 dose levels 
Mucositis/Stomatitis (since prior treatment) 
0, 1 or 2 
Maintain dose level 
Maintain dose level 
3 
Discontinue 5-FU bolus 
Maintain dose level 
4 
Discontinue 5-FU bolus 
and ↓ 1 dose level 
continuous infusion 
Maintain dose level 
Vomiting (since prior treatment) 
0, 1 or 2 
Maintain dose level 
Maintain dose level 
3 
Maintain dose level 
↓ 1 dose level 
4 
Discontinue 5-FU bolus ↓ 1 
dose level continuous 
infusion 
↓ 1 dose level 


27 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Palmar-plantar erythrodysesthesia 
0, 1 or 2 
Maintain dose level 
Maintain dose level 
3 
Discontinue 5-FU bolus ↓ 1 
dose level continuous 
infusion 
Maintain dose level 
Other nonhematologic toxicities (except alopecia and skin-related toxicities)e 
0, 1 or 2 
Maintain dose level 
Maintain dose level 
3 
Discontinue 5-FU bolus ↓ 1 
dose level continuous 
infusion 
↓ 1 dose level 
4 
Discontinue 5-FU bolus↓ 2 
dose 
levels 
continuous infusion 
↓ 2 dose levels 
a   There will be no leucovorin dose reduction.  If 5-FU bolus dropped, leucovorin will be 
discontinued as well. 
b   NCI CTCAE(Version 4.0) (Appendix E) 
c   Absolute Neutrophil Count <1000/mm3 and Temperature ≥ 38.5°C 
d   Despite maximum supportive care 
e   Bilirubin grade 3 and grade 4 hold dose:  once the bilirubin level has resolved to ≤ grade 1 
a dose reduction for 5-FU and irinotecan is required. 
f    If the patient’s starting dose upon enrollment is not full dose FOLFIRI, future dose 
adjustments will be made as to reflect the starting dose (i.e. proceed to the next recommend 
dose) 
 
 
*There will be no leucovorin dose reduction.  If bolus 5-FU dose omitted, leucovorin is also 
omitted 
 
 
 
7.5. 
Panitumumab Dose Modification for Toxicity- (Please refer to Table 3). 
The starting panitumumab dose is 6 mg/kg every 2 weeks. 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%. Panitumumab will be diluted in a minimum of 100 mL of 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 


28 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
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 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 (ie 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 to 90 
minutes ± 15 minutes, as tolerated. 
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. 
See Appendix 6 Pharmacy Guide for information on panitumumab packing and formulation, 
labeling, storage, preparation, supply/return, and accountability. 
 
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 according to institutional guideline or investigator’s discretion. 
 
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 and will be at the discretion of the investigator. Suspected infusion reactions should be 
reported as an adverse event. All subjects who experience such an event will be followed for 
safety. 
 
Toxicity Assessment 
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 (CTCAE) version 4.0 
(Appendix 4), with the exception of skin- or nail-related toxicities, which must be graded using 
CTCAE version 3.0 with modifications (see Appendix 4a). 
 
Panitumumab Dosage Adjustments 
For subjects who experience toxicities while on study, one or more doses of panitumumab may 
need to be withheld, reduced, or delayed (administered at > 14 day intervals). On resolution of 
toxicity, a limited number of attempts to re-escalate reduced panitumumab doses will be allowed 
(outlined in Figure 4). Dose escalations above 6 mg/kg starting dose are not allowed. 
Panitumumab dose reductions are listed in Table 3. 
 
 
 
Table 3.  Panitumumab Dose Reductions 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
Percentage (%) 
100 
80 
50 
mg/kg 
6 
4.8 
3.0 
 


29 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Criteria for Withholding a Dose of Panitumumab 
Skin- or nail-related toxicities: 
• 
Symptomatic skin- or nail-related toxicity requiring narcotics, systemic steroids, or felt to 
be intolerable by the subject 
• 
Skin or nail infection requiring IV antibiotic or IV antifungal treatment 
• 
Need for surgical debridement 
• 
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 (see Section 6.6 and 6.7.1 for diarrhea management 
guidelines) 
• 
Panitumumab will only be withheld for grade ≥ 3 anemia or grade 4 thrombocytopenia 
that can not be managed by transfusion(s) or cytokine therapy 
 
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, and; 
• 
The subject has recovered to the point where symptomatic skin- or nail-related toxicity is 
felt to be tolerable; and, 
• 
Systemic steroids are no longer required, and 
• 
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. 
 
 
Dose Modification Schedule 
• 
Subjects should be assessed for toxicity before each dose.  Dose modification should be 
performed according to the schedule described below and outlined in Figure 1. 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
• 
Subjects who develop a toxicity that does not meet the criteria for withholding a dose of 
panitumumab (Section 6.5) 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 6.5). 
• 
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. The 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 50% 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 50% dose level. 
• 
Subjects who experience toxicity at the 50% 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 6.5). 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 50% 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). 
• 
Subjects who miss 3 or more 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. 
• 
In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, 
crackles, or radiological pulmonary infiltrates, panitumumab should be discontinued until further 
pulmonary investigation 


31 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
Panitumumab Delayed- or Missed-Doses 
Panitumumab should be administered by IV infusion on the first day of each treatment cycle. 
However, if panitumumab dose cannot be administered as scheduled, every attempt should be 
made to administer the drug within 3 days of the scheduled dose (up to 3 days before the 
scheduled dose or up to 3 days after the scheduled dose). If it is necessary to change a subject’s visit 
from the originally scheduled date, the subsequent visits should continue at the previously scheduled 
days/dates. If the dose is not administered within the ± 3-day window, the dose will be considered a 
missed dose, and the next scheduled dose should be given at the time of the regularly scheduled 
dose.  Missed doses will not be made up. 
 
Discontinuation of Panitumumab 
Panitumumab will be administered until subjects are unable to tolerate panitumumab, disease 
progression, death, or study withdrawal by the subject, investigator, or sponsor 
 
Electrolyte Management 
Electrolytes and Magnesium levels will be evaluated as outlined in the schedule of assessment 
table in Section 5.5 . In the presence of abnormal values, patients will be managed as per 
standard institutional practice. If hypomagnesemia is present, replacement should be managed with 
either oral or parenteral replacement, or both, according to institutional practice and to the grade 
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 standard institutional practice, within the 
normal ranges during study treatment. 
Electrolytes will be followed for 8 weeks after completion of the trial to insure proper replacement. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


32 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
Administer panitumumab @ 60% of original dose 
Toxicity recurs?* 
If toxicity recurs* at the 60% 
of the original dose, 
discontinue  panitumumab 
Maintain at 60% of original 
dose (if a previous attempt 
to dose escalate to 80% 
was not tolerated) 
Figure 4.  Dose modification for panitumumab-associated skin toxicity (see below) 
 
Severity of Toxicity 
 
 
No/Mild/Moderate  Toxicity 
Severe Toxicity* 
Life Threatening or 
Disabling Toxicity 
Continue per protocol 
(Symptoms should be treated per 
protocol) 
Withhold panitumumab for 1 dose 
Toxicity resolved? 
 
Discontinue 
Panitumumab 
NO 
 
Withhold an additional dose of panitumumab 
 
 
Toxicity resolved? 
YES 
 
Administer panitumumab @ 100% of original dose 
(recommended but not required) 
If toxicity recurs*, withhold panitumumab 
for 1 or 2 doses‡ 
Toxicity resolved? 
 
 
 
NO 
 
Discontinue 
YES 
YES 
NO 
 
Discontinue 
Panitumumab 
Administer panitumumab @ 80% of original dose 
Panitumumab 
 
Toxicity recurs?* 
 
 
YES 
 
Withhold panitumumab for 1 or 2 
doses‡ 
Toxicity resolved? 
 
 
NO 
YES 
NO 
Administer panitumumab @ 100% of original dose 
(recommended but not required) 
OR 
Maintain at 80% of original dose 
(if a previous attempt to dose escalate to 100% was not 
tolerated) 
 
Discontinue 
Panitumumab 
Administer panitumumab at 50% of original dose 
Toxicity recurs?* 
 
NO 
YES 
 
 
Escalate to 80% of original dose 
(recommended but not required)  OR 
 
If toxicity recurs*, withhold 
panitumumab until toxicity 
resolves and maintain at 60% of 
the original dose 
 
Maintain at 50% of original dose (if a 
previous attempt to dose escalate to 
80% was not tolerated) 
 
 
If toxicity recurs* at 50% of the 
original dose, discontinue 
panitumumab 
Discontinue 
Panitumumab 


33 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
* Assess toxicity before each cycle. Toxicity recurs = meets the criteria for withholding a dose of panitumumab at any time 
during the study (See Section 6.3.1). 
 Assess toxicity before each cycle. Toxicity resolved = meets the criteria for restarting panitumumab (see section 
6.3.2). Subjects from whom > 2 subsequent cycles of panitumumab are required to be withheld should not be re-
treated with panitumumab. 
‡ Up to 2 subsequent doses of panitumumab may be withheld but panitumumab may not be withheld longer than 6 weeks 
from the previous dose.  The second dose should only be withheld if the toxicity has not resolved by the time that the 
subsequent cycle of chemotherapy is due. 
Mild/Moderate: Papules and/or pustules covering <10% BSA, which may or may not be associated with 
symptoms of pruritus or tenderness. Papules and/or pustules covering 10 - 30% BSA, which may or may not 
be associated  with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting 
instrumental ADL 
 
Severe: Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of 
pruritus or tenderness; limiting self care ADL; associated with local superinfection with oral antibiotics 
indicated. Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms 
of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-
threatening consequences 
7.6. 
Special Instructions Regarding Treatment of Toxicity 
 
Infusion-Related Toxicity and Hypersensitivity: 
Careful attention to prophylaxis and bedside monitoring of vital signs is recommended. 
Discontinue therapy for anaphylaxis. Mild symptoms: (e.g., mild flushing, rash, pruritus): 
complete infusion, supervise at bedside. No treatment required. Panitumumab is contraindicated 
in patienst with a history of life-threatening hypersensitivity reaction to panitumumab or any of 
the excipients. 
 
Moderate Symptoms: (e.g., moderate rash, flushing, mild dyspnea, chest discomfort): Stop 
chemotherapy infusion. Give intravenous diphenhydramine 25 
mg and intravenous 
dexamethasone 10 mg. Resume infusion after recovery of symptoms at a low rate of infusion, 20 
mg/hr for 15 minutes. Then, if no further symptoms develop, resume infusion at full dose rate 
until infusion has been completed. If symptoms recur, stop infusion. Remove patient from 
protocol therapy.  Report as an adverse event. 
 
Severe Life-threatening Symptoms: (e.g., hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilator therapy, generalized urticaria): Stop infusion. Give 
intravenous diphenhydramine and dexamethasone, as indicated above. Add epinephrine and / or 
bronchodilators if indicated. If wheezing is present and is not responsive to adrenaline, then 
administer 0.35 ml of nebulized salbutamol solution (or equivalent). Remove patient from 
protocol therapy.  Report as an adverse event. 
 
Diarrhea 
Irinotecan can cause diarrhea, and should be stopped at diarrhea grade ≥ 2, and treated 
symptomatically (recommend IV hydration and use of loperamide for diarrhea, observing 
loperamide dosage recommendation and treatment start, see below).  If control takes longer than 
2 days, medical evaluation including relevant diagnostic procedures, alternative treatment and 
possible investigation of DPD deficiency should be considered. Irinotecan cannot be re-started 
until diarrhea has resolved to grade < 2 with the last loperamide dose given at least 24 hours 
beforehand. 
The recommended dosage regimen for loperamide: 4 mg at the first onset of late diarrhea and 
then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
the patient may take 4 mg of loperamide every 4 hours. Note: This dosage regimen exceeds the 
usual dosage recommendations for loperamide. Premedication with loperamide is not 
recommended. 
The use of drugs with laxative properties should be avoided because of the potential for 
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any 
laxative use. 
 
Grade ≥ 2 Nausea/Vomiting 
For nausea and vomiting the patients must be supplied with anti-emetics in order to help 
themselves in case nausea or vomiting occurs at home. The choice and dose of anti-emetics will 
be determined by the treating physician. Adequate secondary prophylactic treatment and IV 
hydration should be initiated once nausea or vomiting has occurred. If the adverse event recurs 
despite prophylaxis, then dose modifications should also be according to the table above. 
 
Fever/Infection with or without neutropenia 
Chemotherapy should be stopped immediately. Appropriate anti-infective therapy should be 
initiated. When the ANC has recovered to ≥ 1,500/mm3 and the fever or infection has resolved, 
the patient may restart treatment. 
 
Skin Toxicity 
With panitumumab, various degrees of skin toxicity, specifically rash and erythema have been 
reported. Topical emollients have been used with some success in mild cases. If the rash were 
to develop to have small acneiform pustules, topical antibiotic ointments have been used with 
varying amounts of success as well. The rash is self-limiting and dissipates upon cessation of the 
drug in the majority of cases. 
 
It is recommended patients use suncscreen and hats to limit sunexposure while on receiving 
panitumumab. 
 
Pulmonary Toxicity 
Panitumumab may cause pulmonary fibrosis. In case of unexplained respiratory symptoms such 
as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, panitumumab 
should be discontinued until further pulmonary investigation. 
 
 
7.7. 
Supportive Therapy 
 
 
7.7.1. Diarrhea 
Loperamide: All patients will be instructed to begin taking loperamide at the earliest signs of 
diarrhea (i.e. first poorly formed or loose stool, first episode of two or more bowel movements in 
one day) that occurs more than 12 hours after receiving irinotecan. Loperamide should be taken 
in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around-the- 
clock until diarrhea-free for at least 12 hours. Patients may take loperamide 4 mg every 4 hours 
during the night. 
Atropine: Diarrhea or abdominal cramping that occurs during or within one hour after receiving 
irinotecan should be treated with atropine 0.4 mg IM or Subq. Additional antidiarrheal measures 
may be used at the discretion of the treating physician. Atropine should be used with caution in 


35 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
patients with potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, etc.). 
 
7.7.2. Nausea and Vomiting 
Antiemetics: Patients should receive antiemetics prior to chemotherapy administration according 
to institution guidelines. 
 
7.7.3. Myelosuppresion 
Growth Factors: Routine prophylactic use of a colony-stimulating factor (G-CSF or GM-CSF) is 
not permitted. Therapeutic use in patients with serious neutropenic complications such as ANC 
of < 500 for more than 5 days, fever accompanying grade 3-4 neutropenia, or obvious sepsis may 
be considered, at the investigator's discretion. 
Erythopoietin treatment for moderate to severe anemia (< 10 mg/dl) is permitted in the study. 
 
 
7.8. 
Concomitant Medications and Treatments 
5-FU and some of its metabolites are converted principally by liver enzymes (carboxylesterase 
and cytidine deaminase and PyNPase in tumor tissues). At present, it is unknown whether this 
metabolism is likely to be influenced by other treatments or alcohol, which either induce or 
inhibit certain liver enzymes. 
Laxatives:  The use of drugs with laxative properties should be avoided. 
 
7.9. 
Warnings and Precautions regarding specific agents used in this protocol 
 
7.9.1 5-Fluorouracil: 
 
Cardiovascular: Although uncommon, fluorouracil has been associated with chest pain, anginal 
attacks, ischemic electrocardiographic changes, myocardial infarction, cardiomyopathy, and very 
rarely, sudden death. Most commonly, these effects occur when the drug is administered as a 
continuous infusion and within several hours from the start of the infusion. Patients with pre- 
existing coronary artery disease (CAD) appear to be at greater risk; however, most reported cases 
are in those with no previous history of CAD. 
 
Dermatologic: Contact dermatitis, Alopecia, dry skin, fissuring, hand-foot syndrome, nail 
changes, rash, photosensitivity, and vein pigmentation have been reported in patients receiving 
intravenous fluorouracil 
 
Hematologic toxicity: primarily neutropenia, occurred significantly more often in patients 
receiving bolus injections (31% versus 4%, RR 0.14, p less than 0.0001). Anemia and 
thrombocytopenia occurred in less than 5% of all patients. agranulocytosis, anemia, epistaxis, 
pancytopenia, and thrombocytopenia have also been reported during treatment with intravenous 
5-FU. Factors increasing the risk for hematologic toxicity included a poor performance status 
and fluorouracil administration by bolus injection, while increased age, female gender, and a 
good performance status significantly increased the risk for nonhematologic toxicities. In hand- 
foot syndrome, continuous administration of fluorouracil was an additional prognostic factor. 
 
Gastrointestinal: Commonly occurring symptoms during IV fluorouracil therapy are stomatitis, 
esophagopharyngitis, nausea, vomiting, anorexia and diarrhea 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Neurologic: Neurological effects reported with the administration of fluorouracil include 
confusion, disorientation, euphoria, nystagmus, headache, and acute cerebellar syndrome. 
 
7.9.2 
Irinotecan: 
Bone Marrow Suppression: Virtually all phase I and II studies of irinotecan have reported 
neutropenia that may be dose limiting. Anemia and lymphocytopenia have been observed as 
well. 
GI: Diarrhea- abdominal cramping, and diarrhea (early diarrhea) during or shortly after 
irinotecan administration; late diarrhea (diarrhea occurring more than 8 hours after irinotecan 
administration) as the dose-limiting toxicities (depending upon the schedule). Other commonly 
observed adverse events include nausea and vomiting, anorexia, abdominal cramping. Infrequent 
occurrences of mucositis or colitis (sometimes with gastrointestinal bleeding) have been 
observed. 
Skin: alopecia, asthenia. irinotecan may cause local irritation at infusion sites. Extravasation 
necrosis of the skin has not been reported in US studies. 
Constitutional: Dehydration has occurred as a consequence of diarrhea, particularly when 
associated with severe vomiting. Patients may have an acute syndrome of lacrimation, 
diaphoresis, this syndrome is thought to be cholinergically mediated. 
Pulmonary: Sporadic cases of pulmonary 
toxicity, manifested as shortness of breath, 
nonproductive cough, and transient infiltrates on chest X-ray have been reported. 
Renal: Occasionally, abnormalities of serum Creatinine have been observed. 
 
8. 
STUDY OUTCOME MEASURES 
 
8.1. 
Objective Response Rate (ORR) 
Objective response of measurable disease will be in accordance with the criteria described in 
RECIST 1.1 guidelines (45) 
Only measurable lesions which have not been irradiated will be used as indicator lesions. These 
must have a minimum size of at least one diameter of 10 mm for liver, soft tissue lesions, lung, 
skin and lymph node lesions. 
In responding patients, the response must be confirmed at a minimum of 4 weeks. 
 
8.2. 
Progression Free Survival (PFS) 
PFS will be measured as the time from Study Day 1 to the time the patient is first recorded as 
having disease progression or death, whichever comes first. 
 
8.3. 
Overall Survival (OS) 
Survival will be recorded as the time from Study Day 1 to the date of death or the last date the 
patient was known to be alive. 
 
8.4. 
Duration of Response 
Duration of response is defined as the date of first response to the date of first disease 


37 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
progression or death due to any cause, whichever comes earlier, in the subset of subjects with 
confirmed objective response (RECIST criteria in Appendix 5). 
9. 
SAFETY PARAMETERS 
 
9.1. 
Abnormal Laboratory Test Values 
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. 
 
9.2. 
Pregnancy 
The patient will be removed from the study if she becomes pregnant during the study and 
immediately inform the investigator. The investigator should counsel the patient, and discuss the 
risk of continuing with the pregnancy and the possible effects on the fetus. Monitoring of the 
patient should continue until conclusion of the pregnancy. 
Pregnancy occurring in the partner of a patient participating in the study must also be treated as 
described above. 
 
9.3. 
Data Safety Monitoring and Submission: 
 
Data Safety Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at their 
regular Disease Group meetings (at least monthly) and the discussion will be documented in the 
minutes. The PI of the trial will review toxicities and responses of the trial, where applicable, at 
these disease centered meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources, including published literature, scientific 
meetings and discussions with sponsors, to determine if the trial should be terminated before 
completion. Serious adverse events and responses will be reviewed by the OSUCCC Data and 
Safety Monitoring Committee (DSMC). The PI will also submit a progress report (biannually for 
Phase II and quarterly for Phase I) that will be reviewed by the committee per the IRB of record as 
per the policies of the IRB. 
 
Mandatory safety and trial review teleconferences will be scheduled and moderated by the Multi-
Center Trial Program (MCTP). All sites involved in the study are expected to have a representative 
present for every call to review and discuss patients on study and other applicable agenda items. 
Meeting minutes will be used to document each teleconference. The minutes will be stored in the 
MCTP protocol files. 
 
Data Submission 
 
The study will be managed per the Multi-Center Trial Program (MCTP) policies. Subsite data must 
be submitted to the MCTP within 2 weeks of completion of each cycle. Data will be submitted 
using case report forms and the Data Submission Form cover sheet (refer to Supplemental Forms 
Document) supplied by the MCTP. Access to the OSU OnCore database may be provided to 
external participating sites for direct electronic data entry. All data submitted must be accompanied 
by supporting source documents. 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Adverse Events 
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 skin toxicity, which will be graded by modified CTCAE version 3.0 Dermatology Skin 
Assessment (Appendix 4). 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 findings without clinical 
significance (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. 
 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that: 
• 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. 
 
Reporting Procedures for All Adverse Events 
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 on the case report 
form. 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. 
 
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. 
 


39 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
Amgen may request follow-up information. 
 
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. 
 
Serious Adverse Events Reporting Procedures 
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. 
 
Subsite SAE reporting requirements are located at the end of this section. Subsites are NOT 
permitted to report directly to the FDA, Amgen, or the OSU IRB. 
 
The investigator should notify the Sponsor (John Hays, MD, PhD) 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 
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. 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 
AND Principle Investigator:  John Hays, MD, PhD 
AND The Ohio State University IRB: 
 
 
 


40 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
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. 
 
Subsite SAE Reporting Requirements 
Subsites are NOT permitted to report directly to the FDA, Amgen, or the OSU IRB. Subsites 
must notify the OSU PI and OSU Subsite Coordinator of all SAEs within 24 hours of knowledge 
of the event. All SAEs must be reported on a MedWatch 3500A and submitted with the SAE 
Submission Form (Appendix 8) to the OSU Subsite Coordinator within 5 business days of 
knowledge of the event. All subsite SAEs will be reviewed by the OSU PI. Any subsite SAE that 
requires reporting to the FDA, Amgen, or the OSU IRB will be sent by the OSU Subsite 
Coordinator. Subsites should report to their IRB of record per their institutional and IRB policies.


41 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
10. 
STATISTICAL CONSIDERATIONS 
 
HYPOTHESIS AND ENDPOINTS 
With median progression-free survival (PFS) as the primary endpoint, the primary objective of 
this single arm, open-label, phase II study is to determine the median PFS for FOLFIRI and 
panitumumab in patients with metastatic RAS wild-type colorectal carcinoma who have 
previously failed FOLFIRI and bevacizumab. 
The secondary endpoints of this study are the frequency and severity of toxicities of the regimens, 
overall response rate, and overall survival rate at 1 year. 
 
10.1. 
Study design and Sample Size Calculation: 
The PRIME study is a phase III clinical trial, in which patients with metastatic colorectal cancer 
and KRAS (codon 12 and 13) wild-type tumors were randomized to FOLFOX or FOLFOX and 
panitumumab for first-line therapy. Retrospective analysis of the additional RAS mutations 
showed that patients with tumors that were RAS wild-type had a 2.2 month improvement in PFS 
when panitumumab was added to FOLFOX (7.9 vs. 10.1 months [HR 0.72m 95% CI 0.58-0.90, 
p=0.004]) (43). Patients receiving FOLFIRI plus panitumumab after failing first–line non- 
irinotecan containing treatment for RAS wild-type metastatic colorectal cancer patients had a 
reported mPFS of 5.9 months compared to 3.9 months for those treated with FOLFIRI alone 
(36). Also, per the BOND study, patients who had disease progression on prior irinotecan-based 
chemoregimens were randomized to either cetuximab monotherapy or cetuximab and irinotecan. 
Median time to progression was improved by 2.6 months with the combination arm (1.5 vs 4.1 
months, comparing cetuximab vs cetuximab and irinotecan) (34). We expect a similar treatment 
effect for panitumumab and FOLFIRI in our study following FOLFIRI plus bevacizumab failure. 
As such, we expect our group of patients to have an improved mPFS (6 months) compared to the 
historical control of a similar patient population treated with irinotecan and cetuximab (3.98 
months) in RAS wild-type metastatic colorectal cancer (36). 
 
We anticipate a uniform accrual rate of 2 patients per month, no lost to follow-up, and an 
additional 6 months of planned follow-up after accrual is completed. A total of 25 subjects will 
be required to detect the difference between a median PFS of 6 months for our testing treatment 
and a median PFS of 4 months for the historical control assuming exponential PFS distribution. 
The one-sided type I error and the power have been set at 0.10 and 80% respectively when 
calculating the sample size using the online sample size calculator provided by SWOG 
(http://www.swogstat.org/statoolsout.html). 
 
With a total of 25 patients, we will be able to construct 95% confidence intervals no wider than 
20% for proportions. If a specific adverse event occurs with a true probability of 10%, the 
probability of observing one or more patients with the AE in 25 patients will be about 93%. 
 
 
10.2. 
Analysis of Primary and Secondary Efficacy Parameters 
Continuous variables will be expressed by means, standard deviations and 95% confidence 
intervals. Frequencies will be computed for discrete data. Median PFS will be estimated using 
the  Kaplan-Meier  estimator  with  confidence  interval  calculated  based  on  the  Brookmeyer- 
Crowley method (38). Kaplan-Meier estimator will be used also to estimate OS rate at 1 year. 
 


42 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
 
11. 
TISSUE COLLECTION AND CORRELATIVE ANALYSIS 
 
11.1 Tissue collection only applies to patients who were enrolled during previous version of the 
protocol, when only KRAS codon 12 and 13 were assessed for enrollment eligibility.  Tissue is 
collected so that additional RAS mutations can be assessed retrospectively.  Thus, if all RAS 
mutations [KRAS exon 2 (codon 12 and 13),exon 3 (codon 61) and exon 4 (codons 117 and 146) 
and NRAS exon 2 (codons 12 and 13), exon 3 (codon 61), and exon 4 (codons 117 and 146)] are 
checked prior to trial enrollment, then no tissue collection is needed. A new biopsy will is not 
required strictly for purposes of this correlative study. Paraffin-embedded tissue will be obtained 
from OSU Department of Pathology via the Histology Core Facility as per standard. 
 
Diagnostic samples shall be formalin-fixed and paraffin-embedded according to standard 
laboratory procedures, with the purpose of storing for future analysis of additional RAS 
mutations including: KRAS codon exon3 and 4 and NRAS exon 2, 3, and 4. 
 
 
For participating subsites, no tissues in formalin or ethanol should be sent to the Ohio State 
University. Participating subsites will use their own standard laboratory protocol and supplies 
(e.g. formalin, ethanol, paraffin, tissue cassettes, etc) to perform the paraffin-embedding. For 
surgical specimens, we will defer to handling of the specimen as per the institutional standard 
practice of grossing the specimen and preparing it for Surgical Pathology evaluation (e.g. 
surgical margins, histology, lymph node, etc.). 
 
11.2 SPECIMEN SUBMISSION 
 
11.2.1 If the recommended blocks cannot be released to OSU for correlative research, we ask 
that unstained slides are required to be cut as outlined: 
 
1-Tissue Sections diameter >5 mm, include five sections, 10 um in thickness. 
 
2-Tissue sections diameter< 5mm square, include 15-20 sections 10um in thickness. 
3- Please use NON-PLUS slides and one H&E (2-4um) for each block. 
For these molecular studies, multiple tissue sections can be collected on one glass slide, as the tissue 
itself is digested and scraped off the slide, thus there is not a need to mount one section per slide. The 
slides will be air dried (not oven-dried). The slides will be stored at room temperature (>16°C). 
 
 
 
 
 
 
 
 
 
 


43 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
 
11.2.2 Shipping of specimen(s): 
Pathology material including copies of pathology reports for the diagnostic/surgical specimens, tissue 
blocks, H&# stains, or unstained slides to: 
 
John Hays, MD, PhD 
Department of Internal Medicine 
Divison of Medical Oncology 
A445 Starling Loving Hall 
320 West 10th Avenue 
Columbus, OH, 43210 
Clinical office: 614-293-9424 
Fax: 614-293-7520 
Email: John.Hays@osumc.edu 
 
Shipments should be made Monday through Thursday. 
Please notify Dr. Hays by email on or before the day of submission, with the (1) name of the contact 
person, (2) when to expect the sample, and (3) the overnight shipping carrier and tracking number. 
If the submitting institution would like us to return the tissue blocks, please notify Dr. Hays. 
 
 
12. 
REFERENCES 
1. American Cancer Society. Cancer Facts and Figures 2004. 
 
2. Conti JA, Kemeny NE, Saltz LB, et al. Irinotecan is an active agent in untreated subjects 
with metastatic colorectal cancer. J Clin Oncol. 1996;14:709-715. 
 
3. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil 
compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a 
multicenter randomized trial. Lancet. 2000;355:1041-1047. 
 
4. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without 
oxaliplatin as first-line 
treatment in advanced colorectal cancer. J Clin Oncol. 
2000;16:2938-2947. 
 
5. Fyfe, G., et al., Bevacizumab plus irinotecan/5-FU/leucovorin for treatment of metastatic 
colorectal cancer results in survival benefit in all pre-specified patient subgroups. ASCO, 
2004. 23: Abstract 3617. 
 
6. Badarinath S, Mitchell EP, et al. Cetuximab plus FOLFOX for colorectal cancer 
(EXPLORE): Preliminary safety analysis of a randomized phase 3 trial. J Clin Oncol. 
2004; 22(14S): 3531. 
 
7. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Crit Rev Oncol Hematol. 2001 
Apr;38(1):17-23. 
 
8. Yang X-D, Jia X-C, Corvalan JRF, Wang P, Davis CG, Jakobovits A. Eradication of 
established tumors by a fully human monoclonal antibody to the epidermal growth factor 


44 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
receptor without concomitant chemotherapy. Cancer Res. 1999:59:1236-1243. 
 
9. Mendelsohn J, Baselga, J. Status of epidermal growth factor receptor antagonists in the 
biology and treatment of cancer. J Clin Oncol. 2003; 21:2787-2799. 
10. Hecht J, Mitchell E, Baranda J, Malik I, Richards D, Navale L, D'Avirro P, Amado R. 
Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer 
(mCRC) expressing low (1-9%) or negative (<1%) levels of epidermal growth factor 
receptor (EGFr). J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, 
No. 18S (June 20 Supplement), 2006: 3547. 
 
11. Berlin J, Neubauer M, Swanson P, Harker W, Burris H, Hecht J, Navale L. Panitumumab 
antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing 
> 10% epidermal growth factor receptor (EGFr). J Clin Oncol, 2006 ASCO Annual 
Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3548. 
 
12. Marc Peeters, Eric Van Cutsem, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart 
Neyns, Jean Luc Canon, Jean Luc Van Laethem, Joan Maurel, Gary Richardson, The 
Panitumumab Study Team. A phase 3, multicenter, randomized controlled trial (RCT) of 
panitumumab plus best supportive care (BSC) vs BSC alone in patients (pts) with 
metastatic colorectal cancer (mCRC). Abs CP-1. AACR annual meeting 2006. 
 
13. Hecht J, Posey J, Tchekmedyian S, Hu E, Chan D, Malik I., Yang L, MacDonald M, 
Berlin J. Panitumumab in combination with 5-fluorouracil, leucovorin, and irinotecan 
(IFL) or FOLFIRI for first-line treatment of metastatic colorectal cancer (mCRC). 2006 
Gastrointestinal Cancers Symposium, Abstract #237. 
 
14. Panitumumab Investigator’s Brochure, ed. 8.0; Thousand Oaks, CA: Amgen Inc. 2009. 
 
15. Chu E, DeVita VT eds. Cancer Chemotherapy Drug Manual 2004. Boston: Jones and 
Bartlett 
 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
7. 
21. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes- 
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FOLFOX or the reverse sequence in advanced colorectal cancer: A randomized 
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23. Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Carteni G, Agostara 
B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di 
Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, 
Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis 
G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico 
Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the 
treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico 
Dell'Italia Meridionale.  J Clin Oncol. 2005 Aug 1;23(22):4866-75. 
 
24. Dencausse Y, Hartung G, Sturm J, Kopp-Schneider A, Hagmüller E, Wojatschek C, 
Lindemann H, Fritze D, Queisser W. Adjuvant chemotherapy in stage III colon cancer 
with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin. Onkologie. 2002 
Oct;25(5):426-3. 
 
25. DePlacido S, Lopez M, Carlomagno C, Paoletti G, Palazzo S, Manzione L, Iannace C, 
Ianniello GP, DeVita F, FicorellaC, Farris A, Pistillucci G, Gemini M, Cortesi E, Adamo 
V, Gebbia N, Palmeri S, Gallo C, Peronne F, Persico G, Bianco AR. Modulation of 5-FU 
as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL muticentre, 
randomized Phase III study.  Br J Cancer. 2005 Oct 17;93 (8): 896-904. 
 
26. Clarke S, Goldstein D, Mitchell P, Michael M, Beale P, Friedlander M, Zalcberg J, White 
S.  Modification of Leucovorin Dose Within a Simplified FOLFOX Regimen Improves 
TolerabilityWithout Compromising Efficacy. Clin Colorec Ca. 2007 July; 6(8). 
 
27. Dorr RT, Von Hoff DD eds. Cancer chemotherapy handbook. Norwalk: Appleton & 
Lange, 1994:2. 
 
28. Eckardt J, Eckhardt G, Villalona-Calero M, et al. New anticancer agents in clinical 
development. Oncology 1995;9:1191-1199. 
 
29. Kano Y, Suzuki K, Akutso M, et al. Effects of Irinotecan in combination with other anti- 
cancer agents in culture. Int J Cancer 1992, 50: 604-610. 
 
30. Beidler DR, Cheng YC. Camptothecin induction of a time and concentration dependent 
decrease of topoisomerase I and its implication into camptothecin activity. Molecular 
Pharmacology 1995; 47: 907-914. 
 
31. Murren JR, Beidler DR, Cheng Y. Camptothecin (CPT) resistance related to transient 


46 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
TOPO-1 decrease and steps after CPT: TOPO I interaction. The camptothecins: From 
discovery to the patient; NY Academy of Sciences conference 1996; 9. 
 
32. Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, 
Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily 
bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or 
oxaliplatin: results from Intergroup Trial N9741.Cancer. 2004 Nov 15;101(10):2170-6. 
 
33. Maiello E, Gebbia V, Giuliani F, Paoletti G, Gebbia N, Borsellino N, Carteni G, Pezzella 
G, Manzione L, Romito S, Lopez M, Colucci G. FOLFIRI regimen in advanced 
colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale 
(GOIM).Ann Oncol. 2005 May;16 Suppl 4:iv56-iv60. 
 
34. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser 
M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and 
cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J 
Med. 2004 Jul 22;351(4):337-45. 
 
35. Vincenzi B, Santini D, Rabitti C, Coppola R, Beomonte Zobel B, Trodella L, Tonini G. 
Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a 
single centre phase II trial. Br J Cancer. 2006 Mar 27;94(6):792-7. 
36. Peeters, M. et al. Randomized phase 3 study of panitumumab with fluorouracil, 
leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line 
treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-4713. 
 
37. Rothenberg ML, Oza AM, Gigelo R., Berlin J., Marshall J., et al. Superiority of 
oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients 
with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin : Interim 
results of a phase III trial. J Clin Oncol. 2003:21:2059-2069. 
 
38. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz 
MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. Bevacizumab 
in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously 
treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group 
Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. 
 
39. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith 
DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, 
Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research 
Institute Colorectal Clinical Studies Group. Different strategies of sequential and 
combination chemotherapy for patients with poor prognosis advanced colorectal cancer 
(MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. 


47 
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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
40. Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, 
Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P. KRAS mutation 
status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 
2006 Apr 5;66(8):3992-5. 
 
41. Amado R, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman D, Juan T, Sikorski R, 
Suggs S, Radinsky R, Patterson SD, Chang DD.  Wild-Type KRAS Is Required for 
Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer.  JCO Apr 1 2008: 
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42. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky 
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Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III 
trial of panitumumab with infusional fluoruracil, leucovorin, and oxaliplatin (FOLFOX4) 
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43. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, 
Bodoky G, Cunningham D, Jassem J, Rivera F. Kocakova I, Ruff P, Blasinska-Morawiec 
M, Smakal M, Cannon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, 
Patterson SD. Panitumumab-FOLFOX4 Treatment and RAS Mutations in Colorectal 
Cancer. N Enl J Med 2013;369:1023-1034 
 
44. Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in 
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(mCRC) patients. Presented at: European Cancer Congress 2013; The Netherlands: 
Abstract LBA1745.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, 
Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, 
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fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. Ann 
Onc 2008;19(suppl 8): 385P 


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THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
13. 
APPENDICES 
 
Appendix 1:  ECOG Performance Status Scale 
Patient performance status will be graded according to the ECOG Scale: 
 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g. light housework, office work. 
 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Appendix 2: BSA Nomogram 
 
 


50 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
 
Appendix 3: CTC - Common Toxicity Criteria 4.0 
 
Version 4.0 of the NCI "Common Toxicity Criteria” can be found and downloaded from the 
CTEP website, http://ctep.cancer.gov/reporting/ctc.html 
 
Appendix 4a.  Dermatology/Skin/Nail Assessment (from CTCAE version 3.0 with 
modifications) 
 
Adverse Event (Short 
Name) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nail changes (Nail 
changes) 
Discoloration; 
ridging 
(koilonychias; 
pitting) 
paronychia: 
intervention not 
indicated 
Partial or 
complete loss of 
nail(s); pain in 
nailbed(s), 
paronychia: 
intervention 
indicated 
Interfering with 
activities of daily 
living (ADL) 
  
 
Erythema 
(Erythema) 
Painless 
erythema 
Painful 
erythema 
Erythema with 
desquamation* 
Life-threatening; 
disabling 
Pruritis/itching (Pruritis) 
Mild or localized 
Intense or 
widespread 
Intense or 
widespread and 
interfering with ADL 
  
 
Rash: acne/acneiform 
(Acne) 
Intervention not 
indicated 
Intervention 
indicated 
Associated with 
pain requiring 
narcotic analgesics, 
ulceration, or 
desquamation* 
  
 
Rash/desquamation* 
(Rash) 
[Use for non-acneiform 
rash or non-folliculitis 
rash] 
Macular or 
papular eruption 
or erythema 
without 
associated 
symptoms 
Macular or 
papular eruption 
or erythema with 
pruritis or other 
associated 
symptoms; 
localized 
desquamation* 
or other lesions 
covering < 50% 
of body surface 
area (BSA) 
Severe, 
generalized 
erythroderma or 
macular, papular or 
vesicular eruption; 
desquamation* 
covering ≥ 50% 
BSA 
Generalized 
exfoliative, 
ulcerative, or bullous 
dermatitis 
Ulceration (Ulceration) 
  
 
Superficial 
ulceration < 2 
cm size; local 
wound care; 
medical 
intervention 
indicated 
Ulceration ≥ 2 cm 
size; operative 
debridement, 
primary closure or 
other invasive 
intervention 
indicated (eg, 
hyperbaric oxygen) 
Life-threatening 
consequences; 
major invasive 
intervention 
indicated (eg 
complete resection, 
tissue 
reconstruction, flap, 
or grafting) 
 
*Desquamation is defined as sloughing of skin and does not apply to dry flaking skin. 


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IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
Appendix 4: Panitumumab Pharmacy Guide 
Packaging, Formulation, Labeling and Storage 
Panitumumab will be manufactured and packaged by Amgen and distributed using 
Amgen’s clinical trial drug distribution procedures. Each vial of panitumumab will 
contain 10 mL of a sterile 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.  Each vial of panitumumab will be labeled in accordance with 
current ICH GCP, FDA and specific national requirements. 
The supplied investigational drug must be stored at 2-8° C in a secured area upon receipt. 
As panitumumab contains no preservatives, vials are designed for single use only. 
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. 
Records of the actual storage condition during the period of the study must be maintained 
(ie, records of the date and time and initials of person checking, and the “working day” 
temperature of the refrigerator used for storage of trial supplies, continuous temperature 
recordings, or regularly maintained temperature alarm systems used in conjunction with 
temperature recording). 
 
 
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. 
Panitumumab must be prepared as an intravenous infusion using aseptic techniques.  The 
dose of panitumumab will be 6 mg/kg and will be based upon the subject’s baseline 
weight. The dose of panitumumab is required to be recalculated only when the subject’s 
body weight increases or decreases by > 10% from the original screening/baseline 
weight.  This weight will be considered the new baseline weight from which a + 10% 
variance is allowed before another recalculation is necessary.  The calculated amount of 
panitumumab (may be rounded to the nearest ten milligrams [eg, 456 mg rounded to 460 
mg or 312 mg rounded to 310 mg]) will be removed from the vials and added to a 
minimum 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.  In the event a subject’s actual body weight requires greater than a 150-mL 
volume infusion, panitumumab will be administered over 60 to 90 + 15 minutes, as 
tolerated. (6 milligrams/kilogram (mg/kg) intravenously infused over 60 minutes every 
14 days. Infuse doses higher than 1000 mg over 90 minutes. Do not give panitumumab as 
IV bolus. Add doses of up to 1000 mg to a 100 mL bag of 0.9% NS. For doses greater 


52 
THE OHIO STATE UNIVERSITY 
IRB PROTOCOL #: 2012C0033 
OSU PROTOCOL #: 11131 
VERSION: 09/19/2017 
IRB Approved: tracked 
 
 
than 1000 mg, dilute in a 150 mL bag of 0.9% NS. Mix diluted solution by gentle 
inversion. Do not shake. Administer with a low protein-binding 0.22 micron filter set. 
Flush line with NS before and after panitumumab. The panitumumab will be infused 
within 19 hours of dilution and will be labeled per site pharmacy standard operating 
procedures. 
 
 
Supply and Return 
At study initiation and as needed thereafter, panitumumab will be shipped to a 
responsible person (eg, a pharmacist) at the Investigator’s institution, who will check the 
amount and condition of the drug and enter these data into the Proof of Receipt Form and 
Investigational Product Accountability record.  The Proof of Receipt Form should then be 
returned  toAmgen, and the original retained at the site. At the end of the study, or as 
directed, all panitumumab supplies, including unused, partially used, or empty containers, 
will be destroyed at the site or returned to Amgen as directed. 
 
 
Panitumumab Accountability 
An Investigational Product Accountability Record for the must be kept current and 
should contain: 
• 
The dates and quantities of panitumumab received 
• 
Manufacturing batch or lot numbers for product received 
• 
Subject’s identification (subject number) 
• 
Date and quantity of panitumumab dispensed (and remaining, if from individual subject drug 
units) 
• 
The initials of the dispenser 
• 
Dose preparation records 
• 
Date and quantity of drug returned to the investigator/pharmacy, if appropriate 
 
Any discrepancies must be documented and subsequently reported immediately. 
These inventories must be made available for inspection by authorized sponsor representative(s) 
and regulatory agency inspector(s). The investigator is responsible for the accountability of all 
used and unused trial supplies.