Conditions: Colorectal Cancer
Keywords: mucinous adenocarcinoma of the colon recurrent colon cancer signet ring adenocarcinoma of the colon stage III colon cancer stage IV colon cancer mucinous adenocarcinoma of the rectum recurrent rectal cancer signet ring adenocarcinoma of the rectum stage III rectal cancer stage IV rectal cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 136
Healthy volunteers: no

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, 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. Cetuximab and ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer.

PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy.

Detailed description:
OBJECTIVES:

* To evaluate the progression-free survival of patients with advanced K-ras wild-type colorectal cancer, following progression on bevacizumab-contained chemotherapy, treated with irinotecan hydrochloride and cetuximab with versus without ramucirumab as second-line therapy.
* To evaluate the response rate in patients treated with these regimens.
* To evaluate the grade 3-4 toxicity rates of these regimens in these patients.
* To evaluate the overall survival of patients treated with these regimens.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to performance status (0 vs 1), discontinuation of oxaliplatin before disease progression (yes vs no), and time to disease progression since last treatment (≤ 6 months vs \> 6 months). Patients are randomized to 1 of 2 treatment arms.

* Arm A: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride over 60-90 minutes on day 1.
* Arm B: Patients receive ramucirumab IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Arm B was closed early due to excessive toxicities and Arm C was then added to the study with reduced dose of protocol drugs.
* Arm C: Patients receive reduced dose of ramucirumab, cetuximab and irinotecan hydrochloride as in arm B.

In all arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for 5 years.

Arms:
arm 1: Patients receive cetuximab (500 mg/m2) intravenously (IV) over 60-120 minutes and irinotecan hydrochloride (180 mg/m2) over 60-90 minutes on day 1. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities. arm 2: Patients receive ramucirumab (8 mg/kg) IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities. arm 3: Patients receive reduced dose of ramucirumab (6 mg/kg) IV over 60 minutes on day 1 and cetuximab (150 mg/m2) and irinotecan hydrochloride (400 mg/m2) as in arm B. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.

Interventions: intervention 1: cetuximab intervention 2: ramucirumab intervention 3: irinotecan hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
E7208 
 
1 
A Randomized Phase II Study of Irinotecan and 
Cetuximab with or without the Anti-Angiogenic Antibody, 
Ramucirumab (IMC-1121B), in Advanced, K-ras Wild-type 
Colorectal Cancer Following Progression on 
Bevacizumab-Containing Chemotherapy 
STUDY CHAIR: 
Howard S. Hochster, MD 
STUDY CO-CHAIR: 
Deirdre Cohen, MD 
Peter O’Dwyer, MD 
STUDY STATISTICIAN: 
Paul Catalano, Sc D 
GI COMMITTEE CHAIR: 
SWOG CO-CHAIR: 
Al B. Benson III, MD 
Howard S. Hochster, MD 
Version Date:  March 22, 2016 
 
Irinotecan (NSC #616348) Commercially available for this study 
Cetuximab (NSC #714692) Commercially available for this study 
Ramucirumab (NSC #749128) (IND 109448) Supplied by Eli Lilly & Company for this study 
 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
US Sites Only 
 
October 8, 2010 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Addendum #1 – Prior to Activation 
NRG / NRG Oncology Foundation, Inc 
 
Addendum #2 – Prior to Activation 
SWOG / SWOG 
 
Addendum #3 – 12/11 
Cancer Trials Support Unit (CTSU)* 
 
Addendum #4 – 7/12 
 
 
Addendum #5 – 6/14 
 
 
Addendum #6 – 6/14 
 
 
Addendum #7 – 11/14 
 
 
Addendum #8 – 12/14 
 
 
Addendum #9 – 6/15 
 
 
Addendum #10 – 5/16 
 
Rev. 7/12, 11/14 
Rev. 6/14 
Rev. 7/12, 
6/14, 11/14 
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Table of Contents 
A Randomized Phase II Study of Irinotecan and Cetuximab with or without the 
Anti-Angiogenic Antibody, Ramucirumab (IMC-1121B), in Advanced, K-ras 
Wild-type Colorectal Cancer Following Progression on Bevacizumab-
Containing Chemotherapy .................................................................................. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Colon Cancer ............................................................................................. 7 
1.2 Vascular Endothelial Growth Factor and Angiogenesis ............................ 9 
1.3 The Role of VEGF and VEGFR-2 in Angiogenesis and Tumor Growth ..... 10 
1.4 IMC-1121B (Ramucirumab) ..................................................................... 10 
1.5 Summary and Study Rationale ................................................................ 14 
1.6 Summary of Toxicity Review ................................................................... 15 
2. Objectives ......................................................................................................... 16 
2.1 Progression Free Survival ........................................................................ 16 
2.2 Response Rate ......................................................................................... 16 
2.3 Toxicity Rates .......................................................................................... 16 
2.4 Overall Survival ....................................................................................... 16 
3. Selection of Patients ......................................................................................... 17 
3.1 Eligibility Criteria ..................................................................................... 17 
4. Registration and Randomization Procedures ................................................... 20 
4.1 Protocol Number ..................................................................................... 23 
4.2 Investigator Identification ....................................................................... 23 
4.3 Patient Identification .............................................................................. 23 
4.4 Eligibility Verification .............................................................................. 23 
4.5 Additional Requirements ........................................................................ 23 
4.6 Instructions for Patients who Do Not Start Assigned Protocol Treatment23 
4.7 EKG, UPC and Pregnancy Test Reimbursement Guidelines .................... 24 
5. Treatment Plan ................................................................................................. 25 
5.1 Administration Schedule ......................................................................... 25 
5.2 Adverse Event Reporting Requirements ................................................. 25 
5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Cetuximab (NSC 714692) ........................................................................ 36 
5.4 Dose Modifications ................................................................................. 39 
5.5 Supportive Care ....................................................................................... 45 
5.6 Duration of Therapy ................................................................................ 49 
5.7 Duration of Follow-up ............................................................................. 49 
6. Measurement of Effect ..................................................................................... 50 
6.1 Antitumor Effect – Solid Tumors ............................................................. 50 
7. Study Parameters .............................................................................................. 57 
7.1 Therapeutic Parameters.......................................................................... 57 
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8. Drug Formulation and Procurement ................................................................. 59 
8.1 Irinotecan (CPT-11) (NSC-616348) .......................................................... 59 
8.2 Cetuximab ............................................................................................... 61 
8.3 IMC 1121B ............................................................................................... 67 
9. Statistical Considerations .................................................................................. 72 
9.1 Revised Statistical Design - Arms A (IC) and C (mICR) ............................. 72 
9.2 Original Statistical Design (Arms A and B) ............................................... 74 
9.3 Study Monitoring .................................................................................... 75 
9.4 Gender and Ethnicity .............................................................................. 76 
10. Biological Specimen Submissions ..................................................................... 77 
10.1 Materials Required For This Protocol ..................................................... 77 
10.2 Shipping Procedures ............................................................................... 77 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 77 
10.4 Banking .................................................................................................... 78 
10.5 Sample Inventory Submission Guidelines ............................................... 78 
11. Records to Be Kept ............................................................................................ 79 
11.1 Records Retention ................................................................................... 79 
12. Patient Consent and Peer Judgment ................................................................ 79 
13. References ........................................................................................................ 79 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #5] .............................................................. 83 
Appendix II  Pathology Submission Guidelines ....................................................... 84 
Appendix III  Patient Thank You Letter .................................................................... 89 
Appendix IV  Investigational Product Shipment Request Form .............................. 90 
Appendix V  Disposition Form ................................................................................. 91 
Appendix VI  Reimbursement Invoice ..................................................................... 92 
Appendix VII  Substitute W-9 Tax Form .................................................................. 93 
Appendix VIII  E7208 Temperature Excursion Form................................................ 94 
 


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STUDY CHAIR 
Howard S. Hochster, MD 
Yale Cancer Center 
333 Cedar Street, Box 208028 
New Haven, CT 06520 
Telephone: 203-785-2360 (work hours) 
203-200-4422 (evenings and weekends) 
Email: howard.hochster@yale.edu 
 
 
 
 
 
 
 
 
 
 
STUDY CO-CHAIR 
Peter O’Dwyer, MD 
University of Pennsylvania Cancer Center 
1223 Penn Tower 
3400 Spruce Street 
Philadelphia, PA 19104 
Phone: (215) 662-7268 
Fax: (215) 243-3268 
Email: peter.odwyer@uphs.upenn.edu 
 
Rev. 12/11 
Rev. 6/14 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data: 
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206  
Email - 
CTSURegulatory@ctsu.coccg
.org (for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section for 
instructions on using the 
Oncology Patient Enrollment 
(OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office – 
Boston, 
FSTRF, 900 Commonwealth Avenue 
Boston,  MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal mail 
(preferred), however fax is accepted. 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions. 
The most current version of the study protocol and supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at   https://www.ctsu.org 
 
 
Rev. 7/12, 
11/14 
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Schema 
Eligibility: metastatic or advanced CRC, K-ras wild-type, first line therapy with oxaliplatin-containing 
Chemotherapy and bevacizumab, now progressing.
Stratify:
1) PS 
(0 vs. 1)
2) Discontinuation of   Oxaliplatin 
first-line therapy prior to 
progression (yes vs. No)
3) Progression = 6 months of last 
treatment vs. > 6 months
R
A
N
D
O
M
I
Z
E
Irinotecan 180 mg/m2 IV and 
Cetuximab 500 mg/m2 IV q 2 
weeks*
Irinotecan 180 mg/m2 IV and 
Cetuximab 500 mg/m2 IV plus 
Ramucirumab 8 mg/kg q 
2 weeks*
Primary endpoint: PFS; 90% power to detect difference between 4.5 months for control vs. 7.65 months for 
experimental arm (α = 0.10, β = 0.10)
*  Treatment should not be started until at least 28 days after last bevacizumab dose.
** Arm B closed to accrual in Addendum #5. New patients are randomized to Arm A or Arm C.
Accrual Goal = 135
Rev. 12/11
Rev. 12/11
Rev. 12/11,
6/14
Arm A – (IC)
Rev. 12/11,
         6/14
Arm B – (ICR)
CLOSED TO NEW ACCRUAL**
Irinotecan 150 mg/m2 IV and 
Cetuximab 400 mg/m2 IV plus 
Ramucirumab 6 mg/kg q 
2 weeks*
Arm C – (mICR)
Rev. 6/14
Rev. 6/14
Rev. 6/14
Rev. 6/14
 


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1. 
Introduction 
1.1 
Colon Cancer 
1.1.1 
Background 
Colorectal cancer (CRC) is a significant cause of cancer mortality. 
The worldwide incidence of CRC in 2000 was estimated as 944,700 
cases (males: 498,000; females: 446,000 cases) (1). In the United 
States (US) colorectal cancer accounts for approximately 11% of all 
cancer deaths (2). At diagnosis, 40% of the world’s CRC population 
have metastatic or “synchronous metastases.” In the US, 
approximately 20% of newly diagnosed patients with CRC will have 
synchronous metastatic cancer (3). Approximately 25% of patients 
with localized disease at diagnosis will ultimately develop metastatic 
disease.  Unfortunately only a small number of patients with stage IV 
cancer can be cured with multimodality therapy. The majority of 
patients with metastatic, stage IV CRC will ultimately die of their 
disease (4).  
Newly developed, and now standard, therapies for patients with stage 
IV CRC have dramatically improved survival and enhanced quality of 
life.  Thus, in the U.S., initial therapy with combinations of 5-
fluorouracil (5FU) and oxaliplatin (FOLFOX) or 5FU and irinotecan 
(FOLFIRI) have increased response rates to approximately 45 percent 
(5). The addition of bevacizumab to either FOLFOX or FOLFIRI has 
produced response rates of 60%.  Indeed, for approximately eight 
percent of patients with stage IV CRC, the addition of surgery to 
successful chemotherapy will produce a cure (6). Upon progression 
after so-called “first-line therapy,” approximately 20% of patients will 
respond to a second systemic treatment combination. Most important, 
median survival for patients with stage IV CRC is now approaching 
2.5 years (7). It is likely that with a better understanding of how to 
incorporate intratumoral molecular parameters such as mutations in 
the k-ras gene and/or quantitation of a tumor’s repair genes such 
ERCC-1 or XRCC-1 and/or targets such as thymidylate synthase into 
treatment strategies, complete responses and cure rates will continue 
to improve.  
1.1.2 
First Line therapy 
A series of clinical trials in the first line therapy of metastatic CRC 
have improved survival from a median of 12 months to nearly 24 
months.  A series of trial showed that combination therapy using 
oxaliplatin (FOLFOX4) or irinotecan (IFL or FOLFIRI) gave improved 
RR, OS and PFS compared with FU and LV bolus or infusion therapy. 
This was confirmed in the N971 US Intergroup trial showing improved 
RR, OS and PFS for FOLFOX compared with the control arm of IFL 
(5).  Shortly thereafter a randomized trial of IFL with or without 
bevacizumab showed and improved HR for PFS and OS for the 
addition of the anti-VEGF antibody. This has been adopted into 
standard practice with all 5FU based first line therapies, including 
FOLFIRI or FOLFOX.  A more recent study (NO16966) demonstrated 


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improved PFS with the addition of bevacizumab to either FOLFOX or 
CapeOX therapy, though of a smaller benefit due to early stopping of 
chemotherapy (7). As FOLFOX has become the standard first-line 
chemotherapy platform, particularly in the US, second line therapy 
has relied on irinotecan based programs. 
1.1.3 
Second Line Therapy 
A study performed by the GERCOR demonstrated that the sequence 
FOLFOX followed by FOLFIRI was equivalent to the reverse 
sequence (8). As a result, US practice has evolved to use irinotecan 
based regimens as second-line therapy.  Either FOLFIRI or irinotecan 
seem equally useful in this situation and either may be used as there 
is no study showing a synergistic effect of fluoropyrimidines with 
irinotecan.  In the GERCOR multi-center study, patients with 
advanced CRC were treated with FOLFOX followed by FOLFIRI at 
the time of progression or the reverse sequence. In the FOLFOX first 
arm, the response rate for second line FOLFIRI was 4% and PFS was 
2.5 months.  A larger second line study was performed to examine the 
role of the anti-EGF antibody, cetuximab as second line therapy on 
patients progressing on FOLFOX. In this 1300 patient study, the 
subjects were randomized to irionotecan alone or irinotecan plus 
cetuximab (9).  The patient populations were not selected for Kras 
status.  Again the response rate for second line irinotecan was 4.2% 
and PFS was 2.6 months (n = 650).   
Recent reports of the predictive value of K-ras gene mutation (36,37) 
have demonstrated convincingly that patients with mutations in codon 
12 and 13 (as determined by RT-PCR from FFPET) do not benefit 
from the use of anti-EGFR antibodies, either as single agent or in 
combination with chemotherapy programs (10). As such, two 
treatment tracks exist for second-line therapy, based on cetuximab 
use in the K-ras wild-type group and irinotecan based therapy alone in 
those with Kras mutations.  In this study, the patient population will be 
limited to those with Kras wild-type status, as both arms will receive 
cetuximab and irinotecan.   
1.1.4 
Biweekly Dosing of Cetuximab 
Cetuximab is approved for previously treated colon cancer with non-
mutated K-ras (“wild type”).  The standard dose and schedule is 400 
mg/m2 loading dose x 1, then weekly 250 mg/m2.  Because of the long 
half-life of therapeutic monoclonal antibodies, such as cetuximab , 
many such agents have alternate dosing schedules of q2 weeks or 
even q3 weeks.  In this study we have chosen the dose of 500 mg/m2 
every two weeks, for the reasons detailed below, and also to facilitate 
co-administration with the irinotecan (180 mg/m2) biweekly schedule. 
Data supporting the biweekly dose of cetuximab 500 mg/m2 have 
been presented and published.  Tabernero, et al (Tabernero, 
Cervantes, Martinelli, et. Al, J Clin Oncol, 24 (18 Suppl), 142s) 
performed a phase I/PK study demonstrating equivalent 
pharmacokinetic parameters for the drug on the q2w schedule.  10 
patients treated on the standard dose/schedule were used in 
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AUC, half-life, or steady-state clearance between the two schedules 
(Table 1).  In addition, the Phase I portion of the study escalated 
cetuximab dose to achieve a gr 2-3 skin rash, reaching doses of 700 
mg/m2 q2w safely. The study was continuing at the time of 
presentation. 
Table 1 
Schedule 
Cmin (µg/mL) 
AUC (µg/mL*h) 
t1/2 (h) 
CLss (L/h/m2) 
400/250 mg/m2 q1w 
47.0 (37.3) 
17278 (5205) 
110 (24) 
0.016 (0.004) 
400 mg/m2 q2w 
25.6 (11.8) 
27655 (6965) 
124 (25) 
0.015 (0.004) 
500 mg/m2 q2w 
35.2 (13.8) 
34953 (6275) 
134 (33) 
0.015 (0.003) 
Mean (SD)  
This combination of irinotecan 180 mg/m2 and cetuximab 500 mg/m2 
q2w has also been reported in a Spanish phase II study (Martin-
Martorell, et.al. Br J Ca 99: 455-458, 2008). Forty patients were 
treated and a response rate of 23% was reported (compared with 
20% in the EPIC trial, N =1147), with a Disease Control Rate of 60%.  
Median time to progression was 3.4 months and overall survival was 8 
months.  This also is approximately equivalent to the cetuximab arm 
of the EPIC trial.  Toxicity of grade 3-4 severity was reported as 
diarrhea = 10%, neutropenia = 7.5% and skin toxicity = 7.5%, which 
are all somewhat lower than similarly reported toxicity rates in the 
EPIC trial.   In short, this phase II study suggests the activity and 
toxicity is not substantially different using irinotecan and cetuximab 
q2w compared with irinotecan every 3 weeks with weekly cetuximab.  
This biweekly schedule has been widely adopted in practice by US 
oncologists. 
1.2 
Vascular Endothelial Growth Factor and Angiogenesis 
Angiogenesis, the formation of new capillaries and blood vessels, is a tightly-
controlled, multistep process that is a component of normal physiology (including 
development of the embryonic vasculature, wound healing, ovulation, and 
menstruation). Pathologic angiogenesis contributes to tumor growth and 
metastasis, as well as other human diseases such as diabetic retinopathy, 
rheumatoid arthritis, and psoriasis (11-13). A number of growth factors have 
been identified as positive regulators of angiogenesis, including members of the 
vascular endothelial growth factor (VEGF) family, basic fibroblast growth factor, 
transforming growth factor alpha, transforming growth factor beta, tumor necrosis 
factor, platelet-derived endothelial growth factor, hepatocyte growth factor, 
angiogenin, interleukin-8, and placental growth factor (14,15). VEGF-A is one of 
several related cytokines; it is distinct in that it acts as an endothelial cell-specific 
mitogen and is the growth factor most consistently found in conditions associated 
with angiogenesis (16-19). The biological activity of VEGF-A (hereafter VEGF) is 
principally mediated by two structurally-related, high affinity tyrosine kinase 
receptors: the 180 kDa fms-like tyrosine kinase (VEGFR-1 or Flt-1) (20,21); and 
the 200 kDa receptor (VEGFR-2 or kinase insert domain-containing receptor 
[KDR]), or its murine homologue, fetal liver kinase-1 (Flk-1)(20,21).  Targeted 
deletion of genes encoding VEGF, VEGFR-1, or VEGFR-2 in mice is lethal to the 
embryo, demonstrating the physiological importance of the VEGF pathway in 


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blood vessel formation.  Mice lacking even a single VEGF allele die prior to birth 
due to vascular abnormalities (24,25). VEGFR-2-deficient mice have impaired 
blood island formation and lack mature endothelial cells (26), whereas VEGFR-1 
null embryos have abundant endothelial cell-like cells, but fail to develop normal 
vasculature (27). 
1.3 
The Role of VEGF and VEGFR-2 in Angiogenesis and Tumor Growth 
The importance of VEGF and VEGFR-2 in angiogenesis and tumor growth has 
been demonstrated in several animal models.  VEGFR-2 expression is 
associated with activated endothelium and is strongly upregulated in tumor 
endothelium (16,28). Inhibiting the function of the VEGF/VEGFR-2 pathway via a 
number of approaches, including anti-VEGF antibodies, anti-VEGFR-2 
antibodies, anti-VEGF antisense ribonucleic acid expression, VEGF-based 
immunotoxins, soluble VEGF receptors, ribozymes to VEGF receptors, and small 
molecule VEGFR-2 tyrosine kinase inhibitors, has been shown to inhibit new 
blood vessel formation and tumor growth in a variety of animal models (29-32). 
VEGF and VEGFR-2 are overexpressed in the great majority of human cancers, 
including carcinomas of the gastrointestinal tract, pancreas, breast, cervix, 
bladder, ovary, uterus, endometrium, and kidney; Kaposi’s sarcoma; 
glioblastoma multiforme; and hemangioblastomas.  In addition, messenger 
ribonucleic acid for both VEGFR-1 and VEGFR-2 is greatly upregulated in tumor-
associated endothelial cells, but not in the vasculature of the surrounding normal 
tissue.  A correlation between VEGFR-2 expression and tumor microvessel 
density has been associated with poor prognosis, advanced disease, increased 
risk of metastasis and recurrence, and lower relapse-free survival in patients with 
a variety of cancers (13,32). 
Accumulating evidence suggests that the dual autocrine/paracrine mechanism 
also may play an important role in the growth and metastasis of certain solid 
tumors. For example, a VEGF/VEGFR autocrine loop was proposed as a 
mediator of growth and metastasis of several types of tumors, including 
carcinomas of prostate, ovary, pancreas, and breast; malignant pleural 
mesothelioma; and melanoma (32). These observations suggest that anti-
VEGFR-2 antibodies may have potential as antiangiogenic and antitumor agents. 
1.4 
IMC-1121B (Ramucirumab) 
Ramucirumab is a recombinant human monoclonal antibody (MAb) of the 
immunoglobulin G, subclass 1 (IgG1) that specifically binds to the extracellular 
domain of VEGFR-2 with high affinity.  This antibody potently blocks the binding 
of the VEGF ligand to VEGFR-2, inhibits VEGF-stimulated activation of both 
VEGFR-2 and p44/p42 MAP kinases, and neutralizes VEGF-induced 
mitogenesis of human endothelial cells. 
Ramucirumab has been shown to block the interaction of VEGF and VEGFR-2 
(with a concentration that inhibits binding by 50% of approximately 1 nM), and to 
inhibit VEGF-stimulated proliferation of endothelial cells and VEGF induced 
migration of human leukemia cells (33,34). 
Preclinical pharmacodynamic data demonstrate that Ramucirumab binds 
specifically and with high affinity to the VEGFR-2, and is capable of inhibiting 
certain in vitro biological processes.  These include VEGF/VEGFR-2 interaction, 
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VEGF-induced migration of human leukemia cells, and VEGF-induced 
phosphorylation of VEGFR-2 in both human umbilical vein endothelial cells and 
porcine aortic endothelial cells engineered to overexpress VEGFR-2 (34).  These 
processes are likely involved in tumor angiogenesis.  Potent angiogenic and 
antitumor effects are observed when DC101, an antibody to murine VEGFR-2, is 
administered to mice bearing syngeneic tumors or human tumor xenografts.  The 
results of these preclinical pharmacodynamic studies support the investigation of 
Ramucirumab in the treatment of solid tumors. 
Two repeat-dose toxicology studies (5 weeks and 39 weeks) were conducted in 
cynomolgus monkeys.  In the 5-week repeat-dose study, Ramucirumab was 
administered intravenously at doses of 0, 4, 12, or 40 mg/kg.  There were no 
Ramucirumab -related effects seen in clinical signs, body weights, food 
consumption, urinalysis, blood pressure, hematology, coagulation, and serum 
chemistry.  There were also no Ramucirumab -related effects found at gross 
pathology evaluation.  Histopathology evaluation revealed focal muscle fiber 
degeneration and mononuclear cell infiltration in skeletal muscle (quadriceps 
femoris) in test article-treated animals only.  These effects were concluded to be 
not treatment-related due to the focal nature of the lesions and the low incidence 
in females.  The Ramucirumab injection sites had mild reactions consisting of 
mononuclear cells or mononuclear and polymorphonuclear cells in perivascular 
areas.  Based on the results of this study, intravenous administration of 
Ramucirumab was well tolerated at dose levels from 4 to 40 mg/kg for four doses 
and the no-observable-effect level (NOEL) in this study was ≥ 40 mg/kg, the 
highest dose administered. 
In the 39-week repeat-dose study, Ramucirumab was administered via 
intravenous infusion at dose levels of 5, 16, and 50 mg/kg to cynomolgus 
monkeys for 11 weekly doses over 12 weeks (females only) or weekly for 39 
weeks (males and females) of study.  There were no Ramucirumab -related 
effects noted in animals treated at up to 50 mg/kg for 12 weeks of study.  
Thickening and osteochondropathy of the epiphyseal growth plate was noted at 
5 mg/kg and above in animals treated for 39 weeks.  This was an anticipated 
mechanism-related effect.  Treatment with Ramucirumab resulted in renal toxicity 
at the 16- and 50-mg/kg dose levels after 39 weeks.  In addition, clinical 
chemistry and urinalysis parameters indicated that the renal toxicity had 
manifested at 16 mg/kg and 50 mg/kg after 26 weeks.  A NOEL of Ramucirumab 
could not be established when administered intravenously once a week for 39 
weeks in male or female cynomolgus monkeys. 
1.4.1 
Clinical Studies 
Two Phase 1 studies are being conducted to evaluate the safety and 
antitumor effects of Ramucirumab administered either weekly (CP12-
0401) or every other week or every third week (CP12-0402) at doses 
ranging from 2 mg/kg through 20 mg/kg in patients with advanced 
cancer.  Two mechanism-based, dose-limiting toxicities were 
observed at the weekly schedule of 16 mg/kg, symptomatic 
hypertension and deep vein thrombosis, both of which occurred after 
several cycles of Ramucirumab infusion.  Thus, the maximum 
tolerated dose for the weekly study was determined as 13 mg/kg 
administered on a weekly schedule.  The MTD has not been reached 
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A total of 37 patients have been enrolled in study CP12-0401 
(Ramucirumab administered weekly) at doses of 2 to 16 mg/kg; this 
patient population includes 23 males and 14 females, ranging in age 
from 36 to 76 years.  Adverse events ≥ grade 3 considered to be at 
least possibly-related to Ramucirumab were reported in 10 patients 
and include hypertension, deep vein thrombosis, headache, vomiting, 
anemia, increased amylase, hyperphosphatemia, and proteinuria. To 
date, four confirmed partial responses (in melanoma, gastric and 
neuroendocrine tumors, and uterine leiomyosarcoma) have been 
reported, and at least nine patients have experienced prolonged 
stable disease (> 6 months).  At least one of these patients had been 
treated previously with the anti-VEGF agent bevacizumab. 
Importantly, other evidence of clinical benefit has also been noted.  In 
particular, several patients (melanoma [1 patient], gastric cancer [1 
patient], and thyroid cancer [2 patients]) experienced significant pain 
relief along with reductions in analgesic requirements, and a patient 
with refractory pleural effusions experienced significant reductions in 
fluid retention and a lower frequency of thoracenteses. 
A total of 25 patients have been enrolled in study CP12-0402 
(Ramucirumab administered every other week or every 3 weeks), of 
whom 24 have received treatment at doses ranging from 6 mg/kg to 
20 mg/kg.  The MTD has not been reached for the every-other-week 
or the every-third-week schedules; the study is ongoing but currently 
closed to enrollment. 
A total of 13 of 24 (54.2%) patients to date have experienced events 
that were considered possibly, probably, or definitely related (related) 
to treatment with Ramucirumab. The most common (> 10%) 
treatment-related events were proteinuria (16.7%), diarrhea (12.5%), 
and hypertension (12.5%).  Adverse events ≥ Grade 3 considered to 
be at least possibly related to Ramucirumab were reported in three 
patients and include duodenal ulcer hemorrhage (Grade 4), 
hypertension, and fatigue. 
As of 1 September 2008, 19 patients were evaluable for response; of 
these patients, 12 have experienced a best overall response of stable 
disease, including five with SD ≥ 6 months. These five patients had 
cancers of the colon (2 patients), liver (2 patients), and kidney (1 
patient). Three of these patients have had ongoing SD for > 10 
months duration. Six patients remain on study (two patients in the 
10-mg/kg every other week cohort, two patients in the 15-mg/kg every 
three week cohort, and two patients in the 20-mg/kg every three week 
cohort). 
As of January 18, 2010, at least 454 patients had received at least 
one dose of IMC-1121B on ImClone sponsored phase 1-2 studies and 
at least 83 patients had received at least one dose of blinded IMC-
1121B/placebo on ImClone sponsored randomized phase III studies.  
Data safety monitoring committee reviews have been performed 
regularly on phase 2 studies in melanoma (involving combination with 
dacarbazine), prostate cancer (involving combination with 
mitoxantrone/prednisone), ovarian cancer (monotherapy), colorectal 


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cancer (involving combination with mFOLFOX-6) and breast cancer 
(involving combination with docetaxel). 
Some of the published data include:  
a) The Phase 1 Monotherapy Study (Spratlin et al. J Clin Oncol 
2010; 28: e-published 4 Jan 2010).  37 patients treated with 
advanced, refractory solid tumors.  Ramucirumab was given 
weekly as monotherapy.  Reported results included PR in 4/27 
(15%) patients with measurable disease and PR or SD ≥ 6 months 
in 11/37 (30%) of patients. 
b) Initial Phase 2 Presentation for metastatic, TKI-refractory Renal 
Cancer (Garcia et al. ESMO/ECCO Berlin 2009. 40 patients were 
given ramucirumab 8mg/kg q 2 wk. Of these, 50% had prior 
sunitinib, 35% prior sunitinib and sorafenib and15% prior 
sorafenib. The preliminary median PFS is 6 months and 3/40 (7%) 
had confirmed PR. The drug was well-tolerated. 
Additional phase II studies are underway in RCC, HCC, melanoma, 
prostate cancer, NSCLC, ovarian cancer, GBM, colorectal, breast and 
bladder cancer. Phase 3 studies are underway in breast cancer, with 
others planned in HCC, colorectal cancer. Further phase 2 results will 
be presented at GU ASCO (RCC update), ASCO (melanoma, HCC, 
NSCLC) in 2010. 
Additional toxicities (observed in preliminary phase 2 studies) and 
potential toxicities (based on the known toxicity profiles of agents 
which inhibit the VEGF or VEGF-receptor pathway) are presented in 
the most recent Investigator Brochure.  No additional safety patterns 
have been demonstrated conclusively beyond those observed, 
discussed and reported in the most recent Investigator Brochure. 
1.4.2 
Dose Rationale 
Nonclinical data obtained from a murine BxPC-3 xenograft model 
have demonstrated that the efficacy of DC101, a murine analogue to 
Ramucirumab, was evident in vivo at trough concentrations of 18 
µg/mL. The target serum concentration for Ramucirumab is 
hypothesized to be one that maintains Ramucirumab at trough plasma 
concentrations ≥ 20 µg/mL. Preliminary pharmacokinetic (PK) data 
from studies CP12-0401 and CP12-0402 indicate that the minimum 
20 µg/mL target trough concentrations are attainable.  In the every-
other-week protocol, following the initial dose of 6 mg/kg, mean serum 
trough concentrations (immediately prior to the next dose) of 
Ramucirumab were 31 µg/mL (range: 18–64 µg/mL [n=7]).  Analysis 
of the initial 8-mg/kg dose at the same time point yielded a mean 
serum trough concentration of 115 µg/mL (range: 18 - 205 µg/mL 
[n=3]).  To provide a suitable margin above the 20 µg/mL 
Ramucirumab target concentration, the proposed dose and regimen 
for this Phase 3 study will be 8 mg/kg Ramucirumab given every other 
week.  At this dose and regimen, the half-life following the initial 
infusion of IMC-Ramucirumab is approximately 155 hours; following 
later infusions during the first cycle, the half-life is approximately 
300 hours, suggesting that steady state is being approached.  
Supporting this observation is the finding that as the dose of IMC-


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Ramucirumab was increased from 6 to 13 mg/kg, clearance 
decreased from 0.237 mL/hr/kg to a plateau of 0.06 mL/hr/kg 
(clearance at 8 mg/kg was approximately 0.113 mL/hr/kg). 
1.5 
Summary and Study Rationale 
First line therapy of CRC at this time generally includes bevacizumab plus 
combination chemotherapy, which most commonly in the US includes oxaliplatin, 
leucovorin and 5FU (a modified FOLFOX regimen).  Whether continuing anti-
angiogenic therapy after first line therapy is beneficial remains an open question.  
Studies to date have shown benefit for addition of bevacizumab in first line 
therapy and in second line therapy in bevacizumab-naïve patients. In the case of 
patients with Kras wild-type cancers, standard second line therapy would 
generally include irinotecan with cetuximab, based on the EPIC trial which 
demonstrated a doubling in PFS (9).  We have chosen this regimen as the 
control arm for this study, which will compare addition of the anti-VEGFR 
antibody, Ramucirumab.  The goal of this study is to show improved PFS with the 
addition of a novel second line anti-angiogenic antibody. 


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1.6 
Summary of Toxicity Review 
The study was closed to accrual on June 14, 2012 after 35 registrations were 
accrued as per pre-planned toxicity review. 18 patients (17 treated; one case 
never started assigned therapy) were accrued to Arm A (IC) and 17 (16 treated; 
one case was a duplicate registration) to Arm B (ICR). AdEERS Reporting was 
reviewed and real time data were obtained on all treated patients. It was clear 
that more toxicity was seen in Arm B. Worst toxicity per patient is seen in the 
figure below.  The overall grade 3-5 toxicity rates were 17% for Arm A and 75% 
for Arm B. There were 2 toxic deaths in Arm B. Toxicities of higher incidence in 
Arm B included neutropenia, mucositis, diarrhea and GI perforation (including 
peri-anal abscess).  In addition mean dose given in Arm B (mean % RDI) was 
considerably lower in Arm B:  65% for irinotecan, 85% for cetuximab and 92% for 
ramucirumab (even though no dose reductions were allowed in the protocol). 
This compares to 99% irinotecan and 98% cetuximab average %RDI in Arm A. 
Furthermore, only 3/17 patients in Arm A required dose reduction, compared to 
15/16 in Arm B. On the other hand with a median of 8 cycles preliminary analysis 
showed that fewer patients in Arm B went off treatment for progression compared 
with Arm A, and more remained on treatment at the time of the analysis. Of the 
17 treated in Arm A, 8 out of 9 patients off study had progression (PD), while in 
Arm B, of the 16 treated, only 1 out of 5 who went off study, went off for PD. 
These findings suggest potential benefit for the addition of ramucirumab among 
patients who can tolerate therapy. Therefore, we propose a reduced dose 
regimen in Arm C (modified ICR) with irinotecan 150 mg/m2, cetuximab 400 
mg/m2 and ramucirumab 6 mg/m2 as starting doses, more strict eligibility criteria, 
and more aggressive dose modifications for toxicity.  Because those patients on 
protocol who did tolerate the ICR regimen at the reduced doses seemed to stay 
on study longer, we believe the study should be continued as modified at those 
lower doses. The Arm C starting doses are equal to the actual “percent 
recommended dose intensity” received by patients in Arm B. 
 
 
Rev. 6/14, 
6/14 
 
Arm A (n=17) 
Arm B (n=16) 


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2. 
Objectives 
2.1 
Progression Free Survival 
To evaluate the Progression Free Survival (PFS) for the addition of the anti-
angiogenic antibody, Ramucirumab, in combination with irinotecan and 
cetuximab as second line therapy for patients with K-ras wild-type colorectal 
cancer, as compared to the patients without the antibody. 
2.2 
Response Rate 
To evaluate the Response Rate for irinotecan, cetuximab and Ramucirumab in 
this patient population. 
2.3 
Toxicity Rates 
To evaluate the Grade 3-4 toxicity rates for the combination in this patient 
population. 
2.4 
Overall Survival 
To evaluate Overall Survival for irinotecan, cetuximab, and ramucirumab in this 
patient population. 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. _____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date _______________________________________ 
NOTE: All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: Institutions may use the eligibility checklist as source documentation if it 
has been reviewed, signed, and dated prior to registration/randomization 
by the treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years. 
3.1.2 
Women must not be pregnant or breast-feeding due to potential 
danger to the fetus, by therapy including Ramucirumab. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
Female of child bearing potential? (Yes or No) ______ 
If yes: 
Date of blood test or urine study: _______________ 
If no, reason: 
Post menopausal, date of LMP ______ 
Status post TAH: Date of surgery ______ 
Status post tubal ligation: Date of surgery ______ 
3.1.3 
Women of childbearing potential and sexually active males must use 
an accepted and effective method of contraception or agree to abstain 
from sexual intercourse during their participation in the study and for 3 
months following completion of their participation. 
3.1.4 
Patients must have measurable disease as defined in Section 6.1.2. 
3.1.5 
Histologically documented adenocarcinoma (including the histologic 
variants of adenocarcinoma) of the colon or rectum. 
3.1.6 
Patients K-ras status must be wild type (not mutated). K-ras status 
determination may be based on either primary or metastatic tumor. 
NOTE:  The assay must be performed by a Clinical Laboratory 
Improvement Amendments (CLIA) approved laboratory. 
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3.1.7 
Patients must have had prior first-line therapy with oxaliplatin-based 
fluoropyrimidine-containing chemotherapy and bevacizumab for 
metastatic colorectal cancer. 
3.1.7.1 
Was oxaliplatin discontinued before date of progression? 
Yes _____________ No ______________ 
3.1.8 
Registration within 42 days of evidence of disease progression.  
3.1.8.1 
Current date ______________     
3.1.8.2 
Date of progression _________________ 
3.1.9 
[Deleted in Addendum #3] 
3.1.10 
Performance Status 0-1. 
3.1.10.1 
PS 0 _________ 1____________ 
3.1.11 
Adequate Organ Function ≤ 4 weeks prior to registration. 
3.1.11.1 
Hematologic: Absolute neutrophil count (ANC) ≥ 1500/µL, 
hemoglobin ≥ 9 g/dL, and platelets ≥ 75,000/µL. 
ANC: ______ Date: _______ 
Hemoglobin: ______ Date: _______ 
Platelets: ______ Date: _______ 
3.1.11.2 
Renal: Serum creatinine ≤ 1.5 x the ULN, or creatinine 
clearance (measured via 24-hour urine collection) ≥ 40 
mL/minute. 
Serum creatinine: ______ Date: _______ 
Creatinine clearance: ______ Date: _______ 
3.1.11.3 
Proteinuria: Urine protein/creatinine (UPC) ratio < 0.5 or 
urine protein ≤ 1+ on dipstick or routine urinalysis (UA). 
If UPC ≥ 0.5 or urine dipstick or routine analysis is ≥ 2+, a 
24-hour urine collection for protein must demonstrate  
< 1000 mg of protein in 24 hours to allow participation in 
the study. 
UPC < 0.5 (Yes / No) ______ Date: _______ 
Urine protein ≤ 1+ (Yes / No) ______ Date: _______ 
If no, is the 24-hour collection < 1000 mg protein? ______ 
3.1.11.4 
Hepatic: Total bilirubin ≤ 2.0 mg/dL, and aspartate 
transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 
x the institutional upper limit of normal (ULN) [or 5.0 x the 
ULN in the setting of liver metastases]. Albumin within 
institutional normal range. 
Total bilirubin: ______ 
AST: ______ Date: _______ 
ALT: ______ Date: _______ 
Albumin:___________ Date: _________ 
_____
_____
Rev. 12/11, 6/14, 
11/14 
_____
_____
Rev. 12/11 
Rev. 6/14 
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Liver metastases? (Yes / No): ______ Date: _______ 
3.1.11.5 
Coagulation: International Normalized Ratio (INR) ≤ 1.6 
(unless receiving anticoagulation therapy). Patients on full-
dose anticoagulation must be on a stable dose (minimum 
duration 14 days) of oral anticoagulant or low molecular 
weight heparin. If receiving warfarin, the patient must have 
an INR ≤ 3.0 and no active bleeding (i.e., no bleeding 
within 14 days prior to first dose of study therapy). 
INR: ______ Date: _______ 
Is patient receiving warfarin? (Yes / No): ______ 
3.1.12 
No prior therapy with drugs other than oxaliplatin and a 
fluoropyrimidine plus bevacizumab for this disease.  Chemotherapy 
drugs and bevacizumab may be stopped and started as long as no 
prior disease progression requiring change in chemotherapy agents 
occurred. 
3.1.13 
No clinically significant (equivalent to NCI CTCAE grade 3-4) bleeding 
episodes within the prior 3 months.   
3.1.14 
No active infection, symptomatic congestive heart failure, unstable 
angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, 
uncontrolled thrombotic or hemorrhagic disorder.  
3.1.15 
No uncontrolled or poorly-controlled hypertension despite standard 
medical management (e.g. consistently SBP > 160 and DBP > 90 
mmHg). 
3.1.16 
No major surgery within 28 days prior to randomization, or 
subcutaneous venous access device placement within 7 days prior to 
randomization 
3.1.17 
No history of acute arterial thrombotic events within 6 months 
(including CVA, TIA, MI or unstable angina). 
3.1.18 
No brain or CNS metastases. 
3.1.19 
No other cancer requiring therapy within last three years (except in 
situ carcinoma or non-melanoma skin cancer). 
3.1.20 
Patients must not have an acute or subacute intestinal obstruction. No 
history of bowel obstruction, GI perforation, major abdominal surgery 
with bowel resection, or peri-rectal/peri-anal abscess within 6 months 
prior to randomization. 
3.1.21 
Patient must not have a history of inflammatory bowel disease 
requiring pharmacological and/or surgical intervention within the 12 
months prior to randomization. 
3.1.22 
Patient must not have a known allergy to any of the treatment 
components. 
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
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4. 
Registration and Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
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Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E7208 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E7208 
• 
Click on the Site Registration Documents link 
Requirements for E7208 site registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1.  CTSU Regulatory Transmittal Form. 
2.  Copy of IRB Informed Consent Document. 
NOTE:  Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator and 
approved by the IRB. 
3.  A.  CTSU IRB Certification Form. 
 
 
Or 
 
 
 
 
 
 
B.  Signed OMB No. 0990-0263 
 
 
Or 
 
C.  IRB Approval Letter 
NOTE: The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 


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• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. 
Patients must have signed and dated all applicable consents and authorization forms. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at <https://eapps-ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on 
either the LPO or participating organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: The OPEN system will provide the site with a printable confirmation of 
randomization. Please print this confirmation for your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
Patients must not start protocol treatment prior to registration. 
Treatment should start within 10 working days after registration but not less than 
28 days after last dose of bevacizumab. 
Institutions may register eligible patients to this study via the ECOG webpage 24 hours a 
day, 7 days a week, using the Web-based Patient Registration Program 
(https://webreg.ecog.org). If you need assistance or have questions, please telephone 
the Central Randomization Desk at the ECOG-ACRIN Operations Office – Boston at 
(617) 632-2022, Monday through Friday 9:00am – 5:00pm Eastern Time. Please note 
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that a password is required to use this program. The following information will be 
requested: 
4.1 
Protocol Number  
4.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.3 
Patient Identification  
• 
Patient’s initials and chart number 
• 
Patient’s Social Security number 
• 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.0.  An 
eligibility checklist has been appended to the protocol.  A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office – Boston. 
STRATIFICATION FACTORS: 
a.  Performance Status 0 vs. 1 
b.   Discontinuation of oxaliplatin before disease progression:  Yes vs. No 
c.   Time since treatment with chemotherapy or bevacizumab ≤ 6 months vs. > 6 
months. 
4.5 
Additional Requirements  
4.5.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.5.2 
Specimens are to be submitted as outlined in Section 10. 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E7208 Forms Packet. Document the reason for not starting 
protocol treatment on the off-treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives on the Non-Protocol Therapy 
Form. 
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4.7 
EKG, UPC and Pregnancy Test Reimbursement Guidelines 
Lilly has agreed to provide reimbursement towards the non-standard of care 
pregnancy, UPC and EKG time points while patients are on protocol treatment. 
These tests should not be submitted to the patient's insurance for 
reimbursement.  Institutions should submit these costs to the ECOG-ACRIN 
Operations Office – Boston using the E7208 EKG/UPC/Pregnancy Test 
Reimbursement Invoice (Appendix VI). 
Baseline pregnancy test is considered standard of care and should be 
submitted to the patient’s insurance for reimbursement. All additional 
pregnancy tests, all UPC and all EKG time points as outlined in Section 7 of the 
protocol are considered non-standard of care. 
Please refer to the table below for reimbursable time points: 
 
Baseline 
Every Six 
Weeks 
End of 
Treatment 
30 Days After End 
of Treatment 
EKG 
X 
 
X 
 
Pregnancy Test* 
X* 
X 
X 
X 
UPC 
X 
X 
 
 
*Baseline pregnancy test is standard of care and should be submitted to patient’s 
insurance for reimbursement. 
In order to authorize reimbursement, the results of the EKG, UPC and Pregnancy 
test must accompany the E7208 Reimbursement Invoice (Appendix VI) as well 
as the Substitute W-9 Tax Form (Appendix VII). These items should be sent to 
the ECOG-ACRIN Operations Office – Boston, Attn: Drug Orders (fax: 617-632-
2063). The ECOG-ACRIN Operations Office – Boston will review/approve the 
invoices and submit for payment on a quarterly basis. 
If you have any questions about this process, please contact a member of the 
ECOG-ACRIN Industry Team at the ECOG-ACRIN Operations Office – Boston 
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5. 
Treatment Plan 
NOTE: Patients must not start treatment until at least 28 days from last dose of 
bevacizumab. 
5.1 
Administration Schedule 
5.1.1 
Treatment/ARM A – (IC) 
5.1.1.1 
Cetuximab 500 mg/m2 IV q 14 days 
• 
The first infusion is to be administered over 120 
minutes with subsequent infusions over 60 minutes 
5.1.1.2 
Irinotecan 180 mg/m2 IV over 60-90 minutes q 14 days 
Cetuximab should be given prior to irinotecan. 
Repeat cycles every 14 days until progression. 
NOTE: 
Irinotecan pre-medication should be given per 
standard institutional practice. 
5.1.2 
Treatment/ARM B – (ICR) 
CLOSED to accrual in Addendum #5 
5.1.3 
Treatment/ARM C – (mICR) 
5.1.3.1 
Ramucirumab 6 mg/kg IV over 60 minutes q 14 days 
• 
The dose of ramucirumab is to be recalculated should 
the patients weight change by 10% or more. 
5.1.3.2 
Cetuximab 400 mg/m2 IV q 14 days 
• 
The first infusion is to be administered over 120 
minutes with subsequent infusions over 60 minutes. 
5.1.3.3 
Irinotecan 150 mg/m2 IV over 60-90 minutes q 14 days 
Ramucirumab should be given first, followed by cetuximab 
and then irinotecan. 
Repeat cycles every 14 days until progression. 
NOTE:  It is recommended that 50mg of diphenhydramine 
be administered prior to the initial 3 doses of 
ramucirumab, and may or may not be continued 
for subsequent doses per the investigator’s 
discretion.  
NOTE: Irinotecan pre-medication should be given per 
standard institutional practice. 
5.2 
Adverse Event Reporting Requirements  
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
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patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial (please refer to the 
E7208 Forms Packet for the list of forms with directions and 
timeframes for routine adverse event reporting).  
• 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner via 
CTEP-AERS for timelier monitoring of patient safety and care. The 
following sections provide information and instructions regarding 
expedited adverse event reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.   
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
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• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious adverse event when it may jeopardize 
the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) for Arms A, B and 
C and 
• 
the FDA (1-800-332-1088) for Arm A 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to  
• 
the FDA (800-332-0178), for Arm A, in the same timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
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• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. > 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E7208 and outline 
the specific expedited adverse event reporting requirements for 
study E7208.   


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5.2.5 
Steps to Determine if an Adverse Event is to be Reported in an 
Expedited Manner for Arm A 
Identify the type and grade of the event 
using CTCAE v4.0 
Determine if the event is related to the 
protocol treatment (attribution) 
With this information, review the chart in 
Section 5.2.6 to determine if event is 
reportable via CTEP-AERS 
Refer to footnote b in Section 
5.2.6 to determine if the event 
meets the protocol specific 
reporting requirements for this 
study.  If so, report the event 
via CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the event 
via CTEP-AERS 
Determine the expectedness of the 
event.  An unexpected event is defined 
as one where the type of severity of the 
event is not listed in the investigator’s 
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5.2.6 
Expedited Reporting Requirements for Arm A on Protocol E7208 
Commercial Agents: Irinotecan and Cetuximab 
Expedited reporting requirements for adverse events experienced by patients on arms with commercial agents only 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any death 
that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely 
to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event. For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Medical Help Desk at 301-897-7497 or 
aemd@tech-res.com. This will need to be discussed on a case by case basis. 


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5.2.7 
Steps to Determine if an Adverse Event is to be Reported in an 
Expedited Manner for Arms B and C 
5.2.7.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in Section 5.2.8  
Yes 
No 
Identify the type and 
grade of the event using 
CTCAE v4.0 
Determine if the patient 
was hospitalized for ≥ 24 
hours for the event 
With this information, 
review the chart in Section 
5.2.8 to determine if event 
is reportable via CTEP-
AERS 
Refer to Section 5.2.9 to 
determine if the event meets 
the protocol specific reporting 
requirements for this study. If 
so, report the event via 
CTEP-AERS 
Refer to Section 5.2.9 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study. If so, report the event via 
CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the 
event via 
CTEP-AERS 
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5.2.7.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.8, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
NOTE: Any death occurring greater than 30 days after the 
last dose of investigational agent with an 
attribution of possible, probable or definite must be 
reported via CTEP-AERS even if the patient is off 
study 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events   
5.2.8 
Expedited Reporting Requirements for Arms B and C on protocol 
E7208 
Investigational Agents:  Ramucirumab (IMC-1121B) 
Commercial Agents:  Irinotecan and Cetuximab 
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents.   
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1 
NOTE: Footnote 1 instructs how to report serious adverse 
events that occur more than 30 days after the last 
administration of investigational agent/intervention. 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
5.2.9 
Additional instructions, requirements and exceptions for Arms B 
and C on protocol E7208 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
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birth defect events via CTEP-AERS, please contact the AEMD 
Medical Help Desk at 301-897-7497 or aemd@tech-res.com. This will 
need to be discussed on a case by case basis. 
E7208 specific expedited reporting requirements:  
GI Events: 
All grade 2 or higher GI perforations and peri-rectal 
abscess events, regardless of grade or whether or not 
the patient was hospitalized, must be reported via 
CTEP-AERS within the timeframes specified in the table 
in Section 5.2.8. 
5.2.10 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable.    
The drug supporter is obliged to forward reported AEs to the FDA.  A 
drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event.  Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.11 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN confirming 
the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a copy 
of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol).  
Secondary malignancies require both routine and expedited 
reporting as follows: 
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1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under 
a.) leukemia secondary to oncology chemotherapy,  
b.)  myelodysplastic syndrome,  
or  
c.)  treatment related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 


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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Cetuximab 
(NSC 714692) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch 
(IDB). The information listed in the CAEPR(s) below, as well as the other 
resources described in the 'Determination of reporting requirements' part of the 
Adverse Event Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable via CTEP-
AERS (Arm A). Frequency is provided based on 2282 patients. Below is the 
CAEPR for Cetuximab. 
Version 2.1, March 31, 20101 
 
 Adverse Events with Possible  
 Relationship to Cetuximab 
 (CTCAE 4.0 Term) 
[n= 2282] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
EAR AND LABYRINTH DISORDERS 
 
External ear inflammation 
 
 
Tinnitus 
 
EYE DISORDERS 
 
Conjunctivitis 
 
 
Dry eye 
 
 
Uveitis 
 
 
Watering eyes 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Cheilitis 
 
 
Constipation 
 
Diarrhea 
 
 
 
Dry mouth 
 
 
Dyspepsia 
 
 
Mucositis oral 
 
Nausea 
 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
Fever 
 
 
 
Flu like symptoms 
 
 
Infusion related reaction 
 
 
Non-cardiac chest pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis  
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INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
 
 Infections and infestations – Other 
(aseptic meningitis) 
INVESTIGATIONS 
 
Neutrophil count decreased 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hypocalcemia 
 
 
Hypomagnesemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Myalgia 
 
NERVOUS SYSTEM DISORDERS 
Headache 
 
 
 
Syncope 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
 
 
Bronchospasm 
 
 
Cough 
 
 
Dyspnea 
 
 
Hoarseness 
 
 
 
Pneumonitis 
 
 
Respiratory, thoracic, and 
mediastinal disorders - Other (non-
cardiogenic pulmonary edema) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Dry skin 
 
 
 
Nail loss 
 
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
Photosensitivity 
 
 
Pruritus 
 
 
Purpura 
 
Rash acneiform 
 
 
Rash maculo-papular 
 
 
 
Skin ulceration 
 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Hypotension 
 
 
Thromboembolic event 
 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
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Also reported on cetuximab trials but with the relationship to cetuximab still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; 
Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left ventricular 
systolic dysfunction; Myocardial infarction; Paroxysmal atrial tachycardia; Pericardial effusion; 
Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eyelid function disorder; 
Keratitis; Photophobia; Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Esophagitis; Gastritis; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal hemorrhage (including Colonic 
or Gastric hemorrhage or hemorrhage in other sites under the GASTROINTESTINAL 
DISORDERS SOC); Gastrointestinal perforation (Colonic perforation, Duodenal perforation, or 
perforation in other sites under the GASTROINTESTINAL DISORDERS SOC); Gastrointestinal 
ulcer (ulcer includes Duodenal ulcer, Rectal ulcer, or ulcer in other sites under the 
GASTROINTESTINAL DISORDERS SOC); Ileus; Pancreatitis; Rectal fistula 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Sudden 
death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Creatinine increased; Platelet 
count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (myasthenia); 
Musculoskeletal and connective tissue disorder - Other (Sudeck's Atrophy) 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Dysgeusia; Extrapyramidal disorder; 
Intracranial hemorrhage; Nervous system disorders - Other (cholinergic syndrome); Neuralgia; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (acute 
renal failure)  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast 
disorders - Other (balanitis); Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Pleural effusion; Respiratory, 
thoracic and mediastinal disorders - Other (bronchiolitis obliterans-organized pneumonia 
[BOOP]) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hirsutism; Skin hypopigmentation; Skin 
and subcutaneous tissue disorders - Other (skin fissures) 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Vasculitis 
NOTE: Cetuximab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may 
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5.4 
Dose Modifications  
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
Version 4.0 of the CTCAE is identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m. All appropriate treatment areas should have access to a copy of version 
4.0 of CTCAE. 
5.4.1 
General Considerations 
a. A new cycle of treatment may begin when the ANC is ≥ 1,500/mcl, 
the platelet count is ≥ 75,000/mcl, and any treatment-related GI 
toxicity is resolved to ≤ Grade 1.  
b. If the initiation of a new cycle, or treatment during a cycle is 
delayed for ≥ 4 weeks, the patient should be removed from 
protocol treatment.  
c. Held doses are not to be made up. 
d. If one therapeutic agent is permanently discontinued secondary to 
toxicity, then therapy with the other study agents should continue 
and the patient should remain on-study with full adherence to all 
protocol-related requirements 
e. In the event of serious or life-threatening conditions, hold the 
offending agent. If the patient is to continue on therapy, all agents 
should be held until the toxicity resolves to grade < 2. 
f. Dose reductions for all agents are as follows: 
ARM  
AGENT 
INITIAL DOSE 
LEVEL -1 
LEVEL -2 
A (IC) 
Cetuximab 
500 mg/m2 
400 mg/m2 
250 mg/m2 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
B (ICR) 
Closed to accrual 
Ramucirumab 
8 mg/kg 
6 mg/kg 
5 mg/kg 
Cetuximab 
500 mg/m2 
400 mg/m2 
250 mg/m2 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
C (mICR) 
Ramucirumab 
6 mg/kg 
5 mg/kg 
4 mg/kg 
Cetuximab 
400 mg/m2 
250 mg/m2 
200 mg/m2 
Irinotecan 
150 mg/m2 
120 mg/m2 
90 mg/m2 
NOTE: 
In the event that an agent is given at dose level (-2) and dose 
modification rules call for further reduction, the agent should be 
discontinued. 
Rev. 12/11, 6/14 


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5.4.2 
Hematologic toxicities 
No Ramucirumab or cetuximab dose modifications (or delays) will be 
made for hematologic toxicity.  Continue Ramucirumab or cetuximab 
when irinotecan is held for hematologic toxicities. 
Grade 
Dose Modification 
2 
Reduce irinotecan one dose level at the next cycle.  For subsequent cycles, resume at 
the previous dose levels, provided ANC ≥ 1,500/mcl and platelets ≥ 75,000/mcl. 
3-4 
Hold irinotecan. If counts recover to ANC ≥ 1,500/mcl and platelets ≥ 75,000/mcl, 
irinotecan may be resumed at one lower dose level at next cycle. For subsequent 
cycles, continue at the reduced dose levels from the previous cycle. 
Febrile 
neutropenia 
Hold irinotecan.  If fever resolves and counts recover to ANC ≥ 1,500/mcl and platelets 
≥ 75,000/mcl, irinotecan may be resumed at one lower dose level at next cycle.  For 
subsequent cycles, continue at the reduced dose levels from the previous cycle. 
5.4.3 
Diarrhea 
No Ramucirumab dose delay will be made for diarrhea.  Continue 
Ramucirumab when other agents are held. Dose modifications should 
be made for toxicity only when patient is receiving intensive 
loperamide therapy. 
Grade 
Dose Modification 
2 
Be sure intensive loperamide is being taken. For subsequent cycles, resume 
all agents at the previous dose levels, provided diarrhea has fully resolved 
before restarting treatment. 
3 
Be sure intensive loperamide is being taken. If so, and grade 3 diarrhea lasts 
longer than 48 hours, reduce irinotecan one dose level. Do not treat again 
until the diarrhea resolves to ≤ grade 2. 
4 
Be sure intensive loperamide is being taken. Hold irinotecan. If diarrhea 
resolves to ≤ grade 2, irinotecan and cetuximab should be resumed at one 
lower dose level for subsequent cycles. For subsequent cycles, continue both 
agents at the reduced dose levels from the previous cycle. 
5.4.4 
Nausea and/or vomiting 
These dose modifications for nausea and/or vomiting should be made 
only if they persist/occur despite two treatments with adequate 
(combination) antiemetics therapy.   
No Ramucirumab or cetuximab dose modifications (or delays) will be 
made for nausea/vomiting. Continue Ramucirumab or cetuximab 
when irinotecan is held. 
Grade 
Dose Modification 
3-4 
Reduce irinotecan one dose level. For subsequent cycles, continue irinotecan 
at the reduced dose level from the previous cycle. 
Rev. 6/14 
Rev. 6/14 
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5.4.5 
Mucositis 
Grade 
Dose Modification 
2 
Reduce irinotecan one dose level for subsequent cycles. No modifications (or 
delays) will be made for Ramucirumab or cetuximab. 
3 
Hold irinotecan. If mucositis resolves to ≤ Grade 2, resume both irinotecan 
and cetuximab at one lower dose level for subsequent cycles. No 
modifications (or delays) will be made for Ramucirumab. 
4 
Hold ALL protocol treatment. If mucositis resolves to ≤ Grade 2, reduce all 
agents one dose level for all subsequent cycles. 
5.4.6 
Pulmonary Toxicity  
5.4.6.1 
For Grade 2 or worsening pulmonary symptoms unrelated 
to underlying cancer, cetuximab treatment should be 
stopped and symptoms investigated. Cetuximab treatment 
may resume at one lower dose level when symptoms 
resolve to ≤ Grade 1 and cetuximab-related pneumonitis is 
ruled out. 
5.4.6.2 
For ≥ Grade 3 cough, dyspnea, hypoxia, pneumonitis, or 
pulmonary infiltrates, hold cetuximab until interstitial lung 
disease is ruled out. Continue Ramucirumab and 
irinotecan.  Discontinue all protocol treatment if interstitial 
lung disease is confirmed.  
5.4.7 
Hypomagnesemia has been seen with cetuximab. For Grade 3-4 
hypomagnesemia, hold cetuximab until hypomagnesemia resolves to 
≤ Grade 2.  Then restart cetuximab at the -1 dose.  For any grade of 
hypomagnesemia, magnesium supplementation should be provided.  
5.4.8 
Hypertension (Dose delays for Ramucirumab only) 
Treat with anti-hypertensive medication as needed. The goal of BP control should be 
consistent with general medical practice 
Grade 1 
(SBP 120-139 mmHg or DBP 80-89 mm Hg) 
Consider increased BP monitoring; 
start anti-hypertensive medication if 
appropriate 
Grade 2 asymptomatic 
(SBP 140-159 mmHg or DBP 90-99 mm Hg) 
Begin anti-hypertensive therapy 
and continue agent 
• Grade 2 symptomatic 
(SBP 140-160 mmHg or DBP 90-100 mm Hg) 
• Grade 3 
(≥ SBP 160 mmHg or ≥ DBP 100 mmHg 
• Start or adjust anti-hypertensive 
medication 
• Hold agent  until symptoms 
resolve AND BP < 160/90mmHg 
• Grade 4  
(Hypertensive crisis or malignant hypertension) Discontinue agent 
Patients who hold or discontinue Ramucirumab due to hypertension 
may continue other protocol treatment.  
5.4.9 
Venous Thrombotic Events 
Patients should be carefully monitored for evidence of 
thromboembolic disease during treatment. 
Rev. 6/14 
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5.4.9.1 
Grade 3 venous thrombosis or asymptomatic pulmonary 
embolism: Hold Ramucirumab.  Ramucirumab may be 
resumed during the period of full-dose anticoagulation if all 
of the following criteria are met:  
• 
The patient must have an in-range INR (usually 
between 2 and 3) on a stable dose of warfarin or be on 
stable dose of low molecular weight heparin prior to 
restarting Ramucirumab treatment;  
• 
The patient must not have pathological conditions that 
carry high risk of bleeding (e.g. tumor involving major 
vessels);  
• 
The patient must not have had hemorrhagic events 
while on study. 
5.4.9.2 
Grade 4 or for recurrent/worsening venous 
thromboembolic events after resumption of Ramucirumab: 
Discontinue Ramucirumab.  
5.4.9.3 
For symptomatic pulmonary embolism, patients will 
discontinue all protocol treatment.  
5.4.10 
Arterial Thrombotic Events  
5.4.10.1 
For Grade 2 arterial thrombotic events not present at 
baseline or worsened since the initiation of protocol 
therapy, discontinue Ramucirumab. Patients may continue 
other protocol treatment.  
5.4.10.2 
For Grade 3 cerebrovascular ischemia, and/or peripheral 
or visceral arterial ischemia, discontinue Ramucirumab.  
Patients may continue other protocol treatment.  
5.4.10.3 
For Grade 3 cardiac ischemia/infarction, discontinue 
Ramucirumab. Patients may continue other protocol 
treatment.  
5.4.10.4 
For any Grade 4 arterial thrombotic event, including 
cerebrovascular ischemia, cardiac ischemia/infarction, 
peripheral or visceral arterial ischemia, discontinue all 
protocol treatment.  
5.4.11 
Left Ventricular Dysfunction 
5.4.11.1 
Grade 3 LV dysfunction: Symptomatic CHF responsive to 
intervention. 
• 
Discontinue cetuximab (for patients on the control arm) 
or cetuximab and ramucirumab (for patients on the 
experimental arm). Patients may continue other 
protocol treatment.  
5.4.11.2 
Grade 4 LV dysfunction: Poorly controlled refractory CHF; 
intervention such as ventricular assist device or heart 
transplant is indicated. 
• 
Discontinue all protocol treatment. 


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5.4.12 
Hemorrhage/bleeding 
5.4.12.1 
For Grade 3 hemorrhage/bleeding, permanently 
discontinue Ramucirumab and hold other protocol 
treatment; once hemorrhage or bleeding resolves, other 
protocol treatment may be continued at the treating 
physician’s discretion.  
5.4.12.2 
For Grade 4 hemorrhage/bleeding, discontinue all protocol 
treatment.  
5.4.13 
Proteinuria (Dose delays for Ramucirumab only)  
5.4.13.1 
For proteinuria ≥ 2+ or UPC (urinary protein: creatinine 
ratio) > 1.0: Confirm total urine protein with a 24-hour urine 
collection. For 2+ proteinuria, the scheduled dose of 
Ramucirumab may be given while awaiting the results of 
the 24-hour collection. For > 2+ proteinuria, hold 
Ramucirumab while awaiting results of the 24-hour urine 
collection. Other protocol treatment may be continued. If 
proteinuria is 2-3 g/24 hours, hold Ramucirumab until urine 
protein recovers to < 2 g/24 hours, then resume at the -1 
dose level. Continue other protocol treatment. A second 
dose reduction (to 5 mg/kg every other week) is permitted 
if the protein level > 2g/24 hours recurs.  Ramucirumab will 
be discontinued permanently if the protein level is > 3g/24 
hours, if there is a third occurrence of proteinuria > 2 g/24 
hours, or if the protein level does not return to < 2g/24 
hours within 2 weeks. 
5.4.13.2 
If nephrotic syndrome (Grade 4 proteinuria) occurs, 
discontinue Ramucirumab. 
5.4.14 
Cutaneous toxicity (Dose modifications for cetuximab only) 
Grade 3 
Rash  
Cetuximab  
Outcome  
Cetuximab Dose 
Modification  
1st 
occurrence  
Hold infusion 
1 to 2 wks  
If improvement:  
Continue at current dose 
If no improvement: 
Discontinue cetuximab 
2nd 
occurrence 
Hold infusion 
1 to 2 wks 
If improvement:  
Reduce one dose level  
If no improvement: 
Discontinue cetuximab 
3rd 
occurrence 
Hold infusion 
1 to 2 wks 
If improvement:  
Reduce two dose levels  
If no improvement: 
Discontinue cetuximab 
4th 
occurrence 
Discontinue 
cetuximab 
 
 
Grade 4 
Rash 
Discontinue 
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5.4.15 
Infusion Reactions 
Grade 1 
Slow the infusion rate by 50%. 
Monitor the patient for worsening of the condition. 
For subsequent infusions, premedicate with diphenhydramine 
50mg IV (or equivalent); additional premedication may be 
administered at the investigator’s discretion. 
Grade 2 
Stop the infusion. 
Administer diphenhydramine 50mg IV (or equivalent), 
acetaminophen 650 mg orally for fever, and oxygen. 
Resume the infusion at 50% of the prior rate once the infusion 
reaction has resolved or decreased to grade 1; the infusion 
duration should not exceed 2 hours 
For subsequent infusions, premedicate with diphenhydramine 
50mg IV (or equivalent); additional premedication may be 
administered at the investigator’s discretion. 
Grade 3  
and 
Grade 4 
Immediately and permanently discontinue the offending agent. 
Appropriate medical therapy including epinephrine, 
corticosteroids, intravenous antihistamines, bronchodilators, 
and oxygen should be available for use in the treatment of such 
reactions. Patients should be carefully observed until the 
complete resolution of all signs and symptoms.  
For grade 1 or 2 reactions manifesting only as delayed drug fever, see 
Section 5.4.16. 
For grade 4 or allergy related edema and angioedema and 
hypotension, permanently discontinue all medications. 
For a second Grade 1 or 2 infusion reaction, administer 
dexamethasone 10mg IV (or equivalent); then, for subsequent 
infusions, premedicate with diphenhydramine 50mg IV (or equivalent), 
acetaminophen 650 mg orally, and dexamethasone 10mg IV (or 
equivalent). 
5.4.16 
Drug Fever 
In the event of isolated drug fever, the investigator must use clinical 
judgment to determine if the fever is related to the study drug or to an 
infectious etiology. If a patient experiences isolated drug fever, for the 
next dose, pre-treat with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion); repeat antipyretic dose 6 
and 12 hours after cetuximab infusion. The infusion rate will remain 
unchanged for future doses.  
If a patient experiences recurrent isolated drug fever following 
premedication and post-dosing with an appropriate antipyretic, the 
infusion rate for subsequent dosing should be 50% of previous rate. If 
fever recurs following infusion rate change, the investigator should 
assess the patient’s level of discomfort with the event and use clinical 
judgment to determine if the patient should receive further cetuximab. 


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5.4.17 
Other Grade 3 and 4 Toxicities 
For grade 3 events hold the offending agents until the toxicity resolves 
to grade ≤ 1. If grade 4, please discuss with the study chair. 
5.5 
Supportive Care 
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
Diarrhea Management 
For symptoms of diarrhea and/or abdominal cramping that occur at 
any time during a treatment cycle with irinotecan, patients will be 
instructed to begin taking loperamide. Loperamide should be started 
at the earliest sign of (1) a poorly formed or loose stool or (2) the 
occurrence of 1 to 2 more bowel movements than usual in 1 day or (3) 
an increase in stool volume or liquidity. Loperamide should be taken 
in the following manner: 4 mg at the first onset of diarrhea, then 2 mg 
every 2 hours around the clock until diarrhea-free for at least 12 
hours. Patients may take loperamide 4 mg every 4 hours during the 
night. Loperamide should not be used for more than 48 hours. 
Patients should be provided with loperamide at the initial treatment 
visit so that they have sufficient supply on hand in case antidiarrheal 
support is required. Additional antidiarrheal measures may be used at 
the discretion of the treating physician. Patients should be instructed 
to increase fluid intake to help maintain fluid and electrolyte balance 
during episodes of diarrhea.  
5.5.3 
Antibiotics 
Oral fluoroquinolone treatment should be initiated for any of the 
following:  
• 
Diarrhea persisting for more than 24 hours despite loperamide  
• 
 ANC < 500/mcl (even in the absence of diarrhea or fever) 
• 
 Fever with diarrhea (even in the absence of neutropenia)  
• 
Antibiotic therapy should also be initiated in patients who are 
hospitalized with prolonged diarrhea (even in the absence of 
neutropenia). 
5.5.4 
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, 
abdominal cramping, diarrhea, or other symptoms of early cholinergic 
syndrome may occur during or shortly after receiving irinotecan. 
Atropine, 0.25-1.0 mg IV or SC may be used to treat these symptoms. 
In patients with troublesome or recurrent symptoms, prophylactic 
administration of atropine shortly before irinotecan therapy may be 
considered. Additional antidiarrheal measures may be used at the 
discretion of the treating physician. Combination anticholinergic 
medications containing barbiturates or other agents (e.g., Donnatal®) 
should not be used because these may affect irinotecan metabolism. 
Anticholinergics should be used with caution in patients with potential 
contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, 
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Late diarrhea (e.g., developing more than 24 hours after irinotecan) 
should be managed with loperamide as described above. 
5.5.5 
Pegfilgrastim, epoetin and darbepoetin alfa may be administered at 
the treating investigator's discretion. 
5.5.6 
Dermatology Management 
Suggested algorithm for management of cutaneous toxicity and 
paronychia: 
In this protocol, acneiform rash and paronychia will be graded 
according to version 4.0 of the NCI-CTCAE definitions of 
rash/desquamation and nail changes. The patient should be followed 
until resolution of these toxicities. 
Acneiform rash and paronychia should be managed according to the 
algorithms in Table 1-1 and Table 1-2. Cetuximab therapy treatment 
adjustments should be made according to Tables 1-3. Cetuximab 
dose reductions will be permanent (i.e., no dose re-escalations). 
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Table 1-1: Algorithm for Management of Acneiform Rash 
Dermatological Evaluation
Mild (Grade 1)
Moderate or Severe 
(Grades 2+3)
STCN 50 mg BID
and
Topicals BID
STCN 100 mg BID
and
Topicals BID
Reassess in 2 weeks
Reassess in 2 weeks
Increase STCN 
and Topical or 
Oral Antibiotics
2 Weeks STCN and 
Continue Topicals
Reassess in 2 weeks
Worse/No Change
Oral Steroids and 
STCN and Continue 
Topicals
2 Weeks STCN and 
Continue Topicals
Reassess in 2 weeks
Consider: Dose 
Modification or Oral 
Isotretinoin
STCN:
Semisynthetic tetracyclines (doxycycline or minocycline)
Topicals:
Hydrocortisone 2.5% cream or alclomethasone 0.05% cream
Oral Steroids:
Methylprednisolone dose pack
Isotretinoin:
Low doses (10-20 mg a day) or isotretinoin as a single agent
Key:
Improvement
 


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Table 1-2: Algorithm for Management of Paronychia 
Dermatological Evaluation
Mild (Grade 1)
Moderate or Severe 
(Grades 2+3)
Emollients and/or 
Topical Corticosteroids
Culture and Sensitivity, 
then (appropriate) 
Topical or Oral 
Antibiotics or 
Intralesional Steroids
Reassess in 2 weeks
Reassess in 2 weeks
Culture and 
Sensitivity, then 
(appropriate) 
Topical or Oral 
Antibiotics
Emollients and/or 
Topical 
Corticosteroids
Reassess in 2 weeks
Worse/No Change
Partial or Total Nail 
Avulsion
Emollients and/or 
Topical Antibiotics
Reassess in 2 weeks
Consider: Dose 
Modification or Partial or 
Total Nail Avulsion
STCN:
Semisynthetic tetracyclines (doxycycline or minocycline)
Topicals:
Hydrocortisone 2.5% cream or alclomethasone 0.05% cream
Oral Steroids:
Methylprednisolone dose pack
Isotretinoin:
Low doses (10-20 mg a day) or isotretinoin as a single agent
Key:
Improvement
 


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5.6 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.6.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E7208 Forms Packet. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patients should be treated on study with medications as assigned until 
discontinuation for toxicity or disease progression by RECIST criteria.   
5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration. All patients 
must also be followed through completion of all protocol therapy. 
 
 


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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response 
every eight weeks.   
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
• 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall 
tumor burden at baseline to which subsequent measurements will be 
compared. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than four weeks 
before registration. 
2. Measurable disease is defined by the presence of at least one 
measurable lesion. 
3. All measurements should be recorded in metric notation by use of a ruler 
or calipers.  
4. The same method of assessment and the same technique must be used 
to characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the 
definitions stated below.   
(NOTE: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment.  The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 


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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable.  Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected.   
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline 
sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
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Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
in diameter as assessed using calipers (e.g., skin nodules).  In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up 
must be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
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Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 


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residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
FDG-PET 
FDG-PET may not be used as a response assessment in this study. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progression, See Section 
6.1.4.3). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
less that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of eight weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 


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NOTE: 
If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more on-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started).  The 
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achievement of both measurement and confirmation 
criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD 
No 
PR 
 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not 
evaluated 
No 
PR 
SD 
Non-PD/not 
evaluated 
No 
SD 
Documented at least 
once ≥ 8 wks. from 
study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or 
CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**In exceptional circumstances, unequivocal progression in non-target lesions  may 
be accepted as disease progression. 
NOTE: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable 
sites of disease must be done within 4 weeks prior to 
randomization/registration. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks 
before randomization/ registration.  
3. All required prestudy chemistries, as outlined in Section 3, should be done  
≤ 4 weeks before randomization/registration – unless specifically required on 
Day 1 as per protocol.  
Test / Assessment 
Pre-
Study 
Every 
2 weeks 
Every 
4 weeks 
Every 6 
weeks 
Every  8 weeks 
until progression 
Follow-
up1 
Physical 
 
 
 
 
 
 
History and Physical 
X 
X 
 
 
 
X 
Weight and Performance Status 
X 
X 
 
 
 
 
Blood Pressure7 
X 
X 
 
 
 
 
Toxicity Assessment 
X 
 X6 
 X6 
 
 
 
Disease Assessment 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 X5 
Laboratory 
 
 
 
 
 
 
CBC/diff/plts 
 X2 
X 
 
 
 
 
Chemistry Panel (chem. 6 
including creatinine) 
X 
X 
 
 
 
 
Calcium 
X 
 
X 
 
 
 
Albumin 
X 
 
X 
 
 
 
Magnesium 
X 
X 
 
 
 
 
Liver Panel (AST/ALT/Bilirubin) 
X 
X 
 
 
 
 
Urine Protein8 
X 
 
 
X 
 
 
Blood or Urine Pregnancy Test3 
X 
 
 
X 
 
 X9 
K-ras mutation Status 
X 
 
 
 
 
 
PT/INR 
  X10 
 
 
 
 
 
RADIOLOGIC EVALUATION 
 
 
 
 
 
 
CT scans (chest/abd/pelvis) 
X 
 
 
 
 X4 
X 
Pathology Submissions11 
X 
 
 
 
 
 
1. Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from 
study entry. No specific requirements if patient is more than 5 years from study entry. 
2. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hbg, and Hct 
required for protocol therapy must be done < 24 hours prior to the treatment cycle. 
3. Within 2 weeks prior to registration for women of childbearing potential; and every 6 weeks during 
treatment or per institutional guidelines, whichever is shorter. 
4. CT scans every 4 cycles until progression. 
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Rev. 11/14 
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5. At the end of treatment. Repeat as clinically indicated. 
6. Toxicity Assessment every 2 weeks for the first 4 cycles on study and then every 2 cycles thereafter. 
An assessment is also required at the end of treatment and 30 days after the end of treatment. 
7. Blood pressure should be monitored twice per week for the first 4 weeks and then every 2 weeks 
thereafter. 
8. UPC or urine protein on dipstick or routine urinalysis (UA). However, in the occurrence of 2+ urine 
protein on dipstick or UA or a UPC ≥ 0.5, a 24-hour urine collection for protein must be obtained. 
9. At the end of treatment with a 30 day safety followup. Repeat as clinically indicated. 
10. International Normalized Ratio (INR) ≤ 1.6 (unless receiving anticoagulation therapy). Patients on full 
dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or 
low molecular weight heparin. If receiving warfarin, the patient must have an INR ≤ 3.0 and no active 
bleeding (i.e., no bleeding within 14 days prior to first dose of study therapy). 
11. Submit from patients who consent “Yes” to “May your coded samples and related coded information 
be kept for use in research to learn about, prevent, find or treat cancer?” See Section 10. 
 
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8. 
Drug Formulation and Procurement 
8.1 
Irinotecan (CPT-11) (NSC-616348) 
Other Names  Irinotecan hydrochloride trihydrate [CPT- 1 1, (4S)-4, 1 1- diethyl-
4-hydroxy-9- [(4-piperidinopiperidino) carbonyloxy] -IHpyroano [3',4':6, 7l 
indolzino [1 ,2-bl quino line-3, 14(4H, l2H)dione hydrochloride trihydrate] is a 
topoisomerase I inhibitor.  
8.1.1 
Classification  
Topoisomerase I inhibitor  
8.1.2 
Toxicology 
Human Toxicity: Virtually all Phase I and II studies of irinotecan have 
reported neutropenia and diarrhea as the dose-limiting toxicities. It is 
expected that these toxicities will also be encountered in this trial. 
Other Grade 2-3 toxicities seen include nausea and vomiting, 
anorexia, abdominal cramping, cumulative asthenia, 
thrombocytopenia, renal insufficiency, increase in transaminase level 
and hair loss. Sporadic cases of pulmonary toxicity, manifested as 
shortness of breath and nonproductive cough, have also been 
reported. 
8.1.3 
Mode of Action 
Causes single stranded DNA breakage by inhibition of the 
intranuclear enzyme toposisomerase-1.  Leads to apoptotic cell death 
via defects in DNA repair. 
8.1.4 
Pharmacology 
Pharmacokinetics: Several studies describing the pharmacokinetic 
characteristics of irinotecan (CPT-11) and its active metabolite, SN-
38, when administered alone or in combination with other agents 
(including cisplatin) in patients with small cell or non-small cell lung 
cancer have been reported in published literature.  CPT- 11 is 
converted by carboxylesterases to its more active metabolite, SN-38. 
In vitro, SN-38 is 250 to 1,000 fold more potent than CPT-11 in the 
inhibition of topoisomerase I activity.  A reversible, pH-dependent 
hydrolysis converts the closed lactone E ring form of both CPT-11 and 
SN-38 to the open, carboxylate form of each compound. Only the 
closed ring (lactone) forms of CPT-11 and SN-38 are effective 
topoisomerase I inhibitors. The mean terminal half-life of SN-38 in 
plasma is slightly longer than that for CPT-11; 11.5 ± 3.8 hours versus 
6.3 ± 2.2 hours for the lactone forms. Peak plasma concentrations for 
CPT-11 occur at the end of the infusion. The time to peak for SN-38 is 
highly inter-patient dependent occurring at variable times points 30 to 
90 minutes after the end of infusion. Murine studies suggest that the 
liver may concentrate, convert CPT-11 to SN-38, and eliminate both 
compounds as well as the glucuronide conjugate of SN-38 (SN-38G) 
via biliary secretion. In rats, 55% of radiolabeled CPT-11 was 
excreted unchanged in the bile within 24 hours, while 21.7% was 
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concentrations of SN-38G in patients occur 0.5 to 3 hr after the SN38 
peak and plasma levels generally exceeded that of SN-38.  Overall, 
73% of the radioactivity could be recovered from the feces of rats and 
25% from the urine. Bile concentrations of CPT-11 were 10 to 60 fold 
higher than plasma concentrations in one patient during the first 6 
hours following administration, while bile concentrations of SN-38 
were 2 to 9 fold higher.  Renal clearance has not been reported to be 
a major route of elimination for these compounds in humans. 
8.1.5 
Formulation 
The drug is supplied in two forms: 2 ml vials containing 40 mg of drug 
and 5 ml vials containing 100 mg of drug. The drug is supplied in 
brown vials and appears as a pale-yellow-to-yellow crystalline powder 
and pale yellow transparent solution when reconstituted. 
8.1.6 
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 24 hours in glass bottles or plastic bags after reconstitution 
with D5W. 
8.1.7 
Dose Specifics  
8.1.7.1 
rms A (IC) and B (ICR) 
Irinotecan will be given at a dose of 180 mg/m2 
intravenously over 60-90 minutes every 2 weeks. 
8.1.7.2 
Arm C (mICR) 
Irinotecan will be given at a dose of 150 mg/m2 
intravenously over 60-90 minutes every 2 weeks. 
8.1.8 
Preparation  
Irinotecan will be diluted with D5W to a total volume of 500 ml and 
infused intravenously over 60-90 minutes. Nothing else should be 
added to the bag. 
8.1.9 
Route of Administration  
Intravenous administration only. 
8.1.10 
Incompatibilities  
Do not mix with any other compound. 
8.1.11 
Availability  
This drug is commercially available for purchase by a third party.  This 
drug will not be supplied by the NCI. 
8.1.12 
Side Effects  
Hematologic: Leukopenia, neutropenia, anemia, thrombocytopenia, 
neutropenic fever, hemorrhage 
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Gastrointestinal: Diarrhea (early and late – see administration above), 
nausea and vomiting, anorexia, abdominal pain, flatulence, stomatitis, 
dyspepsia, dehydration 
Hepatic: Elevated transaminases. 
Cardiovascular:  Vasodilation, hypotension, myocardial infarction, 
stroke, edema  
CNS:  Dizziness, confusion, somnolence, insomnia, back pain 
Respiratory: Pulmonary embolism,  
Dermatologic: Alopecia, rash 
Other: Asthenia, thrombophlebitis, sweating, weight loss, chills 
8.1.13 
Nursing/Patient Implications  
Premedicate with antiemetics in anticipation of mild to moderate 
nausea and vomiting.  When used in combination with 5-fluroruracil 
and leucovorin the nausea and vomiting will likely be worse. 
Fatalities have been reported with thromboembolic events and 
neutropenic sepsis in patients receiving 5-fluorouracil, leucovorin and 
irinotecan. 
Monitor for diarrhea. Diarrhea occurring within one hour of irinotecan 
has been treated with atropine 0.25 to 1mg IV or SC. Loperamide has 
been effective in treating later diarrhea and the patient should be 
instructed on its immediate use at the first loose stool following the 
irinotecan (see Section 5.5.2). 
Monitor CBC, platelets, and liver function tests. 
Dose modifications per the protocol or the package insert should be 
followed for hematologic and gastrointestinal toxicity. 
Advise patient of likely post-treatment neutropenia and instruct in 
appropriate neutropenic precautions. 
Administration of an oral quinolone antibiotic may decrease the risk of 
neutropenic sepsis in patients receiving 5-fluorouracil/leucovorin and 
irinotecan. 
8.2 
Cetuximab  
8.2.1 
IMC-C225, Erbitux®, NSC-714692 
8.2.2 
Classification 
Anti-EGF Receptor antibody 
8.2.3 
Mode of Action  
Cetuximab, a chimerized antibody of the IgG1 subclass, was originally 
derived from a mouse myeloma cell line. Cetuximab was genetically 
engineered by cloning the heavy and light chains of cetuximab and 
adapting them for expression together with the constant regions of the 
human kappa light chain and human gamma 1 heavy chain. The 
chimerization resulted in an antibody with binding affinity to epidermal 


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growth factor receptors (EGFR) greater than the natural ligand 
epidermal growth factor (EGF). Cetuximab blocks binding of EGF and 
transforming growth factor alpha (TGFα) to EGFR and inhibits ligand-
induced activation of this tyrosine kinase receptor. Cetuximab also 
stimulates EGFR internalization, effectively removing the receptor 
from the cell surface for interaction with ligand. 
8.2.4 
Storage and Stability 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. 
Cetuximab is expressed in SP2/0 myeloma cell line, grown in large 
scale cell culture bioreactors and purified to a high level purity using 
several purification steps including protein A chromatography, ion 
exchange chromatography, low pH treatment and nanofiltration. 
Cetuximab is not known to be a vesicant. 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). DO NOT 
FREEZE. Increased particulate formation may occur at temperatures 
at or below 0°C. This product contains no preservatives. Preparations 
of cetuximab in infusion containers are chemically and physically 
stable for up to 12 hours at 2°C to 8°C (36°F to 46°F) and up to 8 
hours at controlled room temperature (20°C to 25°C; 68°F to 77°F). 
Discard any remaining solution in the infusion container after 8 hours 
at controlled room temperature or after 12 hours at 2°C to 8°C.  
Discard any unused portion of the vial. 
8.2.5 
Dose Specifics 
8.2.5.1 
Arms A (IC) and B (ICR) 
Cetuximab will be given as a 500 mg/m2 dose every 2 
weeks. 
8.2.5.2 
Arm C (mICR) 
Cetuximab will be given as a 400 mg/m2 dose every 2 
weeks. 
8.2.6 
Preparation  
The product is formulated to 2 mg protein/mL with phosphate buffered 
saline, pH 7.2 ± 0.2 and aseptically filled into sterile glass vials, 100 
mg per 50 cc vial, and stored as a liquid at 2 to 8°C. Each vial 
contains the following active and inactive ingredients per 1.0 mL: 2 mg 
of cetuximab, 145 nmol/L sodium chloride, and 10 mmol/L sodium 
phosphate. 
Preparation and Administration: Cetuximab is supplied as a 50-mL, 
single-use vial containing 100 mg of cetuximab at a concentration of 2 
mg/mL in phosphate buffered saline. The solution should be clear and 
colorless and may contain a small amount of easily visible white 
amorphous cetuximab particulates. DO NOT SHAKE OR DILUTE. 
• 
Cetuximab must not be administered as an IV push or bolus. 
• 
Cetuximab must be administered with the use of a low protein 
binding 0.22-micrometer in-line filter.  
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Cetuximab can be administered via infusion pump. 
8.2.7 
Route of Administration  
Administration of Cetuximab: In an effort to prevent a hypersensitivity 
reaction, all patients should be premedicated with diphenhydramine 
hydrochloride 50 mg (or an equivalent antihistamine) by IV given 30-
60 minutes prior to the first dose of cetuximab.  Premedication may be 
administered prior to subsequent doses, but at the Investigator’s 
discretion, the dose of diphenhydramine (or a similar agent) may be 
reduced. 
The initial dose of cetuximab is 400 mg/m2 or 500 mg/m2 as assigned 
intravenously administered over AT LEAST 120 minutes, followed by 
ONE HOUR infusions every 2 weeks. Cetuximab should not be 
given at a rate faster than 5 ml/min for the first dose. Patients 
must be continuously observed during the infusion for signs of 
anaphylaxis. 
Patients will be closely monitored for treatment-related adverse 
events, especially hypersensitivity reactions, during the infusion and 
the post-infusion observation hour. For the duration that patients are 
on study therapy, adverse event monitoring will be done continuously. 
Patients will be evaluated for adverse events at each visit and are to 
be instructed to call their physician to report any clinically significant 
adverse events between visits. 
Severe infusion reactions occurred with the administration of 
cetuximab in approximately 3% (17/633) of patients, rarely with fatal 
outcome (< 1 in 1,000). Approximately 90% of severe infusion 
reactions were associated with the first infusion of cetuximab despite 
the use of prophylactic antihistamines. These reactions were 
characterized by the rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), urticaria and/or hypotension. 
Caution must be exercised with every cetuximab infusion, as there 
were patients who experienced their first severe infusion reaction 
during later infusions. 
Cetuximab can be administered via infusion pump or syringe pump. 
Infusion Pump: 
1. Draw up the volume of a vial using a sterile syringe attached to an 
appropriate needle (a vented spike or other appropriate transfer 
device may be used). 
2. Fill cetuximab into a sterile evacuated container or bag such as 
glass containers, polyolefin bags (e.g., Baxter Intravia), ethylene 
vinyl acetate bags (e.g., Baxter Clintec), DEHP plasticized PVC 
bags (e.g., Abbott Lifecare), or PVC bags. 
3. Repeat procedure until the calculated volume has been put in to 
the container.  Use a new needle for each vial. 
4. Administer through a low protein binding 0.22-micrometer in-line 
filter (placed as proximal to the patient as practical). 
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5. Affix the infusion line and prime it with cetuximab before starting 
the infusion. 
6. Maximum infusion rate should not exceed 5 mL/min. 
7. Use 0.9% saline solution to flush line at the end of infusion. 
Cetuximab should be piggybacked to the patient’s infusion line.  
Following the cetuximab infusion, a 1-hour observation period is 
recommended. 
8.2.8 
Incompatibilities  
Cetuximab should not be mixed with any other drug. 
8.2.9 
Availability  
Cetuximab is approved for this indication and is commercially 
available. Please refer to the commercial package insert for complete 
prescribing and toxicity information. 
8.2.10 
Anticipated Adverse Events 
Except where indicated, the data described below reflect exposure to 
cetuximab in 633 patients with advanced metastatic colorectal cancer.  
Cetuximab was studied in combination with irinotecan (n=354) or as 
monotherapy (n=279). Patients receiving cetuximab plus irinotecan 
received a median of 12 doses (with 88/354 [25%] treated for over 6 
months), and patients receiving cetuximab monotherapy received a 
median of 7 doses (with 26/279 [9%] treated for over 6 months).  The 
population had a median age of 59 and was 60% male and 91% 
Caucasian.  The range of dosing for patients receiving cetuximab plus 
irinotecan was 1-84 infusions, and the range of dosing for patients 
receiving cetuximab monotherapy was 1-63 infusions. 
The most serious adverse reactions associated with cetuximab 
were:   
Infusion reaction (3%); 
Dermatologic toxicity (1%); 
Interstitial lung disease (0.5%); 
Fever (5%); 
Sepsis (3%); 
Kidney failure (2%); 
Pulmonary embolus (1%); 
Dehydration (5%) in patients receiving cetuximab plus irinotecan, 2% 
in patients receiving cetuximab monotherapy; 
Diarrhea (6%) in patients receiving cetuximab plus irinotecan, 0% in 
patients receiving cetuximab monotherapy. 
Thirty-seven (10%) patients receiving cetuximab plus irinotecan and 
14 (5%) patients receiving cetuximab monotherapy discontinued 
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The most common adverse events seen in 354 patients receiving 
cetuximab plus irinotecan were acneiform rash (88%), 
asthenia/malaise (73%), diarrhea (72%), nausea (55%), abdominal 
pain (45%), and vomiting (41%).  
The most common adverse events seen in 279 patients receiving 
ERBITUX monotherapy were acneiform rash (90%), asthenia/malaise 
(49%), fever (33%), nausea (29%), constipation (28%), and diarrhea 
(28%).  
Because clinical trials are conducted under widely varying conditions, 
adverse reaction rates observed in the clinical trials of a drug cannot 
be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice. The adverse reaction 
information from clinical trials does, however, provide a basis for 
identifying the adverse events that appear to be related to drug use 
and for approximating rates. 
Data in patients with advanced colorectal carcinoma in the following 
table are based on the experience of 354 patients treated with 
cetuximab plus irinotecan and 279 patients treated with cetuximab 
monotherapy. [ERBITUX TM (Cetuximab) package insert. ImClone 
Systems Incorporated and Bristol-Myers Squibb Company. 2004 ER-
B00001-02-04]. 
NOTE: There have been reports of hypomagnesemia during 
cetuximab therapy. The majority of the cases have been 
documented as decreased serum magnesium levels 
observed in routine electrolyte monitoring, and not as a result 
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Incidence of Adverse Events (≥ 10%) in Patients with Advanced Colorectal Carcinoma 
Body System  
Preferred Term1 
ERBITUX plus Irinotecan (n=354) 
ERBITUX Monotherapy (n=279) 
Grades 1 - 4 
Grades  3 and 4 
Grades 1 - 4 
Grades 3 and 4 
% of Patients 
Body as a Whole 
Asthenia/Malaise2 
73 
16 
49 
10 
Abdominal Pain 
45 
8 
25 
7 
Fever3 
34 
4 
33 
0 
Pain 
23 
6 
19 
5 
Infusion Reaction4 
19 
3 
25 
2 
Infection 
16 
1 
11 
1 
Back Pain 
16 
3 
11 
3 
Headache 
14 
2 
25 
3 
Digestive 
Diarrhea 
72 
22 
28 
2 
Nausea 
55 
6 
29 
2 
Vomiting 
41 
7 
25 
3 
Anorexia 
36 
4 
25 
3 
Constipation 
30 
2 
28 
1 
Stomatitis 
26 
2 
11 
<1 
Dyspepsia 
14 
0 
7 
0 
Hematic/Lymphatic 
Leukopenia 
25 
17 
1 
0 
Anemia 
16 
5 
10 
4 
Metabolic/Nutritional 
Weight Loss 
21 
0 
9 
1 
Peripheral Edema 
16 
1 
10 
<1 
Dehydration 
15 
6 
9 
2 
Nervous 
Insomnia 
12 
0 
10 
<1 
Depression  
10 
0 
9 
0 
Respiratory 
Dyspnea3 
23 
2 
20 
7 
Cough Increased 
20 
0 
10 
1 
Skin/Appendages 
Acneiform Rash5 
88 
14 
90 
10 
Alopecia 
21 
0 
5 
0 
Skin Disorder 
15 
1 
5 
0 
Nail Disorder 
12 
<1 
16 
<1 
Pruritus  
10 
1 
10 
<1 
Conjunctivitis 
14 
1 
7 
<1 
1 Adverse events that occurred (toxicity Grades 1 through 4) in ≥ 10% of patients with refractory 
colorectal carcinoma treated with ERBITUX plus irinotecan or in ≥ 10% of patients with refractory 
colorectal carcinoma treated with ERBITUX monotherapy. 
2 Asthenia/malaise is defined as any event described as “asthenia”, “malaise”, or “somnolence”. 
3 Includes cases reported as infusion reaction. 
4 Infusion reaction is defined as any event described at any time during the clinical study as “allergic 
reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as 
“allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever” or “dyspnea”. 
5 Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular 
rash”, “dry skin”, or “exfoliative dermatitis”. 


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8.2.11 
Nursing/Patient Implications  
Resuscitation equipment and medications to treat hypersensitivity 
reactions should be available during and for one hour following each 
cetuximab infusion. 
Blood pressure, pulse and temperature should be taken pre-infusion, 
at midpoint, end of infusion and one hour post-infusion. 
Patients should be observed for 1 hour following the initial dose and 
30 minutes following the weekly doses. 
Patients should be observed for signs of hypersensitivity/anaphylaxis. 
Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves, and 
Class II vertical-laminar-airflow safety cabinets are recommended 
during preparation and handling. Opened vials must be disposed of at 
the investigational center as chemotherapy or biohazardous waste 
provided documented procedures for destruction are in place. For 
questions regarding cetuximab destruction please contact Lilly at 
iits_usmail-oncology@lilly.com. 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to cetuximab, murine proteins, or any component of 
this product. 
It is recommended that patients wear sunscreen and hats and limit 
sun exposure while receiving cetuximab as sunlight can exacerbate 
any skin reactions that may occur. 
8.3 
IMC 1121B  
8.3.1 
Other Names 
Ramucirumab, 1121B 
8.3.2 
Classification:  
Recombinant anti-VEGF human monoclonal antibody 
8.3.3 
Mode of Action:  
IMC-1121B is a recombinant human monoclonal antibody of the IgG1 
subclass that specifically binds to the extracellular domain of the 
VEGFR-2. This antibody effectively blocks VEGF/VEGFR-2 
interaction, inhibits VEGF-stimulated activation of VEGFR-2 and 
p44/p42 mitogen-activated protein kinases, and neutralizes VEGF-
induced mitogenesis of human endothelial cells. 
8.3.4 
Storage and Stability  
Chemical and physical in-use stability has been demonstrated for up 
to 24 hours below 25°C (77°F). DO NOT FREEZE OR SHAKE IMC-
1121B. From a microbiological point of view, the prepared product 
should be used immediately. If not used immediately, in-use storage 
time and conditions are the responsibility of the user and would 
normally not be longer than 24 hours at 2°C - 8°C (36F° - 46°F). IMC-
1121B should be protected from light when being stored. In the event 
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of a temperature excursion, please contact iits_usmail-
oncology@lilly.com. 
8.3.5 
Dose Specifics  
8.3.5.1 
Arm B (ICR): 
Patients will receive 8 mg/kg of IMC-1121B every 2 weeks, 
administered as an I.V. infusion over 1 hour. The dose of 
IMC-1121B will be dependent upon the patient’s baseline 
body weight in kilograms.  This dose will be recalculated if 
there is a 10% change in body weight from baseline. IMC 
1121B is formulated at 10 mg/mL (with a dose of 8 mg/kg). 
Premedication 
Premedication is recommended but not required prior to 
infusion of ramucirumab. Recommended premedication 
agents include histamine H1 antagonists such as 
diphenhydramine hydrochloride 50 mg I.V. (or equivalent). 
Additional premedication may be provided at investigator 
discretion. 
8.3.5.2 
Arm C (mICR):  
Patients will receive 6 mg/kg of IMC-1121B every 2 weeks, 
administered as an I.V. infusion over 1 hour. The dose of 
IMC-1121B will be dependent upon the patient’s baseline 
body weight in kilograms. This dose will be recalculated if 
there is a 10% change in body weight from baseline. IMC 
1121B is formulated at 10 mg/mL (with a dose of 8 mg/kg). 
Premedication 
Premedication is recommended but not required prior to 
infusion of ramucirumab. Recommended premedication 
agents include histamine H1 antagonists such as 
diphenhydramine hydrochloride 50 mg I.V. (or equivalent). 
Additional premedication may be provided at investigator 
discretion. 
8.3.6 
Preparation  
IMC-1121B drug product are sterile, preservative-free, injectable 
liquids in single-use 50-mL vials containing 500 mg/50 mL IMC-1121B 
in a histidine-buffered formulation at a final concentration of 10 
mg/mL. Each vial is packaged and labeled in accordance with local 
regulations. 
The dose of IMC-1121B should be aseptically withdrawn from the vial 
and transferred to a sterile AVIVA, ethylene vinyl acetate, polyolefin, 
or polyvinyl chloride I.V. bag, or an evacuated United States 
Pharmacopeia Type II (or local equivalent) glass I.V. container. For 
dose volumes < 250 mL, a sufficient quantity of sterile normal saline 
(0.9% weight/volume) solution must be added to the container (or 
removed in the case of a prefilled bag such as AVIVA) to make the 
total volume 250 mL. For dose volumes > 250 mL, the addition of 
sterile normal saline is not required.   
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The container should be gently inverted to ensure adequate mixing. 
Different drug product lots or formulations must not be mixed in a 
single infusion. 
Chemical and physical in-use stability has been demonstrated for up 
to 24 hours below 25°C (77°F). DO NOT FREEZE OR SHAKE IMC-
1121B. From a microbiological point of view, the prepared product 
should be used immediately.  If not used immediately, in-use storage 
time and conditions are the responsibility of the user and would 
normally not be longer than 24 hours at 2°C - 8°C (36F° - 46°F). IMC-
1121B should be protected from light when being stored. 
8.3.7 
Route of Administration  
The infusion should be delivered over 60 minutes. The infusion rate 
should not exceed 25 mg/minute. An infusion set (non-vented for 
plastic or vented for glass container) equipped with a downstream 
in-line, 0.2-µm or 0.22-µm protein-sparing filter is required for 
administration of IMC-1121B or placebo.  The infusion tubing must be 
flushed with normal saline to ensure delivery of the calculated dose. 
8.3.8 
Incompatibilities  
No formal drug interaction studies have been performed with IMC-
1121B in humans. 
8.3.9 
Availability  
Ramucirumab is an investigational agent (IND 109448), available free 
of charge and distributed by Eli Lilly and Company (Lilly). 
Ramucirumab is available as an injectable solution, in single-use, 50-
ml vials containing 500 mg at a concentration of 10mg/ml. The 
histidine buffer contains 10mM histidine, 75mM sodium chloride, 
133mM glycine and 0.01% Tween® -80. 
Drug may be ordered following submission and approval of the 
required regulatory documents as outlined in Section 4. Please 
place an order when you have a potential patient or a consented 
patient. A five cycle supply (ten 50-ml vials containing 500 mg at 
a concentration of 10mg/ml) of Ramucirumab will be provided. 
Investigators must email a completed E7208 Drug Request Form 
(See Appendix IV) to iits_usmail-oncology@lilly.com and 
data_account_usmail-sdc@lilly.com.  
Ramucirumab will be shipped to a responsible person (e.g., a 
pharmacist) at the investigator’s institution. Vials are shipped in 
refrigerated shippers to maintain temperature between 2ºC - 8ºC. 
Vials must be kept refrigerated between 2ºC - 8ºC at all times. IMC-
1121B should be protected from light when being stored. DO NOT 
FREEZE OR SHAKE IMC-1121B. 
Institutions should allow 10 business days (excluding Fridays) for 
shipment of drug from Lilly from receipt of the E7208 Drug Request 
Form. Shipments will be made from Lilly on Monday through Thursday 
for delivery on site Tuesday through Friday. There will be no weekend 
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or holiday delivery of drugs. The E7208 Drug Request Form can be 
downloaded from the ECOGACRIN website in WORD format. 
Important Reorder Instructions 
Once it is determined that the patient will continue treatment, please 
reorder study drug immediately. Reorders should be a sufficient 
number of vials to complete three cycles (i.e. six week supply at 
8mg/kg IV every two weeks) based on the patient’s weight in “kg” at 
the time of patient registration.  Dose and volume of the drug are 
dependent upon the patient’s baseline body weight in kilograms.  The 
dose should be recalculated if there is a 10% change in body weight 
from baseline.   
Institutions should allow 10 business days (excluding Fridays) for 
shipment of drug from Lilly from receipt of the E7208 Drug Request 
Form. Shipments will be made from Lilly on Monday through Thursday 
for delivery on site Tuesday through Friday. There will be no weekend 
or holiday delivery of drugs. 
The E7208 Drug Request Form can be downloaded from the ECOG-
ACRIN website in WORD format. 
Drug Destruction and Return 
When all patients have completed treatment at your institution, all 
unused, partially used, expired or empty containers must be 
destroyed at the site according to the institution’s policy for drug 
destruction. Please maintain appropriate records of the disposal, 
including dates and quantities. Sites are required to complete the 
Certificate of Destruction Form located in Appendix V. A copy of this 
form should be sent to iits_usmail-oncology@lilly.com. 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried. 
Please note that expiration dates are not listed on the vials. Lot 
numbers and related expiration dates are listed on the Drug Product 
Request Shipment Form which is shipped with the vials. Sites should 
keep a copy of this form as part of their drug inventory records.  
8.3.10 
Side Effects  
Adverse events of concern, which may or may not be associated with 
IMC-1121B therapy, include infusion reactions, hypertension, arterial 
or venous thrombotic events, proteinuria, bleeding, headache and 
fatigue. 
8.3.11 
Nursing/Patient Implications  
1.  Monitor patient closely during infusion, for infusion related events.  
2. Monitor blood pressure prior to each dose to assess for 
development of hypertension. 
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3.  Instruct patient to monitor and report signs/symptoms of: bleeding 
(nose bleeds, blood in sputum), wound healing problems, 
abdominal pain, thromboembolic problems (chest or leg pain, 
dyspnea, vision changes, severe headache, cough, swelling) 
4.  Baseline urine protein must be performed and repeated every six 
weeks. If elevated, 24 hour urine collection must be performed. 
5.  Treat pain, arthralgias, etc. with acetaminophen, or other pain 
relief strategies that do not interfere with the clotting cascade. 
Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves, and 
Class II vertical-laminar-airflow safety cabinets are recommended 
during preparation and handling.  Opened vials must be disposed of 
at the investigational center as chemotherapy or biohazardous waste 
provided documented procedures for destruction are in place. For 
questions regarding IMC-1121B destruction please contact Lilly at 
iits_usmail-oncology@lilly.com. 
IMC-1121B therapy should be used with caution in patients with 
known hypersensitivity to cetuximab, murine proteins, or any 
component of this product. 
It is recommended that patients wear sunscreen and hats and limit 
sun exposure while receiving IMC-1121B as sunlight can exacerbate 
any skin reactions that may occur. 
 
 
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9. 
Statistical Considerations 
9.1 
Revised Statistical Design - Arms A (IC) and C (mICR) 
Safety Monitoring 
The revised investigational regimen (that is, Arm C (mICR), a revision of the 
previous investigational Arm B) will be examined among the first 16 patients 
enrolled to Arm C post the re-activation of the randomized trial. Randomization 
will commence to Arms A and C and for purposes of adverse event evaluation, 
close monitoring of the study will occur until 16 patients have been enrolled to 
Arm C and followed through 2 cycles of therapy. During this safety evaluation 
period all patients will be followed closely with monthly conference calls of the 
study team and independent toxicity monitor to review all real-time CTEP-AERS 
reports and any case report form reported treatment-related adverse events. At 
the time of suspension of this study prior to reactivation, the accrual rate was 
about 3-4 patients per month. Given this expected recruitment pattern upon 
initially re-opening the study, it appears reasonable to have calls on a monthly 
basis. Once fully reactivated, the accrual rate should be 10 patients per month. If 
the accrual pattern is substantially higher during the first few months after 
reactivation, the study team will convene calls every two weeks. 
The toxic death rate on Arm B (ICR) prior to study suspension was 2/16 patients 
or 12.5%. With 16 patients on Arm C (mICR) evaluated under the new regimen 
the probability of observing 1 or more toxic deaths is 81.5% if the true toxic death 
rate is 10% and 88.2% under a true toxic death rate of 12.5%. No toxic deaths 
were observed in Arm A prior to suspension among 17 treated patients. Under 
the revised design with 16 patients evaluated on Arm C (mICR) the probability of 
observing one or more toxic deaths under a true toxic death rate of 0.77% is 
11.6%. If one or more toxic deaths occur at any point during the 16 patient 
evaluation of Arm C, the study will close to accrual and the regimen will be 
abandoned. 
The safety evaluation will also closely assess all treatment-related toxicities other 
than those of grade 5 with a particular emphasis on evaluating grade 3 and 4 
events. Prior to suspension the grade 3 or higher treatment-related adverse 
event rate on Arm A was 16.7%. With 16 patients on Arm C there is 81% power 
to detect a true grade 3 or higher toxicity rate of 39% (versus a null of 16.7%) 
and 90% power to detect a true rate of 44% using a one-sided exact binomial 
test at the 11% significance level (evaluating Arm C separately as the power for 
the two-group comparison is limited). The observed grade 3 or higher toxicity rate 
on Arm B was 87.5%. If the grade 3 or higher toxicity test is significant after 16 
patients on Arm C, the study will suspend accrual and the feasibility of the 
revised regimen will be evaluated by the study team and independent toxicity 
monitor, including a detailed review of all grade 3 or higher treatment related 
events. In addition to the above safety monitoring plan, the study will suspend 
upon the report of any colonic perforation event, regardless of treatment 
attribution or grade. A detailed review of the circumstances surrounding the event 
will be conducted and, in the case of the event occurring on Arm C, the feasibility 
of the revised regimen will be evaluated by the study team and toxicity monitor. 
The colonic perforation rate on Arm B (ICR) prior to study suspension was 2/16 
patients or 12.5%. With 16 patients on Arm C (mICR) evaluated under the new 
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regimen the probability of observing 1 or more colonic perforations is 81.5% if the 
true rate is 10% and 88.2% under a rate of 12.5%. No toxic deaths were 
observed in Arm A prior to suspension among 17 treated patients. 
In addition, the evaluation of 16 patients randomized to Arm C will allow 
estimation of any given toxicity with a 90% confidence interval that is no wider 
than 44.3 percentage points and there is 56.0% probability of observing any 
given event (1 or more out of 16 patients) with a true frequency of 5% and 81.5% 
probability observing 1 or more events with true frequency of 10%. 
Primary Efficacy Design 
Patients will be randomized equally between the two treatment arms A (IC) and 
C (mICR) with stratification based on performance status (0 vs. 1), 
discontinuation of oxaliplatin before disease progression (Yes vs. No), and time 
frame of progression (within 6 months of last treatment vs. > 6 months since last 
treatment). Patients previously randomized to arms A and B before the redesign 
of the experimental regimen will not be part of the formal efficacy evaluation and 
will be reported separately. 
With 48 eligible patients per arm followed for progression-free survival (disease 
progression or death without evidence of progression), this study has over 85% 
power to detect a difference of 4.5 months median PFS in the control arm A 
(40% PFS at 6 months assuming exponential failure) versus 7.65 months median 
PFS (58% PFS at 6 months) in the experimental arm (Arm C) using a one-sided 
stratified log rank test conducted with 15% type 1 error. The study will require 
approximately 10 months of accrual at 10 patients per month and 6 additional 
months of follow-up to achieve the events required (67 PFS events) to provide at 
least 85% power for the stated alternative of a 48% increase in median PFS. 
Response, overall survival, and toxicity are secondary endpoints and will be 
reported at the time of primary PFS analysis.  With 48 eligible patients per arm, 
the width of any 90% confidence interval on a binomial proportion will be no 
wider than 26 percentage points.  In addition, the probability of observing a rare 
(2% probability) toxicity in either arm is greater than 62% at full accrual. Allowing 
for roughly 5% ineligibility and including the 35 patients who were previously 
randomized to Arms A and B of the study prior to its redesign, this study will 
require a total of 135 patients and 100 patients will be accrued to the revised 
study (Arm A versus Arm C). 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC) for early stopping due to efficacy and futility. One interim 
stratified log rank test for efficacy will be performed at 60% PFS information (40 
PFS events), expected to occur roughly at the time accrual completes and six 
months before full information is achieved. Type I error control will be 
accomplished using an O'Brien-Fleming type boundary, with Lan-Demets use 
function methodology to adjust the boundary for the exact information time 
achieved at the interim analysis. If the study is positive, the DSMC may 
recommend early reporting; there is at least 55% probability of rejecting the null 
at the interim analysis if the alternative hypothesis is true. At the interim analysis 
time, the PFS hazard ratio will also be computed from a stratified proportional 
hazards regression model. If the HR exceeds 1 (that is, evidence that PFS is 
worse in the experimental Arm C), the DSMC may recommend abandoning the 
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on the operating characteristics of the trial is fairly small (less than 1% absolute 
effect on significance level and power). 
Additional Safety Monitoring 
In addition to the safety monitoring that will occur in the first 16 patients 
randomized to Arm C (described above), interim analyses of toxicity are 
performed twice yearly for all ECOG-ACRIN studies. Reports of these analyses 
are sent to the ECOG-ACRIN Principal Investigator or Senior Investigator at the 
participating institutions. Expedited reporting of certain adverse events is 
required, as described in Section 5.2 and ECOG-ACRIN Operations Office – 
Boston’s real-time monitoring of events through CTEP-AERS report notifications 
will be in place for this trial. This system provides monthly notifications to the 
study chair, study statistician and independent toxicity monitor of certain 
reportable grade 4 or higher events and all grade 5 events. 
9.2 
Original Statistical Design (Arms A and B) 
Patients will be randomized equally between the two treatment arms with 
stratification based on performance status (0 vs. 1), discontinuation of oxaliplatin 
before disease progression (Yes vs. No), and time frame of progression (within 6 
months of last treatment vs. > 6 months since last treatment). With 70 eligible 
patients per arm followed for progression-free survival (disease progression or 
death without evidence of progression), this study has 90% power to detect a 
difference of 4.5 months median PFS in the control arm (40% PFS at 6 months 
assuming exponential failure) versus 7.65 months median PFS (58% PFS at 6 
months) in the experimental arm using a one-sided log rank test conducted with 
10% type 1 error.  The study will require approximately 7 months of accrual at 20 
patients per month and 7 additional months of follow-up to achieve the events 
required (100 PFS events) to provide 90% power for the stated alternative of a 
70% increase in median PFS.  Response, overall survival, and toxicity are 
secondary endpoints and will be reported at the time of primary PFS analysis.  
With 70 eligible patients per arm, the width of any 90% confidence interval on a 
binomial proportion will be no wider than 21 percentage points.  In addition, the 
probability of observing a rare (1% probability) toxicity in either arm is greater 
than 50% at full accrual. Allowing for 5% ineligibility, this study will require a total 
of 147 patients. 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2 and 
ECOG-ACRIN Operations Office – Boston’s real-time monitoring of events 
through CTEP-AERS report notifications will be in place for this trial. This system 
provides monthly notifications to the study chair, study statistician and 
independent toxicity monitor of certain reportable grade 4 or higher events and all 
grade 5 events.  
In addition to ECOG-ACRIN’s routine semi-annual reporting of case report form 
toxicities through interim study reports and real-time monitoring of adverse 
events through CTEP-AERS, this study will include a detailed toxicity review of 
both treatment arms after 20 patients on each arm have been treated with at 
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least two cycles of therapy. After 20 patients have been randomized per arm, the 
study will suspend accrual. After the first 20 patients have been treated with at 
least 2 cycles of therapy, there will be a formal toxicity review once all cycle 2 
treatment forms and associated adverse event forms through this treatment 
period have been submitted to the ECOG-ACRIN Operations Office – Boston. 
The study statistician will prepare a report of all case report form and CTEP-
AERS reportable events for review by the study team and independent toxicity 
monitor. The study will remain suspended until the review is complete.  
With 20 patients per arm, there is greater than 55% probability of observing one 
or more rare (true probability of 4%) toxicities on either arm and greater than 
87% chance of observing one or more toxicities with true rate in excess of 10%. 
If 4 or more patients experience grade 4 or worse treatment-related events in an 
arm, consideration will be given to closing the trial or modifying the treatment 
regimens. Under this monitoring rule, there is less than 2% probability of meeting 
the monitoring boundary if the true grade 4 or higher toxicity probability is 5% but 
89% chance of meeting the boundary if the true probability is 30%. For other true 
grade 4 probabilities of 10%, 20% and 25%, the corresponding probabilities of 
reaching the boundary are 13%, 59% and 77%, respectively. Toxicity analyses 
will be conducted separately in each arm.  In addition to grade 4 toxicities, 
differences between the treatment arms with respect to all grade toxicities, grade 
3-4 toxicities, and non-hematologic toxicities will be assessed. If it is deemed 
necessary by the study team/independent toxicity monitors, an additional interim 
safely assessment will be conducted. 
Grade 5 events will also be separately monitored and reported. The recently 
reported EPIC trial (Sobrero et al., 2008) observed a toxic death rate of 0.77% in 
the cetuximab plus irinotecan arm (5 deaths among 650 patients). Taking 0.77% 
as the null toxic death rate for either arm in this trial and 5% or higher as an 
unacceptable alternative toxic death rate, we will consider modifying or closing 
the trial if in either arm 1 or more treatment-related toxic deaths are observed 
among the first 20 treated patients. Under the null hypothesis there is a 14% 
probability of observing one or more grade 5 events in the first 20 patients and 
64% probability under the alternative. If the true grade 5 event rate is as high as 
10%, there is 88% probability of observing 1 or more toxic deaths in the first 20 
patients treated on an arm. In addition to the toxicity analysis at suspension, 
grade 5 events will be continuously monitored, reported and reviewed as 
indicated above. At full accrual, the probability of observing 2 or more grade 5 
events out of 70 patients in an arm is 10% under the null hypothesis and 87% 
under the alternative hypothesis. 
9.3 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
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outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 
9.4 
Gender and Ethnicity  
Based on previous data from E3200 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
4 
4 
Not Hispanic or Latino 
50 
81 
131 
Ethnic Category: Total of all subjects 
50 
85 
135 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
5 
7 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
45 
78 
123 
Racial Category: Total of all subjects 
50 
85 
135 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
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10. 
Biological Specimen Submissions 
Paraffin-embedded tumor and normal mucosa tissue specimens are to be submitted for 
research from patients who consent “Yes” to “May your coded samples and related 
coded information be kept for use in research to learn about, prevent, find or treat 
cancer?” Paraffin blocks are being collected from this study for the purpose of tissue 
banking for use in future research and will be retained indefinitely at the ECOG-ACRIN 
Central Repository for use in future studies.   
Appendix II, Pathology Submission Guidelines, is available for distribution to the 
pathologist, outlining the submission requirements. 
NOTE: ECOG-ACRIN requires that all samples submitted must be entered and tracked 
via the online ECOG-ACRIN Sample Tracking System. See Section 10.3. 
10.1 
Materials Required For This Protocol 
10.1.1 
Forms – Must be sent with each submission 
• 
A copy of the surgical pathology report 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest  
10.1.2 
Biological Material 
• 
One H & E stained slide of the tumor 
• 
One paraffin block from representative sections of primary tumor 
• 
One paraffin block from normal colon tissue  
NOTE: If tissue blocks are not available, please contact the ECOG-
ACRINCentral Biorepository and Pathology Facility (CBPF) at 
1-844744-2420 or eacbpf@mdanderson.org to discuss 
alternative submission requirements. If pathology materials 
cannot be submitted, please indicate the in STSand include a 
letter of explanation. 
10.2 
Shipping Procedures  
Tissue specimens and the required forms and reports are to be submitted within 
1 month of patient registration to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
10.3 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
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the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the 
software. A user manual and interactive demo are available by 
clicking this link: http://www.ecog.org/general/stsinfo.html. Please 
take a moment to familiarize yourself with the software prior to using 
the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu 
Study Specific Notes 
If STS is unavailable at time of sample submission, submit the specimens using 
the ECOG-ACRIN Generic Specimen Submission Form (#2981) with the 
required documentation and retroactively enter the information when STS is 
available. Notify the CBPF the day of by faxing a copy of the submission form to 
713-563-6506. 
10.4 
Banking 
Specimens submitted will be retained at the ECOG-ACRIN Central Repository for 
possible use in future ECOG-ACRIN approved studies. Residual blocks will be 
available for purposes of individual patient management on specific written 
request. If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. 
10.5 
Sample Inventory Submission Guidelines  
Inventories of all samples, submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston upon request in an electronic format defined by the 
ECOG-ACRIN Operations Office-Boston. 
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11. 
Records to Be Kept 
Please refer to the E7208 Forms Packet for the forms submission schedule and copies 
of all forms. The E7208 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office – Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study is being conducted under an IND. All records pertaining to the trial 
(including source documents) must be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 
2000. Int J Cancer 2001 94 (2): 153-156.  
2. Landis SH, Murray T, Bolden S, et al. Cancer statistics 1998. CA Cancer J Clin 
1999;49 (1): 8-31.  
3. Jemal A, Siegel R, Ward E, et al. Cancer Statistics 2007; 57 (1): 43-66.  
4. Dy GK, Krook JE, Green EM, et al. Impact of complete response to chemotherapy on 
overall survival in advanced colorectal cancer: Results from Intergroup N9741. J Clin 
Oncol 2007 25: 3469-3474. 
5. Goldberg RM, Sargent DJ, Morton RF et al.  A randomized controlled trial of 
fluorouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with 
previously untreated metastatic colorectal cancer.  J Clin Oncol 2004; 22 (1): 23-30. 
6. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, 
leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) compared with infusional 


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fluorouracil and irinotecan as first-line treatment for metastatic colorectal cancer.   J 
Clin Oncol 2007; 25 (13): 1670-1676 
7. Saltz LB, Clark S, Diaz-Rubio et al. Bevacizumab in combination with oxaliplatin-
based chemotherapy as first-line therapy in metastatic colorectal cancer: a 
randomized phase II study.  J Clin Oncol 2008; 26 (12): 2013-2019. 
8. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, 
Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI 
followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a 
randomized GERCOR study.J Clin Oncol. 2004 Jan 15;22(2):229-37.  
9. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-
Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, 
Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: 
phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin 
failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 
10;26(14):2311-9.  
10. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, 
Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, 
Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in 
advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. 
11. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat 
Med. 1995;1:27-31. 
12. Kerbel RS.  Tumor angiogenesis: past, present and the near future. Carcinogenesis. 
2000;21:505-515. 
13. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 
2000;407:249-257. 
14. Klagsbrun M, D'Amore PA. Vascular endothelial growth factor and its receptors. 
Cytokine Growth Factor Rev. 1996;7:259-270. 
15. Liekens S, De Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. 
Biochem Pharmacol. 2001;61:253-270. 
16. Ferrara N. The role of vascular endothelial growth factor in pathological 
angiogenesis. Breast Cancer Res Treat. 1995;36:127-137. 
17. Brown LF, Detmar M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF. Vascular 
permeability factor/vascular endothelial growth factor: a multifunctional angiogenic 
cytokine. EXS. 1997;79:233-269. 
18. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis 
via vascular endothelial growth factor receptors. Cancer Res. 2000;60:203-212. 
19. Ferrara N.  Molecular and biological properties of vascular endothelial growth factors. 
J Mol Med. 1999;77:527-543. 
20. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M. 
Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase 
gene (flt) closely related to the fms family. Oncogene. 1990;5:519-524. 
21. De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like 
tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 
1992;255:989-991. 


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22. Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR. A 
receptor tyrosine kinase cDNA isolated from a population of enriched primitive 
hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci 
USA. 1991;88:9026-9030. 
23. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, 
Gospodarowicz D, Bohlen P.  Identification of the KDR tyrosine kinase as a receptor 
for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 
1992;187:1579-1586. 
24. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, et al. Heterozygous 
embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 
1996;380:439-442. 
25. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. 
Abnormal blood vessel development and lethality in embryos lacking a single VEGF 
allele. Nature. 1996;380:435-439. 
26. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh 
AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. 
Nature. 1995;376:62-66. 
27. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor 
tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 
1995;376:66-70. 
28. Plate KH, Breier G, Millauer B, Ullrich A, Risau W. Up-regulation of vascular 
endothelial growth factor and its cognate receptors in a rat glioma model of tumor 
angiogenesis. Cancer Res. 1993;53:5822-5827. 
29. Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P, Bohlen P. 
Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-
angiogenic therapeutic strategy.  Cancer Metastasis Rev. 1998;17:155-161. 
30. Zhu Z, Witte L. Inhibition of tumor growth and metastasis by targeting tumor-
associated angiogenesis with antagonists to the receptors of vascular endothelial 
growth factor. Invest New Drugs. 1999;17:195-212. 
31. Hicklin D, Witte L, Zhu Z, Liao F, Wu Y, Li Y, Bohlen P. Monoclonal antibody 
strategies to block angiogenesis. Drug Discovery Today. 2001; 6:517-528. 
32. Zhu Z, Bohlen P, Witte L. Clinical development of angiogenesis inhibitors to vascular 
endothelial growth factor and its receptors as cancer therapeutics. Curr Cancer Drug 
Targets. 2002;2:135-156. 
33. Lu D, Jimenez X, Zhang H, Bohlen P, Witte L, Zhu Z. Selection of high affinity human 
neutralizing antibodies to VEGFR2 from a large antibody phage display library for 
antiangiogenesis therapy. Int J Cancer. 2002;97:393-399. 
34. Lu D, Shen J, Vil MD, Zhang H, Jimenez X, Bohlen P, et al. Tailoring in vitro 
selection for a picomolar affinity human antibody directed against vascular 
endothelial growth factor receptor 2 for enhanced neutralizing activity. J Biol Chem. 
2003;278:43496-43507. 
35. Lacouture M, et al. The SERIES clinic: An Interdisciplinary Approach to the 
Management of Toxicities of EGFR Inhibitors. J Support Oncol.  2006;236-238. 
36. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, 
Simes RJ,      Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, 


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Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in 
advanced colorectal cancer. N Engl J Med. 2008  Oct 23;359(17):1757-65. 
37. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, 
D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar 
S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial 
treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-
17. 
 


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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #5] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #5 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
 


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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E7208 
4. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
Instructions: 
1. 
Provide the following information with all specimens submitted: 
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG-ACRIN sequence number; for 
intergroup studies, include both the ECOG-ACRIN and other group's 
sequence numbers) 
Patient's hospital number 
Institution 
Affiliate (if appropriate) 
2. 
Complete blank areas of the pathologist's instructional memo and forward it, 
along with the List of Required Material, The Generic Specimen Submission 
Form, may be used as a tool to capture information for entering information into 
STS.The pathologist should return the required pathology samples and surgical 
pathology reports, along any additional information required. If any other reports 
are required, they should be obtained from the appropriate department at this 
time. 
3. 
Keep a copy of STS shipping manifest or Submission Form for your records. 
(The original should be sent to the CBPF.) 
4. 
Double-check that ALL required forms, reports and pathology samples are 
included in the package to the Central Biorepository and Pathology Facility. (See 
appropriate List of Required Material.)  
 
Pathology specimens submitted WILL NOT be processed by the 
Biorepository and Pathology Facility until all necessary items are received. 
 
5. 
Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420  
(713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility by telephone 1-844-744-2420 or by email: eacbpf@mdanderson.org 
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List of Required Material 
E7208:  A Randomized Phase II Study of Irinotecan and Cetuximab with or without the 
Anti-Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type 
Colorectal Cancer Following Progression on Bevacizumab-Containing 
Chemotherapy 
Pre-Treatment 
1. 
Institutional pathology report (must be included with EVERY pathology 
submission). 
2. 
Biological materials 
• 
One H & E stained slide of the tumor 
• 
One paraffin block from representative sections of primary tumor 
• 
One paraffin block from normal colon tissue  
NOTE: If tissue blocks are not available, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility (CBPF) at 1-844-744-2420 
to discuss alternative submission requirements. 
 
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MEMORANDUM 
TO:  
_______________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
_______________________________________ 
SUBJECT: 
Submission of Pathology Materials for E7208: A Randomized Phase II 
Study of Irinotecan and Cetuximab with or without the Anti-Angiogenic 
Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal 
Cancer Following Progression on Bevacizumab-Containing 
Chemotherapy 
______________________________________________________________________ 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for banking for future research. 
Please complete PART B of the Submission Form. Keep a copy for your records and 
return the completed Submission Form, the surgical pathology report(s), the slides 
and/or blocks and any other required material (see List of Required Material) to the 
Clinical Research Associate (CRA). The CRA will forward all required pathology material 
to the ECOG-ACRIN Central Biorepository and Pathology Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies. Paraffin blocks will be returned upon written requested for 
purposes of patient management. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 1-844-744-2420 or by email at 
eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
 
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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix IV 
 
Investigational Product Shipment Request Form 
Shipping Investigational Products and Related Supplies: 
MQS442-010-TL36-v1 
Investigational Product Shipment Request Form 
Investigational Product Shipment Request Form 
Please send a completed form to: 
Data_account_USMAIL-SDC@lilly.com & iits_usmail-oncology@lilly.com 
Protocol Trial Alias/Study Code I4E-IE-I004 (E7208) 
Ship-to-address* 
 
 
 
 
 
E-mail address*  
 
Site Number* 
Investigator Name* 
Attention to, or Other 
Recipient, Name* 
Phone Number of 
Recipient* 
101 - ______ 
  
 
 
*Make sure required fields match information in Drug Shipment and Site Identification information 
provided. 
Is this an initial Lilly drug order request? 
 Yes    
 No 
If YES, please include a copy of your IRB with your drug order - IP Shipment form. 
Planned Due Date on Site 
Indicate date material must be received by: 
Please allow 5 Business days for non-refrigerated shipments.  
Please allow 10 working days for refrigerated shipments. Refrigerated shipments will 
not be sent on Fridays. 
 
Are there any restrictions to specific days or times that product cannot be received? 
If “Yes,” please indicate restrictions below. 
 Yes    
 No 
Delivery Restrictions:  
 
             Internal Use Only 
Item Number 
Lot Number 
(Optional) 
Product Description 
Qty 
NDC 0002-7678-01 
 
Cyramza (Ramucirumab) Injection 500mg/50ml 
 
NDC 0002-7669-01 
 
Cyramza (Ramucirumab) Injection 100mg/50ml 
 
 
Comment   
Eli Lilly and Company © 2013 
Confidential 
Page 1 of 1 
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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix V 
 
Disposition Form 
 
 
To Be Completed By Site Personnel and email to its usmail-oncology@lilly.com 
Investigator:
Site Name / No.: 
Protocol Number:E7208/MED-P12-10001 
Product: Ramucirumab (IMC-1121B) 
Lot #:
Quantity:
 
 Returned 
 Destroyed at Site: (Complete reason,
method, and location of destruction) 
 Transfer to:
 Reason for Destruction: 
 Method of Destruction:  
 Location of Destruction: 
 Pharmacist: 
Phone #: 
 Signature: 
Date: 
To Be Completed By Eli Lilly & Company 
 I. Reason for Return: 
 
 
 
 
 
 
 
 
 
Is an Investigation Required? 
  Yes 
  No 
 II. Inspection: 
Date Received: 
 
 
Quantity Received:   
 
 
 
 
Shipper Container Integrity 
  Satisfactory 
  Unsatisfactory 
Product Container Integrity 
  Satisfactory 
  Unsatisfactory 
Temperature Indicator 
  Satisfactory 
  Unsatisfactory 
 Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 III. Disposition: 
 
  Preclinical Inventory 
 
Quantity  
 
 
  Destroyed 
 
Quantity  
 
 
 Approval 
 
 
 
 
 
Signature 
 
 
 
 
 Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix VI 
 
Reimbursement Invoice 
PLACE PATIENT ID LABEL HERE 
 
Invoice Number 
(ECC Use only)  
 
 
Patient Initials (Last, First)                             ________ 
ECOG-ACRIN Protocol # 
 
ECOG-ACRIN Patient ID __________ 
Participating Group Protocol # _____________________ 
Participating Group Patient ID                        _____ 
Institution/Affiliate ______________________________ 
 
 
 
 
Payee Address 
 
 Payee/W-9 Name: 
      
 
 
Payee Tax ID #: 
      
 
Attention To: 
      
 
Date: 
      
CTEP 
ID: 
      
Street Address: 
      
 
Name of 
Investigator: 
      
 
City, State, Zip: 
      
 
NCI 
Investigator 
ID #: 
      
 
Any Requested Reference on 
Payment (i.e. Invoice #): 
      
 
Time Point 
Date of Service 
Type of Biopsy 
Performed  
Amount Requested (please itemize costs) 
Please Note:   
Amount requested may not exceed $150 per 
EKG, $50 per UPC and $75 per Pregnancy Test. 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
 
      
 
 
A copy of the test results for each service performed is attached. 
 
If there are problems with this invoice, please contact:  
 
Name 
 
Phone 
 
Fax 
 
Email 
 
      
      
      
      
If you have questions about the reimbursement process, please contact the EA drug team at 
900.drugorder@jimmy.harvard.edu or 617-632-3610. 
Please fax the completed form along with the related test results to 617-632-2063. 
Rev. 5/16 


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A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix VII 
 
Substitute W-9 Tax Form 
Instructions 
1. This form is a substitute to the Internal Revenue Service W-9 Tax Form. In addition to 
capturing all of the information required by the IRS, it also collects other information that is 
needed for our records. Questions regarding this form should be directed to the 
Pharmaceutical Liaison at the ECOG-ACRIN Operations Office – Boston 617-632-3610. 
Please note that only US-based institutions can use this form. 
2. Complete all requested information and sign the substitute W-9 form. The original copy 
should be submitted to the ECOG-ACRIN Operations Office – Boston as soon as possible.  
Please provide the legal name and address of the organization associated with the Federal Tax 
Identification Number listed in this section. (Generally, the corporate headquarters address of the 
university, hospital, or business should be provided. This information will be used for income reporting to 
the IRS and your organization). 
Legal Name:_______________________________________________________________________________ 
Corporate Address: ________________________________________________________________________ 
                                   ________________________________________________________________________ 
                                   ________________________________________________________________________ 
City:_____________________________________ State:___________________ ZipCode:________________ 
NCI CTEP ID:___________________________________ 
Federal Tax Identification Number:_______________________    Phone Number:_____________________ 
 
Please identify the organization’s preferred payment address. ECOG-ACRIN will use this information for 
mailing checks to the organization. Please note that while ECOG-ACRIN can submit payment to an alternate 
address, it cannot make checks payable to a different organizational name or to a third party. 
Payment Address:__________________________________________________________________________ 
City:____________________________________ State:__________________ ZipCode:__________________ 
Phone Number: _________________  Fax Number:__________________  E-mail: _____________________ 
Is this payment address affiliated with the Federal Tax ID listed above?:_____________________________  
 
Please identify whether the organization has a special status as defined by the following criteria: 
(Select all that apply) 
Minority Business Enterprise (at least 51% minority-owned and managed business) 
 
 
Woman’s Business Enterprise (at least 51% woman-owned and managed business) 
 
 
Small Disadvantaged Business (as certified by the SBA) 
 
 
Veteran Business Enterprise (at least 51% veteran-owned business) 
 
 
Historically Underutilized Small Business (as certified by the SBA) 
 
 
None of the Above 
 
 
 
 
 
 
Under penalties of perjury, I certify that all of the information provided above is correct and that my 
organization is not subject to back-up withholding. 
Printed Name:____________________________________  Title:__________________________________ 
Signature:________________________________________ Date:__________________________________ 


ECOG-ACRIN 
E7208 
Cancer Research Group 
Version Date: March 22, 2016 
94 
A Randomized Phase II Study of Irinotecan and Cetuximab with or without the Anti-
Angiogenic Antibody, Ramucirumab, in Advanced, K-ras Wild-type Colorectal Cancer 
Following Progression on Bevacizumab-Containing Chemotherapy 
Appendix VIII 
 
E7208 Temperature Excursion Form 
 
 
 
 
 
 
 
 
For a copy of the Temperature Excursion Form please contact iits_usmail-oncology@lilly.com 
Rev. 12/11, 5/16