A Phase II Trial of External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas (POE08-01)
Phase: PHASE2
Conditions: Brain Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

                      Memorial Sloan-Kettering Cancer Center 
                                                                               IRB Protocol 
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A phase II trial of external beam radiation therapy and cetuximab followed by irinotecan and 
cetuximab for children and young adults with newly diagnosed diffuse pontine tumors and high-
grade astrocytomas (POE08-01) 
Principal investigator: Ira Dunkel, Memorial Sloan-Kettering Cancer Center 
Co-principal investigator: Nicholas Foreman, University of Colorado Health Sciences Center 
POETIC institutions and co-investigators 
Healthcare of Atlanta/Emory University School of Medicine: Drs. Howard 
Katzenstein1 & Anna Janss2 
Dana-Farber Cancer Institute: Drs. Mark Kieran1 & Susan Chi2 
MD Anderson Cancer Center: Drs. Cynthia Herzog1 & Soumen Khatua2 
Memorial Sloan-Kettering Cancer Center: Drs. Tanya Trippett1 & Ira Dunkel2 
1 & Michael Etzl2 
Sidney Kimmel Cancer Center at Johns Hopkins: Drs. Robert Arceci1 & Ken Cohen2 
Hospital: Drs. Aru Narendran1 & Lucie Lafay-Cousin2
University of Colorado Health Sciences Center: Drs. Lia Gore1 & Nicholas Foreman2 
: Dr. Kathleen Neville 1-2 
MD Anderson Cancer Center Orlando at Arnold Palmer Hospital for Children: Dr. Amy Smith1-2
 
POETIC collaborating institutions 
1-2  
The Hospital for Sick Children: Drs. James Whitlock1 & Eric Bouffet2 
1: Institutional POETIC primary investigator 
2: Institutional pediatric neuro-oncologist 
Other investigators 
Study biostatistician: Irina Ostrovnaya, PhD, Memorial Sloan-Kettering Cancer Center 
Study neurosurgeon: Dr. Mark Souweidane, Memorial Sloan-Kettering Cancer Center 
Study pharmacist: Dr. Michael Kellick, Memorial Sloan-Kettering Cancer Center 
Study radiation oncologist: Dr. Suzanne Wolden, Memorial Sloan-Kettering Cancer Center 
Study nurse: Geraldine Wright, RN, MS, Memorial Sloan-Kettering Cancer Center 
CSF proteomics project co-
 

 
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Table of Contents 
1.0
Protocol summary and/or schema
 
 
 
 
 
1 
2.0
Objectives and scientific aims 
 
 
 
 
 
1 
3.0
Background and rationale 
 
 
 
 
 
 
2 
4.0
Overview of study design/intervention
 
 
 
 
10 
5.0
Therapeutic/diagnostic agents 
 
 
 
 
 
11 
6.0
Criteria for subject eligibility  
 
 
 
 
 
15 
7.0
Recruitment plan
 
 
 
 
 
 
 
16 
8.0
Pretreatment evaluation  
 
 
 
 
 
 
18 
9.0
Treatment/intervention plan  
 
 
 
 
 
19 
10.0
Evaluation during treatment/intervention 
 
 
 
 
25 
11.0
Toxicities/side effects  
 
 
 
 
 
 
33 
12.0
Criteria for therapeutic response/outcome assessment 
 
 
41 
13.0
Criteria for removal from study 
 
 
 
 
 
42 
14.0
Biostatistics 
 
 
 
 
 
 
 
 
42 
15.0
Research participant registration and randomization procedures 
 
44 
16.0
Data management issues 
 
 
 
 
 
 
46 
17.0
Protection of human subjects  
 
 
 
 
 
49 
18.0
Informed consent procedures  
 
 
 
 
 
55 
19.0
Appendices 
 
 
 
 
 
 
 
 
56 
 
 

 
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1.0
PROTOCOL SUMMARY AND/OR SCHEMA  
In this protocol 
followed by irinotecan and cetuximab for children and young adults with newly diagnosed 
diffuse pontine tumors and high-
 patients will be enrolled after maximal 
safe neurosurgical resection (HGA patients) or radiological diagnosis (diffuse pontine tumor 
patients). They will then receive protocol-prescribed therapy: 
 External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab 
(250 mg/m2/dose). 
 4-8 week rest 
 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly 
cetuximab (250 mg/m2/dose) at about 21 day intervals 
 
Research biological evaluations will be performed in consenting patients as an optional 
portion of the study. 
 
2.0
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objectives: 
 
1. To determine the proportion of patients with high-grade astrocytoma and diffuse pontine 
tumors achieving one year progression free survival. 
2. To determine the safety of cetuximab administered weekly in conjunction with involved 
field external beam radiation therapy for diffuse pontine tumors and high-grade 
astrocytomas. 
 
Secondary objectives: 
 
1. To estimate the response rate, time to progression, and overall survival in 2 cohorts of 
patients (diffuse intrinsic pontine tumors, high-grade astrocytomas) treated on this 
protocol. 
2. To explore whether there are any potential associations between primary tumor tissue 
molecular markers and tumor response. 
3. To identify CSF protein markers that might indicate the presence of a brain tumor, to 
validate proteomic methodology by correlating protein and ELISA measurements of 
known proteins implicated in angiogenesis and tumor progression (VEGF, bFGF, SPARC, 
attractin), and to explore whether there are any potential associations between histology 
(grade) with protein and ELISA measurements of those proteins. 
4. To investigate whether the rash associated with cetuximab is secondary to an 
inflammatory pathway initiated and mediated by the action of cetuximab on host cells. 

 
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3.0
BACKGROUND AND RATIONALE 
3.1
DIFFUSE INTRINSIC PONTINE TUMORS 
 
 
Diffuse intrinsic pontine tumors remain one of the most difficult challenges in pediatric 
oncology. While the prognosis for children with most forms of cancer has steadily improved 
over time, the dismal prognosis for children with diffuse intrinsic pontine tumors has not yet 
been altered. 
Patients with typical diffuse pontine tumors usually present with a short history of signs or 
symptoms, and physical examination at presentation typically reveals abducens palsy among 
other neurological findings. MRI scan reveals infiltrative expansion of the pons, typically with 
high signal on T2 weighted images, little or no enhancement, and no significant exophytic 
component. Envelopment of the basilar artery is commonly present [Cancer 2000, 89:1569-
1576]. 
About 30,000 to 40,000 children worldwide develop brain tumors each year [Childs Nerv Syst 
1999, 15:758-763]. Data from 1990 to 1999 from the population-based German Childhood 
Cancer Registry reveal that 1 of 2,500 children will be diagnosed with a central nervous system 
tumor within the first 15 years of life [Cancer 2001, 92:3155-3164], with brain stem tumors 
representing 13.8% of the total. Primary pons and brain stem tumors make up 10.7% of the 
central nervous system tumors. Assuming that most of those represent diffuse pontine tumors, 
we can estimate that about 1 of 23,000 children will develop a diffuse pontine tumor by the age 
of 15 years. 
While rare, diffuse pontine tumors represent a significant portion of the deaths due to childhood 
cancer. The German registry included 16,826 pediatric oncology patients enrolled over a 10 year 
period. If we assume that 75% of the children were cured, then about 4,200 children died of all 
forms of cancer. There were 351 patients with brain stem and pontine tumors. If we assume that 
90% of those died (as would be expected based on current data), then this group represents about 
8% of the total deaths due to childhood cancer, a number that far exceeds its proportional 
representation in the distribution of pediatric cancer diagnoses. 
 
3.2 
RADIATION THERAPY IS VERY RARELY CURATIVE FOR DIFFUSE INTRINSIC  
PONTINE TUMORS 
 
External beam radiation therapy is the standard therapy for diffuse pontine tumors, but several 
approximately 10% of patients achieve 3-year survival despite dose-escalation as high as 7800 
cGy via hyperfractionation.  
POG 9239 was a phase III trial of conventional radiation therapy versus hyperfractionated 
radiation therapy in children with newly diagnosed diffuse intrinsic brainstem tumors [Int J 
Radiat Oncol Biol Phys 1999, 43:959-964]. Conventionally treated patients received 5400 cGy in 

 
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180 cGy daily fractions, while patients on the experimental arm received 7020 cGy in 117 cGy 
fractions administered twice daily. Two year survival rates were 7.1% and 6.7%, respectively 
(p=0.65). One year event-free survival was approximately 10%.  
Accelerated fractionation (conventional fraction doses administered twice daily, resulting in a 
shorter total treatment duration) was studied in the United Kingdom. While the treatment was 
tolerable, it was also associated with very poor survival [Int J Radiat Oncol Biol Phys 1997, 
38:925-929]. 
 
3.3 
CHEMOTHERAPY HAS NOT BEEN EFFECTIVE FOR DIFFUSE INTRINSIC 
PONTINE TUMORS 
 
Conventional-dose chemotherapy (usually administered in conjunction with external beam 
radiation therapy) has not been proved to be effective for diffuse pontine tumors. CCG 9941 was 
a randomized phase II trial of 2 intensive pre-radiation chemotherapy regimens for children with 
newly diagnosed diffuse pontine tumors [J Clin Oncol 2002, 20:3431-3437]. Thirty-two patients 
received regimen A: vincristine (1.5 mg/m2), carboplatin (600 mg/m2/day x 2) and etoposide 
(167 mg/m2/day x 3). Thirty-one received regimen B: vincristine (1.5 mg/m2), cisplatin (100 
mg/m2), cyclophosphamide (1500 mg/m2/day x 2) and etoposide (167 mg/m2/day x 3). Regimen 
A resulted in a 10% (+/- 
-dimensional tumor 
size) while regimen B resulted in a 19% (+/- 8%) objective response rate. All patients then 
received hyperfractionated radiation therapy (7200 cGy) and 2-year event-free survival for the 
entire group was only 6%. These results were not considered to be superior to the historical 
results with radiation therapy alone. Additionally, high-dose thiotepa-based chemotherapy 
regimens with stem cell rescue explored by MSKCC/CCG [J Neurooncol 1998, 37:67-73] and 
French [Cancer 2000, 88:685-692] investigators have similarly not been effective for diffuse 
pontine tumors.  
 
A variety of agents have been used in conjunction with radiation therapy, often as putative 
radiation sensitizers, including high-dose tamoxifen [J Clin Oncol 2000, 18:1246-1253], 
topotecan [Neurooncol 2003, 5:8-13], and etanidazole [Int J Radiat Oncol Biol Phys 2003, 
55:1182-1185]. None has yet been demonstrated to be superior to radiation therapy alone, and 
there is some evidence that the combined use of external beam radiation therapy and 
radiosensitizers may actually be worse than radiation therapy alone. POG investigators non-
randomly compared patients with diffuse pontine tumors treated with hyperfractionated radiation 
therapy alone (7020 cGy) on POG 8495 with those treated with the same radiation therapy plus 
concurrent cisplatin on POG 9239. A strong trend towards inferior 1-year survival amongst 
patients treated with combined therapy was noted [Int J Radiat Oncol Biol Phys 2000, 47:561-
564]. 
 
3.4 
NON-PONTINE HIGH-GRADE ASTROCYTOMAS ALSO HAVE A DISMAL 
PROGNOSIS 
 
While surgery is often an additional treatment modality available for pediatric patients with non-
pontine high-grade astrocytomas, their prognosis also remains very poor. The current standard of 
care is maximal safe surgical resection, involved-field radiation therapy, and chemotherapy. The 
largest published pediatric trial to date (CCG-945) compared vincristine, lomustine and 

 
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prednisone to the "eight-in-one" chemotherapy regimen in 185 children diagnosed with high-
grade astrocytomas between 1985 to 1990 [J Clin Oncol 1995; 13:112-123]. There was no 
difference in progression-free survival between the two regimens. Overall, patients with AA had 
a 5-year progression-free survival of 28% versus 16% for patients with GBM. Patients with a 
gross total resection (> 90%) fared better than did those with less radical surgery (5-year 
progression-free survival for patients with AA, 42% vs 14%, respectively; for patients with 
GBM, 27% vs 4%). Thus, perhaps apart from those who had gross total resection, the prognosis 
for children with newly diagnosed high-grade astrocytomas was very poor. COG ACNS 0126 
subsequently treated children with newly diagnosed high-grade astrocytomas with post-operative 
external beam radiation therapy and concurrent daily temozolomide (90 mg/m2/day x 42), 
followed by post-RT temozolomide (200 mg/m2/day x 5 per cycle, for ten 28 day cycles). The 
results have not yet been published, but the preliminary results have been presented on multiple 
occasions and they do not appear superior to the historical results seen in CCG-945. One year 
EFS for patients with AA and GBM was 31% +/- 8% and 36% +/- 7%, respectively [ISPNO 
2006 abstract TMZ-02, p 57]. 
3.5 
CETUXIMAB 
Cetuximab is a human/mouse chimerized antibody of the IgG1 subclass. It is composed of the Fv 
regions of a murine anti-EGFR antibody (M225) which human IgG1 heavy and kappa light chain 
constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced 
and inhibits ligand-induced activation. In addition, cetuximab binding stimulates EGFR 
internalization, effectively removing the receptor from the cell surface for interaction with 
ligand. In 2004 the FDA approved cetuximab to be used in combination with irinotecan in adult 
patients with metastatic colorectal cancer who had failed a prior irinotecan-containing regimen, 
or as a single agent in patients intolerant to irinotecan. 
 
3.6
CETUXIMAB WITH EXTERNAL BEAM RADIATION THERAPY 
 
The combination of cetuximab and external beam radiation therapy has not previously been 
investigated in pediatric patients. However, this combination has been determined to be tolerable 
[J Clin Oncol 2001; 19:3234-3243] and effective in adults with head and neck cancer. A phase 
III trial comparing RT to RT + cetuximab revealed the addition of cetuximab was associated 
with improved locoregional control, decreased mortality, and was not associated with increased 
RT-associated side effects [N Engl J Med 2006; 354:567-578].  
3.7
CETUXIMAB FOR BRAIN TUMORS
Clinical data are not yet available regarding cetuximab for brain tumors in either adults or 
children, with the exception of data discussed below in Section 3.9. Pre-clinical work with an 
EGFR-amplified glioblastoma multiforme cell line implanted into the flanks or intra-cranially in 
nude mice yielded encouraging results. Animals treated with cetuximab achieved a significant 
increase in median survival versus the control animals. Radiation therapy was noted to augment 
the effect of cetuximab [Neurosurgery 2005; 56:155-162].  

 
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Limited information is available regarding the biology of diffuse intrinsic pontine tumors 
because they are usually diagnosed radiographically and a biopsy is not performed. However, a 
series of 28 samples (18 obtained via biopsy, 10 via autopsy) was studied and the results 
suggested that EGFR signaling is worthy of study as a therapeutic target [Clin Cancer Res 2003; 
9:3620-3624]. Similarly, while EGFR amplification has been infrequently found in pediatric 
high-grade astrocytomas, increased expression has been frequently found and targeting EGFR 
has been suggested as a novel strategy worthy of investigation [Clin Cancer Res 1999; 5:1786-
1792]. 
3.8 
IRINOTECAN IS ACTIVE VERSUS PEDIATRIC HIGH-GRADE ASTROCYTOMAS 
Duke investigators performed a phase II study of irinotecan (125 mg/m2/dose IV weekly x 4 
weeks, followed by a 2 week rest) in children with high-risk malignant brain tumors [Neurooncol 
2002; 4:102-108]. Responses (complete + partial) were seen in 4 of 9 patients with high-grade 
astrocytomas, but none of the 5 with recurrent diffuse intrinsic pontine tumors. However, a POG 
phase I study of irinotecan (30-65 mg/m2/dose IV x 5 days every 21 days) included 3 patients 
with brainstem gliomas and 1 achieved stable disease [Clin Cancer Res 2001; 7:32-37]. 
The effectiveness of irinotecan is known to be schedule-dependent, and St Jude investigators 
have suggested that the most effective regimen is likely to be 20 mg/m2/dose IV daily x 5 days x 
2 weeks, every 3 weeks, based on strong pharmacologic and pharmacokinetic data [J Clin Oncol 
1999; 17:1815-1824].  
3.9
POETIC PHASE I CETUXIMAB-IRINOTECAN EXPERIENCE 
 
POETIC performed the first pediatric phase I study of the irinotecan and cetuximab combination 
(CA225085), which was also the initial experience using cetuximab in pediatric oncology 
patients and in patients with primary tumors of the central nervous system. The preliminary 
results of this study were presented at the 2007 meeting of the American Society of Clinical 
Oncology (ASCO) and help justify the exploration of this combination in patients with newly 
diagnosed disease. 
Thirty-five heavily pre-treated patients with refractory solid tumors were enrolled, including 16 
patients with high-grade, refractory astrocytomas or progressive brainstem gliomas. Weekly 
cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250 mg/m2/dose weekly; 
irinotecan was given at 16 or 20 mg/m2/day over 1 hour (daily x 5) for two weeks, every 21 
days. Patients were treated in two age cohorts (ages 1-12 years = Group A, and 13-18 years = 
Group B). Pharmacokinetic analyses showed linearity, with similar t1/2, clearance, and volume 
of distribution between the groups. Irinotecan-related DLT in 2/6 patients in Group A/dose 2 
necessitated dose de-escalation from 20 mg/m2/dose to 16 mg/m2/dose. Three patients 
experienced Grade 3 hypersensitivity infusion reaction and were discontinued. A patient with an 
EGFR-negative high-grade glioma (dose level 1) achieved a >70% reduction in tumor size and 
remains on study for 22+ months. A patient with ependymoma experienced a confirmed partial 
response (PR) and continues on treatment for more than 12 cycles. Nine patients received >4 
cycles of therapy. Sixteen patients had a best response of stable disease or PR (mean 17 wks, 
range 5-66+ wks) for an overall clinical benefit rate of 45%. The authors concluded that the 
combination of cetuximab and irinotecan is well-tolerated over multiple repeat cycles without 

 
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cumulative toxicity in children with refractory CNS and non-CNS solid tumors and that 
promising preliminary anti-cancer activity was observed in a variety of pediatric solid tumors, 
including high-grade and refractory tumors of the central nervous system. 
3.10
CORRELATION OF MOLECULAR MARKERS & TUMOR RESPONSE TO 
THERAPY (Project leaders: Dr. Nicholas Foreman & Andrew Donson, University of Colorado 
Health Sciences Center, Denver, CO) 
 
While cetuximab has been approved for the treatment of metastatic colorectal cancer and head 
and neck cancer, and has shown promise in treating a number of other solid tumors either as a 
single agent or in combination with other treatments, EGFR over-expression was found to be 
non-predictive for cetuximab response [Mol Cancer Ther 2006; 5:104-113]. The over-expression 
of EGFR has, therefore, not been used as an inclusion criterion in clinical trials of cetuximab. 
Consequently, there is interest in alternative predictors of response to cetuximab. These 
molecular predictors could be used to select patients who may have a better response to 
cetuximab whilst sparing those patients who will not respond to ineffective therapy.  
The laboratory investigations described in Section 10.1 will be performed using tumor specimens 
from patients enrolled in this trial in order to identify predictive markers for response to this 
regimen. Cetuximab, in combination with RT and/or irinotecan, may prove to be effective in a 
fraction of the patients treated, and the goal of this objective is to identify a target or targets 
whose expression pattern predicts treatment response. 
3.11
CSF PROTEOMICS (Project leaders
Atlanta, GA 
) 
Current diagnostic and therapeutic monitoring of brain tumor patients are significantly hindered 
due to limited understanding of brain tumor biology and response to therapy. The majority of 
CNS tumors cannot be identified or followed by expression of serum or CSF markers. However, 
if available, such markers would be highly desirable and could be used to: 
 Detect minimal residual disease 
 Predict response to specific targeted therapies 
 Distinguish tumor recurrence from post surgical changes or post-radiation changes on 
neuroimaging 
 Augment current histopathologic classification systems 
Improve current clinical and pathological treatment stratification schemata
 Assess efficacy of and tumor response to specific biologic targeted therapies that may not 
impact tumor size as a primary tumor endpoint (e.g., small molecule inhibitors or anti-
angiogenic strategies) 
 
While such markers would be useful to prognosticate, monitor and treat all CNS tumors, the 
need is greatest in the care of children with malignant glial tumors, especially diffuse brainstem 
gliomas. These tumors are infrequently amenable to complete resection due to the eloquence of 
brain tissue they infiltrate, and extension of neoplastic cells beyond tumor margins identified by 
radiologists or neurosurgeons. As a result, surgery is often limited to diagnostic biopsy or 
ventricular decompression. In the case of diffuse intrinsic pontine tumors diagnosis is 

 
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radiographic and tumor tissue is not obtained unless neuroimaging features are atypical and/or 
the diagnosis is in question. This has led to a dearth of pathologic material for scientific 
examination and limited understanding of the biology of these terminal pediatric brain tumors. 
While technologic advances in neuro-imaging, neurosurgery, radiation therapy and 
chemotherapy have improved outcomes for many childhood brain tumors, survival for children 
with diffuse malignant gliomas has not changed in over 30 years. It is unlikely to improve 
without elucidation of their biology throughout the clinical course.  
 
CNS biologic material in CSF 
Malignant glial tumors tend to disseminate locally along white matter tracts rather than through 
sub-arachnoid seeding. While autopsy studies have identified such dissemination in over 50% of 
patients at time of death, mortality and morbidity of malignant glial tumors is most often due to 
local tumor expansion and resultant brain injury or obstructive hydrocephalus. Thus examination 
of CSF cytology for these tumors is not standard. Given limitations of identifying tumor cells in 
the CSF, methodologies that could improve our understanding of CNS tumors of all types, and 
particularly malignant glial tumors are needed. This would provide a significant improvement in 
currently available knowledge about the biology of these tumors, and could elucidate potential 
therapeutic avenues. 
 
Proteomics, a relatively new area of research whereby total protein complement of a tissue 
compartment is analyzed, has successfully been used to identify novel biomarkers in solid 
tumors [J Neuropathol Exp Neuro 2003; 62:855-862]. Because proteins are effectors of all 
cellular functions, their measurement should represent the most direct means of cellular 
characterization and hence tumor biology. Because cells and their environment exist in an 
integrated state, it has been possible to interrogate the proteins of extra-cellular compartments to 
assess the presence and impact of tumor cells. This has been done primarily using serum or 
plasma to establish a method of screening for the presence of low stage tumors. 
 
An analogous extra-cellular compartment for use in brain tumors would be cerebrospinal fluid 
(CSF). It circulates throughout the CNS and exchanges proteins with the extra-cellular fluid of 
the brain and spinal cord. CSF is continuously created and reabsorbed, providing a real time 
steady state proteome. Unlike serum, which contains a highly complex protein mixture ranging 
from very low abundance proteins in the 10-30 pg/mL range to very abundant proteins in the 35-
55 mg/mL range, CSF contains a less complex protein mixture [Proteomics 2005; 5:32223-
3225]. Therefore, the CSF is more likely to contain higher relative concentrations of tumor-
specific proteins (higher signal to noise ratio) than serum. Taken together this makes CSF and 
attractive alternative to serum for detection of brain tumor related biomarkers. 
Unlike leukemia and many solid tumors outside the CNS, where serial biopsies are readily 
performed, tumors of the CNS are not easily accessible other than at the time of initial or repeat 
resection or biopsy. While studies on these samples provide important findings regarding tumor 
biology, serial analyses during treatment are not reasonable. By contrast, the CSF of tumor 
patients can be more readily sampled in most pediatric patients. With the development of 
proteomic technology, investigation of tumor related signals at the time of diagnosis through 
treatment, and then in remission and/or at the time of recurrence or progression is possible. 

 
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While CSF for seeding tumors is readily available and routinely obtained for cytology, the 
systematic evaluation of the proteins within these samples could be of considerable scientific 
importance. In addition to identifying potential makers of disease or response to therapy, the 
glycosylation and phosphorylation status of many proteins can also be evaluated. Studies in 
tumor tissue show that such information reveals activity of different enzymes that correlate with 
treatment response [N Engl J Med 2005; 353:2012-2024, N Engl J Med 2005; 352:997-1003] or 
progression of leptomeningeal metastases [Neurooncol 2006; 8:127-136].  
Proteomics 
amyotrophic lateral sclerosis, multiple sclerosis, acute brain injury and Creutzfeldt-Jakob disease 
[Int J Neuropsychopharmacol 2001; 4:93-102]. Reports of its use in neuro-oncology are limited, 
but demonstrate the potential of this technology to effectively identify tumor biomarkers. One 
study used two dimensional polyacrylamide (2-D) gel electrophoresis to measure the relative 
quantities of two pre-selected markers, N-Myc and l-CaD, in the CSF of brain tumor patients [J 
Neuropathol Exp Neuro 2003; 62:855-862]. Another used ELISA of CSF to identify Ostopontin 
as predictive of AT/RT and correlated with response to therapy [Am J Clin Pathol 2005; 
123:297-304]. CSF proteomics using 2-D gel electrophoresis in combination with mass 
spectroscopy and cleavable isotope Coded Affinity Tag (cICAT) was used to evaluate 60 
samples of CSF and tumor cyst fluid taken from adults with brain tumors and non-neoplastic 
controls. These techniques were used to find a panel of proteins differentially expressed in lower 
vs. higher-grade gliomas. Findings were confirmed using Western Blot analysis probing for eight 
selected proteins based on implied role in gliomagenesis and availability of antibodies. This 
report, which has been accepted for publication pending revisions, identified 21 potential CSF 
biomarkers for astrocytoma. 
 
As mentioned above, there is evidence that a significant number of brainstem tumors and 
gliomas of low and high grade disseminate through the subarachnoid space. The presence of 
leptomeningeal dissemination of glial tumors is significant because it demonstrates that glial 
tumor cells have access to the CSF space, and thus, proteins secreted from these tumors have the 
ability to access the CSF space and may be detected by CSF proteomics. 
Proteins involved in angiogenesis 
The role of angiogenesis and neovascularization in tumor progression and migration is well 
established for malignant glial tumors [Anticancer Res 1997; 17:4747-4753, Brain Pathol 2005; 
15:342-363]. A large number of cytokines have been identified that up regulate angiogenesis and 
are balanced by natural inhibitors of this process. Putrefaction of this balance of stimulators and 
inhibitors increases vascularity and promotes tumor growth. In fact, factors that regulate 
angiogenesis have been identified and correlate with the degree of malignancy in both non-CNS 
and CNS tumors [Adv Anat Pathol 2002; 9:24-36, Neurooncol 2005; 7:134-153]. The presence 
of abnormal neovascular structures is a diagnostic criterion for malignant gliomas and the 
aberrant regulation of angiogenic cascades is well documented in malignant glial tumors in both 
adults and children. While angiogenic regulatory molecules act locally within the tumor vascular 
bed, these molecules are routinely identified in urine and blood, but can also be identified in the 
CSF [Neurosurgery 2004; 55:562-567]. Improving our understanding of the angiogenic profile in 
pediatric malignant gliomas may allow better selection of targeted drugs that specifically inhibit 

 
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this process. VEGF and bFGF are two integral ligands in the angiogenic cascade and will be 
studied in this objective. 
Proteins involved in tumor growth and migration 
Tumor progression is the result of growth and migration facilitated by a complex interplay of 
mitogenic triggers and proteins that regulate integrity of CNS architecture. While these proteins 
are important in development and regeneration of the brain, they can be manipulated to promote 
expansion of tumor and infiltration of neoplastic cells. 
Secreted protein with acidic and cysteine rich domains (SPARC), also known as osteonectin is a 
glycoprotein mitogen found in low levels in normal tissue. Its production is increased in 
malignant gliomas [J Neurooncol 2002; 60:213-226], and it has been identified in the CSF of 
adults with glial tumors (grades II-IV). 
Attractin is a cell adhesion and guidance protein that exists in both a secreted and transmembrane 
form due to alternative splicing [Adv Ex Med Biol 2000; 477:173-185]. The transmembrane 
form (200 kDa) is implicated in axonal regeneration and maintenance of normal CNS 
architecture because it is upregulated in the former condition and its absence results in juvenile 
neurodegeneration [Proc Natl Acad Sci USA 2001; 98:559-564]. In contrast, secreted attractin 
(175 kDa) can interfere with neuronal differentiation by regulation of the neuronal extra-cellular 
matrix [J Neuropathol Exp Neurol 2002; 61:767-777]. Interestingly, secreted attractin is 
normally absent in the CSF, but was selectively elevated in the CSF of adults with malignant 
gliomas by both western blot and proteomic analysis. 
 
As part of this objective, we will study attractin and SPARC levels in the CSF of children with 
malignant glial tumors and diffuse intrinsic brainstem gliomas to determine if the observation in 
adults can be generalized to pediatrics, and to evaluate their potential as biomarkers or 
therapeutic targets. 
3.12
ANALYSIS OF SERUM INFLAMMATORY CYTOKINE LEVELS IN PATIENTS 
TREATED WITH CETUXIMAB: BIOLOGICAL CORRELATIVE STUDIES ON CUTANEOUS 
MANIFESTATIONS AND DRUG ACTIVITY  
(Project leader: Dr. Aru Narendran, Alberta Children's Hospital, Calgary, Alberta) 
EGFR inhibitors are generally well tolerated but frequently cause signs of skin toxicity [Ann 
Oncol 2005; 16:1425-33]. A number of recent reports have suggested a correlation between the 
acneiform eruption and EGFR inhibitor antitumour activity [J Clin Oncol 2004; 22:1201 1208]. 
Consequently, there is an ongoing interest in the use of skin side effects as a surrogate marker for 
-to-
 strategy to titrate the 
EGFR inhibitor dose in individual patients to a level that causes detectable skin rash [Clin Cancer 
Res 2003; 9:2389 2390]. Steroids per se are not appreciably effective and are not used as routine 
treatment for the rash in patients receiving EGFR targeted agents [Ann Oncol 2005; 16:1425-33]. 
However, as shown previously, EGFR directed therapies may affect the immune system more 
directly as well, by unblocking cutaneous chemokine production resulting in an inflammatory 
type reaction [Am J Pathol 2003; 163:303 312].  We hypothesize that the evaluation of serum 
levels of inflammatory cytokines in patients who develop the characteristic rash would provide 

 
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an effective means of biological correlative analysis during this study.  Based on published 
literature, we have selected approximately 40 cytokines that have been shown to be associated 
with inflammatory processes involving the skin (Table 1). Antibodies to these molecules have 
been validated for their ability to detect serum levels of these cytokines and are commercially 
available in an array format (Ray Biotech, Norcross, GA). The experimental design using 
cytokine antibody arrays to detect inflammatory cytokines during treatment is described in 
section 10.3. 
4.0
OVERVIEW OF STUDY DESIGN/INTERVENTION 
This is a 2-group parallel (high-grade astrocytoma, diffuse pontine tumor), single stage study 
investigating cetuximab in conjunction with external beam radiation therapy, followed by 
cetuximab and irinotecan in pediatric and young adult patients. Optional exploratory components 
of the study include (1) correlation of tumor molecular markers with outcome, (2) CSF 
proteomics, and (3) assay of serum cytokine levels in patients who develop a cetuximab-
associated rash. 
5.0
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1
CETUXIMAB 
 
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. 
Supplier/How Supplied: Bristol-Myers Squibb (BMS) will supply cetuximab free of charge to 
the patient. The product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a 
small amount of easily visible, white, amorphous cetuximab particulates. Each single-use 50-mL 
vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and is formulated in a 
preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium 
phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate monobasic monohydrate, and 
water for injection, USP. 
 
Packaging and Labeling: Cetuximab for injection will be supplied by BMS in single-use, ready-
to-use 50-mL vials containing 2 mg/mL of product. 
Handling and Dispensing of Cetuximab: Cetuximab must be dispensed only from official study 
sites by authorized personnel according to local regulations. Cetuximab should be stored in a 
secure area according to local regulations. It is the responsibility of the Investigator to ensure that 
study drug is only dispensed to study patients. 
Storage Requirement/Stability: 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) or up to 8 hours 

 
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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 to 8 C. 
Discard any unused portion of the vial. 
Preparation and Administration: Cetuximab must not be administered as an IV push or bolus. 
 
Cetuximab must be administered with the use of a low protein binding 0.2 or 0.22-micrometer 
in-line filter. 
 
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 can be administered via infusion pump or syringe pump. 
Infusion Pump: 
 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). 
 Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), 
DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags. 
 Repeat procedure until the calculated volume has been put in to the container. Use a new 
needle for each vial. 
 Administer through a low protein binding 0.2 or 0.22-micrometer in-line filter (placed as 
proximal to the patient as practical). 
Affix the infusion line and prime it with cetuximab before starting the infusion.
 Maximum infusion rate should not exceed 5 mL/min. 
 Use 0.9% saline solution to flush line at the end of infusion. 
Syringe Pump: 
 Draw up the volume of a vial using a sterile syringe attached to an appropriate needle (a 
vented spike may be used). 
 Place the syringe into the syringe driver of a syringe pump and set the rate. 
 Administer through a low protein binding 0.2 or 0.22-micrometer in-line filter rated for 
syringe pump use (placed as proximal to the patient as practical). 
 Connect the infusion line and start the infusion after priming the line with cetuximab. 
 Repeat procedure until the calculated volume has been infused. 
 Use a new needle and filter for each vial. 

 
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 Maximum infusion rate should not exceed 5 mL/min. 
 Use 0.9% saline solution to flush line at the end of infusion. 
 
Following the cetuximab infusion, a 1-hour observation period is recommended. 
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. Otherwise, opened vials 
must be returned to BMS for disposal. For questions regarding cetuximab destruction please 
contact BMS at 1-800-743-9224. 
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. 
Cetuximab 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 and disposed. Records or logs must comply with applicable 
regulations and guidelines, and should include: 
 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each patient, including unique patient identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount returned to Sponsor. 
BMS will provide forms to facilitate inventory control if the staff at the investigational site does 
not have an established system that meets these requirements. 
Drug Ordering and Accountability: Following submission and approval of the required 
regulatory documents, a supply of cetuximab may be ordered from BMS. Investigators must 
complete a Drug Request Form and email it to (cetuximab.drug@bms.com).  

 
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Keep in mind that you will need 4-6 vials for weekly maintenance doses, dependent on patient's 
BSA. Cetuximab is shipped in quantities of 24. Allow 5 business days for shipment of drug from 
BMS receipt of the C225 (Cetuximab) Clinical Supply Shipment Request form. Drug is protocol 
specific, but not patient specific. 
All product will be shipped via Federal Express in a temperature-controlled container. Shipments 
will be made from BMS on Monday through Thursday for delivery onsite Tuesday through 
Friday. There will be no weekend or holiday delivery of drugs. Please contact BMS at 
cetuximab.drug@bms.com if you have questions or cannot send the form electronically. 
It is possible that sites may have more than one cetuximab clinical study ongoing at the same 
time. It is imperative that only product designated for this protocol number be utilized for this 
study. To help segregate product for this study from other investigational or marketed product, 
stickers bearing the protocol number will be provided and should be affixed to the front of the 
outer carton just above the company names so as not to obscure any marking. 
has remained at the appropriate temperature during shipping may be included. This unit may be 
triggered) or a black bar and the number(s) 1-4 (indicating an alarm/alarms have been triggered). 
Should an alarm be triggered, follow the instructions on the attached information card. Display 
results should be recorded on the packing list. For questions regarding drug requisitioning or 
shipment contact Bristol-Myers Squibb at cetuximab.drug@bms.com. 
Important Reorder Instructions: Reorders should be emailed directly to BMS using 
cetuximab.drug@bms.com for shipment within 5 days. When assessing need for resupply, 
institutions should keep in mind the number of vials used per treatment dose (~4-6 for weekly 
doses, dependent on patient's BSA), and that shipments may take 5 business days from BMS 
receipt of request. Cetuximab is shipped in quantities of 24. Drug is not patient specific. Be sure 
to check with your pharmacy regarding existing investigational stock to assure optimal use of 
drug on hand. 
nd attached 
information card (see above for description) and a clinical supply packing list (CSPL). If 
included, the pharmacist/study personnel responsible for the clinical study product will need to 
indicate the condition of the shipment, record the TagAl
designated areas. The pharmacist/study personnel will keep a photocopy for the site's records, 
and return the original to BMS, using the enclosed, pre-
can be discarded after the reading is recorded on the CSPL. 
Drug Destruction and Return: At the end of an infusion for an individual patient, any remaining 
study drug should be destroyed 
destruction. At the completion of the study, all unused study drugs will also be destroyed at the 
site as per institutional policy for drug destruction. Please maintain appropriate records of the 
disposal, including dates and quantities. If approved procedures are not in place, please contact 
Bristol-Myers Squibb at cetuximab.drug@bms.com for assistance. 

 
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Drug Inventory Records: It is the responsibility of the Investigator to ensure that a current record 
of study drug disposition is maintained at each study site where the study drug is inventoried and 
disposed. Records or logs must comply with applicable regulations and guidelines. 
5.2
IRINOTECAN 
Route of administration: Intravenous 
Supplier: Commercially available 
Formulation: 100 mg single use vial (20 mg/ml; 5 ml vials) 
Storage: Store vials at room temperature. Do not freeze.  
Stability: Refrigerated  infusions prepared in D5W are stable for 48 hours.  
Room temperature  infusions prepared in D5W are stable for 24 hours. 
Preparation: Investigators should use the approved package insert for complete preparation and 
administration information. 
 
 Must be diluted prior to infusion in Dextrose in D5W. Solutions prepared in Sodium 
Chloride 0.9% should not be refrigerated. 
 Final concentration range from 0.12 to 2.8 mg/ml. 
6.0
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1
SUBJECT INCLUSION CRITERIA 
 
Patients must have either (1) histologic proof of a high-grade astrocytoma 
reviewed by a POETIC institutional pathologist or (2) a radiological diagnosis via 
MRI scan of a typical diffuse pontine tumor made by a POETIC institutional 
neuroradiologist. Patients with a radiological diagnosis via MRI scan of a typical 
diffuse pontine tumor will be enrolled on the diffuse pontine tumor arm of the 
study regardless of histology in cases that are biopsied. Note: For collaborating 
non-POETIC institutions, the reviews may be done by an institutional 
pathologist/neuroradiologist. 
 
Patients must begin study prescribed therapy within 42 days of neurosurgical 
resection or biopsy of the tumor (high-grade astrocytoma patients) or radiological 
diagnosis (diffuse pontine tumor patients). 
 
-years and < 22-years-old. 
 
Brain MRI (and any other studies done according to clinical indications) must not 
show any definitive evidence of leptomeningeal or extra-neural metastases. 

 
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Patients must have adequate hematopoietic function as defined by: 
/
 
 
 
Patients must have adequate organ function as defined by: 
Hepatic: total bilirubin < 1.5 mg/dl
x the upper limit of normal.
Renal: serum creatinine 
for age, or calculated 
2. 
 
5
patients > 16 years of age). Both performance scales are available in Appendix 1. 
 
The patient, or for minors, a parent or legal guardian, must give informed written 
consent indicating they are aware of the investigational nature of this study. 
6.2
SUBJECT EXCLUSION CRITERIA 
 
Evidence of leptomeningeal or extra-neural metastatic disease. 
 
Prior radiation therapy or chemotherapy 
 
Pregnancy, mothers unwilling to refrain from breast-feeding, and sexually mature 
patients unwilling to practice an effective form of birth control 
 
Other significant concomitant medical illnesses that would compromise the 
 
 
Prior therapy which specifically and directly targets the EGFR pathway. 
 
Prior severe infusion reaction to a monoclonal antibody. 
 
Significant history of uncontrolled cardiac disease; i.e., uncontrolled 
hypertension, unstable angina, recent myocardial infarction (within prior 6 
months), uncontrolled congestive heart failure, and cardiomyopathy with 
decreased ejection fraction. 
 
.
7.0
RECRUITMENT PLAN 
Patients will be offered the opportunity to participate in this trial if they meet all eligibility 
criteria. There will be no discrimination against females or minorities. Informed consent will be 
obtained from the patient, or if they are non-emancipated minors, their parent or legal guardian. 
Consent will be obtained by an investigator authorized to obtain consent. Patients will not 
receive any payment for their participation in this study. 

 
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7.1 
Patients or their parent/legal guardian will be required to sign a statement of informed 
consent indicating the investigational nature of this study. 
 
7.2
The investigators listed on the cover page and their qualified designees at each institution 
as listed on the FDA 1572 for this study may obtain consent and care for the patients according 
to good clinical practice and protocol guidelines. 
 
7.3
One to three copies of the informed consent will be signed and dated by the patient, 
parent or the patient's legally authorized representative and by the physician obtaining informed 
consent, as per institutional guidelines. If institutional guidelines mandate that only one original 
copy is signed, the following sentences will refer to photocopies of the original. One copy will be 
given to the patient/parent/legal guardian to be retained for their personal records. One copy will 
be maintained on file at the Data and Coordinating Center. The third copy will be confidentially 
maintained by the participating institution.  
 
7.4
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the patient and/or his/her parents, to the degree of their 
understanding, acknowledge and accept the risk of participation in this study. 
 
7.5
Written consent must be documented on the appropriate consent form approved by the 
Institutional Review Board at the respective POETIC center. Attainment of the written consent 
must be verified by the Data and Coordinating Center (or equivalent entity) of the participating 
institution prior to entry on study. A copy of the consent form, along with the eligibility 
checklist, and Health Insurance Portability and Accountability Agreement (HIPAA) must be 
submitted to the Clinical Trials Office at the Data and Coordinating Center prior to enrollment of 
any subject on this study. Verification of subject enrollment on this study will be sent by FAX or 
email the participating center immediately on receipt of the required documents.  
 
Every effort will be made to include women, children of both sexes and minorities in the study 
population for this trial. No patient will be excluded from participation in this trial on the basis of 
gender, ethnicity, or race. Review of accrual to past pediatric multicenter studies of new agents 
demonstrates the accrual of both genders and all NIH-identified ethnicities to such studies. The 
small number of patients entered into this trial will obviate any analysis of variation in toxicity 
profile or response rate with gender or ethnicity. 
 
Data from the institutions participating in this trial have been reviewed with respect to 
enrollment of patients of different races and genders. It is anticipated that enrollment of the 
current study will follow the same pattern.  
 
 
 
Institution 
Number of 
Patients 
White 
Non-Hispanic 
Black 
Non-Hispanic 
Hispanic 
(%) 
Other 
(%) 

 
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(%) 
(%) 
MSKCC 
147 
61.0 
19.0 
15.0 
5.0 
UAHSC 
40 
35.0 
3.0 
53.0 
9.0 
JHMC 
77 
73.0 
21.0 
1.0 
5.0 
UCHSC 
154 
75.0 
0.0 
20.0 
5.0 
MDACC 
146 
60.0 
5.0 
29.0 
6.0 
VMC 
116 
83.0 
15.0 
1.0 
1.0 
UF 
93 
81.5 
16.5 
0.8 
0.8 
PCH 
137 
65.7 
< 0.1 
27.7 
6.5 
CHOA 
276 
60.5 
27.2 
9.4 
2.9 
8.0
PRETREATMENT EVALUATION  
 
 
Review of the pathology by a POETIC institutional pathologist (not required for 
patients with unbiopsied diffuse pontine tumors) Note: For collaborating non-
POETIC institutions, the review may be done by an institutional pathologist 
 
Pre-operative brain MRI with/without contrast 
 
Post-operative brain MRI with/without contrast (high-grade astrocytoma patients 
only) 
 
Complete blood count 
 
Liver function tests: Total bilirubin, AST 
 
Renal function tests: Creatinine (Creatinine clearance or nuclear GFR study if 
serum creatinine > 1.5 x upper limit of normal for age) 
 
For females of child-bearing potential: Urine or serum pregnancy test according 
to local institutional standards 
 
All of these pre-treatment evaluations (other than pathology review, pregnancy 
testing, and the pre-operative brain MRI with/without contrast) must be 
performed  30 days before registration onto study. Pregnancy testing must be 
 
 
Physical exam 

 
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Appendix 2 also provides a summary of these pre-treatment evaluations 
9.0
TREATMENT/INTERVENTION PLAN 
Patients will receive 2 phases of therapy, as described below. 
 
9.1.0
FIRST PHASE: RADIATION THERAPY & CETUXIMAB 
 
Cetuximab will be given at 250 mg/m2/weekly for 6 doses. On days when both the radiation 
therapy and cetuximab are administered, there is no mandated order of administration or timing 
between the 2 treatments. Regardless of the order of administration, it is important to note that 
the patient should be carefully monitored for signs of anaphylaxis for at least 1 hour following 
completion of the infusion in an appropriate area with readily available resuscitation equipment 
and medications (as per protocol section 9.1.2). Patients will be treated for about 6 ½ weeks 
during this phase (33 daily fractions of radiation therapy and 6 weekly doses of cetuximab). 
Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 
1 of each week. 
The dose of cetuximab will be rounded off to the nearest 10 mg. 
There will be no dose modification of the radiation therapy for toxicity. For dose modifications 
of cetuximab see section 9.3 below.  
9.1.1
RADIATION THERAPY GUIDELINES 
 
Technique: 
All radiotherapy techniques are permitted including 3D conformal, IMRT and proton therapy. 
Lateral fields may be used for diffuse pontine tumors though 3D target definition is 
recommended.
Dose and volume: 
All tumors will be treated to 5940 cGy in 33 once daily 180 cGy fractions. 
The initial PTV for high-grade gliomas will be determined by adding a 2 cm margin to the area 
of T1 enhancement (GTV) based on the pre-operative MRI scan. For non-enhancing tumors, the 
MRI sequence that best defines the extent of disease should be used. A conedown to the post-
operative tumor bed, including any residual disease plus a 1cm margin is allowed at 5400 cGy. 
The GTV for diffuse pontine tumors will consist of the tumor best demonstrated on MRI. The 
MRI sequence that best defines the extent of disease should be used. A 1 cm margin is added in 
all directions to determine the PTV. 
Volumes and doses may be modified as necessary to prevent overdosing of critical normal 
tissues such as spinal cord and optic chiasm, based on institutional practices. 

 
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The dose and source will be documented in the Case Report Forms. 
Radiation must be performed at a POETIC institution or at a designated academic or professional 
partner institution, according to standard institutional practice for patients on clinical trials.  
Radiation may not be performed at a local or private facility that is not a partner for academic 
purposes. 
9.1.2
CETUXIMAB ADMINISTRATION 
Strong consideration should be given to antihistamine premedication prior to cetuximab to try to 
reduce the risk of a hypersensitivity reaction. Diphenhydramine (1 mg/kg IV or orally) is 
recommended.
Cetuximab will be administered as an intravenous infusion over about 60 minutes +/- 10 
minutes, and must be administered at a POETIC institution. The infusion rate should not exceed 
10 mg/minute (5 ml/minute). Patients should be carefully monitored for signs of anaphylaxis for 
at least 1 hour following completion of the infusion in an appropriate area with readily available 
resuscitation equipment and medications. 
9.2
SECOND PHASE: IRINOTECAN & CETUXIMAB 
Between 28 and 56 days after completion of radiation therapy (based on the discretion of the 
investigator and resolution of compromising radiation-induced toxicities) patients will begin 
irinotecan and cetuximab. 
Patients who cannot begin the 
second phase of therapy within 56 days will be considered study failures and will be removed 
from the study and not replaced. 
Irinotecan will be administered at a dose of 16 mg/m2/day IV over about 60 minutes  +/- 10 
minutes x 5 consecutive days x 2 weeks every 21 days. Cetuximab will be administered at a dose 
of 250 mg/m2/dose IV over 60 minutes +/- 10 minutes weekly x 3 weeks per cycle (see section 
9.12 for administration instructions). The dose of cetuximab will be rounded off to the nearest 10 
mg and the dose of irinotecan to the nearest 1 mg. These doses of irinotecan and cetuximab were 
determined to be safe and tolerable in the POETIC phase I study (CA225085). On days when 
both irinotecan and cetuximab are administered, the cetuximab will be administered first and the 
irinotecan infusion will begin about 60 minutes following completion of the cetuximab infusion. 
Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 
1 of each week. 
Subsequent cycles of irinotecan will begin 21 days following the start of the previous cycle if the 
of any other toxicity. If adequate recovery has not taken place by day 21,  the start of the cycle 
will be delayed until sufficient recovery. If the cycle must start more than 28 days following the 
start of the prior cycle the dose modification section below should be consulted. Patients are 
intended to receive 10 cycles unless a criterion for removal from study is met (section 13.0). 
However, for patients whose disease remains stable or better at the completion of 10 cycles, 

 
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therapy may be continued at the discretion of the patient and physician until a criterion for 
removal from the study is met. 
The cetuximab must be administered at a POETIC center, but the irinotecan may be administered 
at another center or via homecare if such a regimen is more convenient for the patient. In such 
cases, adequate documentation must be sent to the Data and Coordinating Center at MSKCC in a 
timely fashion and in compliance with all study guidelines and requirements. Local institutions 
will be responsible for securing all documentation as required on the Case Report Forms 
regarding irinotecan administration. 
9.3
CHEMOTHERAPY/BIOLOGIC DOSE MODIFICATION RULES 
 
9.3.1
CETUXIMAB 
Management of Infusion Reactions 
Severe infusion reactions require the immediate interruption of cetuximab therapy and 
permanent discontinuation from further treatment. 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. 
In previous clinical trials, mild to moderate infusion reactions were managed by slowing the 
infusion rate of cetuximab and by continued use of antihistamine pre-medications (eg, 
diphenhydramine) in subsequent doses. If the patient experiences a mild or moderate (Grade 1 or 
2) infusion reaction, the infusion rate should be permanently reduced by 50%. For grade 1 or 2 
reactions manifesting only as delayed drug fever, see paragraph below. Cetuximab should be 
immediately and permanently discontinued in patients who experience severe (Grade 3 or 4) 
infusion reactions. 
Treatment of Isolated 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 
should receive further cetuximab. 
Management of Pulmonary Toxicity 
In the event of acute onset (grade  2) or worsening pulmonary symptoms which are not thought 
to be related to underlying cancer, cetuximab therapy should be interrupted and a prompt 
investigation of these symptoms should occur. Cetuximab retreatment should not occur until 

 
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these symptoms have resolved to grade 1. If interstitial lung disease is confirmed, cetuximab 
should be discontinued and the patient should be treated appropriately.  
Management of rash 
Cetuximab Dose Modification Guidelines 
Grade 3 
Acneform Rash/ 
desquamation 
Cetuximab 
Outcome 
Cetuximab Dose 
Modification 
1st occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
Continue at 250 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
2nd occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
Reduce Dose Level -1 
 
 
No Improvement 
Discontinue cetuximab 
3rd occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
Reduce to Dose Level -2 
 
 
No Improvement 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab
 
 
Cetuximab Dose Levels 
 
Weekly Cetuximab dose 
Starting dose 
250 mg/m2 
Dose Level -1 
200 mg/m2 
Dose Level -2 
150 mg/m2 
Cetuximab in Combination with Radiation Therapy 
Cetuximab in combination with radiation therapy should be used with caution in patients with a 
history of coronary artery disease, congestive heart failure, and arrhythmias. Although the 
etiology of these events is unknown, close monitoring of serum electrolytes, including serum 
magnesium, potassium, and calcium, during and after cetuximab therapy is recommended. 
Management of Hypomagnesemia 
Hypomagnesemia has been reported with Cetuximab when administered as a single agent and in 
combination with multiple different chemotherapeutic regimens. The incidence of 
hypomagnesemia (both overall and severe [NCI CTC grades 3 & 4]) is increased in patients 
receiving chemotherapy and Cetuximab as compared with those receiving chemotherapy alone 
based on controlled clinical trials. Patients receiving Cetuximab therapy should be monitored for 
hypomagnesemia. Magnesium repletion may be necessary based on clinical judgment. 

 
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9.3.2
IRINOTECAN 
 GI Toxicity: Grades 3 or 4 despite maximal medical management will mandate a dose 
reduction by 2 mg/m2/day.
 Hepatic impairment: Irinotecan should not be administered if the total bilirubin is > 2 
mg/dL. It may be restarted i
 2 mg/dL. 
 If a cycle cannot start by day 28 due to hematopoietic toxicity (ANC < 1000 and/or 
platelet count < 100,000), the dose of irinotecan should be reduced by 2 mg/m2/day.  
9.4
SUPPORTIVE CARE 
Clinical judgment may be used to alter the following guidelines without being a protocol 
violation: 
During all phases of therapy 
Anti-emetics may be used.
Filgrastim (G-CSF) may be used according to institutional practice and/or ASCO guidelines. 
Patients developing dermatologic toxicities while receiving cetuximab should be monitored for 
the development of inflammatory or infectious sequelae, and appropriate treatment of these 
symptoms initiated. Dose modifications of any future cetuximab infusions should be instituted in 
case of severe (grade 3) acneform rash/desquamation (section 9.3.1). Treatment with topical 
and/or oral antibiotics should be considered; topical corticosteroids are not recommended. If a 
patient experiences severe acneform rash/ desquamation, cetuximab treatment adjustments 
should be made according to the table above (section 9.3.1). In patients with mild and moderate 
skin toxicity, treatment should continue without dose modification. 
During the second phase of therapy (while patients are receiving irinotecan) 
 
Anti-convulsants: Enzyme-inducing anti-convulsants (phenytoin, phenobarbital, carbamazepine) 
should be avoided. Patients who require an anti-convulsant should be treated with a non-enzyme 
inducing anti-convulsant for a minimum of 4 half-lives of the anti-convulsant agent prior to 
starting treatment with irinotecan. Documentation of this should be included on the Concomitant 
Medication form in the Case Report Forms. 
Diarrhea: Prophylaxis with an oral cephalosporin (such as cefixime 8 mg/kg/day, maximum 400 
mg/day) may be used [J Clin Oncol 2006; 24:563-570]. For early onset diarrhea (during 
irinotecan infusion or shortly after the infusion), consider atropine (0.01 mg/kg, maximum 0.4 
mg) and octreotide. For later onset diarrhea, consider prompt use of loperamide, and consider 
octreotide if that does not adequately control diarrhea. Suggested loperamide (1 caplet = 2 mg, 1 
teaspoon = 5 ml = 1 mg) dosing follows: 

 
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 Patients > 43 kg: Take 4 teaspoons or 2 caplets after the 1st loose bowel movement 
followed by 2 teaspoons or 1 caplet every 2 hours. During the night the patient may take 
2 caplets every 4 hours rather than 1 caplet every 2 hours. 
 Patients > 30 to 43 kg: Take 2 teaspoons or 1 caplet after the 1st loose bowel movement 
followed by 1 teaspoon or ½ caplet every 2 hours. During the night the patient may take 1 
caplet every 4 hours rather than ½ caplet every 2 hours. 
 Patients > 20 to 30 kg: Take 2 teaspoons or 1 caplet after the 1st loose bowel movement 
followed by 1 teaspoon or ½ caplet every 3 hours. During the night the patient may take 1 
caplet every 4 hours rather than ½ caplet every 3 hours. 
 Patients > 10 to 20 kg: Take 1 teaspoon after the 1st loose bowel movement followed by 1 
teaspoon every 3 hours. During the night the patient may take 1 teaspoon every 4 hours 
rather than every 3 hours. 
 Patients 8 to 10 kg: Take 1 teaspoon after the 1st loose bowel movement followed by ½ 
teaspoon every 3 hours. During the night the patient may take ¾ teaspoon every 4 hours 
rather than every 3 hours. 
 
Pneumocystis carinii (PCP) prophylaxis: Patients should receive PCP prophylaxis, according to 
any standard regimen chosen by the attending pediatric oncologist in agreement with local 
determination. 
10.0
EVALUATION DURING TREATMENT/INTERVENTION 
 
The mandated observations are summarized in Appendix 2.
During the first phase of therapy (Radiation therapy with cetuximab) 
Physical exams will be performed and potassium, calcium, and magnesium levels will be 
obtained once a week, prior to each cetuximab infusion. 
CBC and other laboratory work will be obtained as clinically indicated. 
During the second phase of therapy (irinotecan with cetuximab) 
Physical exams will be performed and a CBC, potassium, calcium, magnesium, total bilirubin, 
AST, and creatinine will be obtained prior to each cycle. Laboratory work during a cycle will be 
obtained as clinically indicated. 
Assessment of tumor status via brain MRI will be performed about 3 weeks after completing RT 
(pre-cycle 1 chemotherapy), then during every 3rd cycle of irinotecan-cetuximab (during cycles 
3, 6, and 9).  
Following completion of therapy 
For patients who complete protocol therapy and remain on study progression-free, MRI scans of 
the brain will be performed at about 3, 6, 9, 12, 18, 24, 30, 36, and 42 months post-completion of 
therapy or until the patient has been removed from the study. Subsequent scans will be 
performed at the clinician's discretion and are not mandated by this protocol, but are 
recommended approximately annually. 

 
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Mandated evaluations including lab work and MRI scans may be performed at other (non-
POETIC) centers if deemed clinically indicated as long as they are submitted to the POETIC 
investigator in a timely fashion. 
10.1
TUMOR TISSUE ANALYSES 
Analysis of EGFR and associated molecules HER2 and HER3 expression  
Although over-expression of EGFR was not shown to be predictive for cetuximab response in 
previous studies, it cannot be assumed that it will not be predictive in pediatric patients with 
high-grade glial tumors. We will therefore screen tumor samples for EGFR gene amplification, 
and EGFR protein over-expression. HER2 and HER3 heterodimerize with EGFR to affect EGFR 
activity, and HER2 has previously shown some value in predicting cetuximab response. We will 
therefore study HER2 and HER3 gene amplification and over-expression in tumor specimens. 
Both procedures will be performed on paraffin sections of tumor (5 micron thickness). To ensure 
consistency of results between specimens received from different institutions we recommend a 
standardized fixation procedure, but this is a guideline only and institutional practices may be 
substituted. Tissue samples will be dissected to a thickness of no greater than 5 mm and fixed in 
10% NBF 24-48 hours. Samples will then be transferred to 70% ethanol where they can remain 
indefinitely with no deterioration of antigen. All subsequent experimentation will be performed 
at a single institution, the University of Colorado Denver (UCD), to ensure consistency of 
results. 
 
Gene amplification will be assessed using fluorescence in-situ hybridization (FISH). This 
procedure requires fifteen paraffin sections per tumor sample. FISH will be performed at the 
University of Colorado Cancer Center DNA Core facility, managed by Dr Leila Garcia. This 
core facility has relevant experience in that it has performed standardized FDA approved FISH 
analysis of EGFR, HER2 and HER3 in previous cetuximab lung cancer clinical trials. 
 
Gene over-expression will be assessed using immunohistochemistry (IHC). IHC will be 
performed by IHCtech (www.ihctech.net), an IHC dedicated facility located on the UCHSC 
campus that routinely performs standardized staining for EGFR and HER2 in clinical samples. 
Analysis of surrogate biomarkers predictive for cetuximab and RT or irinotecan response 
To identify surrogate predictors of response to cetuximab and RT or irinotecan, we will perform 
a global gene analysis of tumor specimens using microarray technology. We will generate gene 
the profiles of 
those patients who responded to treatment against those who did not respond. This analysis may 
provide a small number of genes whose expression, or lack thereof, accurately predicts response 
to therapy. The Pediatric Neuro-oncology Laboratory at UCHSC has performed similar analyses 
in the identification of prognostic genes for ependymoma recurrence [J Neuro-Oncol 2006; 
78:41-46]. Cetuximab-predictive genes identified using gene-expression microarrays would be 
validated by Western blot analysis and IHC. For microarray and Western blot analyses we would 
require at least 6 mm3 of tumor tissue, snap frozen in liquid nitrogen at the time of surgery. This 
would provide a sufficient quantity and quality of RNA and protein to perform the proposed 
analyses. Fifteen paraffin sections will be required for IHC validation of specific microarray 
results. 

 
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Analysis of MGMT expression 
MGMT promoter methylation status has been shown to influence both survival and response to 
therapy in pediatric glioblastoma multiforme [Pediatr Blood Cancer 2006; 48:403-407]. MGMT 
methylation status of patients enrolled in this clinical trial will be studied. This procedure 
requires 1 microgram of DNA, preferably obtained from snap frozen tumor, but also retrievable 
from paraffin embedded material. In addition, MGMT expression will be measured by IHC. 
Data Analysis 
Data obtained by FISH, IHC, microarray analysis and MGMT methylation analysis will be 
analyzed to identify therapeutic response correlates. The biological data can be correlated to 
response both to the RT-cetuximab and irinotecan-cetuximab as response data to both modalities 
will be potentially evaluable on this study. These data will help to elucidate the anti-tumor 
mechanisms of cetuximab in high-grade gliomas of childhood. Correlates of response may also 
help to select patients with high-grade astrocytomas for treatment with cetuximab in future 
clinical trials. 
The data obtained from these studies directly on high grade gliomas will be correlated with the 
CSF proteomics data (described below). This will hopefully provide additional insight into the 
biology of the diffuse pontine gliomas, which is clearly lacking in the literature at this time. 
Table of material requirements 
Submission of paraffin material is mandatory for high-grade gliomas outside the pons and 
optional for diffuse pontine gliomas. Submission of the number of paraffin section below is 
encouraged, but patients will not be excluded from the study if fewer samples or less material are 
available. Submission of frozen tumor material is strongly encouraged, but not mandatory for 
study participation. 
Analysis 
Technique 
Tissue requirement per patient 
EGFR, HER2, HER3 gene 
amplification 
FISH 
12 paraffin sections (5 micron 
thickness) 
 
EGFR, HER2, HER3 protein 
overexpression 
IHC 
Microarray gene expression 
analysis and subsequent Western 
blot analysis 
Affymetrix U133+2 
microarray analysis 
and Western blot 
6 mm3 of tumor snap frozen 
immediately at resection 
IHC analysis subsequent to 
microarray results 
IHC 
3 paraffin sections (5 micron 
thickness) 
MGMT methylation analysis 
Methylation specific 
PCR 
2 mm3 of tumor snap frozen 
immediately after resection 
Specimen collection 
These samples should be forwarded via FedEx, Monday through Thursday to the following 
address: 

 
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Attn: Andrew Donson 
UCD, Pediatrics 
Bldg RC1, Rm P18-4402F 
12800 E 19th Ave 
Aurora CO 80010-7174 
No weekend deliveries are permitted. Sites should contact 303-724-4012 to notify of shipment. 
10.2
CSF PROTEOMICS 
Patient specimens 
Participation in this component of the study is optional. Patients excluded from this 
biological study will include those in whom procurement of CSF is deemed unsafe by the 
attending physician and in those participants whose family declines the evaluation. 
CSF will be obtained prior to initiation of any post-operative radiation therapy or cetuximab. 
CSF will be obtained via lumbar puncture, ventricular or cisternal sample at the time of flow 
diversion or aspiration of an external ventricular drain or surgical procedure. In patients where 
more than one site of CSF fluid has been accessed, analysis from each site will be undertaken 
when possible.  
CSF cytology will be evaluated for presence of tumor cells by an institutional pathologist using 
standard methods. Approximately 3 ml of CSF will be requested for proteomic analysis. After 
acquisition, the CSF should be kept on wet ice or in a 4 degree refrigerator until processing. 
Processing should be performed within 6 hours of sample acquisition. The CSF will be spun at 
400-500 g for 10 minutes to remove cellular contaminants. The first 2 ml of CSF supernatant 
will be aliquoted into four 500 mcl units (taking care to leave the cellular pellet behind) and 
frozen at -20 to -80 degrees Celsius to be used for proteomic analysis. Each tube must be labeled 
with the POETIC patient accession number, the sample type and the time it was drawn. 
If sample is insufficient for both laboratories priority is to send sample to Dr. Hathout 
Sample collection and shipping dates must be documented in the clinical research core. These 
samples should be forwarded via FedEx, Monday through Thursday. No weekend deliveries are 
permitted. Sites should contact Yetrib Hathout, PhD, at 202-476-3136 to notify of shipment. All 
CSF biologic samples should be shipped on dry ice, along with a completed biologic specimen 
transmittal form to: 
Attention: Yetrib Hathout, PhD 
CRI, Room 5700 
111 Michigan Avenue, NW 
Washington, DC 20010 
Phone: 202-476-3136 
Email: YHathout@cnmcresearch.org  
The remaining 1 ml of CSF will be aliquoted in 200 mcl units and frozen at -20 to -80 degrees 
Celsius to be evaluated for cytokines. Each tube must be labeled with the POETIC patient 

 
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accession number, the sample type, site from where the sample was obtained, and the time it was 
drawn.
These samples should be forwarded on dry ice via FedEx, Monday through Thursday to the 
following address:
Attn: Andrew Donson 
UCD, Pediatrics 
Bldg RC1, Rm P18-4402F 
12800 E 19th Ave 
Aurora CO 80010-7174 
No weekend deliveries are permitted. Sites should contact 303-724-4012 to notify of shipment. 
Laboratory analysis 
a. Proteomic Biomarker Evaluation 
Criteria for a successful proteomic methodology for identification of a usable biomarker include 
high throughput, reproducibility and toleration of real world collection and shipping conditions. 
In addition, such methods must be able to identify differentially expressed proteins in an 
unsupervised manner as well as provide information about specific proteins of interest. 
Currently, there is not a single mature technology available to meet all these criteria. Therefore, a 
combined approach will be employed in this exploratory study to attempt to fit all of these 
characteristics and improve the body of knowledge about the utility of these strategies.  
 
All these approaches will require concentration and desalting of the samples. Proteins can be 
precipitated using 15% trichloracetic acid, re-suspended in denaturing buffer and stored at -20 to 
-80 degrees Celsius until the time of analysis. 
The first component of the proteomic approach will employ 2-D gel electrophoresis to separated 
proteins in two dimensions according to their size and charge. The gels are then stained with 
Gelsoft coomasie stain (Bio-Rad) and then scanned by a high resolution scanner. Relative spot 
positions and intensities are quantitated by pixel reading software (PDQuest and Ludesi). 
Individual spots are normalized to total signal [Proteomics 2003; 3:1962-1979]. Individual 
proteins that are found to be differentially expressed between groups will be subjected to in-gel 
ith this methodology 
has successfully fractionated CSF derived proteins and identified differentially expressed 
proteins in white matter disease [Clin Chem 2005; 51:2031-2042]. 
The second approach employed will be label free quantification. MS-based proteome profiling is 
a powerful method by which a large number of proteins across large sets of complex samples can 
peptide level) that are originated from different samples. New and emerging techniques such as 
stable isotope labeling (SILAC, iTRAQ, 18O) are either expensive (iTRAQ, SILAC) or unstable 
(18O). With the improvement of liquid chromatography (LC) as well as mass spectrometry (MS) 
techniques, the new trend in proteome profiling is label-free methodology. The idea behind this 

 
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method is first to generate reliable and reproducible LC-MS runs using trypsin digested proteins 
from CSF samples. In order to accommodate minor discrepancies between subsequent runs, each 
sample will be spiked with a known amount of non-native protein. Peaks generated by this 
protein will be used for internal normalization, as well as for normalization across sample sets. 
Given that peptides elute and behave similarly between different runs, peak heights (at MS or 
MS/MS stage) representing peptides can be extracted, calculated, and normalized to the internal 
(spiked) standard. From these data, differential protein expression can be calculated across 
inter/intra sample populations to identify potential biomarkers.  
b. ELISA for confirmation/correlation of target proteins 
CSF samples will be evaluated for expression of specific secreted proteins implicated in tumor 
progression, migration and response to therapy. These target proteins, described above, have 
well-characterized, commercially available antibodies including VEGF, dFGF, attractin, SPARC 
and EGF. 
10.3
SERUM ANALYSIS OF INFLAMMATORY CYTOKINE LEVELS 
Participation in this component of the study is optional.  
Experimental design 
Sera will be collected before the first dose of cetuximab and at the time of the development of the 
characteristic skin rash and at its distinct stages of progression. A scoring system will provide a 
standardized evaluation of the rash (Table 1).  
 
Table 1. Simplified classification of acneiform eruption caused by EGFR inhibitors  
NCI CTCAE v3.0 
Rash/desquamation
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lesions without 
symptoms 
Lesions with 
symptoms < 50% 
body surface
Lesions with symptoms 
 50% body surface 
Exfoliative, ulcerative 
or bullous erythroderma
 
Rash: acne/acneform 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Intervention not 
indicated 
Intervention indicated
Pain, disfigurement, 
ulceration or 
desquamation 
- 

 
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Using a sensitive antibody array technique, the presence of approximately 40 separate cytokines 
(Table 2) will be detected and quantified as described previously [Anal Biochem 2001; 294:55-62, 
http://www.raybiotech.com/principle.asp?m=6]. Briefly, blood will be collected at specified times 
and sera will be incubated with cytokine arrays that contain capture antibodies. Commercially 
available normal human sera will be used as additional control. Following three washing steps to 
remove unbound proteins, enzyme labeled detection antibodies will be added and the arrays will be 
developed using conventional ECL reagents. The resulting X-ray films will be scanned and analyzed 
by digital image processing. Significant changes will be validated by ELISA or Western blot 
analysis. Data will be analyzed using GraphPad Prism version 3.00 statistical software (GraphPad 
Software, San Diego, CA). Changes more than a standard deviation seen in normal sera will be 
considered significant. Correlative analysis will be carried out with clinical parameters indicated in 
the protocol. 
EOTAXIN 
GCSF 
GM-CSF 
ICAM-1 
IFN-g 
I-309 
IL-1ª 
IL-1b 
IL-2 
IL-3 
IL-4 
IL-6 
IL-6sR 
IL-7 
IL-8 
IL-10 
IL-11 
IL-12 
p40 
p70 
IL-13 
IL-15 
IL-16 
IL-17 
IP-10 
MCP-1 
MCP-2 
M-CSF 
MIG 
MIP-1a 
MIP-1b 
MIP-1d 
MIP-1d 
RANTES 
TGF-b1 
TNF-a 
TNF-b 
sTNFRI 
sTNFRII 
PDGF-BB 
TIMP-2 
 
 
 
 
 
 
 
Table 2. Inflammation related cytokines to be analyzed in the sera of patients who develop rash 
during treatment on protocol. 
Timing of sample collections  
Blood will be collected from patients prior to the first dose of cetuximab in the phase I portion of the 
study as a control. Sera will also be collected from patients who do not develop rash prior to the first 
4 cycles of irinotecan and cetuximab in the Phase II portion of the study. If a patient develops a rash 
at any point during the Phase I portion of the study or during cycles 1-3 of the Phase II portion of the 
study they are not to be considered a control subject anymore and are not to have any further pre-
cycles 1-4 blood samples taken. Additional samples will be drawn when there is an incremental 
increase in the severity score of the rash (see guidelines, Table 1). Specific information regarding the 
rash will be collected based on the key clinical features and classification of dermatologic adverse 
reactions of EGFR targeted agents described by Agero et al [J Am Acad Dermatol 2006; 55:657-
670].  To minimize patient inconvenience, blood draws will be done to coincide with other routine 
blood draws or IV access.  
Sample collection, processing and transport 
Collect 1 ml of blood and allow for clotting on ice or in a refrigerator for approximately 15- 30 
minutes. Separate and collect the serum, preferably in an Eppendorf microcentrifuge tube. If micro 
centrifuge tubes are not available, any cloudy plastic tube can be used. Sera will be separated from 
the clot by centrifugation (1,200 RPM for 5 minutes), transferred to an Eppendorf tube and stored 
frozen in a -20 C freezer until shipment.  
Ship sera on dry ice by next day delivery. Send samples only on Monday through Thursday. Public 
holidays in Canada can be found in: http://www.pch.gc.ca/progs/cpsc-ccsp/jfa-ha/index_e.cfm 

 
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The following information should be included with each sample:, Site ID, study number, study time 
point, date and time of collection. Please attach 3 copies of the completed customs form below on 
the outside of your shipment box. Shipments with less then 3 customs forms and are not 
located on the outside of the box will not be considered for shipment. Please send an email 
notification of the shipment including the tracking number to the following addresses: 
a.narendran@ucalgary.ca, Janice.Hamilton@calgaryhealthregion.ca 
Laboratory personnel will be available to answer questions regarding this process by phone at all 
times as indicated in the sample processing form. 
Information for Customs Canada Form 
Date:  
Description: Human sera, Research use only, non-living, not known to be infectious, non-
radioactive, no commercial value. 
Country of Origin: USA 
Transport/ Packaging: ICE/Dry Ice
 
To: Dr. Aru Narendran 
Alberta Cancer Research Institute 
HRIC Lab 2a34 
3280 Hospital Drive NW 
Calgary, Alberta, T2N 4Z6 
CANADA Tel: (403) 210-6402    
Pager: (403) 955-7211 request #2700 
 
 
 
11.0
TOXICITIES/SIDE EFFECTS 
 
Toxicities will be assessed via the NCI Common Terminology Criteria for Adverse Events 
(CTCAE, version 3.0, http://ctep.cancer.gov/forms/CTCAEv3.pdf). All toxicities, grades 1-4, 
will be recorded in both phases of the protocol until 30 days after the last dose of cetuximab.  
Any patients consented after the memo sent to participating sites dated December 15, 2010 need 
to have all grades toxicities collected 
The most common side effects expected are alopecia (likely), nausea and vomiting due to RT 
and/or chemotherapy (likely), myelosuppression (blood product transfusions and need for 

 
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hospitalization for fever and neutropenia both possible), infertility (possible), and second 
malignancies due to RT and/or chemotherapy (unlikely, but very severe should one occur).  
Possible risks also include unexpected side effects from the addition of cetuximab to the external 
beam radiation therapy and chemotherapy. 
11.1
RADIATION THERAPY 
Acute toxicities: Nausea with or without emesis is an anticipated side effect of radiation therapy 
and may be treated with antiemetic medications. Fatigue may occur. Patients generally have 
transient focal alopecia in the radiation field and may have permanent epilation in some regions. 
Skin erythema is expected but is rarely severe. Temporary xerostomia and dysphagia may occur. 
Standard supportive care according to institutional guidelines will be delivered in an attempt to 
ameliorate any of these relevant effects. 
Late effects: Common late effects of radiation, depending on the field of radiation, include 
neurocognitive dysfunction, growth impairment, hearing loss, and endocrine dysfunction 
(hypothalamic/pituitary, thyroid, and gonadal). Rare but severe late effects may include 
secondary malignancies (approximately 5%) and necrosis of central nervous system tissue, 
including brainstem (approximately 1-2%). 
11.2
CETUXIMAB 
Anticipated Adverse Events (all data in this section 11.2 provided by Bristol-Myers Squibb) 
Please see updated Investigators brochure dated 10/21/2010 
Squamous Cell Cancer of the Head and Neck  
Except where indicated, the data described below reflect exposure to cetuximab in 208 patients 
with locally or regionally advanced SCCHN who received cetuximab in combination with 
radiation and as monotherapy in 103 patients with recurrent or metastatic SCCHN. Of the 103 
patients receiving cetuximab monotherapy, 53 continued to a second phase with the combination 
of cetuximab plus chemotherapy. Patients receiving cetuximab plus radiation therapy received a 
median of 8 doses (range 1-11 infusions). The population had a median age of 56; 81% were 
male and 84% Caucasian. Patients receiving cetuximab monotherapy, received a median of 11 
doses (range 1-45 infusions). The population had a median age of 57; 82% were male and 100% 
Caucasian. The most serious adverse reactions associated with cetuximab in combination with 
radiation therapy in patients with head and neck cancer were:  
 Infusion reaction (3%) 
 Cardiopulmonary arrest (2%) 
 Dermatologic toxicity (2.5%) 
 Mucositis (6%) 
Radiation dermatitis (3%)
 Confusion (2%)
 Diarrhea (2%) 

 
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Fourteen (7%) patients receiving cetuximab plus radiation therapy and 5 (5%) patients receiving 
cetuximab monotherapy, discontinued treatment primarily because of adverse events.  
 
The most common adverse events seen in 208 patients receiving cetuximab in combination with 
radiation therapy were acneform rash (87%), mucositis (86%), radiation dermatitis (86%), 
weight loss (84%), xerostomia (72%), dysphagia (65%), asthenia (56%), nausea (49%), 
constipation (35%), and vomiting (29%).  
 
The most common adverse events seen in 103 patients receiving cetuximab monotherapy were 
acneform rash (76%), asthenia (45%), pain (28%), fever (27%), and weight loss (27%).  
 
The data in the table below are based on the experience of 208 patients with locoregionally 
advanced SCCHN treated with cetuximab plus radiation therapy compared to 212 patients 
treated with radiation therapy alone [Cetuximab package insert. ImClone Systems Incorporated 
and Bristol-Myers Squibb Company 2006. ER-B0001-03-06]. 
Incidence of selected adverse events ( 10%) in patients with loco-regionally advanced 
SCCHN 
Body System  
Preferred Term 
Cetuximab plus Radiation 
(n=208) 
Radiation Therapy Alone  
(n=212) 
Grades 1  4  
Grades 3 and 4  
Grades 1  4  
Grades 3 and 4  
% of Patients 
Body as a Whole 
 
 
 
 
Asthenia/Malaise
56 
4 
48 
5 
Fever1
29 
1 
13 
<1 
Headache 
19 
<1 
8 
<1 
Infusion Reaction2 
15 
3 
2 
0 
Infection 
13 
1 
9 
1 
Chills1 
16 
0 
5 
0 
Digestive 
 
 
 
 
Mucositis/Stomatitis 
93 
56 
94 
52 
Xerostomia 
72 
5 
71 
3 
Dysphagia 
65 
26 
63 
30 
Nausea 
49 
2 
37 
2 

 
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Constipation 
35 
5 
30 
5 
Vomiting 
29 
2 
23 
4 
Anorexia 
27 
2 
23 
2 
Diarrhea 
19 
2 
13 
1 
Dyspepsia
14
0
9
1
Metabolic/Nutritional 
Weight Loss 
84 
11 
72 
7 
Dehydration
25
6
19
8
Respiratory 
Pharyngitis 
26 
3 
19 
4 
Cough Increased 
20 
<1 
19 
0 
Skin/Appendages 
 
 
 
 
Acneform Rash3 
87 
17 
10 
1 
Radiation Dermatitis 
86 
23 
90 
18 
Application Site Reaction 
18 
0 
12 
1 
Pruritus
16
0
4
0
1 Includes cases also reported as infusion reactions 
2 
3 
 
 

 
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Late Radiation Toxicity 
The overall incidence of late radiation toxicities (any grade) was higher in cetuximab in 
combination with radiation therapy compared with radiation therapy alone. The following sites 
were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue 
(49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin 
(42% versus 33%), brain (11% versus 9%), lung (11% versus 8%), spinal cord (4% versus 3%), 
and bone (4% versus 5%). The incidence of Grade 3 or 4 late radiation toxicities were generally 
similar between the radiation therapy alone and the cetuximab plus radiation treatment groups. 
 
Colorectal Cancer 
Except where indicated, the data described below reflect exposure to cetuximab in 774 patients 
with advanced metastatic colorectal cancer. Cetuximab was studied in combination with 
irinotecan (n=354) or as monotherapy (n=420). 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 36/420 (9%) treated for 
over 6 months]. The population had a median age of 59 and was 59% 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 (0.4%) 
 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, 0.2% in patients receiving 
cetuximab monotherapy 
Thirty-seven (10%) patients receiving cetuximab plus irinotecan and 17 (4%) patients receiving 
cetuximab monotherapy discontinued treatment primarily because of adverse events.  
The most common adverse events seen in 354 patients receiving cetuximab plus irinotecan were 
acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), nausea (55%), abdominal pain 
(45%), and vomiting (41%).  
The most common adverse events seen in 420 patients receiving cetuximab monotherapy were 
acneform rash (90%), asthenia/malaise (48%), nausea (29%), fever (27%), constipation (26%), 
abdominal pain (26%), headache (26%), and diarrhea (25%).  

 
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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 table below are based on the 
experience of 354 patients treated with cetuximab plus irinotecan and 420 patients treated with 
cetuximab monotherapy. 

 
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Infusion Reactions 
Severe infusion reactions occurred with the administration of cetuximab in approximately 3% 
Incidence of Adverse Events ( 10%) in Patients with Advanced Colorectal Carcinoma 
Body System  
Preferred Term1 
Cetuximab plus Irinotecan  
(n=354) 
Cetuximab Monotherapy 
(n=420) 
Grades 1 - 4  
Grades 3 and 4  
Grades 1  4  
Grades 3 and 4  
% of Patients 
Body as a Whole 
 
 
 
 
Asthenia/Malaise2 
73 
16 
48 
10 
Abdominal Pain 
45 
8 
26 
9 
Fever3
34 
4 
27 
<1 
Pain 
23 
6 
17 
5 
Infusion Reaction4 
19 
3 
21 
2 
Infection 
16 
1 
14 
1 
Back Pain 
16 
3 
10 
2 
Headache 
14 
2 
26 
2 
Digestive 
 
 
 
 
Diarrhea 
72 
22 
25 
2 
Nausea 
55 
6 
29 
2 
Vomiting 
41 
7 
25 
3 
Anorexia 
36 
4 
23 
2 
Constipation 
30 
2 
26 
2 
Stomatitis 
26 
2 
10 
<1 
Dyspepsia 
14 
0 
6 
0 
Hematic/Lymphatic 
 
 
 
 
Leukopenia 
25 
17 
<1 
0 
Anemia 
16 
5 
9 
3 
Metabolic/Nutritional 
 
 
 
 
Weight Loss 
21 
0 
7 
1 
Peripheral Edema 
16 
1 
10 
1 
Dehydration
15 
6 
10 
3 
Nervous 
 
 
 
 
Insomnia 
12 
0 
10 
<1 
Depression  
10 
0 
7 
0 
Respiratory 
 
 
 
 
Dyspnea3 
23 
2 
17 
7 
Cough Increased 
20 
0 
11 
1 
Skin/Appendages 
 
 
 
 
Acneform Rash5 
88 
14 
90 
8 
Alopecia 
21 
0 
4 
0 
Skin Disorder 
15 
1 
4 
0 
Nail Disorder 
12 
<1 
16 
<1 
Pruritus  
10 
1 
11 
<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 cetuximab plus irinotecan or in 10% of patients with refractory colorectal carcinoma treated with cetuximab 
monotherapy. 
2
3 Includes cases reported as infusion reaction. 
4 Infusion reaction is defined as any event 
 
5
 

 
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(46/1485) of patients, rarely with fatal outcome (<1 in 1000). 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, hypotension, and/or cardiac arrest. 
Caution must be exercised with every cetuximab infusion, as there were patients who 
experienced their first severe infusion reaction during later infusions. A 1-hour observation 
period is recommended following the cetuximab infusion. Longer observation periods may be 
required in patients who experience infusion reactions. 
 
A 20-mg test dose was administered intravenously over 10 minutes prior to the initial dose to all 
patients in earlier studies. The test dose did not reliably identify patients at risk for severe 
allergic reactions. 
In the Southeastern region of the United States a higher number of infusion-related anaphylactic 
reactions to cetuximab have been reported in adult studies than in other areas of the United States 
[J Clin Oncol 2007, 25:3644-3648 and N Engl J Med 2008, 358:1109-1117]. 
Pulmonary Toxicity 
Interstitial lung disease (ILD) was reported in 3 of 774 (<0.5%) patients with advanced 
colorectal cancer and in 1 of 796 patients with head and neck cancer receiving cetuximab.  
Among these four cases, interstitial pneumonitis with non-cardiogenic pulmonary edema 
resulting in death was reported in one patient with colon cancer. In two of the remaining cases, 
the patients had pre-existing fibrotic lung disease and experienced an acute exacerbation of their 
disease while receiving cetuximab in combination with irinotecan. The onset of symptoms 
occurred between the fourth and eleventh doses of treatment in all reported cases. In the event of 
acute onset or worsening pulmonary symptoms, cetuximab therapy should be interrupted and a 
prompt investigation of these symptoms should occur. If ILD is confirmed, cetuximab should be 
discontinued and the patient should be treated appropriately [Cetuximab package insert. ImClone 
Systems Incorporated and Bristol-Myers Squibb Company 2006. ER-B0001-03-06]. 
 
Dermatologic Toxicity 
In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times 
the weekly human exposure (based on total body surface area), resulted in dermatologic findings, 
including inflammation at the injection site and desquamation of the external integument.1 At the 
highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were 
similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due 
to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after 
approximately 13 weeks of treatment. 
In clinical studies of cetuximab, dermatologic toxicities, including acneform rash, skin drying 
and fissuring, and inflammatory and infectious sequelae (eg, blepharitis, cheilitis, cellulitis, cyst) 
were reported. In patients with advanced colorectal cancer, acneform rash was reported in 89% 
(686/774) of all treated patients, and was severe (Grade 3 or 4) in 11% (84/774) of these patients. 
Subsequent to the development of severe dermatologic toxicities, complications including S. 
aureus sepsis and abscesses requiring incision and drainage were reported.  

 
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Non-suppurative acneform rash described as 
 was observed in patients receiving cetuximab plus 
irinotecan or cetuximab monotherapy. One or more of the dermatological adverse events were 
reported in 88% (14% Grade 3) of patients receiving cetuximab plus irinotecan and in 90% (8% 
Grade 3) of patients receiving cetuximab monotherapy. Acneform rash most commonly occurred 
on the face, upper chest, and back, but could extend to the extremities and was characterized by 
multiple follicular- or pustular-appearing lesions. Skin drying and fissuring were common in 
some instances, and were associated with inflammatory and infectious sequelae (eg, blepharitis, 
cellulitis, cyst). Two cases of S. aureus sepsis were reported. The onset of acneform rash was 
generally within the first two weeks of therapy. Although in a majority of the patients the event 
resolved following cessation of treatment, in nearly half of the cases, the event continued beyond 
28 days. 
A related nail disorder, occurring in 14% of patients (0.4% Grade 3), was characterized as a 
paronychial inflammation with associated swelling of the lateral nail folds of the toes and 
fingers, with the great toes and thumbs as the most commonly affected digits.  
Cetuximab Use With Radiation Therapy 
The safety of cetuximab in combination with radiation therapy and Cisplatin has not been 
established. Death and serious cardiotoxicity were observed in a 21 patient single-arm study of 
patients with locally advanced squamous cell cancer of the head and neck. Patients received 
cetuximab, delayed, accelerated (concomitant boost) fractionation radiation therapy and 
Cisplatin (100 mg/m2) [Cetuximab package insert. ImClone Systems Incorporated and Bristol-
Myers Squibb Company 2006. ER-B0001-03-06].  
In a randomized, controlled trial in patients with squamous cell carcinoma of the head and neck 
(SCCHN), cardiopulmonary arrest and/or sudden death occurred in 4/208 patients (2%) treated 
with radiation therapy and cetuximab as compared to none of 212 patients treated with radiation 
therapy alone. Three patients with prior history of coronary artery disease died at home, with 
myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and 
one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of 
cetuximab. One patient with no prior history of coronary artery disease died one day after the last 
dose of cetuximab. 
Electrolyte Depletion 
In 244 patients evaluated in ongoing, controlled clinical trials, the incidence of hypomagnesemia, 
both overall and severe, was increased in patients receiving cetuximab alone or in combination 
with chemotherapy as opposed to those receiving best supportive care or chemotherapy alone. 
Approximately one-half of these patients receiving cetuximab experienced hypomagnesemia and 
10-15% experienced severe hypomagnesemia1.  
Cardiac Toxicity 
Cardiac arrest and / or sudden death occurred in 2% (4/208) of patients with squamous cell 
carcinoma of the head and neck treated with radiation therapy and cetuximab as compared to 
none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 
days after the last Cetuximab treatment. Cetuximab in combination with radiation therapy should 
be used with caution in head and neck cancer patients with known coronary artery disease, 

 
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congestive heart failure, and arrhythmias. Although the etiology of these events is unknown, 
close monitoring of serum electrolyte, including serum magnesium, potassium and calcium, 
during and after Cetuximab therapy is recommended. 
11.3
IRINOTECAN 
Common 
Dermatologic: Alopecia 
Hematologic: Drug-induced eosinophilia 
Serious
Gastrointestinal: Diarrhea, Nausea and Vomiting 
Hematologic: Leukopenia, Neutropenia, Thrombocytopenia, Lymphopenia 
Hepatic: Decreased liver function 
Respiratory: Interstitial lung disease 
12.0
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
primary aim is to increase the proportion of patients achieving 1-year progression-
free survival. Progression-free is defined as lack of unequivocal tumor progression or treatment-
associated death. Unequivocal tumor progression will be determined (usually via brain MRI) by 
a POETIC institutional radiologist. If radiological studies suggest possible, but not unequivocal 
progression, the patient may remain on study until unequivocal progression has been determined. 
In select cases biopsy may be necessary to distinguish tumor recurrence from radiation effect. 
In this study, we will compare the product of 2-dimensional measures of the tumor on the 
baseline and follow-up MRI scans. Modified Macdonald criteria will be used [J Clin Oncol 
1990; 8:1277-1280]. Responses will be defined as: 
Complete response: Complete resolution of all tumor. 
-dimensional size of the tumor. 
Stable disease: < 50% decrease to < 25% increase in the 2-dimensional size of the tumor. 
-dimensional size of the tumor, or (2) any new 
tumor focus, or (3) worsening neurological status that cannot be explained by any other cause 
associated with increase in tumor size (but < 25%). 
Determination of favorable responses will be made via comparison to the baseline MRI, while 
determination of progressive disease will be via comparison to the nadir 
13.0
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
13.1
Criteria for Removal from Protocol Therapy 

 
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 Tumor recurs or progresses 
 Second malignancy 
 Intolerable toxicity occurs 
 Unable to start the second phase of therapy (irinotecan and cetuximab) within 56 days of 
completion of RT 
 The patient is significantly non-compliant with the treatment plan 
 The patient withdraws consent for protocol-prescribed therapy 
 Completion of protocol-prescribed therapy 
13.2
Off study criteria 
 Death occurs 
 Withdrawal of consent for any further data submission 
14.0
BIOSTATISTICS 
 
14.1
DEFINITION OF ENDPOINTS 
The primary endpoint of this study is progression free survival at one year. Progression will be 
measured from initiation of therapy until first documented progression of disease. Death or the 
unlikely event of loss to follow-up, within one year will also be counted as progression.  Those 
who are alive and progression free one year after initiation of therapy will be considered 
treatment successes for the evaluation of the primary endpoint.
Response is considered as a secondary endpoint. All patients who have initiated therapy will be 
evaluated for response. Only patients who were declared ineligible and removed prior to 
receiving any treatment will be excluded. 
14.1.1
 
DIFFUSE PONTINE TUMORS 
 
For this group of patients the goal is to effectively discriminate between progression free survival 
rates at one year of < 10% and > 30% using a single stage design. 
 
The progression free proportion is deemed unacceptable if it is lower than 10% and is promising 
if greater than 30%. The null hypothesis that the proportion progression free at one year (p) is 
t the alternative hypothesis that p is 
greater than or equal to 0.30 (H1: p  0.30). For this group of tumors, we will accrue 25 patients. 
If 6 or more are alive and progression free at one year, the treatment will be declared effective 
and worthy of further testing. If 5 or fewer are alive and progression free at one year, then this 
group of the trial will be declared to have a negative result. This design yields  80% probability 
of a positive result if the true percentage of patients alive and progression free at one year is  
30% (80% power). It yields  95% probability of a negative result if the true percentage is  
10% (5% type I error). 

 
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14.1.2
 
HIGH-GRADE ASTROCYTOMAS 
 
For this group of patients the goal is to effectively discriminate between progression free survival 
rates at one year of < 35% and > 60%, using a single stage design. 
The progression free proportion is deemed unacceptable if it is lower than 35% and is promising 
if greater than 60%. The null hypothesis that the proportion progression free at one year (p) is 
greater than or equal to 0.60 (H1: p  0.60). For this group of tumors, we will accrue 26 patients. 
If 14 or more are alive and progression free at one year, the treatment will be declared effective 
and worthy of further testing. If 13 or fewer are alive and progression free at one year, then this 
group of the trial will be declared to have a negative result. This design yields  80% probability 
of a positive result if the true percentage of patients alive and progression free at one year is  
60% (80% power). It yields  95% probability of a negative result if the true percentage is  
35% (5% type I error). 
14.2 
EARLY STOPPING RULE FOR TOXICITY 
 
In order to confirm the safety of the radiation therapy and cetuximab component of this regimen, 
patients will continuously be monitored for excessive toxicity and early stopping rules for 
toxicity will be employed. Unacceptable toxicity is defined as any grade 4 or higher non-
hematological toxicity (with the exception of diarrhea, infection, electrolyte abnormalities, 
nausea and vomiting, hypersensitivity reactions, and neurological dysfunction clearly due to 
tumor rather than treatment) that does not resolve to less than or equal to grade 2 within 7 days. 
Stopping rules and the corresponding power calculations are provided in the table below. 
# failures/toxicities need to 
stop the study 
Projected probability 
of failure/toxicity in 
the populations 
Probability of study 
completion (based on 
projection) 
2 in the first 6 patients 
3 in the first 15 patients 
4 in the first 26 patients 
5 in the first 50 patients 
6 in all 51 patients 
0.05 
.90 
0.09 
.60 
0.15 
0.17 
 
14.3 
SECONDARY BIOLOGICAL AIMS 
 
 
14.3.1 Progression free and overall survival will be calculated using the methods of Kaplan and 
Meier, separately for the diffuse pontine and high-grade groups. The response rates will 
be provided along with their 95% confidence intervals for all patients receiving any 
study medication or radiation. 
 

 
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14.3.2 It is not known how many patients will agree to participate in the components of the 
study involving (1) correlation of molecular markers and tumor response to therapy, (2) 
CSF proteomics, and (3) serum inflammatory cytokine levels. These endpoints are 
exploratory in nature and any analyses will be purely descriptive. Continuous endpoints 
will be summarized using medians and ranges, categorical data will be tabulated. 
Changes in measurements will be given in terms of percent change from baseline and 
change in absolute value. 
15.0
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1
RESEARCH PARTICIPANT REGISTRATION 
All patients must be centrally registered by the  Data and Coordinating Center, at Memorial 
Sloan-Kettering Cancer Center. Registrations will be handled by the RSA at the Pediatrics 
Clinical Trials Office at MSKCC. The contact telephone number is 646-888-5714 or 646-888-
5715 and the fax number is 646-888-5726. Registrations will occur between 9:00 am and 5:00 
pm Eastern Standard Time (EST), Monday through Friday and will include review of the signed 
consent form, HIPAA research authorization form, eligibility checklist, eligibility source 
documentation and Patient Enrollment form. The RSA will also verify, via a FAX copy, that the 
written informed consent is obtained and dated prior to subject entry on the study.  
 
The participating sites must contact the Research Study Assistant (RSA) at the Data and 
Coordinating Center to reserve a slot on the protocol when a patient is being considered for a 
trial. To begin a registration the participating site must fax the signed consent form and HIPAA 
research authorization to the RSA within 48 hours of the patient signing consent. To complete 
the registration, the completed eligibility checklist, patient eligibility source documentation and 
the Patient Enrollment form must be faxed to the RSA at MSKCC prior to protocol treatment or 
any research tests. Registrations must be faxed to the Clinical Trials Office and the Research 
Study Assistant (RSA) at MSKCC will verify eligibility and complete the registration with the 
PPR Office.  
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant number).  
This number is unique to the participant and must be written on all data and correspondence for 
the participant.  This protocol participant number will be relayed back to study staff at the 
registering site via e-mail and will serve as the enrollment confirmation.  The participating site 
must not begin treatment until receiving this email from the Data and Coordinating Center. 
Written consent must be documented on the appropriate consent form and Research 
Authorization designated and approved by the Institutional Review Board at the institution at 
which the patient is enrolled. The POETIC Principal Investigators or consenting professionals at 
their institution  
The registration procedure is summarized below. 

 
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Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
15.2
RANDOMIZATION 
This study is not randomized. 
 
16.0
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) at the Memorial Sloan-Kettering Cancer Center will be 
assigned to the study. The responsibilities of the RSA include project compliance, data 
collection, abstraction and entry, data reporting, regulatory monitoring, problems and 
prioritization. In addition, coordination between the RSA and Research Staff at the participating 
POETIC institutions is necessary in order for a complete process. The Clinical Research  
Coordinator (CRC) will also be responsible for being the liaison among all staff involved 
including the principal investigators, attending physicians and nurses. 
Case report forms will be drafted in a standard format and will be provided to each participating 
institution by the Data and Coordinating Center. Required study tools for each protocol including 
correlative studies, vital signs, drug administration and protocol evaluations will also be provided 
to each participating institution by the Data and  Coordinating Center. Case report forms, study 
tools and source documentation are required to be submitted to the Data and Coordinating Center 
on a weekly basis. 
The data collected for this study will be entered into a secure database by the MSKCC RSA. 
Data will be collected, stored, and monitored at an institutional level via the Clinical Research 
Database (CRDB) system. Data will be provided from CRDB to protocol-defined sponsors 
(CTEP, FDA, etc.) as required, through the Data Management Resource Division, a division of 
the Office of Clinical Research.  
Source documentation will be available to support the computerized patient record and must be 
submitted with the case report forms and required study tools. Case report forms will not be 
considered source documentation. Variables that will be recorded include the patient's birth date, 
date of diagnosis, date of study entry and histologic diagnosis. The results of the pretreatment 
and end of therapy evaluations, including the extent of disease evaluation (history, physical 
examination and imaging studies), baseline laboratory values, renal and hepatic function, as 

 
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defined per protocol, will be recorded. All study related treatment data and concomitant drugs 
will be recorded. The presence of toxicity at baseline, during and for 30 days after administration 
of the investigational agent will be monitored and recorded. The results of the extent of disease 
evaluation (history, physical examination and imaging studies) following each course of 
treatment will be recorded. The patient's disease status and last follow-up will be recorded. If 
disease progresses or recurs, the results of the repeat extent of disease evaluation will be 
recorded. 
Research staff will be assigned at each POETIC center. Lead research personnel will be 
identified at each site. Their responsibilities will include maintaining file documentation of data 
for the clinical trial, pharmacokinetic or other biologic correlative study collection and analysis 
as outlined in this study, for each patient enrolled on study. They will also be responsible for 
maintaining a regulatory binder for each protocol. The designated research staff will also be 
responsible for submitting the data on a weekly basis by fax or mail to the RSA at MSKCC. Case 
report forms and required study tools along with supporting source documentation should be 
faxed or mailed to:  
 
Pediatric Clinical Trials Office  
Memorial Sloan-Kettering Cancer Center  
405 Lexington Avenue, Room 3-512 
New York, NY 10174 
Telephone: 646-888-5714/5715 
Fax: 646-888-5726 
The protocol will be conducted as a single research study effort and data from each participating 
institution will be included in the analysis of results. 
The Protocol Chair will be responsible for the conduct of the study, and the monitoring of the 
progress and will review all case report forms from each participating institution.  
Initial Protocol Submission 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC IRB/PB. Prior to implementing this protocol at the participating centers, approval must 
   
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants:  
 Local IRB of Record approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
 Local IRB of Record membership 
 
 
 Curriculum vitae and medical license for each investigator and consenting professional 
 Documentation of Human Subject Research Certification and HIPAA training for 
investigators and key staff members 
 Signed and dated FDA Related Forms 1572/1571 (if applicable) 

 
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 Lab Certifications and Reference Ranges for each lab listed on the 1572 
Protocol Amendments/Status Changes 
Each change to the protocol must be organized and documented by the Data and Coordinating 
Center. The Protocol Chair at the lead institution will submit the amendment locally for 
approval. After approval at the lead institution, the Data and Coordinating Center will distribute 
the amendment to the participating institutions, for approval by their local IRB within 60 days of 
the amendment date. The participating sites will ensure that documentation for all IRB approved 
amendments are sent to the  Data and Coordinating Center and are maintained in the regulatory 
binder. This documentation will include the IRB approval letter referencing the protocol version 
date and amendment number, IRB approved protocol, IRB approved appendices and IRB 
approved consent forms. 
The amendment will be written so that no other institution will need to reformat the information 
but can simply copy and distribute. An amendment memo as well as highlighted and clean copies 
of the protocol, appendices and consent forms will be distributed to the participating sites. The 
consent form will be a sample that may be edited in order to adhere to local IRB guidelines. The 
amendment must be submitted at each site to the IRB for review and approval before patients can 
be enrolled on the study and within 90 days of the amendment version date. The amendment 
number and version date will also be displayed on each amendment. 
Additional IRB Correspondence 
Annual re-approval  
Annual re-
MSKCC at the time re-approval is granted. The most current approved version of the consent 
form should also be submitted to MSKCC at that time. Failure to submit the re-approval will 
result in suspension of accrual privileges. 
Deviations and Violations 
If a deviation from the protocol is proposed for a potential or existing participant at a 
participating site, approval from the MSKCC IRB/PB is required prior to the action. Please be 
sure to inform the DCC as soon as possible to ensure IRB approval. 
For protocol violations that are reported after they occur, the participating site should report to 
MSKCC as soon as possible. The MSKCC PI will in turn report the violation to the MSKCC 
IRB/PB.  
 
Participating sites should report deviations and violations to the Local IRB of Record as they 
occur. Approvals/acknowledgments from the Local IRB of Record for protocol deviations and 
violations should be submitted to MSKCC as received.  
 
Other correspondence 
Participating sites should submit other correspondence to their local IRB of Record according to 
local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.1
QUALITY ASSURANCE 

 
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This will be a central responsibility of the Data and Coordinating Center and it will be achieved 
by frequent review, constant oversight and input from objective advisors. Each project will 
maintain a steering committee that will meet in conference call on a weekly basis to critically 
review the scientific progress of the clinical trial. The steering committee will include the 
principal investigators, research staff and the biostatistical support team under the direction of 
the lead biostatistician. 
Monitoring visits will be conducted by the Clinical Research Coordinator (CRC) from the Data 
and Coordinating Center as needed. During this visit, the CRC will: 
 
 Review regulatory binders for protocol documentation; 
 Ensure that case report forms are source data verified according to the monitoring plan;  
 Verify drug accountability is complete and accurate; 
 Verify compliance to GCPs, ICH guidelines, FDA regulations, and applicable SOPs. 
Internal audits will be conducted by the Data and Coordinating Center. Audits may be 
accomplished in one of two ways: (1) source documents and research records for selected 
patients are brought from participating sites to the Data and Coordinating Center for audit, or (2) 
selected patient records may be audited on-site at participating sites. Each site is responsible for 
having all source documents, research records, all IRB approval documents, Drug Accountability 
Record Forms, patient registration lists, response assessments scans, x-rays, etc. available for the 
audit.
 
16.2
DATA AND SAFETY MONITORING
The Data and Safety Monitoring Committee (DSMC) at Memorial Sloan-Kettering Cancer 
Center will be responsible for monitoring the data safety of the protocol. The DSMC meets 
quarterly, and will review data from respective trials on a semi-annual basis. A copy of the 
MSKCC Data and Safety Monitoring policy document has been distributed to local sites and is 
on file at the Data and Coordinating Center. 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The plans address the new 
http://cancertrials.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines. The MSKCC Data and 
Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at: 
http://mskweb2.mskcc.org/irb/index.htm. The Data and Safety Monitoring Committee (DSMC) 
monitors all Phase I and II clinical trials and reports to the Research Council and Institutional 
Review Board.  
 
17.0
PROTECTION OF HUMAN SUBJECTS 
 
All of the patients on this study will be children, adolescents, and young adults. Patients of both 
sexes and all ethnic backgrounds are eligible for the study. Participation will be voluntary. The 

 
IRB#: 09-014 A(7) 
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hypothesized potential benefits include superior event-free survival. Alternatives include external 
beam radiation therapy alone or in conjunction with other chemotherapy regimens, including, but 
not limited to (1) temozolomide, (2) vincristine and lomustine, or other investigational protocols. 
 
Patients are responsible for all costs of their care including (but not limited to) physician visits, 
hospitalizations, medications (except for cetuximab), MRI scans, and laboratory work (except for 
the optional research biology studies performed on blood, tumor tissue and CSF). Cetuximab 
will be supplied by Bristol Myers-Squibb in collaboration with Imclone Systems Incorporated, 
via a research and development agreement. The costs of all research-only related studies will be 
covered by the study and participating institutio
 
 
Patient confidentiality will be protected, but records may be reviewed by appropriate staff of the 
Memorial Sloan-Kettering Cancer Center, the participating institutions, and representatives from 
the FDA, Bristol Myers-Squibb, and Imclone Systems Incorporated.
17.1
PRIVACY 
All institutional, local, federal, FDA, and NCI requirements for human subjects research must be 
met. This study will be carried out in compliance with the regulations of the Health Insurance 
Portability and Accountability Act (HIPAA). Each participating institution will have an 
appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The 
Data and Coordinating Center is responsible for assuring that each participating institution has an 
OHRP assurance and must maintain copies of IRB approvals from each participating site. The 
Data and Coordinating Center is responsible for assuring that IRB approval has been obtained at 
each participating site prior to the first patient registration from that site. 
The risks and benefits of participation in this study will be reviewed with the patient and/or 
parent/legal guardian. 
Enrollment on this study is on a voluntary basis and every effort will be made to maintain 
privacy and confidentiality. The patient's records will be confidential. Only authorized 
individuals or agencies may inspect the records. No identifying information will be used in 
reports or publications resulting from this study. 
17.2
SERIOUS ADVERSE EVENT (SAE) REPORTING 
The Protocol Chair is responsible for monitoring the safety of patients who enroll in the study. 
All AEs and SAEs occurring after any administration of the study drug regardless of drug 
attribution will be followed to the end of the study including 30 days after the last administration 
of study drug, as well as any SAEs designated possibly, probably or definitely related to 
treatment 
that 
occur 
greater 
than 
30 
days.  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0 will be used for adverse event and serious adverse event 
reporting. All participating sites should have access to a copy of the CTCAE version 3.0. A copy 
of 
the 
CTCAE 
version 
3.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/reporting/ctc.html).  

 
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The Protocol Chair is required to report all adverse events that occur during the clinical study 
starting with the first dose of study drug throughout 30 days of stopping the investigational 
agent, must be reported to the appropriate protocol-defined study sponsors. Serious adverse 
events must be reported either by telephone or in person to the Protocol Chair, Data and 
Coordinating Center and local IRB within 24 hours of knowledge of their occurrence. A written 
SAE report including source documentation must be sent to the Protocol Chairman and Data and 
Coordinating Center within another 3 calendar days, using the Serious Adverse Event case report 
form. 
Additionally, the Protocol Chair is responsible for submitting follow-up reports for all SAEs 
condition stabilizes (in the case of persistent impairment), or the patient dies. 
A serious adverse event (SAE) is any adverse drug experience that occurs at any dose that results 
in any of the following outcomes: 
 Death 
 Life-threatening adverse drug experience 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 For the purpose of this study, hospitalizations for protocol-scheduled procedures, 
blood product transfusions, or for social reasons (ie, awaiting transport home) will 
not be considered SAEs 
 Persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Requires medical or surgical intervention to prevent one of the outcomes listed 
above 
 
 
 
 
 
 
 
 
 
 
 
Reporting Requirements for Adverse Events That Occur on Treatment and Within 30 Days1 of 
the Last Dose of Study Drug (Please see section 17.2.1 for exception to the table) 

 
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Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 5
 
Unexpected 
and Expected
with or with-
out 
hospitalization
        Unexpected
Expected 
Unexpected 
Expected 
Unexpected 
and 
Expected 
 With 
Hospitali
zation 
without 
Hospitaliz
ation 
With  
Hospitali
zation 
Without 
Hospitaliza
tion 
With  
Hospitali
zation 
Without 
Hospitali
zation 
With  
Hospitalizat
ion 
Without 
Hospitaliz
ation 
Unrelated
Unlikely 
Not 
Required 
SAE 
Report 
Required
Not 
Required
SAE 
Report 
Required
Not 
Required
SAE 
Report 
Required
Not 
Required
SAE 
Report 
Required
Not 
Required
SAE Report 
Required 
Possible
Probable
Definite 
Not 
Required 
SAE 
Report 
Required
SAE 
Report 
Required
SAE 
Report 
Required
Not 
Required
SAE 
Report 
Required
SAE 
Report 
Required
SAE 
Report 
Required
Not 
Required
SAE Report 
Required 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of study 
treatment require an SAE report as follows: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 4 unexpected events  
 
Grade 5 expected events and unexpected events 
 
Initial notification for all SAEs must include: 
 Grade of event 
 Date of event  
 A brief description of the event 
 Attribution to the investigational agent 
Patient Status
Relationship of any adverse event to study drug should use the following criteria:  
 Definite - The adverse event is clearly related to  
 Probable - The adverse event is likely related to  
 Possible - The adverse event may be related to 
 Unlikely - The adverse event is doubtfully related to 
 Unrelated - The adverse event is clearly NOT related to  
 
SAEs must be reported within 24 hours by phone or e-mail to: 
 Data and Coordinating Center 
 Lead Principal Investigator of the protocol / Protocol Chair 
 Local IRB 
SAE contact information for the Data and Coordinating Center is listed below:  
Memorial Sloan-Kettering Cancer Center  
Pediatric Clinical Trials Office  
 
405 Lexington Avenue, Room 3-512 

 
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New York, NY 10174 
Telephone: 646-888-5714/5715 
Fax: 646-888-5726 
Contact information for the Primary Investigator is listed below:  
Ira Dunkel, MD
Memorial Sloan-Kettering Cancer Center  
1275 York Avenue
New York, NY 10065 
Telephone (212) 639-2153 
Fax (212) 717-3239 
E-mail: dunkeli@mskcc.org  
 
In the event of an AE, appropriate medical and supportive care will be administered. All efforts 
will be made to minimize the side effects and to support the patient until the toxicity resolves. 
 
comply with regulatory requirements.  
All serious AEs whether related or unrelated to investigational product, must be immediately 
reported to the Data and Coordinating Center by confirmed facsimile transmission. If only 
limited information is initially available, follow-up reports are required. The original SAE 
form must be kept on file at the study site. 
All SAEs should simultaneously be faxed or emailed to Data and Coordinating Center (see 
above) who will submit the information to Bristol-Myers Squibb at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804
Email: WorldWide.Safety@bms.com 
 
 Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed by BMS. Thus, follow-up information which 
becomes available as the SAE evolves, as well as supporting documentation (e.g., hospital 
discharge summaries and autopsy reports), should be collected subsequently, if not available 
at the time of the initial report, and immediately sent using the same procedure as the initial 
SAE report. 
 An overdose is defined as the accidental or intentional ingestion of any dose of a product that 
is considered both excessive and medically important. For reporting purposes, BMS 
considers an overdose, regardless of adverse outcome, as an important medical event (see 
Serious Adverse Events). 
 In BMS supported trials, all SAEs must be collected which occur within 30 days of 
discontinuation of dosing or completion of the patient
scheduled visit occurs at a later time. In addition, the Investigator should notify BMS of any 

 
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SAE that may occur after this time period which they believe to be certainly, probably or 
possibly related to investigational product. 
17.2.1
AGENT-SPECIFIC EXPECTED ADVERSE EVENTS LIST  
The list below guides the investigator in determining which AEs require expedited reporting. 
Those AEs that do not require expedited reporting are reported in routine study data submissions. 
Hospitalization for the following expected events and toxicities will not be considered serious 
adverse events (SAE) and will not require reporting to the Institutional Review/Ethics Boards: 
 Therapy administration 
 Fever and neutropenia 
 Central venous catheter-associated infection 
 Possible septicemia 
 Vomiting and/or dehydration 
 Diarrhea 
Similarly, non-life threatening grade 3 and 4 toxicities clearly attributed to the external beam 
-threatening 
infections or other life-threatening side effects will be considered SAE's and will be promptly 
reported. 
17.2.2 SERIOUS ADVERSE EVENT (SAE) REPORTING 
SAE Reporting (This section pertains to guidelines for Memorial Sloan-Kettering only) 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org containing the following information: 
Fields populated from the CRDB: 
 
initials if it will be sent outside of   
MSKCC) 
 Medical record number 
Disease/histology (if applicable)
 Protocol number and title 
 Concomitant medication 
Data needing to be entered: 
 The date the adverse event occurred 
 The adverse event 
 Relationship of the adverse event to the treatment (drug, device, or intervention) 
 If the AE was expected 
 The severity of the AE 

 
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 The intervention 
 Detailed text that includes the following information: 
 An explanation of how the AE was handled 
 A description of the subject's condition 
 Indication if the subject remains on the study 
 If an amendment will need to be made to the protocol and/or consent form 
 
signature and the date it was signed are required on the completed report. 
 
18.0
INFORMED CONSENT PROCEDURES
Regulatory agencies have issued regulations to provide protection for human patients in clinical 
investigations and to describe the general requirements for informed consent. 
 
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care under applicable regulations. In addition, the investigator should be 
aware that some regulations require that he/she permit regulatory agencies to conduct inspections 
and review records pertaining to this clinical investigation. 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form.
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
18.1
RESEARCH AUTHORIZATION 
 

 
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Procedures for obtaining Research Authorization: Before any protocol-specific procedures are 
carried out, investigators and/or designated staff will fully explain the details of the protocol, 
study procedures, and the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must sign the Research Authorization 
component of the informed consent form. The Research Authorization requires a separate set of 
signatures from the patient. 
medical record, and each patient will receive a copy of the signed documents. 
19.0
APPENDICES 
 
Appendix 1: Performance scales 
Appendix 2: Table of mandated observations