Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: Head and Neck Cancer Squamous cell carcinoma of the head and neck HNSCC Cetuximab IMC-A12 Tumor Biomarkers Phospho-AKT Surgical resection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to give cetuximab and/or IMC-A12 before surgery for squamous cell carcinoma of the head and neck, in order to learn if these study drugs may cause changes in biomarkers. Biomarkers are chemical "markers" in the blood and/or tissue that may be related to a reaction to study treatment.

The safety of the study treatments will also be studied.

Detailed description:
The Study Drugs Cetuximab and IMC-A12 are both designed to block proteins that are thought to cause cancer cells to grow. This may help to slow the growth of tumors.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to 1 of 3 groups. There is an equal chance of being assigned to any group.

* Group 1 will receive cetuximab alone.
* Group 2 will receive IMC-A12 alone.
* Group 3 will receive cetuximab and IMC-A12 in combination.

If you are assigned to group 2 or 3 you will have a hearing test within 90 days before starting treatment with the study drug.

Study Treatment:

Groups 1 and 3:

Cetuximab will be given by vein on Days 1 and 8. The first dose will be given over 2 hours. The second dose will be given over 1 hour.

To lower the risk of allergic reaction, Groups 1 and 3 will also receive diphenhydramine by mouth or by vein before the first dose of cetuximab. If the study doctor decides it is needed, diphenhydramine may also be given before the second dose of cetuximab (and the third, if applicable).

Groups 2 and 3:

IMC-A12 will be given by vein over 1 hour on Days 1 and 8.

All Groups:

You will have surgery on Day 10. If for some reason the surgery is delayed, the study doctor may decide that you will receive a third dose of your assigned study drug(s) on Day 15. In that case, cetuximab will be given over 1 hour and/or IMC-A12 will be given over 1 hour, depending on which group you are in.

You will sign a separate consent form that describes the surgery and its risks in more detail.

Study Tests:

Within 5 days before your second dose of study drug(s), and again within 5 days before your third dose (if applicable), the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will be asked about any side effects you may be experiencing.
* You will have a physical exam, including measurement of vital signs.
* Blood (about 3 teaspoons) will be drawn for routine tests.

On the day before surgery, you will have a CT scan or MRI of the head and neck. If needed, these tests can instead be done before surgery but sometime after the last dose of the study drug(s).

On the day of surgery, blood (about 3 teaspoons) will be drawn for routine tests and your vital signs will be measured. If needed, these tests can instead be done up to 2 days before surgery.

Length of Study Drug Dosing:

After your last dose of the study drug(s), on Day 8 or Day 15, your participation in the study treatment period will be over. You will be taken off the study drug(s) early if the disease gets worse or intolerable side effects occur.

Follow-Up:

If you return to the clinic within 30 days after surgery, the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any side effects that may have occurred.

Otherwise if you do not have a visit scheduled during that time, the study staff will call you by phone instead. You will be asked how you are doing.

If you are experiencing side effects from the study drug(s) at the time of the follow-up visit or call, you may have additional follow-up if the doctor decides it is needed. The follow-up tests, procedures, and schedule will be the doctor's decision depending on the side effects.

You will have a repeat hearing test within 90 days after surgery if you received at least 1 dose of IMC-A12.

Long-Term Follow-Up:

On a long-time basis after surgery, the study staff may review your medical record to collect information about your health. During this time, you or your family members may be contacted and asked to confirm or provide information about your health. The contact may occur during clinic visits or by phone, mail, or e-mail.

This is an investigational study. Cetuximab is commercially available and FDA approved to treat squamous cell carcinoma that has spread or come back, in patients who did not respond to platinum-based therapy.

Using cetuximab in combination with surgery is investigational.

IMC-A12 is not FDA approved or commercially available. At this time, IMC-A12 is only being used in research.

Up to 60 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Cetuximab: 400 mg/m2 i.v. over 120 minutes on week 1, and 250 mg/m2 on week 2 and 3 i.v. over 60 minutes arm 2: IMC-A12: 6 mg/kg/week i.v. over 1 hour on weeks 1 and 2 and 3. arm 3: Cetuximab: 400 mg/m2 i.v. over 120 minutes on week 1, and 250 mg/m2 on week 2 and 3 i.v. over 60 minutes.

IMC-A12: 6 mg/kg/week i.v. over 1 hour on weeks 1 and 2 and 3.

Interventions: intervention 1: Cetuximab intervention 2: IMC-A12 intervention 3: Surgical tumor resection
Intervention descriptions: intervention 1: First dose of 400 mg/m\^2 by vein on Days 1 and 8 over 2 hours, second dose of 250 mg/m\^2 on week 2 and 3 (if applicable) given over 1 hour. intervention 2: 6 mg/kg/week by vein on Days 1 and 8 over 1 hour on weeks 1 and 2 and 3 (if applicable). intervention 3: Surgical tumor resection on Day 10.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Study title: An exploratory study to assess the modulation of biomarkers 
in patients with squamous cell carcinomas of the head and neck randomized 
to receive preoperative treatment with cetuximab and/or IMC-A12, an anti- 
insulin-like growth factor-1 receptor monoclonal antibody 
 
 
 
Investigators:   M au r a Gi l l i s o n ,  MD 
 
 
 
 
 
Statistician:          J. Jack Lee 
 
 
 
 
Study Centers: The University of Texas M. D. Anderson Cancer Center, 
Houston,TX. 
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Synopsis 
 
 
Title of Study: An exploratory study to assess the modulation of biomarkers in patients 
with squamous cell carcinomas of the head and neck randomized to receive preoperative 
treatment with cetuximab and/or IMC-A12, an anti-insulin-like growth factor-1 receptor 
monoclonal antibody 
Study Center(s): The University of Texas M. D. Anderson Cancer Center, Houston, TX. 
Concept and Rationale: Cetuximab, a monoclonal antibody directed to the epidermal 
growth factor receptor (EGFR), has been recently approved for the treatment of locally
advanced (concurrent with radiation) or recurrent (as single agent) cisplatin-refractory
squamous cell carcinoma of the head and neck (HNSCC). However, in the setting of 
recurrent disease, response rates to this agent are in the range of 13%. The reason why the
majority of patients do not respond to EGFR-targeted drugs is poorly understood. The
majority of HNSCC present overexpression and overstimulation of the insulin-like growth
factor-1 receptor (IGF-1R) in cancer cells as compared to the adjacent normal mucosa.
The IGF-1R shares common intracellular signaling pathways with EGFR (e.g.,
phosphatidil-inositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]) and might
function as an EGFR-independent activator of these pathways, driving cell proliferation
and survival. IGF-1R signaling has been shown to mediate resistance to EGFR or HER-2 
targeted drugs in breast, colon, prostate, and non-small cell lung cancer cell lines. In 
HNSCC, IGF-1R blockade leads to an increase in apoptosis in vitro, and the combination
of IGF-1R and EGFR tyrosine kinase inhibitors results in an enhanced anti-neoplastic
effect as compared to either drug alone. This effect has been shown to occur through
down-regulation of phospho-Akt, ultimately leading to enhanced apoptosis, in part
through inhibition of m-TOR mediated survivin synthesis. Taken together, these results
indicate that signaling through the IGF-1R is an important stimulus for cancer growth and
might be responsible for the de novo and / or acquired resistance of HNSCC to EGFR-
targeted drugs. Therefore, therapeutic strategies directed to the inhibition of both IGF-1R 
and EGFR could potentially exhibit additive or synergistic anti-neoplastic effects. 
 
IMC-A12 is a monoclonal antibody against the IGF-1R produced by ImClone, Inc. Phase 
I studies of this drug demonstrated a favorable toxicity profile, with hyperglycemia
consisting of the most prevalent and clinically significant adverse event (4/21 patients). 
 
As described above, there is a strong biological rationale to clinically develop the antibody
in combination with EGFR-targeted drugs (e.g., cetuximab), which are now established
treatment options for patients with HNSCC. The characterization of the molecular
effects of cetuximab +/- IMC-A12 on HNSCC biomarkers will provide important
information, so as to further elucidate the mechanism of resistance to EGFR- targeted
drugs in these tumors and to define better treatment strategies in the palliative- or curative-
intent setting of this disease. 
 
Although the combination of cetuximab and IMC-A12 has not been extensively studied
in humans, the non-overlapping toxicity profile of both drugs and their routes of 
elimination do not suggest a potential for enhanced side effects of this doublet. Initial 
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experience  with  the  combination  in  patients  with  colorectal  cancer  revealed  no 
unexpected toxicity and good tolerance. A phase II study is ongoing at M. D. Anderson 
Cancer Center to investigate the efficacy and safety of this regimen in patients with
recurrent cisplatin-refractory HNSCC. 
 
The present study will evaluate the effects of a 2- to 3-week treatment period of cetuximab
+/- IMC-A12 on the modulation of biomarkers of patients with HNSCC for whom
surgical treatment is planned. This is a window of opportunity study targeting patients
that typically do not receive any anti-neoplastic pre-operative treatment as part of their
standard care. Cetuximab will be given at the FDA-approved dose (loading dose of 400
mg/m2, followed by 250 mg/m2 on week 2, intravenously). IMC-A12 will be given at the
recommended dose derived from the phase I study (6 mg/kg/week for 2 weeks,
intravenously). A third dose of the study agent(s) might be given in case surgery is
delayed. Although the phase I study was terminated before the maximal tolerated dose 
had been reached, IMC-A12 6 mg/kg/week maintained the serum levels of the drug 
above the therapeutic threshold (determined from animal xenograft models) for at least 7 
days. 
Objectives: The objective of this study is to assess modulation of biomarkers resulting 
from a short, pre-operative course of treatment of cetuximab and/or IMC-A12 in patients 
with HNSCC. Safety of the combination and its effects on glucose metabolism (with an 
emphasis on the pathophysiology of hyperglycemia) will also be evaluated. Objective 
response to, and histopathological changes after the short course of treatment will be 
determined as well. 
Study Design: This is a randomized, biomarker driven study with a pharmacodynamic
primary endpoint. Patients with a histologically confirmed diagnosis of HNSCC for 
whom surgical treatment is planned will be stratified according to the primary site (i.e., 
mucosal or cutaneous primary site) and need for any anti-hyperglycemic pharmacological
treatment, and randomized into three different treatment groups: cetuximab alone, IMC-
A12 alone, or cetuximab + IMC-A12. Two weekly doses of the investigational agent(s)
will be administered, followed by surgical resection. A third dose of the study agent(s)
might be given in case surgery is delayed. Baseline and post-treatment imaging studies
will be obtained. Optional biopsies of skeletal muscle and adipose tissue will be
performed at the time of surgery. Biomarkers on the surgical specimen and at baseline
will be assessed for the evaluation of the primary and secondary pharmacodynamic
endpoints. Toxicity, effects on intermediary metabolism, post-treatment molecular
changes in the skeletal muscle and adipose tissue, objective response to treatment and
post-treatment histopathological changes will also be determined. 
Number of Patients: We plan to enroll 60 patients (20 per group). The sample size will
provide us 90% power to detect the modulation between two groups with a 5% two-sided
type I error rate. The sample size calculation is based on the following assumptions: (1) 
Wilcoxon rank sum test is applied to compare the modulation between any two of the 
three groups. (2) The effect size is assumed to be 1.5. Specifically, we assume that the 
difference between the phospho-AKT means of any two groups is 1.5 standard
deviations. Consequently, the probability of phospho-AKT reduction in one group being 
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greater than in the other group is 0.856. (3) 10% inevaluable rate. 
 
Main Criteria for Inclusion/Exclusion: 
 
Inclusion criteria: 
 
1. 
The patient has a histologically or cytologically-confirmed diagnosis of squamous 
cell carcinoma of the head and neck (excluding carcinomas of the nasopharynx types II 
and III according to the World Health Organization criteria), for whom surgical resection 
of the tumor is planned  as part of the  treatment. Patients with skin squamous  cell 
carcinomas of the head and neck region will also be included in this study. 
2. 
There is availability of a baseline, paraffin-embedded, tumor specimen for 
biomarker evaluation. No anti-neoplastic treatment is allowed between the time from 
obtaining the baseline tumor specimen and randomization. If a baseline tumor specimen 
is not available, a biopsy of the tumor will be performed prior to randomization. 
3. 
Prior treatment with biological agents targeted to the epidermal growth factor 
receptor is allowed, provided the time from last exposure to this treatment was 
 6 
months. 
4. 
The patient has a fasting serum glucose < 130 mg/dL and HbA1C < 7.0%. 
Patients with a history of diabetes mellitus are allowed to participate, provided that they 
are on a stable dietary or therapeutic regimen for this condition. 
5. 
The patient has adequate renal function, defined by serum creatinine  1.5 x the 
institutional upper limit of normal (ULN), or creatinine clearance 60 mL/min for patients 
with creatinine levels above the ULN 
6. 
Because the teratogenicity of cetuximab and IMC-A12 is not known, women of 
childbearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation. 
7. 
The patient is age  18 years. 
8. 
The patient or the pa
 legally authorized representative has the ability to 
understand and the willingness to sign a written informed consent document. 
9. 
ECOG performance status of 0-2 
Exclusion criteria 
1. 
Patients receiving any other agent (investigational or not) with potential anti- 
neoplastic activity within 3 weeks prior to obtaining the baseline tumor specimen for 
biomarker evaluation. 
2. 
Patients receiving concomitant radiation 
3. 
Prior treatment with an agent targeted at the insulin-like growth factor-1 receptor 
4. 
History of allergic reactions attributed to compounds of chemical and biological 
composition similar to those of cetuximab or IMC-A12 
5. 
Pregnant patients, or patients who are breast feeding (patients who have a positive 
pregnancy test within the first 30 days before the first dose of treatment are excluded) 
6. 
Patients with uncontrolled illnesses which, in the opinion of the  investigator, 
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could be aggravated by the administration of the study drug(s) 
Intervention and Mode of Delivery: Following randomization, the patients will receive 
weekly cetuximab, weekly IMC-A12, or weekly cetuximab followed by IMC-A12 at the 
following doses: 
 
Cetuximab: 400 mg/m2 i.v. on week 1, and 250 mg/m2 i.v. on week 2 and 3 (if applicable) 
IMC-A12: 6 mg/kg/week i.v. on weeks 1, 2 and 3 (if applicable) 
Duration of Intervention and Evaluation: Patients  will receive the investigational 
treatment(s) for 2 doses pre-operatively, followed by surgical resection. A third dose may 
be given in case surgery is delayed. Only patients who had surgery within 10 days of the
last treatment will be evaluable for the primary endpoint. A 30 day post-operative follow-
up visit or telephone call is planned for assessment of toxicity, in addition to the regular
follow-up visits in the surgical clinic. Objective response to treatment will be determined
by comparing baseline imaging studies to scans obtained between the last dose of treatment
and surgery. 
Primary Endpoints/Criteria for Evaluation: The primary endpoint of this study 
consists of the modulation of phospho-Akt in the post-treatment, surgical tumor specimen 
as compared to the baseline tumor specimen in the different treatment groups. An IHC 
scoring system will be used to quantify phospho-Akt levels based on staining intensity x 
extension. Staining intensity will be graded as undetectable (0), weak (1), medium (2), or 
strong (3). Staining extension will be graded as percentage of positive cells per high 
power field at x20 magnification. The final score will therefore range from 0 to 300. 
Secondary Endpoints: Secondary endpoints will include evaluation of pre- (if
applicable) and post-treatment blood-based biomarkers, tumor specimens biomarkers, 
biomarkers in the skeletal muscle and adipose tissue, toxicity, objective response to
treatment and histopathological changes after treatment. 
 
Blood-based biomarkers will be evaluated in Dr. Hai 
 laboratory. Tumor tissue-
based biomarkers will be evaluated in the laboratories of Drs. Adel K. El-Naggar, Ho-
Young Lee and Jeffrey Meyers. 
 
Tumor-tissue based biomarkers will include (but are not restricted to): IGF-1R, phospho-
IGF-1R,  IGF-2R,  IGF-1,  IGF-2,  IGFBP-3,  EGFR,  phospho-EGFR,  survivin,  Ki-67, 
caspase-3, HIF-1 alpha, CD31, MMP-2, MMP-9, phosphorylation status of multiple
kinases (using antibody arrays), micro-RNA and messenger-RNA expression levels (using
high-throughput microarray chips), high-throughput proteomic analysis, genomic analysis
and other biomarkers that may emerge to be important related to the use of EGFR
and/or IGF-1R-targeted therapy. 
 
Skeletal muscle and adipose tissue-based biomarkers will include (but are not restricted
to): insulin receptor, phosphorylated insulin receptor (phospho-tyrosine and phospho-
serine) and its downstream effectors, insulin receptor substrate-1 (phospho-tyrosine and 
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phospho-serine), glucose transporter-1, glucose transporter-4, hexokinase, PPAR-alpha, 
PPAR-gamma, phosphorylation status of multiple kinases (using antibody arrays), micro-
RNA and messenger-RNA expression levels (using high-throughput microarray chips),
high-throughput proteomic analysis, genomic analysis and other biomarkers that may 
emerge to be important for anti-IGF-1R therapy-induced toxicity. 
 
Blood-based biomarkers will include (but are not restricted to): free and total IGF-1 and
IGF-2, IGFBP-3, insulin, peptide C, free fatty acids, triglycerides, fructosamine, a panel
of 59 cytokine and angiogenic factors measured by available luminex multiplex beads
kits (Bio-Plex 27-Plex & 23-Plex Kits [Bio-Rad, Hercules, CA] and Human CVD 
Biomarker Panel 1 kit [Linco Research, Inc., St, Charles, MO]), VEGF, solubleVEGFR-
1, soluble VEGFR-2, osteopontin, high-throughput proteomic analysis, genomic analysis
and other biomarkers that may emerge to be important for characterization of cetuximab 
and/or IMC-A12 activity and/or toxicity. 
 
Toxicity: evaluated by the National Cancer Institute Common Terminology Criteria of 
Adverse Events version 3.0. 
Objective response to treatment: evaluated by RECIST guidelines and waterfall plots.
Histopathological changes after treatment:  tumor tissue changes (necrosis, dyskeratosis, 
keratinization, and apoptosis) and host tissue changes (fibrosis, immune response, 
granulomatous inflammation, dystrophic features, and angiogenesis) 
Correlative Studies:  Correlative  studies  are  described  in  the  secondary  endpoints 
section. They are assumed to represent pharmacodynamic indicatives of efficacy or 
toxicity of the investigational drug(s), or might predict response to treatment at the
molecular level. 
Statistical Methods: Modulation of phospho-Akt (difference in IHC score between the 
surgical specimen and the baseline biopsy) and other biomarkers will be compared
between any two of the three treatment arms with the use of the Wilcoxon rank sum test.
Type I error of alpha=0.05 (two-sided test) will be used. The correlation between
biomarkers and molecular response or toxicity will be performed in an exploratory
fashion. 
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Table of Contents 
 
 
 
1 INTRODUCTION 
11 
 
1.1 BACKGROUND: CETUXIMAB 
11
1.1.1
CETUXIMAB IN HNSCC
12
1.2
BACKGROUND: THE INSULIN-LIKE GROWTH FACTOR AXIS 
13
1.2.1
INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR AND HUMAN CANCER 
15
1.2.2
INSULIN-LIKE GROWTH FACTOR AXIS AND HNSCC
16
1.2.3
TARGETING THE INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR IN THE TREATMENT OF 
CANCER 
17
1.3
HUMAN ANTI-INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR, IMC-A12
18
1.3.1
PRE-CLINICAL STUDIES WITH IMC-A12
18
1.3.2
PHASE I STUDIES OF IMC-A12
1
1.4
RATIONALE 
6
1.4.1
RATIONALE: CETUXIMAB 
6
1.4.2
RATIONALE: IMC-A12
7
1.4.3
RATIONALE FOR COMBINATION OF CETUXIMAB AND IMC-A12 IN HNSCC
9
1.4.4
RATIONALE: SELECTION OF PHOSPHO-AKT MODULATION AS PRIMARY ENDPOINT 
10
1.4.5
RATIONALE: SELECTION OF BIOMARKERS FOR SECONDARY ENDPOINTS 
12
 
2 STUDY OBJECTIVES 
14 
 
2.1 PRIMARY OBJECTIVE  
14 
2.2 SECONDARY OBJECTIVES  
14 
3 PATIENT SELECTION 
14 
3.1 STUDY POPULATION  
14 
3.2 INCLUSION CRITERIA  
14 
3.3 EXCLUSION CRITERIA  
16 
3.4 PATIENT ENROLLMENT  
16 
3.4.1 SCREENING  
17 
3.5 METHODS FOR ASSIGNING PATIENTS TO TREATMENT GROUPS  
17 
4 INVESTIGATIONAL PLAN 
18 
4.1 OVERALL STUDY DESIGN AND PLAN  
18 
5 STUDY TREATMENTS 
20 
5.1 TREATMENTS  SAFE HANDLING AND ADMINISTRATION  
20 
5.1.1 IMC-A12  
20 
5.1.2 CETUXIMAB  
22 
5.2 TREATMENT COMPLIANCE  
23 
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5.3 PACKAGING AND LABELING  
23 
5.3.1 IMC-A12  
23 
5.3.2 CETUXIMAB  
24 
5.4 STORAGE  
25 
5.4.1 IMC-A12  
25 
5.4.2 CETUXIMAB  
25 
5.5 ACCOUNTABILITY  
25 
5.6 RETURN OF INVESTIGATIONAL PRODUCT  
26 
5.7 INVESTIGATIONAL PRODUCT RETENTION AT STUDY SITE  
26 
6 STUDY PROCEDURES 
27 
6.1 INFORMED CONSENT  
27 
6.2 MEDICAL HISTORY  
27 
6.3 PHYSICAL EXAMINATION  
27 
6.4 VITAL SIGNS  
27 
6.5 CLINICAL LABORATORY TESTS  
27 
6.6 BASELINE TISSUE SPECIMENS  
28 
6.7 IMAGING STUDIES  
29 
6.8 AUDIOMETRY  
29 
6.9 SURGICAL PROCEDURE AND POST-TREATMENT TISSUE SPECIMENS  
29 
6.10 PHARMACODYNAMIC ASSESSMENTS  
30 
6.10.1 BIOMARKER EVALUATION IN TUMOR SPECIMENS  
30 
6.10.2 BIOMARKER EVALUATION IN ADIPOSE TISSUE AND SKELETAL MUSCLE  
31 
6.10.3 BLOOD-BASED BIOMARKERS  
32 
7 REQUIRED EVALUATIONS 
32 
7.1 PRE-TREATMENT EVALUATIONS  
32 
7.2 TREATMENT PERIOD  
33 
7.3 END OF THERAPY  
33 
7.4 FOLLOW-UP  
33 
7.5 STUDY EVENTS TABLE  
35 
8 ADVERSE EVENTS ASSESSMENT 
36 
8.1 PERFORMING ADVERSE EVENTS ASSESSMENTS  
36 
8.2 IMPORTANCE OF ADVERSE EVENT REPORTING  
36 
8.3 ADVERSE EVENTS DEFINITION  
36 
8.3.1 ADVERSE EVENT  
36 
8.3.2 SERIOUS ADVERSE EVENT  
37 
8.4 ASSESSMENT OF CAUSALITY  
39 
8.5 COLLECTION OF SAFETY INFORMATION  
40 
8.6 EXPECTEDNESS  
41 
8.7 CLINICAL SIGNIFICANCE  
42 
8.7.1 PREGNANCY  
42 
8.8 CLINICAL LABORATORY ADVERSE EVENT  
43 
8.9 HANDLING OF SERIOUS ADVERSE EVENTS  
44 
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9 TREATMENT EMERGENT ADVERSE EVENTS 
45 
9.1 CETUXIMAB  
45 
9.1.1 CETUXIMAB INFUSION REACTIONS  
45 
9.1.2 ACNEIFORM RASH  
47 
9.1.3 HEMATOLOGIC TOXICITIES  
47 
9.1.4 NONHEMATOLOGIC TOXICITIES  
47 
9.1.5 ELECTROLYTE MONITORING  
47 
9.2 IMC-A12  
48 
9.2.1 IMC-A12 INFUSION REACTIONS  
48 
9.2.2 HYPERGLYCEMIA (DIABETES)  
49 
9.2.3 PERI-OPERATIVE COMPLICATIONS  
50 
10 DOSE MODIFICATIONS AND STUDY COMPLETION 
50 
10.1 DOSE MODIFICATIONS  
50 
10.2 REMOVAL OF PATIENTS FROM THERAPY  
51 
10.3 STUDY COMPLETION  
52 
11 CRITERIA FOR TUMOR RESPONSE EVALUATION 
53 
11.1 CLINICAL RESPONSE  
53 
11.1.1 BASELINE TUMOR ASSESSMENT  
53 
11.1.2 METHOD OF TUMOR RESPONSE ASSESSMENT  
53 
11.1.3 DEFINITIONS  
54 
11.1.4 DEFINITIONS OF RESPONSE  
54 
11.1.5 DETERMINATION OF OVERALL CLINICAL RESPONSE  
56 
11.2 HISTOPATHOLOGICAL CHANGES  
56 
11.2.1 TUMOR TISSUE  
57 
11.2.2 HOST TISSUE  
57 
12 PLANNED STATISTICAL METHOD 
57 
12.1 PRIMARY ENDPOINT  
57 
12.2 SECONDARY ENDPOINTS  
57 
12.2.1 TISSUE- AND BLOOD-BASED BIOMARKERS  
57 
12.2.2 OBJECTIVE RESPONSE TO TREATMENT  
59 
12.2.3 HISTOPATHOLOGICAL CHANGES AFTER TREATMENT  
59 
12.2.4 SAFETY  
59 
12.3 ANALYSIS POPULATION  
59 
12.4 SAMPLE SIZE  
60 
12.5 STATISTICAL ANALYSIS  
60 
12.6 INTERIM ANALYSIS  
61 
12.6.1 INTERIM EFFICACY ANALYSIS  
61 
12.6.2 INTERIM SAFETY ANALYSIS  
61 
13 ADMINISTRATIVE CONSIDERATIONS 
62 
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13.1 INSTITUTIONAL REVIEW BOARD APPROVAL  
62 
13.2 ETHICAL CONDUCT OF THE STUDY  
62 
13.3 COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS  
63 
13.4 PATIENT INFORMATION AND CONSENT  
63 
13.4.1 INFORMED CONSENT PROCEDURES  
64 
13.4.2 UPDATE OF THE INFORMED CONSENT  
64 
13.5 STUDY MONITORING  
65 
13.6 CASE REPORT FORMS AND STUDY RECORDS  
65 
13.7 ACCESS TO SOURCE DOCUMENTATION  
66 
13.8 RETENTION OF DATA  
66 
13.9 PUBLICATION AND DISCLOSURE POLICY  
66 
14 REFERENCES 
66 
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1 Introduction 
 
 
Head and neck cancer is the sixth most common form of cancer,1 with a worldwide 
incidence of half a million or more.2 In 2008, cancers of the oral cavity and pharynx were 
estimated to account for more than 30,000 new diagnoses in the United States (US); the 
vast majority of cases are squamous cell carcinoma of the head and neck (HNSCC),3 
which collectively account for 3%-4% of all US cancers.4 
A variety of therapeutic avenues are available to patients with HNSCC, including 
surgery, radiotherapy, combined chemo- and radiotherapy, and, more recently, targeted 
agents. The availability of multimodal and novel approaches has allowed for gradual 
improvement in the management of HNSCC; 5-year survival of patients with oral cavity 
and pharyngeal carcinomas has increased from 54% during the period 1974-1976 to 59% 
in the period 1995-2000.5  However, a substantial percentage of patients will still develop 
 
incurable disease, despite aggressive, multimodality, upfront treatment; in turn, recurrent 
 
/ metastatic disease responds only poorly to the available treatment options, including 
biologic agents (i.e., cetuximab). Therefore, understanding of the mechanisms of 
resistance to the current available treatments is clearly needed, as well as the 
development of strategies to overcome this resistance, leading to improved systemic 
management of HNSCC in both the curative and palliative settings. 
 
 
1.1 
Background: cetuximab 
 
 
Cetuximab (Erbitux®, C-225) is a chimerized monoclonal antibody of the IgG1 subclass. 
It was created by chimerization of the murine monoclonal antibody (M225) developed at 
the University of California, San Diego.6  Cetuximab was genetically engineered by 
cloning the heavy and light chains of M225 and adapting them for expression together 
with constant regions of the human kappa light chain and human gamma 1 heavy chain. 
The chimerization process resulted in an antibody with binding affinity to the epidermal 
growth factor receptor (EGFR) greater than the natural ligand epidermal growth factor 
(EGF); cetuximab blocks binding of EGF and transforming growth factor alpha (TGF- ) 
to EGFR and inhibits ligand-induced activation of this tyrosine kinase receptor.7 
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Cetuximab also stimulates EGFR internalization, effectively removing the receptor from 
the cell surface for interaction with the ligand.8 
 
 
1.1.1 Cetuximab in HNSCC 
 
 
A number of clinical studies have demonstrated the utility and safety of cetuximab in the 
treatment of HNSCC. Trigo, et al,9 administered cetuximab (at 400 mg/m2 initial dose 
and 250 mg/m2 weekly thereafter) to 103 patients with stage III/IV, platinum-refractory, 
recurrent or metastatic HNSCC; the objective response rate (ORR) in this population was 
13%, with a median time to progression of 2.3 months and median overall survival (OS) 
of 5.9 months. Adverse events were considered manageable. 
 
 
On the basis of this and other phase II studies,9-11 a pair of pivotal phase III studies were 
initiated, both examining cetuximab in this setting. In the first, 117 patients with 
metastatic or recurrent HNSCC were randomized to either cetuximab (as described  
above) plus cisplatin (100 mg/m2 every 28 days) or cisplatin plus placebo. The addition 
of cetuximab to cisplatin improved ORR (26% vs. 10%, p=0.03), median PFS (4.2 
months vs. 2.7 months, hazard ratio for progression 0.78, 95% CI 0.54-1.12)), and 
median OS (9.2 months vs. 8.0 months, p=0.21). Although the study did not achieve its 
statistical endpoint of improving PFS, the increased response rate and trends to improved 
PFS and OS suggest benefit of combined therapy.2  Cetuximab therapy was associated 
with increases in the risk of neutropenia, acneiform rash, and dyspnea, but the treatment 
was generally well tolerated. The second phase III trial enrolled 424 patients with 
locoregionally advanced stages III-IV HNSCC; subjects were randomized to cetuximab + 
radiotherapy (RT) or RT alone. Median PFS rates in the cetuximab/RT group and the RT 
alone group were 17.1 months and 12.4 months, respectively, with combination therapy 
yielding an OS of 49 months versus 29.3 months on RT alone. The primary observed 
adverse event in this trial was acneiform rash, encountered at a rate of 17% in the 
cetuximab/RT group and only 1% in the control group.12 
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Based on this data, cetuximab is currently Food and Drug Administration (FDA)- 
approved for use in combination with radiotherapy in the treatment of locally or 
regionally advanced HNSCC, and as a single agent in the treatment of patients with 
recurrent or metastatic HNSCC for whom prior platinum-based therapy has failed. 
In June 2007, preliminary results from the phase III EXTREME trial, which compared 
cetuximab in combination with either cisplatin plus 5-fluorouracil (5-FU) or carboplatin 
plus 5-FU with combinations of cisplatin/5-FU or carboplatin/5-FU alone, were reported 
in abstract form, indicating a statistically significant survival benefit associated with 
adding cetuximab to these regimens.13 
 
 
1.2 
Background: the insulin-like growth factor axis 
 
 
The insulin-like growth factor axis is composed of multiple receptors (insulin-like growth 
factor receptors 1 and 2, insulin receptors A and B, and the orphan insulin-receptor- 
related receptor), three ligands (insulin-like growth factors-1 and -2, and insulin), and six 
binding proteins (insulin-like growth factor binding proteins 1-6).14 
The insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane tyrosine kinase. It 
 
binds and is activated by two high affinity binding ligands, insulin-like growth factor-1 
(IGF-1) and insulin-like growth factor-2 (IGF-2).15  Unlike many cell surface receptors, 
the IGF-1R exists in the cell membrane as a disulfide-linked dimer composed of two 
extracellular -chains and two membrane-spanning -chains in a disulfide-linked - - - 
configuration.16 Both polypeptides are encoded by a single gene product that is 
 
proteolytically processed following translation. Because the IGF-1R exists as a 
preformed dimer, it requires domain rearrangements rather than receptor oligomerization 
for cell signaling. Upon ligand binding, the IGF-1R undergoes a conformational change, 
thereby activating its tyrosine kinase activity and enabling autophosphorylation of a 
series of tyrosine residues within its cytoplasmic domain as well as on one or more 
adaptor proteins, such as insulin receptor substrate-1 (IRS-1), that initiate signal 
transduction from the IGF-1R.16 The principal pathways for transduction of the IGF 
signal are the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3- 
kinase (PI3K)/Akt pathways.15  The MAPK pathway is primarily responsible for the 
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mitogenic signal elicited following insulin-like growth factor (IGF) stimulation, but may 
also play a role in cell survival. IGF-dependent signaling through PI3K elicits survival 
processes including the phosphorylation and activation of the anti-apoptotic protein Akt 
and, as a result, has been shown to protect cells from damage-induced apoptosis. 
The insulin-like growth factor-2 receptor (IGF-2R) binds IGF-2, among other proteins, 
but lacks tyrosine kinase activity and does not transduce signals. It seems to serve as a 
sink for IGF-2 and it has been hypothesized that loss of functional IGF-2R allows for 
enhanced interaction of IGF-2 with IGF-1R.17 
 
 
The insulin receptor (IR) shares a high degree of homology to IGF-1R. It occurs in two 
isoforms (IR-A, more common in fetal tissues, and IR-B, more common in adult tissues). 
IGF-2 binds IR-A with high affinity, whereas IGF-1 does not18. Evidence from gene 
deletion studies suggest that the functions of IR and IGF-1R, although physiologically 
distinct, are still partially overlapping, with IR capable of stimulating growth and IGF-1R 
able to regulate a metabolic response.19,20 
 
 
Many cells and tissues have hybrid receptors assembled with one chain of the IGF-1R 
and one of the IR. IGF-1R/IR-B hybrids have higher affinity for IGF-1, whereas IGF- 
1R/IR-A hybrids have equal affinity for IGF-2 and insulin.21 
 
 
IGF-1 and IGF-2 are abundant in the serum of adults.22  IGF-1 is secreted primarily by 
the liver as a result of stimulation by human growth hormone (GH), but can also be 
produced locally in tissues including muscle and bone. IGF-2 is not dependent upon GH 
and is expressed in a variety of tissues. 
 
 
Six well-characterized insulin-like growth factor binding proteins (IGFBP-1 through -6) 
associate with IGF ligands in serum to stabilize these growth factors and modulate their 
ability to associate with IGF-1R. As a result of their association with the IGFBPs, only 
about 2% of IGF ligands exist in free form in serum.22 
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The IGF-1R is ubiquitously expressed in normal tissues at low levels. Functional aspects 
of IGF-1R signaling include the regulation of cellular metabolism, cell proliferation, cell 
size, and cellular differentiation.15,16,22  Knockout and transgene overexpression studies 
have identified tissues in which alterations in IGF-1R signaling can influence normal cell 
growth and development. Specific ablation of IGF-1R results in perinatal death,23 which 
is believed to occur from a failure to inflate the lungs due to poor development of the 
diaphragm and intercostal muscles. IGF-1 or IGF-2 knockout mice are also growth 
retarded (approximately 60% of normal), but IGF-1-/- mice exhibit a low degree of 
postnatal viability, whereas IGF-2-/- mice are viable at birth and survive to maturation. 
This suggests that these ligands play different roles in embryonic development.24 
Overexpression of either IGF-1 or IGF-2 in transgenic mice has demonstrated a growth- 
promoting effect on most tissues.25  Notably, ligand overexpression increased the organ 
weights of the brain, heart, kidney, spleen, thymus, and uterus. 
 
 
1.2.1 Insulin-like growth factor-1 receptor and human cancer 
 
A large number of preclinical and clinical studies have implicated the IGF-1R and its 
ligands, IGF-1 and IGF-2, in the development, maintenance, and progression of 
cancer.15,22,26 Immunohistochemical analysis of human tumor samples has indicated that a 
majority of tumor sections across many tissue types stained positive for IGF-1R.27  In 
tumor cells, upregulation or overexpression of the receptor, often in concert with 
overexpression of IGF ligands, leads to potentiation of receptor signaling and, as a result, 
enhances cell proliferation and survival. A critical role of the IGF-1R in cell proliferation 
and transformation was demonstrated in experiments of IGF-1R knockout-derived mouse 
embryo fibroblasts. These primary cells grow at significantly reduced rates in culture 
medium containing 10% serum and fail to transform in the presence of several oncogenes 
including SV-40 Large T antigen gene. Upon reintroduction of IGF-1R into these cells  
by transfection with IGF-1R complementary deoxyribonucleic acid, it was determined 
that a surface receptor density of <15,000 receptors/cell was insufficient to elicit an IGF- 
1-dependent mitogenic signal.16,28  However, an increase in receptor density to 
 
22,000 receptors/cell or greater was sufficient to elicit a ligand-dependent mitogenic 
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signal and confer anchorage-independent growth in soft agar, suggesting that small 
increments in IGF-1R density could affect the mitogenic and transformation potential of 
cells in culture. Importantly, upregulation of expression and not amplification of IGF-1R 
is considered to be the primary mechanism for receptor activation in cancer development 
and progression.26 
 
 
IGFs have been shown to be strong mitogens for a variety of solid tumors,15,24,26,28 
including melanoma, osteosarcoma, brain (such as gliomas and medulloblastomas), 
breast, colon, prostate, ovarian, pancreatic, esophageal, liver, and lung cancers; this effect 
is mediated through the IGF-1R. IGFs are also mitogens for hematologic malignancies, 
including multiple myeloma.26,28  Results from multiple studies suggest that the risk of 
various cancers, including prostate, colon, and breast cancer, is increased in individuals 
who possess higher circulating levels of IGF-1.26  Overexpression of IGF-2 in cell lines 
and tumors occurs with high frequency and may result from loss of genomic imprinting  
of the IGF-2 gene.15,26,28  Loss of heterozygosity of the IGF-2R, a nonsignaling IGF-2 
binding receptor that has been proposed to act as a sink for free IGF-2, has also been 
shown to correlate with increased IGF-2-dependent tumor cell proliferation.26  In some 
instances, highly metastatic cancer cells have been shown to display higher expression of 
IGF-2 and IGF-1R than tumor cells that are less likely to metastasize.29  IGF signaling 
through IGF-1R has also been shown to protect tumor cells from the cytotoxic effects of 
chemotherapy and radiation and may be an important factor in tumor cell drug 
resistance.30,31  Additional recent evidence suggests that resistance to the anti-HER2 
antibody trastuzumab (Herceptin®) in some forms of breast cancer may be due to 
activation of IGF-1R signaling.24,32  IGF-1 and IGF-2 may also contribute to tumor 
angiogenesis; these factors are capable of inducing VEGF synthesis in tumor cells.33,34 
 
1.2.2 Insulin-like growth factor axis and HNSCC 
 
 
The  role  of  the  insulin-like  growth  factor  axis  in  HNSCChas  been  evaluated  in 
observational studies in humans and pre-clinical investigations with cell lines. 
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Wu et al. conducted a nested case-control study within a chemoprevention trial of retinoids 
for prevention of head and neck second primary tumors.35 The results indicated that 
baseline higher levels of IGF-1 and lower and higher levels of IGFBP-3 were 
associated with an increased risk of second primary tumor development. A second study 
from the same group demonstrated a joint-effect of mutagen sensitivity (an indication of 
higher intrinsic carcinogen sensitivity) and circulating IGF-1 (an indication of proliferation 
potential) in raising the risk of second primary head and neck cancers.36 These results 
indicate that, by enhancing cell proliferation, IGF-1 might increase the likelihood of 
propagation of genetic errors in cells with deficient DNA repair mechanisms, thus 
contributing for carcinogenesis. 
 
In patients with oral cancer or oral pre-malignant lesions, reduced expression of IGFBP-3 
evaluated by immunohistochemistry is associated with shorter disease-specific survival 
and adverse prognosis, respectively.37 
 
In eight HNSCC established cell lines, IGF-1R expression was detected in all samples. 
IGF-1 stimulated a significant increase in S-phase entry in 5 of these cell lines, associated 
with an enhancement of Akt and Erk activity. Treatment of one of these cell lines (SCC- 
9) with IGFBP-3 reduced the IGF-1 stimulated S-phase entry. This effect was more 
pronounced when cells were treated with both IGFBP-3 and an IGF-1R tyrosine kinase 
inhibitor (NVP-AEW541), indicating a role for IGF-1R receptor signaling-mediated cell 
proliferation. Co-targeting the IGF-1R and EGFR (with IGFBP-3 and the EGFR tyrosine 
kinase inhibitor AG1478) resulted in a synergistic inhibitory effect on S-phase entry in 
these cells.38 
 
 
Taken together, the clinical and pre-clinical data indicate that IGF-1R might represent a 
novel and valid target for the treatment of HNSCC. 
 
1.2.3 Targeting the insulin-like growth factor-1 receptor in the 
treatment of cancer 
 
A variety of strategies have been developed to inhibit the IGF-1R signaling pathway in 
tumor cells. Approaches utilizing antisense oligonucleotides, inhibitory peptide, soluble 
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receptor, and dominant-negative receptor mutants that target IGF-1R have been effective 
at inhibiting the proliferation of tumor cell lines in vitro and in experimental cancer 
models in vivo.15,26  Murine antibodies directed against the human IGF-1R have also been 
shown to inhibit the proliferation in vitro and in vivo of a variety of human tumor cell 
types. 
These studies have established targeting IGF-1R as an attractive anticancer therapeutic 
strategy and validated an antibody approach as an effective mechanism to inhibit IGF-1R 
signaling. However, murine antibodies are not ideal human therapeutics, due to their 
propensity to induce specific immune or allergic reactions. Fully human antibodies offer 
the greatest potential for success as human therapeutics since they are less likely to elicit 
an immune response and in general possess a longer half-life in vivo. 
 
 
1.3 
Human anti-insulin-like growth factor-1 receptor, IMC-A12 
 
 
ImClone Systems has developed a fully human IgG1 monoclonal antibody, IMC-A12, 
which specifically targets the human IGF-1R.39,40  IMC-A12 possesses high affinity for 
IGF-1R and acts as an antagonist of IGF-1 and IGF-2 ligand binding and signaling. 
IMC-A12 does not bind to or recognize the human insulin receptor. In addition to 
blockade of ligand binding, mechanistically, this antibody inhibits the IGF-1R pathway 
by effecting the internalization and degradation of IGF-1R, leading to a reduction in 
surface receptor density on treated cells. Hybrid receptors containing IGF-1R have also 
been shown to be downregulated by IMC-A12. IMC-A12 inhibits the proliferation and 
growth of a variety of human tumor cell lines, both in vitro and in vivo.39  Based on this 
antitumor cell activity in tumor cell models, IMC-A12 has been advanced into human 
clinical studies. 
 
 
1.3.1 Pre-clinical studies with IMC-A12 
 
 
The toxicity and pharmacokinetics of intravenously administered IMC-A12 has been 
evaluated in three studies in cynomolgus monkeys that received one, four, or 13 weekly 
doses of IMC-A12; In addition, mice have been treated in numerous xenograft studies 
exploring the activity of IMC-A12. These results are briefly summarized below. 
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A single-dose pilot PK study was conducted in cynomolgus monkeys. Animals were 
administered 2 and 10 mg/kg and observed for 42 days. No adverse effects were noted 
other than vomiting in one monkey after dosing. PK analysis indicated that the area 
under the serum concentration versus time curve from time zero extrapolated to infinity 
(AUCinf) and maximum serum concentration (Cmax) increased in a greater than dose- 
proportional manner. In the 5-week (4-dose) monkey toxicology study, animals were 
dosed on days 1, 15, 22, and 29 with 6, 22, or 80 mg/kg. The 2-week gap after the first 
dose allowed detailed PK characterization. Data from the 5-week study indicate that the 
main toxicities in cynomolgus monkeys were mild weight loss and thymic atrophy. The 
thymic atrophy was completely reversible at 6 mg/kg, partially reversible at 22 mg/kg, 
and not reversible within the 7-week recovery period at 80 mg/kg. There were 
decreasing trends in erythrocytic parameters, but this effect also occurred in the control 
group and was likely due to the frequent blood sampling. Only one of 24 evaluable 
monkeys exhibited an immune response to IMC-A12. Pharmacokinetics were nonlinear 
and the low dose produced serum levels for 2 days that exceeded the minimum trough 
level associated with activity (60-158 µg/mL) in murine colorectal (Colo205) and 
pancreatic (BxPC-3) xenograft models. 
 
 
Final data from the 13-week monkey toxicology study indicated that the weight loss and 
thymic atrophy became more pronounced and appeared at lower doses when the same 
doses were administered over a longer duration. The decreased thymus weight was 
associated with minimal to marked atrophy, depletion of cortical thymocytes, and loss of 
a distinct corticomedullary junction. Thymic tissue was replaced by adipose tissue and 
consisted of a loose fibro-adipose capsular tissue with abundant white and brown fat that 
often formed variably thick anastomosing fibrovascular trabeculae separating less 
densely populated cortical lobules. Despite the effects on the thymus, no effects were 
seen on the distribution of lymphocyte subsets in blood as assessed by flow cytometry. 
The toxicologic consequences of thymic atrophy are uncertain, but this target organ 
toxicity does not appear to pose a significant concern for adult patients with advanced 
cancers. In addition to the effects on thymus, IMC-A12 caused decreasing trends in red 
blood cells, hematocrit, and hemoglobin in both sexes (statistically significant in high- 
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20
 
dose females) as well as decreased mean platelet volume in all treated female groups. 
Decreased absolute and relative uterine weights associated with diffuse hypoplasia were 
noted. Ovarian immaturity consisting of a relative increase in the ovarian cortex with a 
less developed medulla and decreased follicles in different stages of development was 
seen in the 22- and 80-mg/kg groups. The ovarian immaturity and corresponding effects 
on the uterus may have been an adaptive response of the animals to nutritional stress and 
weight loss, but a direct effect of the test article cannot be ruled out. An increasing trend 
was observed in relative heart to body weights in all males and mid-dose females. This 
finding may be a result of the effects of IMC-A12 on body weight, since the heart to 
brain weight ratios were not statistically significantly different from the control animals 
and there was no electrocardiographic, heart rate, blood pressure, or histopathologic 
correlates. No serious toxicity affecting any vital organ has been observed following 
IMC-A12 administration for up to 13 doses. 
 
 
Mice studies demonstrated that IMC-A12 cross-reacts with the mouse IGF-1R and binds 
with kinetics similar to the human IGF-1R (ImClone Systems, Inc., 
 
Brochure). In a variety of wild-type and immunodeficient mice treated with 
intraperitoneal IMC-A12, decreased weight gain and weight loss were occasionally seen. 
The effects on body weight were reversible upon cessation of treatment. A cross- 
reactivity study in a panel of human and monkey tissues indicated that IMC-A12 cross- 
reactivity was consistent with the immunohistochemical distribution of IGF-1R in human 
tissues, as reported in the literature. The same human tissue types that expressed IGF-1R 
were stained in the cynomolgus monkey tissues. However, in some cases staining was 
observed in tissues of the cynomolgus monkey (granulosa and luteal cells, cytoplasmic 
staining of oocytes, thyroid C-cells, and lymphocytes in bronchial-associated lymphoid 
tissues) that were not observed in the human tissues. No unanticipated cross-reactivities 
were observed. The similarities in tissue profiles IMC-A12 cross-reactivity suggested 
that the cynomolgus monkey provides an appropriate animal model for nonclinical 
toxicity testing of the antibody. 
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1.3.2 Phase I studies of IMC-A12 
 
 
As of 30 April 2011, data were available from 14 ImClone/Lilly-sponsored clinical 
 
studies. Study design and enrollment information 
 
are summarized in Table 6.1; data 
 
obtained from these studies in the table below, as well as in the DCSI. 
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2
 
 
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3
 
 
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4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cixutumumab is subject to a co-development agreement with the Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), 
National Cancer Institute (NCI). Based on this agreement a total of 23 clinical trials are 
conducted, as of December 2010 and 572 patients have been treated in these trials. For 
these trials CTEP reports all serious and/or unexpected adverse events to the FDA in 
accordance with the reporting obligations of 21 CFR 312.32 and forwards all such reports 
to ImClone/Lilly within 24 to 48 hours. In addition annual reports and other pertinent 
investigational new drug (IND) data are provided to ImClone/Lilly as they become 
available. For non-ImClone/Lilly -sponsored trials, further safety information is provided 
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to ImClone/Lilly at the discretion of CTEP. Since ImClone/Lilly does not own this data, 
the quantity is beyond the control of ImClone/Lilly and the quality cannot be validated. 
 
 
Thus information pertaining to serious adverse reactions presented in IB is based on the 
total number of patients enrolled in ImClone/Lilly-sponsored trials and patients treated in 
CTEP sponsored trials combined, whereas information from the clinical database 
(adverse events, adverse reactions) is based on the number of patients enrolled in 
ImClone/Lilly-sponsored trials only. 
 
1.3.2.1 Hyperglycemia 
 
Hyperglycemia was the most common adverse event in the CP13-0501 trial (4 patients) 
and the only grade 
 3 toxicity (2 patients) observed. Three patients had a better 
characterization of hyperglycemia. Although known diabetes was an exclusion criteria 
for participation in the trial, all 3 patients with hyperglycemia had evidence of pre- 
existing glucose intolerance prior to initiation of the study on retrospective chart review. 
Increases in blood glucose levels occurred soon after the first dose (in 2 patients), were in 
the range of 350 mg/dL, and responded to oral hypoglycemic agents (glipizide or 
glyburide, and/or metformin).41 
 
 
In a phase II trial of another anti-IGF1-R antibody (CP-751,871) given in combination 
with carboplatin and paclitaxel to 48 patients with lung cancer, grades 3-4 hyperglycemia 
occurred in 20% of patients (10% grade 3, 10% grade 4). However, there is no published 
data on further characterization of these hyperglycemic episodes, nor a detailed study of 
the pathophysiologic processes involved in this adverse event.42 
 
Anti-IGF-1R-induced hyperglycemia might occur due to peripheral impaired glucose 
metabolism or decreased insulin secretion. IGF-1 has hypoglycemic effects in vivo in 
humans, which are thought to be mediated by the IGF-1R in adipose tissue and skeletal 
muscle and by the IR in the liver (since adults do not express IGF-1R in hepatocytes). In 
adipose tissue, IGF-1 induces pre-adipocyte differentiation into adipocytes by a 
mechanism involving PPAR-gamma, whereas in skeletal muscle, IGF-1R activation leads 
to increased GLUT-4 mediated glucose uptake. In the liver, IGF-1 has been shown to 
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decrease hepatic glucose production.43 The role of IGF-1R signaling in insulin production 
by pancreatic beta-cells has also been recently characterized: both the presence of IR and 
IGF-1R (and their hybrid receptors) in these cells seems to be necessary for adequate 
insulin secretion.44 IGF-1R also seems to play a major role in pancreatic beta-cells 
survival in the long term.45 
 
Due to the complexity of the interactions of the insulin and insulin-like growth factor 
axis, the pathophysiologic mechanisms of anti-IGF-1R mediated hyperglycemia cannot 
be readily inferred. In vivo, impaired glucose uptake by skeletal muscle and adipose 
tissue might contribute to hyperglycemia. A compensatory raise in insulin release would 
be expected, in turn. However, it is unknown whether anti-IGF-1R also decreases insulin 
secretion due to downregulation of IGF-1R and IGF-1R/IR hybrids in pancreatic beta- 
cells. Furthermore, the compensatory increase of IGF-1 levels following anti-IGF-1R 
therapy41 might counteract some of the hyperglycemic effects by reducing hepatic glucose 
production. On the other hand, growth hormone also seems to be up-regulated following 
anti-IGF-1R antibody treatment42, which by itself produces hyperglycemic effects. 
Therefore, a better characterization  of the hormonal and metabolic changes following anti-
IGF-1R antibody administration to humans is needed. 
 
1.4 
Rationale 
 
 
This trial is a 
 of 
 study to establish the pharmacodynamic activity 
of a short, pre-operative course of treatment of cetuximab and/or IMC-A12 in patients 
with HNSCC. Safety of the combination and its effects on glucose metabolism (with an 
emphasis on the pathophysiology of hyperglycemia) will also be evaluated. 
 
 
1.4.1 Rationale: cetuximab 
 
 
Cetuximab has a well-established and documented history of efficacy and safety in the 
treatment of HNSCC, both in combination with radiotherapy (for patients with locally 
advanced disease) and as a single-agent in the treatment of patients with recurrent 
HNSCC that has progressed on prior platinum-based therapy; the product has been 
approved by the US FDA for use in these settings. A detailed description of the clinical 
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findings leading to this approval may be found in Section 1.1. These previous studies 
support the importance of EGFR-inhibition as a key strategy to improve clinical 
outcomes in patients with HNSCC. 
 
 
1.4.2 Rationale: IMC-A12 
 
 
1.4.2.1 Molecular rationale 
 
 
IMC-A12 is a fully human monoclonal antibody of the IgG1 subclass that possesses high 
affinity for IGF-1R receptor and acts as an antagonist of IGF-1 and IGF-2 ligand binding 
and signaling. IMC-A12 does not bind to or recognize the human insulin receptor.16 In 
addition to blockade of ligand binding, mechanistically, this antibody inhibits the IGF-1R 
pathway by effecting the internalization and degradation of IGF-1R (through a lysosomal 
pathway), leading to a reduction in surface IGF-1 receptor density on treated or target 
cells.15 As a result, IMC-A12 inhibits the proliferation and growth of a variety of human 
tumor cell lines both in vitro and in vivo. In preclinical study, IMC-A12 inhibited 
proliferation in the SCC1483 and SCC6 head and neck cancer cell lines (30%-50% of 
control); minimal (<20% of control) antiproliferative effects were also observed in the 
SCC1 and SCC22B cell lines.46 Because IMC-A12 is a fully human IgG1 antibody, it is 
also capable of inducing antibody dependent cell-mediated cytotoxicity that may inhibit 
the growth of tumor cells in vivo. 
 
1.4.2.2 Clinical rationale 
 
 
IMC-A12 has been studied in the clinical setting in two phase 1 trials, one of which has 
been presented in abstract form (please refer to section 1.3.2).41 The antibody has been 
found to be well tolerated, with possible clinical activity against breast cancer, 
hepatocellular carcinoma, pheochromocytoma, pancreatic carcinoma and 
lymphangiomatosis (stable disease  4-6 months). 
 
 
Three other anti-IGF-1R antibodies (AMG-479, CP-751,871, and R1507) have also been 
studied in humans so far. AMG-479 has shown activity against neuroendocrine 
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carcinomas (1 partial response and 1 minor response) and Ewing sarcoma (1 complete 
response) in a phase I study. The agent was also well tolerated, with thrombocytopenia 
considered dose limiting in one patient.47 CP-751,871 has been given in combination with 
carboplatin and paclitaxel in a randomized phase 2 study of patients with non-small cell 
lung cancer. Response rates were higher in the experimental arm as compared to the 
chemotherapy-only arm (46 versus 32%, respectively), with 71% of patients with 
squamous cell carcinoma presenting an objective response. The drug was also well 
tolerated (dehydration and hyperglycemia were the most common grades 3-4 adverse 
events and easily manageable).42 R1507 has been studied in two phase I studies given in 
different schedules, and has shown activity in Ewing sarcoma (2 partial responses) and 
disease stabilization in a number of tumor types (including soft tissue sarcomas, non- 
colorectal gastrointestinal cancer, colorectal cancer, melanoma, prostate cancer, 
mesothelioma, cervical cancer, and HNSCC). 48,49. A trend toward increase glucose in 
serial oral glucose tolerance tests was detected in both studies of R1507. 48,49 
The safety of the antibodies against the IGF-1R receptor, and the early efficacy signals, 
especially in patients with squamous cell carcinomas, provide clinical rationale for testing 
IMC-A12 in the treatment of HNSCC. 
 
 
1.4.2.3 Pharmacokinetics data and dose rationale 
 
Pharmacokinetics data from the CP13-0501 phase I trial of weekly IMC-A12 indicate 
that there is a dose-dependant elimination of the drug and non-linear exposure, consistent 
with a saturable clearance mechanism. After the first administration, minimum serum 
concentrations of IMC-A12 given at 6 or 10 mg/kg were above 58 mcg/mL 7 days after 
the initial infusion. At steady-state, the 6 and 10 mg/kg cohorts exhibited a half-life of 
209 and 202 hours. The minimum serum concentrations two weeks post- infusion of the 
drug were 146 and 259 mcg/mL for the 6 and 10 mg/kg doses, respectively.41 
 
The target serum concentration for IMC-A12 is hypothesized to be one that maintains 
IMC-A12 trough concentrations at approximately 58 mcg/mL, which is the threshold 
level of IMC-A12 that demonstrated inhibition of growth in human tumor xenograft 
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models in mice. Therefore, the recommended dose for future studies, derived from the 
CP13-0501 phase I trial, was 6 mg/kg/week, and will be used in this trial as well. 
 
 
1.4.3 Rationale for combination of cetuximab and IMC-A12 in HNSCC 
 
 
The IGF-1R interacts with a variety of structurally distinct receptor families, including  
the HER family. Crosstalk between the IGF-1R and the EGFR was first identified in 
murine 3T3 fibroblasts, in which functional IFG-1R signaling is essential for EGF- 
induced mitogenesis.50  This effect has been linked to prolonged activation of ERK2.51  In 
mammary epithelial organ cultures, IGF-1 stimulated cell cycle progression weakly in the 
absence of EGF and, by upregulating cyclin E, was found to be essential for EGF- 
induced progression past the G1-S checkpoint.52  An EGFR tyrosine kinase inhibitor, 
gefitinib, was found to block IGF-1-induced ERK1 and ERK2 signaling in the mammary 
epithelial cell line, HB4A. IGF-1 was found to promote tyrosine phosphorylation of both 
IGF-1R and EGFR in these cells and increased existing levels of a complex containing 
both receptors.53  However, in breast cancer cell lines that all express IGF-1R, an EGFR 
TKI had no effect on MAPK signaling and IGF-1-induced proliferation was unimpeded  
in MCF-7 cells, which have a high level of IGF-1R expression.53  These findings suggest 
that there is no requirement for a co-receptor to transduce signaling in these fully 
transformed cells, and therefore that cancer cells could circumvent blockade of EGFR- 
mediated signaling by increased utilization of the IGF-1R pathway; in such a case, 
targeting both pathways would be a useful strategy. 
 
Preclinical research has demonstrated a synergistic antitumor effect associated with the 
combination of cetuximab and agents targeting the IGF-1R in BxPC-3 pancreatic 
carcinoma xenograft line,54 HCT-8 colorectal cancer xenografts,55 GEO xenografts,56 
H226 lung cancer lines,46 and other cancer cell lines, with no observable side effects 
versus monotherapy. In many of these cell lines, exposure to EGFR or HER2 inhibitors 
increases levels of IGF-1R and EGFR or HER2 hetero-oligomers in a protein complex, 
the nature of which remains to be elucidated. It has also been shown that m-TOR 
mediated survivin synthesis could rescue lung cancer cells from the effects of erlotinib, 
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an EGFR TKI, suggesting that signaling through PI3K/AKT is involved in mediating 
resistance to EGFR inhibitors in this model.57  As reported in other types of cancer cells, 
inhibition of IGF-1R restored sensitivity to erlotinib in these cells. 
 
 
M.D. Anderson investigators have specifically studied the effects of the IGF-1R TKI 
OSI868, alone and in combination with an EGFR TKI (erlotinib), on HNSCC cell lines. 
Their data indicate that single agent treatment with OSI868 or erlotinib reduced the 
viable number of SqCC/Y1 cells with lower levels of pIGF-1R, IGF-1R, and EGFR 
expression compared to other cell lines. Cells with higher levels of pIGF-1R or EGFR 
expression showed very mild response to single agent treatment; the antiproliferative 
effect of combined erlotinib and OSI868 was significantly enhanced in such cells. 
Ultimately, the combination of erlotinib and OSI868 exhibited significantly enhanced 
growth inhibition compared to single agent treatment under both hypoxic and normoxic 
conditions (personal communication, Dr. HY Lee, Houston, TX). These observations in 
preclinical models provide rationale for simultaneous targeting of IGF-1R and EGFR in 
the clinic. 
 
Currently, a phase II clinical trial of IMC-A12 alone or with cetuximab in patients with 
platinum-refractory recurrent and/or metastatic HNSCC is accruing at M. D. Anderson 
Cancer Center. Amendments to this protocol will be submitted should data  from that 
study show any concerns as regards safety of the combination. 
 
1.4.4 Rationale: selection of phospho-Akt modulation as primary 
endpoint 
 
Three major intracellular signaling pathways downstream the EGFR are believed to 
mediate its neoplastic effects: Ras/Raf/MAP-kinase, PI3-kinase/Akt/mTOR and STAT3. 
The Ras/Raf/MAP-kinase pathway has been implicated in cell proliferation, whereas the 
PI3-kinase/Akt/mTOR pathway has been implicated in cell survival.58 Similarly, the two 
major IGF-1R downstream signaling pathways have been shown to involve 
Ras/Raf/MAP-kinase and PI3-kinase/Akt/mTOR.14 
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Phosphorylated Akt has been demonstrated to be associated with failure of local disease 
control by radiation therapy in patients with HNSCC.59 Moreover, patients with oral 
cancer harboring high levels of expression of phospho-Akt have a statistically significant 
inferior disease-free survival, independently of stage and nodal status.60 
 
In non-small cell lung cancer, high basal levels of phospho-Akt (but not phospho-MAP- 
kinase) have been identified as a predictive marker of response in patients treated with 
the EGFR TKIs.61,62 Interestingly, gefitinib-treated patients whose tumors were EGFR 
positive (independently of the method of EGFR assessment), had a better response rate, 
disease control rate, time to progression and survival if they had concomitant higher 
levels of phospho-Akt, as compared to EGFR positive/phospho-Akt negative tumors. The 
double positive EGFR/phospho-Akt group also had better outcome when compared to the 
group negative for EGFR and positive for phopsho-Akt, indicating that aberrant and not 
EGFR-dependant phospho-Akt activation may lead to gefitinib resistance.63 Indeed, Lee 
et. al demonstrated that IGF-1R dependant Akt phosphorylation is associated with EGFR 
 in lung cancer cell lines, and when phospho-Akt is reduced by IGF- 
1R blocking, sensitivity to EGFR-targeted drugs is restored.64 This effect is mediated by 
mTOR and survivin, both of which are downstream of phospho-Akt. Decreased phospho- 
Akt levels have also been demonstrated following IGF-1R signaling blockade in HNSCC 
cell lines, and combining EGFR and IGF-1R inhibitors led to an enhanced decrease in the 
number of viable cells in vitro, as compared to either drug alone (personal communication, 
Dr. HY Lee, Houston, TX). 
 
Given the fact that phospho-Akt represents a crosstalk point between EGFR and IGF-1R 
intracellular signaling pathways, is inhibited by drugs targeted to both receptors, and has 
been implicated in mediating resistance to EGFR-targeted agents in non-small cell lung 
cancer in vitro, it has been selected as the primary endpoint for this biomarker-driven 
trial. Nonetheless, there is currently no standard method for assessing molecular response 
to either cetuximab or IMC-A12 in HNSCC and it is possible that phospho-Akt might not 
reflect molecular activity of these agents. To overcome this potential problem, 
modulation of several other biomarkers will be evaluated as secondary endpoints in this 
study as well. 
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Of note, biomarker modulation in tumors cells has been observed minutes to days after 
exposure to the investigational agents in pre-clinical models.39,57 
 
1.4.5 Rationale: selection of biomarkers for secondary endpoints 
 
 
Biomarkers chosen as secondary endpoints will be assessed in the following tissues: 
tumor, skeletal muscle , adipose tissue, and blood. 
 
In the tumor tissue, markers of activation of the EGFR pathway (i.e. EGFR, phospho- 
EGFR) will be analyzed, so as to determine the activity of cetuximab +/- IMC-A12 
upstream of phospho-Akt. Morgillo et al. have demonstrated that IGF-1R 
transphosphorylates EGFR in an in vitro models64. However, the magnitude of this novel 
mechanism of EGFR activation in vivo, and the ability of IMC-A12 to inhibit this 
transactivation and, accordingly, the activation of downstream signaling molecules is 
unknown. Similarly, markers of IGF-1R activation upstream of phospho-Akt (IGF-1R 
and phospho-IGF-1R) will also be evaluated. Local synthesis of IGF-1 and IGF-2 by 
cancer cells in response to IGF-1R and/or EGFR inhibition will also de determined, as 
well as the synthesis of a carrier protein responsible for regulating the bioavailability of 
IGF to its receptor (i.e., IGFBP-3)14, and IGF-2R, a nonsignaling IGF-2 binding receptor 
that has been proposed to act as a sink for free IGF-226. Modulation of these molecules 
could   account   for   differences   in   the   efficacy   of   IMC-A12   in   regulating   Akt 
phosphorylation in the tumors studied. Expression of survivin and HIF-1 alpha will be 
determined as a marker of activity downstream of phospho-Akt64. The degree of 
apoptosis (through caspase-3 staining) and proliferation (through Ki-67 staining) after 
treatment will also be evaluated, as markers of the effects of the targeted agents at the 
cellular level. Markers of invasiveness and angiogenesis (i.e., CD31, MMP-2, and MMP- 
9) will also be assessed. Additionally, the phosphorylation status of multiple kinases will 
be assessed using antibody arrays, as well as micro-RNA and messenger-RNA expression 
levels using high-throughput microarray chips, and proteomics (using high throughput 
methods), in an attempt to identify predictive markers of response. 
 
In the blood, the levels of free (i.e., not bound to IGF binding proteins) and total IGF-1, 
IGF-2 and IGFBP-3 will be evaluated and will be correlated with both toxicity and levels 
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of apoptosis and proliferation. IGF-1 levels have been previously demonstrated to rise in 
response to IGF-1R inhibition, but the significance of this phenomenon is yet unknown 
and could potentially represent a mechanism of resistance to IGF-1R-targeted therapy41. 
Similarly, modulation of circulating IGF-2 and IGFBP-3, as well as modulation of the 
levels of a panel of 59 cytokines and angiogenic factors measured by available luminex 
multiplex beads kits (Bio-Plex 27-Plex & 23-Plex Kits [Bio-Rad, Hercules, CA] and 
Human CVD Biomarker Panel 1 kit [Linco Research, Inc., St, Charles, MO]), VEGF, 
soluble VEGFR-1, soluble VEGFR-2, osteopontin, and other proteins measured by high- 
throughput proteomic analysis could also be related with both efficacy and toxicity of 
cetuximab and/or IMC-A12. 
 
With respect to intermediary metabolism markers, the levels of glucose, insulin, peptide 
C (which is secreted in equimolar levels to insulin), triglycerides and free fatty acids 
(which reflect the levels of lypolysis), and fructosamine (a marker of sustained 
hyperglycemia) will be determined, so as to evaluate the response of insulin secretion and 
the degree of insulin resistance following IGF-1R inhibition. The mechanisms of 
potential insulin resistance will also be evaluated, by determining the levels of the insulin 
receptor, its substrates (i.e. insulin receptor substrate-1) and downstream effectors, and 
their phosphorylated forms in adipose and skeletal muscle tissues. These sites represent, 
together with the liver, the main targets of insulin-mediated metabolic regulation65. Of 
 
note, phosphorylation of the insulin receptor and the insulin receptor substrate-1 in serine 
sites has been shown to be associated with impaired insulin action in these cells66. 
Glucose transporter-1 and 4 expression, which is up-regulated by insulin and plays a key 
role in clearing glucose from the blood65, will also be determined in skeletal muscle and 
adipose tissues, as well as the phosphorylation status of multiple kinases (using antibody 
arrays), micro-RNA and messenger-RNA expression levels (using high-throughput 
microarray chips), high-throughput proteomic analysis 
 
Since this study represents in essence a biomarker-driven, discovery trial, evaluation of 
other biomarkers will be performed in the samples obtained, as new knowledge becomes 
available on the potential mechanisms of action, resistance and toxicity of cetuximab and 
IMC-A12. 
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2 Study objectives 
 
 
2.1 
Primary objective 
 
 
The primary objective of this study is to assess the degree of modulation of phospho- 
AKT in HNSCC after a short, pre-operative course of treatment with cetuximab and/or 
IMC-A12. 
 
2.2 
Secondary objectives 
 
 
The secondary objectives of this study are to assess: 
 
 
1. Safety of cetuximab and/or IMC-A12 (particularly in the pre-operative setting), 
 
 
2. Effects of IMC-A12 on glucose metabolism (with an emphasis on the pathophysiology 
of hyperglycemia). 
 
3. Modulation of a panel of biomarkers in HNSCC after treatment with cetuximab and/or 
IMC-A12 and attempt correlation with clinical outcomes. 
 
4. Objective  response  to,  and  histopathological  changes  after  the  short  course  of 
treatment. 
 
3 Patient selection 
 
 
3.1 
Study population 
 
 
Patients will be recruited from a population of HNSCC patients treated at the MDACC, 
for whom surgical resection of the tumor is indicated as part of the standard treatment 
plan. 
 
It is anticipated that 60 patients (4/month) will be accrued over a period of 15 months. 
 
 
3.2 
Inclusion criteria 
 
 
Each patient must meet all of the following criteria to be enrolled in this study: 
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1. 
The patient has a histologically or cytologically-confirmed diagnosis of squamous 
cell carcinoma of the head and neck (excluding carcinomas of the nasopharynx types II 
and III according to the World Health Organization criteria), for whom surgical resection 
of the tumor is planned  as part of the  treatment. Patients with skin squamous  cell 
carcinomas of the head and neck region will also be included in this study. 
 
2. 
There is availability of a baseline, paraffin-embedded, tumor specimen for 
biomarker evaluation. No anti-neoplastic treatment is allowed between the time from 
obtaining the baseline tumor specimen and randomization. If a baseline tumor specimen 
is not available, a biopsy of the tumor will be performed prior to randomization. 
 
3. 
Prior treatment with biological agents targeted to the epidermal growth factor 
receptor is allowed, provided the time from last exposure to this treatment was 
 6 
months. 
 
4. 
The patient has a fasting serum glucose < 130 mg/dL and HbA1C < 7.0%. 
Patients with a history of diabetes mellitus are allowed to participate, provided that they 
are on a stable dietary or therapeutic regimen for this condition. 
 
5. 
The patient has adequate renal function, defined by serum creatinine  1.5 x the 
institutional upper limit of normal (ULN), or creatinine clearance 60 mL/min for patients 
with creatinine levels above the ULN 
 
6. 
Because the teratogenicity of cetuximab and IMC-A12 is not known, women of 
childbearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation. 
 
7. 
The patient is age  18 years. 
 
 
8. 
The patient or the pa
 legally authorized representative has the ability to 
understand and the willingness to sign a written informed consent document. 
 
9. 
ECOG performance status of 0-2 
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3.3 
Exclusion criteria 
 
 
A patient who meets any of the following criteria will be excluded from the study: 
 
 
1. 
Patients receiving any other agent (investigational or not) with potential anti- 
neoplastic activity within 3 weeks prior to obtaining the baseline tumor specimen for 
biomarker evaluation. 
 
2. 
Patients receiving concomitant radiation 
 
 
3. 
Prior treatment with an agent targeted at the insulin-like growth factor-1 receptor 
 
 
4. 
History of allergic reactions attributed to compounds of chemical and biological 
composition similar to those of cetuximab or IMC-A12 
 
5. 
Pregnant patients, or patients who are breast feeding (patients who have a positive 
pregnancy test within the first 30 days before the first dose of treatment are excluded) 
 
6. 
Patients with uncontrolled illnesses which, in the opinion of the investigator, 
could be aggravated by the administration of the study drug(s) 
 
3.4 
Patient enrollment 
 
 
All patients meeting the eligibility requirements will be considered for enrollment 
regardless of sex, race, or religion. Discussions regarding protocol enrollment and 
patient eligibility will begin with any of the investigators named on the protocol. Patients 
will be made aware of the protocol, its specific aims and objectives, and the potential 
risks and benefits the patient may incur. Each patient or pa
 legally acceptable 
representative will be required to read, agree to, and sign a current Institutional Review 
Board (IRB)-approved informed consent form prior to being enrolled and/or any study- 
related procedure is performed. There will be no financial compensation for patients 
enrolling on this protocol. Baseline evaluations will be performed as described in section 
7.1. 
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3.4.1 Screening 
 
 
Patients will be referred from the head and neck surgical or medical oncology clinics for 
consideration for participation in this study. The trial has the full support of the chairs of 
the departments of Thoracic/Head and Neck Medical Oncology and Head and Neck 
Surgery. As part of this collaboration, we have added this clinical protocol to an 
interactive database managed by the department of Head and Neck Surgery. This  
database will alert research personnel of patients with certain characteristics, such as 
potentially resectable head and neck cancer, that have been evaluated for the first time in 
the Head and Neck Surgery clinic. Through this mechanism, these patients may be 
identified and, after obtaining permission from the primary attending physician, the 
patients will be contacted to discuss possible participation in this clinical trial. Also, 
eligible patients will be identified during the weekly Head and Neck planning conference, 
during which cases are discussed with the multidisciplinary team to define the treatment 
plan. These patients will also be contacted for possible study participation after obtaining 
permission from the primary attending physician. 
 
 
3.5 
Methods for assigning patients to treatment groups 
 
 
Patients will be stratified according to the primary site of the head and neck cancer (i.e., 
non-skin primary or skin primary), and the current use of any anti-hyperglycemic 
pharmacologic agent and will be then randomly assigned 1:1:1 to one of the three 
treatment groups: 
 
Arm A: cetuximab alone 
 
 
Arm B: IMC-A12 alone 
 
 
Arm C: cetuximab + IMC-A12 
 
 
Patients will be assigned to each treatment arm by M. D. 
 computer-based 
CORE system. The randomization code will be generated by the study biostatistician and 
stored in the CORE database prior to initiation of the trial. The investigators will be 
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blinded to the code. Since we have two stratification factors, four sets of codes (one for 
each strata) will be produced.  Random permuted block design with a block size of 3 or 6 
will be used within each one on of the four strata. 
 
Since there is limited data on the use of IMC-A12 in diabetic patients, as added 
precautions, if toxicity data on this study and on the randomized phase II conducted at M. 
D. Anderson in the setting of platin-refractory recurrent HNSCC raise concern about 
including diabetic patients, additional considerations will be made to include diabetes as 
an exclusion criteria and, as a result, stratification of patients according to the use of anti- 
hyperglycemic pharmacologic agent will no longer be performed. 
 
After enrollment, patients will be assigned a unique study identification number and 
cohort. The study identification number and the 
s initials will be recorded on 
PDMS and/or CORE databases and correspondence regarding the patient. 
 
4 Investigational plan 
 
 
4.1 
Overall study design and plan 
 
 
This randomized, open-label study will enroll approximately 60 patients (20 in Arm A, 
20 in Arm B, 20 in Arm C) with HNSCC for whom surgical resection of the tumor is 
planned as part of the standard treatment. 
 
After obtaining informed consent, patients will undergo baseline screening to determine 
eligibility. These will include clinical laboratory tests (as described in section 6.5), 
imaging scans (as described in section 6.7), and assessment of the baseline biopsy for 
confirmation of diagnosis and adequacy for biomarker evaluation. If necessary, a baseline 
tissue specimen will be obtained (as described in section 6.6). The tentative date of tumor 
surgical resection (herein defined as day 0) will be recorded. Patients will be randomized 
to one of the treatment arms and will receive the study drug(s), before surgery, on day -9 
(+/- 3 days) and day -2 (+/- 3 days). A third dose of the study treatment(s) may be 
administered 7 days (+/- 3 days) after the second dose, in case surgery is delayed. 
Repeated imaging studies will be performed after the last treatment and before surgery. 
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D-9 
D-2* 
D0
D1-30
(+/- 3 days)
(+/- 3 days)
Surgery will be performed on day 0. However, surgery may be moved up or postponed if 
judged necessary by the attending physician. In this event, the reason for modifying the 
surgical date should be recorded. Optional biopsies of skeletal muscle and adipose tissue 
will be obtained at the time of surgery (as described in section 6.10). A post-operative 
follow-up visit or telephone call is planned for assessment of toxicity (Fig. 1), in addition 
to the regular follow-up visits in the surgery clinic. The complete study events table is 
outlined in section 7.5. 
 
 
 
 
 
 
TIME (days) 
 
Eligible 
patients 
with 
HNSCC for 
whom 
surgical 
resection is 
planned 
Obtain 
adequate 
baseline tumor 
specimen 
(archival or 
new biopsy) 
S 
Stratification factors: 
R 
t 
a 
r 
- anti-hyperglycemic 
n 
a 
pharmacologic therapy 
d 
t 
(yes or no) 
o 
i 
m 
f 
- primary site (skin or 
i 
y 
non-skin primary) 
z 
e 
C 
C 
 
 
A 
A 
 
 
C+A 
C+A 
 
 
 
Surgery 
 
 
Post- 
surgical 
follow-up 
 
 
 
 
 
 
BASELINE BIOMARKERS IN 
TUMOR TISSUE AND BLOOD 
POST-TREATMENT 
BIOMARKERS IN TUMOR 
TISSUE, SKELETAL MUSCLE / 
ADIPOSE TISSUE AND BLOOD 
 
 
 
 
 
 
Figure 1: Time-line of events during the study. C = cetuximab; A = IMC-A12. 
 
 
* A third dose of the study treatment(s) may be administered 7 days (+/- 3 days) after the 
second dose, in case surgery is delayed. 
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5 Study treatments 
 
 
5.1 
Treatments safe handling and administration 
 
 
5.1.1 IMC-A12 
 
 
Patients will receive IMC-A12 6 mg/kg i.v. via infusion over 1 hour in arms B and C. In 
arm C, IMC-A12 will be given 1 hour after the end of the cetuximab infusion. Patients do 
not need to be premedicated prior to administration of IMC-A12. The dose of IMC-A12 
will be dependent upon the 
 baseline body weight in kilograms. This dose will  
be recalculated if there is a 10% change in body weight from baseline. The dose of IMC- 
A12 will be aseptically withdrawn from the vial and transferred to a sterile ethylene vinyl 
acetate i.v. bag or an evacuated USP Type II glass i.v. container. For dose volumes < 250 
mL, a sufficient quantity of sterile normal saline (0.9% weight/volume) solution will be 
added to the container to make the total volume 250 mL. 
 
 
The container will be gently inverted to ensure adequate mixing. Different drug product 
lots should not be mixed in a single infusion. An infusion set with an in-line, 0.22- m, 
protein-sparing filter will be required for administration of IMC-A12. Use 0.9% normal 
saline to flush the line at the end of the infusion. Please see Section 5.4.1 for storage 
requirements for IMC-A12. 
 
 
Cixutumumab is an anti-IGF-IR recombinant human monoclonal antibody of the IgG1 
class. Cixutumumab drug product (DP) is a sterile, preservative-free solution for infusion 
of cixutumumab formulated in an aqueous solution at a concentration of 5 mg/mL (250 
mg/50 mL) or 10 mg/mL (500 mg/50 mL vial) or 15 mg/mL (750 mg/50 mL). The buffer 
contains 10mM sodium citrate, 100mM sodium chloride, 100mM glycine, and 0.01% 
polysorbate 80. 
 
 
Cixutumumab DP is a clear or slightly opalescent and colorless or pale yellow liquid 
without visible particles. The pH is 6.5. The osmolality is 310 mmol/kg. 
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All excipients used for the manufacture of cixutumumab DP are of pharmacopoeial 
grade. No animal-derived components are used in the manufacture of cixutumumab DP 
excipients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration: 
 
a)To administer using pre-filled IV infusion containers: 
 
Calculate the respective dose and remove the corresponding volume of 0.9% 
normal saline from the prefilled 250 mL container of the correct composition. 
Aseptically transfer the calculated dose of cixutumumab DP to the container to 
bring the final volume in the container back to 250 mL. Gently invert the 
container to mix. 
 
 
b)To administer using empty IV infusion containers: 
 
Aseptically transfer the calculated dose of cixutumumab DP into an empty I.V. 
container of the correct composition and add a sufficient quantity of sterile normal 
saline (0.9% weight/volume) to the container to bring the total volume to 250 mL. 
Gently invert the container to mix. 
 
 
Only 0.9% normal saline should be used for dilution and post-infusion flushing of 
infusion line. 
 
 
The infusion rate must never exceed 25 mg/minute. Different lot numbers of 
cixutumumab must not be mixed in a single infusion. 
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The infusion set must be flushed post-infusion with sterile normal saline equal to or 
exceeding the infusion line hold-up volume to ensure delivery of the calculated dose. 
 
 
CAUTION: Infusion reactions may occur during or following IMC-A12 administration 
(see Section 9.2.1 for definitions of grade 3 or 4 infusion reactions). 
 
 
 
 
5.1.2 Cetuximab 
 
 
Cetuximab is prepared by ImClone Systems under appropriate manufacturing conditions 
as an injectable solution, in single-use 50-mL vials containing 2 mg/mL of product. 
Cetuximab requires no dilution. Different cetuximab lot numbers must not be mixed in a 
single infusion. Cetuximab will be administered as indicated on the package insert. 
All patients will be premedicated with diphenhydramine hydrochloride, 50 mg oral or i.v. 
(or a similar agent), prior to the first dose of cetuximab in an effort to prevent an infusion 
reaction. Premedication is recommended prior to subsequent doses; however, the dose of 
diphenhydramine hydrochloride (or a similar agent) may be reduced or eliminated at the 
s discretion. 
 
 
Patients will receive cetuximab intravenous infusions via infusion pump or gravity drip, 
through a non-PVC tubing. In arms A and C, the initial dose of cetuximab is 400 mg/m2 
and is administered over 120 minutes. The second and third (if applicable) dose of 
cetuximab is 250 mg/m2 administered over 60 minutes, in arms A and C. The dose of 
cetuximab is dependent upon the 
 baseline body weight in kilograms. This dose 
will be recalculated if there is a 10% change in body weight from baseline. The infusion 
rate must never exceed 10 mg/minute (5 mL/minute). Patients should be observed 
closely during each infusion of cetuximab. Infusion times may be increased for patients 
who experience grade 1 through 3 allergic reactions. 
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Prior to infusion, the appropriate volume of cetuximab will be drawn from the vial with a 
sterile syringe. Cetuximab will be transferred from the syringe into a sterile evacuated 
container. Cetuximab will then be filtered through a 0.22-µm protein-sparing or low- 
protein binding in-line filter. At the end of the infusion, 0.9% normal saline will be used 
to flush the line. 
 
 
CAUTION: Infusion reactions, including severe reactions, may occur during or 
following cetuximab administration. Most infusion reactions occur with the first infusion 
of cetuximab, but some 
 first infusion reactions have been reported following 
subsequent doses. The infusion reaction may occur during the infusion or may be  
delayed until any time after the infusion. A nurse must be present in the immediate 
treatment area throughout the infusion period. A physician must be in close proximity to 
the patient treatment area. In the event of an infusion reaction, the patient should be 
treated as described in Section 9.1.1. Patients should be instructed to report any delayed 
reactions to the investigator immediately. 
 
 
5.2 
Treatment compliance 
 
 
Trained medical personnel will administer IMC-A12 and cetuximab. Treatment 
compliance will be monitored by drug accountability (Section 5.5); IMC-A12 and 
cetuximab administration will also be recorded in the 
 medical record. 
 
5.3 
Packaging and labeling 
 
 
5.3.1 IMC-A12 
 
 
Cixutumumab is an anti-IGF-IR recombinant human monoclonal antibody of the IgG1 
class. Cixutumumab drug product (DP) is a sterile, preservative-free solution for infusion 
of cixutumumab formulated in an aqueous solution at a concentration of 5 mg/mL (250 
mg/50 mL) or 10 mg/mL (500 mg/50 mL vial) or 15 mg/mL (750 mg/50 mL). The buffer 
contains 10mM sodium citrate, 100mM sodium chloride, 100mM glycine, and 0.01% 
polysorbate 80. 
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Cixutumumab DP is a clear or slightly opalescent and colorless or pale yellow liquid 
without visible particles. The pH is 6.5. The osmolality is 310 mmol/kg. 
 
 
All excipients used for the manufacture of cixutumumab DP are of pharmacopoeial 
grade. No animal-derived components are used in the manufacture of cixutumumab DP 
excipients. 
 
 
Cixutumumab DP is compatible with infusion containers composed of polyolefin, 
polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and evacuated glass (USP Type 
II or local equivalent). An infusion bag composed of polyolefin, polypropylene, and 
polyethylene prefilled with 0.9% Sodium Chloride Injection, such as AVIVA, may also 
be used. The following have been found to be compatible for cixutumumab DP infusion: 
 A polyethylene-lined PVC infusion set with a 0.22 
m downstream high- 
 
pressure, protein-sparing in-line filter made of polyethersulfone of 10 cm2 surface 
area 
 A PVC infusion set with a 0.2 
m protein-sparing filter made of 
 
polyethersulfone of 4.2 cm2 surface area 
 
 A polyethylene-lined PVC infusion set with a 0.2 
m protein-sparing in-line 
filter made of polyethersulfone of 10 cm2 surface area 
 A polyurethane infusion set with a 0.2 
m protein-sparing in-line filter made of 
 
polyethersulfone of 10 cm2 surface area 
 
 A polybutadiene tubing with a 0.2 m protein-sparing in-line filter made of 
polysulfone of 9 cm2 surface area 
 
 
5.3.2 Cetuximab 
 
 
Cetuximab for injection is supplied by ImClone Systems in single-use, 50 mL vials 
containing 2 mg/mL of product. 
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5.4 
Storage and Preparation 
 
 
5.4.1 IMC-A12 
 
 
 
 
Storage: Storage conditions of the drug product are located in section 4.2.1 of the 
 Brochure for Cixutumumab. 
PREPARED CIXUTUMUMAB DOSING SOLUTION FOR INFUSION: Chemical and 
 
physical in-use stability for the prepared cixutumumab dosing solution has been 
demonstrated for up to 24 hours below 25°C (77°F). However, it is recommended that the 
prepared dosing solution be used immediately in order to minimize the risk of microbial 
contamination. If not used immediately, the prepared cixutumumab dosing solution must 
be stored under refrigeration at 2°C to 8°C (36°F to 46°F) for a duration not to exceed 24 
hours. If the prepared solution is held at room temperature (below 25°C (77°F)) it must  
be used within 4 hours. DO NOT FREEZE AND/OR SHAKE PREPARED 
CIXUTUMUMAB DOSING SOLUTION FOR INFUSION. 
 
 
5.4.2 Cetuximab 
 
 
Cetuximab must be stored under refrigeration at 2 C to 8 C (36 F to 46 F). DO NOT 
FREEZE CETUXIMAB. Drug supplies must be kept in a secure, limited-access storage 
area under the recommended storage conditions. Once cetuximab is removed from the 
vial, the recommended maximum time at room temperature is 8 hours. 
 
 
5.5 
Accountability 
 
 
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 products are 
inventoried and disposed. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
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 the amount received and placed in the storage area 
 
 
 the amount currently in the storage area 
 
 
 the label identification number or batch number 
 
 
 
the dates and initials of the person responsible for each investigational product 
inventory entry/movement 
 
 the amount dispensed to each patient, including unique patient identifiers 
 
 
 the amount transferred to another area for dispensing or storage 
 
 
 non-study disposition (eg, lost, wasted, broken) 
 
 
 the amount returned to ImClone Systems or a designee 
 
 
 the amount destroyed at the study site, if applicable 
 
 
 retained samples sent to a third party for bioavailability/bioequivalence, if applicable 
 
 
5.6 
Return of investigational product 
 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational products must be returned to ImClone Systems or a designee, if not 
authorized by ImClone Systems or a designee to be destroyed at the site. 
5.7 
Investigational product retention at study site 
 
 
Opened vials may be disposed of at the investigation center as chemotherapy or 
biohazardous waste. 
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6 Study procedures 
 
 
6.1 
Informed consent 
 
 
Written informed consent will be given by each patient prior to undergoing protocol- 
specific evaluations and prior to receiving treatment. 
 
6.2 
Medical history 
 
 
Medical history will be documented at baseline. Medical history of follow-up visits may 
only include interim changes from last evaluation. 
 
Concurrent medications will be documented in the patien
 medical records but will not 
be recorded in the case report form (CRF). 
 
6.3 
Physical examination 
 
 
Evaluation by pertinent body system, height (pretreatment only), weight, and body 
surface area (BSA), as well as ECOG performance status (pretreatment only) should be 
documented. 
6.4 
Vital signs 
 
 
Vital signs will be recorded and should include temperature, pulse rate, and blood 
pressure. 
 
6.5 
Clinical laboratory tests 
 
The blood-based clinical laboratory tests will include: 
 
 
 
Hematology profile: complete blood count with differential and platelet count 
 
 
 
Chemistry profile: fasting glucose, creatinine, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase, 
total bilirubin, sodium, potassium, carbon dioxide, magnesium, and amylase 
 
 
Pregnancy test: serum or urine pregnancy test 
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Additional tests: 26 mL of blood will be collected and stored for additional 
studies of interest, including (but not restricted to) fasting insulin, fasting peptide C, 
triglycerides, fasting free-fatty acids and evaluation of blood-based biomarkers (refer to 
section 6.9.3). Briefly, blood will be collected using one EDTA (10 mL) tube and two 9- 
mL CPT tubes for blood cells separation and storage. Samples will be forwarded to the 
core laboratory to be processed within one hour of collection. Blood will be centrifuged 
in a standard clinical centrifuge at 2500 RPM at 4 oC for 10 minutes. Aliquots of 2.0-2.5 
 
mL of serum should then be transferred into 2 (two) cryovials, labeled with the protocol 
number and the 
 unique study identification number. Cryovials will be stored at - 
80 oC. Peripheral blood cells will also be stored at -80 oC. 
 
6.6 
Baseline tissue specimens 
 
 
Baseline tumor tissue specimens will be obtained before initiation of the investigational 
treatment and will be used for confirmation of diagnosis and adequacy for evaluation of 
biomarkers. Archival paraffin-embedded tissue may be used as the baseline specimen, 
provided no anti-neoplastic therapy has been administered to the patient from the time of 
the biopsy to study entry, in which case a new biopsy should be obtained. In the event the 
baseline tissue has been considered inappropriate for biomarker evaluation, a new baseline 
biopsy should also be obtained. Additional baseline biopsies may be performed if 
considered necessary by the investigator. For the purpose of this study, these additional 
baseline tumor biopsies will consist of an outpatient core biopsy, or a punch-biopsy 
performed under local anesthesia with a minimum of 4-5 mm diameter (which allows for 
the preparation of at least 30 slides). These specimens should be fixed in 10% formalin, 
preferably immediately and not more than 1 (one) hour after excision. Fixed biopsy 
samples will be processed for paraffin-embedding according to the Institutional Standard 
Operating Procedures. The paraffin blocks and slides should be labeled with the protocol 
number and the 
 unique study identification number and stored at room 
temperature. A portion of the specimen obtained may also be embedded in optimal 
cutting temperature compound immediately after received and not more than 1 (one) hour 
after excision, frozen, and stored at -80 oC for future biomarker analysis. All samples 
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stored at -80 oC should be placed in appropriate containers, labeled with the protocol 
number and the 
 unique study identification number. 
 
6.7 
Imaging studies 
 
 
Computerized tomography scans or magnetic resonance imaging of the head and neck 
will be obtained within 30 days before treatment initiation and will be repeated in the 
period between the last dose of the study drug(s) and the surgical procedure to assess 
objective response to treatment. 
 
 
 
 
 
6.8 Audiometry 
 
 
Patients randomized to receive treatment with IMC-A12 (i.e. Arm B and Arm C) are 
required to have an audiometric evaluation within 90 days before starting treatment with 
the study drug(s). For all patients who received at least 1 dose of IMC-A12, a repeat 
audiometric evaluation will be performed within 90 days after surgery. 
 
6.9 
Surgical procedure and post-treatment tissue specimens 
 
 
The extent of surgical resection of the tumor should be performed as originally planned 
by the attending physician and should not take into account response to the 
investigational treatment. The type of surgery will be recorded in the Operative Note 
(OP) and/or Procedure Note (PR) of the 
 medical record.. 
 
The surgically resected tumor specimen will be evaluated for efficacy endpoints as 
described in section 6.10. During surgery, an optional specimen of adipose tissue and 
skeletal muscle tissue from the surgical field will also be collected for post-treatment 
biomarker evaluation, if the patient has previously given consent and if the collection of 
these additional tissues is considered feasible (i.e., not associated with unreasonable 
risks) by the surgeon during the operative procedure. Surgery should not be extended for 
collection of skeletal muscle and adipose tissue. The recommended procedure for 
obtaining the tissue specimens is as follows: the primary tumor should be identified on 
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exam under anesthesia and at least 2 (two) large-cup forceps biopsies obtained prior to 
ligation of the tumor vessels, to avoid ischemia-induced activation of phosphatases. A 
portion of the tissue will be fixed in 10% formalin immediately after received and not 
more than 1 (one) hour after excision. Fixed biopsy samples will be processed for 
paraffin-embedding according to the Institutional Standard Operating Procedures. The 
paraffin blocks and slides should be labeled with the protocol number and the 
 
unique study identification number and stored at room temperature. Another portion of 
the tumor specimen (preferably one sample  2 mm3  or 100 mg) will be embedded in 
optimal cutting temperature compound immediately after received and not more than 1 
(one) hour after excision, frozen and stored at -80 oC for future biomarker analysis. 
Skeletal muscle and adipose tissue (preferably two or more samples  2 mm3 or 100 mg) 
may be obtained at the time of surgery (preferably prior to vessel ligation) or separated 
from the en block resected specimen containing the tumor in the pathology laboratory. A 
portion will be formalin-fixed (not more than 1 (one) hour after excision) and processed 
for paraffin-embedding according to the Institutional Standard Operating Procedures, 
while another portion will be embedded in optimal cutting temperature compound (not 
more than 1 (one) hour after excision), frozen and stored at -80 oC for future biomarker 
analysis. The remaining specimens resected during surgery (including the tumor, skeletal 
 
muscle and adipose tissue) and not used for routine histopathological diagnosis will also 
be stored for future biomarker studies. 
 
6.10 
Pharmacodynamic assessments 
 
 
6.10.1 
Biomarker evaluation in tumor specimens 
 
 
Both baseline and post-treatment tumor specimens will be evaluated for modulation of 
biomarkers which could potentially indicate the molecular activity of the investigational 
treatments, or which could represent predictive markers of activity of such treatments. 
These will include: 
 
phospho-Akt: modulation of phospho-Akt constitutes the primary endpoint of the trial. 
Phospho-Akt levels should be determined in paraffin-embedded tissues by 
immunohistochemistry both at baseline and in the post-treatment surgical specimens. A 
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scoring system based on staining intensity x extension will be used to quantify the 
phospho-Akt levels. Staining intensity will be graded as undetectable (0), weak (1), 
medium (2), or strong (3). Staining extension will be graded as percentage of positive 
cells per square at x20 magnification. The final score will therefore range from 0 to 300. 
 
 
additional biomarkers: additional biomarkers in paraffin-embedded tumor specimens at 
baseline and after treatment will be evaluated depending on the availability of adequate 
amounts of tissues for such studies. The modulation of these biomarkers by the 
investigational treatments and their correlation with activity of the drugs will be analyzed 
in an exploratory fashion. The biomarkers proposed to be studied include (but are not 
restricted to): IGF-1R, phospho-IGF-1R, IGF-2R, IGF-1, IGF-2, IGFBP-3, EGFR, 
phospho-EGFR, survivin, Ki-67, caspase-3, HIF-1 alpha, CD31, MMP-2, MMP-9, 
phosphorylation status of multiple kinases (using antibody arrays), micro-RNA and 
messenger-RNA expression levels (using high-throughput microarray chips), high- 
throughput proteomic analysis, genomic analysis and other biomarkers that may emerge 
to be important related to the use of EGFR and/or IGF-1R-targeted therapy. 
Investigators evaluating the endpoints involving pharmacodynamic markers (e.g., 
phospho-Akt) will be blinded to the clinical data of the patients, as well as treatment 
received. 
 
 
6.10.2 
Biomarker evaluation in adipose tissue and skeletal 
muscle 
 
Because the most common and clinically relevant toxicity of IGF-1R inhibitors identified 
so far is hyperglycemia, the characterization of the molecular effects of IMC-A12 in key 
organs of intermediary metabolism may help elucidate the pathophysiology of impaired 
glucose handling in these patients, leading to the development of the most appropriate 
strategies for treatment of this adverse effect. Therefore, skeletal muscle and adipose 
tissue specimens obtained during resection of the HNSCC (i.e., after exposure to the 
investigational treatments) will be evaluated for the following biomarkers related to 
glucose metabolism (depending on the availability of adequate amounts of tissues for 
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such studies): insulin receptor, phosphorylated insulin receptor (phospho-tyrosine and 
phospho-serine) and its downstream effectors, insulin receptor substrate-1 (phospho- 
tyrosine and phospho-serine), glucose transporter-1, glucose transporter-4, hexokinase, 
PPAR-alpha, PPAR-gamma, phosphorylation status of multiple kinases (using antibody 
arrays), micro-RNA and messenger-RNA expression levels (using high-throughput 
microarray chips), high-throughput proteomic analysis, genomic analysis and other 
biomarkers that may emerge to be important for anti-IGF-1R therapy-induced toxicity. 
Correlation of these biomarkers with activity and toxicity of the study drugs will be 
analyzed in an exploratory fashion. 
 
6.10.3 
Blood-based biomarkers 
 
 
Blood will be obtained at baseline, before the second treatment with the study drug(s), 
before surgical resection, and within 30 days after surgery, preferably in the morning, 
after at least 12 hours of fasting. The blood samples will be stored for the evaluation of 
biomarkers indicative of, or predictive of activity and / or toxicity of the investigational 
agents. These may include (but are not restricted to): free and total IGF-1 and IGF-2, 
IGFBP-3, insulin, peptide C, free fatty acids, triglycerides, fructosamine, a panel of 59 
cytokine and angiogenic factors measured by available luminex multiplex beads kits 
(Bio-Plex 27-Plex & 23-Plex Kits [Bio-Rad, Hercules, CA] and Human CVD Biomarker 
Panel 1 kit [Linco Research, Inc., St, Charles, MOsa]), VEGF, solubleVEGFR-1, soluble 
VEGFR-2, osteopontin, high-throughput proteomic analysis, genomic analysis and other 
biomarkers that may emerge to be important for characterization of cetuximab and/or 
IMC-A12 activity and/or toxicity. Correlation of these biomarkers with efficacy and 
toxicity outcomes will be analyzed in an exploratory fashion. 
 
7 Required evaluations 
 
 
7.1 
Pre-treatment evaluations 
 
 
Pre-treatment evaluation will include screening (to determine patient eligibility), medical 
history, physical examination, vital signs, clinical laboratory tests, imaging studies as 
described in sections 6.2, 6.3, 6.4, 6.5 and 6.7, audiometric evaluation (as described in 
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section 6.8), as well as adverse events assessment (as described in section 8). These 
should be completed no later than 30 days prior to administration of the first dose of 
treatment. Additionally, a baseline tumor tissue specimen should be obtained as described 
in section 6.6. 
Results of pre-treatment evaluations must be reviewed by the principal investigator or 
his/her designee to ensure that all eligibility criteria have been satisfied prior to patient 
randomization. Written informed consent must be obtained prior to any study-specific 
screening evaluations and prior to receiving treatment. 
 
 
7.2 
Treatment period 
 
 
Medical history, physical examination, vital signs, clinical laboratory tests, and imaging 
studies (as described in sections 6.2, 6.3, 6.4, 6.5, and 6.7), as well as adverse events 
assessment (as described in section 8) will be obtained within 5 days prior to the second 
treatment. 
 
7.3 
End of therapy 
 
 
Vital signs and clinical laboratory tests (as described in sections 6.4 and 6.5) should be 
obtained preferably on the day of surgery, or within 2 days before surgery. 
 
7.4 
Follow-up 
 
 
One post-operative evaluation should be completed within 30 days after surgery. At this 
time, a medical history, physical examinational, vital signs (as described in sections 6.2, 
6.3, 6.4), adverse events assessment (as described in section 8), and optional blood-based 
biomarkers (as described in section 6.5) should be obtained. Alternatively, a telephone 
call to assess adverse events may substitute for a medical history, physical examination, 
and vital signs in the event the patient is not evaluated by the investigator or his/her 
designee within 30 days after surgery. Audiometric evaluation should be obtained within 
90 days after surgery in all patients who received at least one dose of IMC-A12 (as 
described in section 6.8). If toxicities related to the investigational drugs have not been 
resolved at the time of the post-operative evaluation, regular follow-ups are strongly 
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enforced with frequency to be determined by the investigator. After the end of therapy, 
patients should continue to be assessed by their primary physicians for long-term follow- 
up. Data on progression-free survival, and possible long-term toxicities will be 
retrospectively obtained through chart reviews. Patients (or their family members) might 
also be contacted (during clinic visits, by telephone, in writing, or electronic mail) to 
confirm or provide information on long-term follow-up. 
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7.5 
Study events table 
 
Procedure 
Pre-
Treatment Period
End of
Follow-Up
Treatment 
Therapy 
Evaluations 
(within 30 
(within 5 days 
(day of 
(within 30 
days before 
before second and 
surgery, 
days after 
first dose of 
third dose of 
preferably, or 
surgery) 
treatment) 
treatment) 
within 2 days 
before surgery)
Eligibility Assessments 
 
X1 
Informed Consent 
Inclusion/Exclusion Criteria 
X 
Medical History and Physical Examination 
X 
Pregnancy Test 
X 
Safety Assessments 
Medical History and Physical Examination2 
Vital   Signs   (blood   pressure,   heart   rate, 
temperature) 
 
Toxicity Assessments/Adverse Events 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X8 
X8 
 
X2 
Laboratory Tests 
Hematology Profile 
Serum Chemistry Profile 
 
X 
X 
 
X 
X 
 
X 
X 
Imaging studies 
 
CT Scan or MRI of the H&N 
 
X 
 
X4 
Audiometry 
X9 
X9 
Pharmacodynamic Assessments 
 
Tumor specimen biomarkers 
 
Skeletal muscle/adipose tissue biomarkers6 
Blood-based biomarkers3 
 
X5 
 
 
 
X 
 
 
 
 
 
X7 
 
X 
X 
X 
 
 
 
 
 
 
X 
1  Informed consent should be obtained prior to registering for trial, undergoing protocol-specific evaluations, or receiving 
treatment. 
2  Initial medical history should include past or current medical conditions, current medications, date of diagnosis, stage (using 
the American Joint Committee on Cancer Staging Manual, Sixth Edition or higher), pathological confirmation of HNSCC and 
tentative date of surgery (if available).  Any pre-existing toxicity should be documented and recorded as well. The physical 
examination will include an evaluation by pertinent body system, height (pretreatment only), weight, and body surface area 
(BSA), as well as ECOG performance status (pretreatment only) should be documented. 
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3 26 mL of blood (optional) will be collected and stored for additional studies of interest
4 May be obtained at any time-point between the last dose of the study drug(s) and the surgical procedure. However, 
preferably, scans will be performed the day before surgery. 
5 Baseline tumor tissue may be obtained more than 30 days prior to treatment initiation. 
6 Collection of skeletal muscle / adipose tissue is optional and will only be obtained if the patient has previously given consent 
and if the collection of these additional tissues is considered feasible (i.e., not associated with unreasonable risks) by the 
surgeon during the operative procedure. 
7 Blood-based biomarkers will be obtained only before the second dose of treatment. 
8 A telephone call to assess adverse events may substitute for a medical history, physical examination, and vital signs in the 
event the patient is not evaluated by the investigator or his/her designee within 30 days after surgery 
9 Patients randomized to receive treatment with IMC-A12 (i.e. Arm B and Arm C) are required to have an audiometric 
evaluation within 90 days before starting treatment with the study drug(s). For all patients who received at least 1 dose of 
IMC-A12, a repeat audiometric evaluation will be performed within 90 days after surgery. 
 
 
8 Adverse events assessment 
 
 
8.1 
Performing adverse events assessments 
 
 
The assessment of reported adverse events will be performed at least within 5 days before 
the second and, if applicable, third treatment course, and within 30 days after surgery. 
Adverse events will be classified according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 
 
8.2 
Importance of adverse event reporting 
 
 
Timely and complete reporting of safety information assists in identifying any untoward 
medical occurrence, thereby allowing: (1) protection of safety of study patients; (2) a 
greater  understanding  of  the  overall  safety  profile  of  the  investigational  products; 
(3) recognition of dose-related investigational product toxicity; (4) appropriate 
modification of study protocols; (5) improvements in study design or procedures; and 
(6) adherence to worldwide regulatory requirements. 
 
 
8.3 
Adverse events definition 
 
 
8.3.1 Adverse event 
 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
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finding, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational or marketed) product, whether or not considered related to the 
medicinal (investigational or marketed) product. Planned medical interventions (e.g., 
planned surgical resection) will not be considered an adverse event. For the purpose of 
this study, adverse events that in the opinion of the treating investigator are related to 
planned surgical procedure (e.g., usual pain, usual bleeding, intra- or post-operative 
electrolyte imbalances and other clinically insignificant laboratory abnormalities) will not 
be captured and/or reported. 
 
8.3.2 Serious adverse event 
 
 
Serious Adverse Event Reporting (SAE) Language for M. D. Anderson-sponsored 
IND Protocols 
 
An adverse event or suspected adverse reaction is considered 
 if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 
 Deat
h 
 
 A life-threatening adverse drug experience  any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
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 Important medical events as defined above may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
 
 All events except events that in the opinion of the treating physician are related to 
planned surgical procedure occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy on Reporting Serious Adverse 
 Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
 
 The MDACC 
 SAE Report Form for Prompt Report
 will be used for 
reporting to the IND Office. 
 
 
 Serious adverse events will be captured from the time the patient signs consent until 
30 days after the last dose of drug. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, progression 
of the event has stabilized, or there has been acceptable resolution of the event. 
 
 
 Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may include 
the development of a secondary malignancy. 
 
 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
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It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the spon
 guidelines, and Institutional Review 
Board policy. 
 
SAE Investigator Communication of with Supporting Companies: 
 
Adverse events classified as 
s  must be recorded on the MDACC Internal Adverse 
Event Reporting Form and reported to the Sponsor (Safety Project Manager ORE&RM) 
and to Eli Lilly & Co. to comply with regulatory requirements. These SAEs will include 
deaths, regardless of their causal relationship to investigational product. All SAEs must 
be reported using the MDACC Internal Adverse Event Reporting Form. To the extent 
possible, the descriptive terminology and other SAE attributes entered on the MDACC 
Internal Adverse Event Reporting Form should approximate similar information in the 
s medical record. Study site personnel must alert Lilly or its designee of any 
serious adverse event (SAE) within 24 hours of investigator awareness of the event via a 
Sponsor-approved method. Alerts issued via telephone are to be immediately followed 
with official notification on study-specific MDACC Internal Adverse Event Reporting 
Form. The completed MDACC Internal Adverse Event Reporting Form must be faxed to 
 Global Product Safety Fax Number for all SAEs at 866-644-1697 or 317-453- 
3402 within 24 hours of the study site personnel s initial notification/awareness of the 
event. Duly authorized study site personnel may sign completed forms; however, it is 
recommended that the investigator sign each final SAE report. 
 
 
 
8.4 
Assessment of causality 
 
 
The following categories and definitions for assessing the causal relationship of an event 
to the investigational product(s) are provided as a guide to be used for every event 
reported in Eli Lilly & Co. clinical trials: 
 
 
 
Definite/Certain: 
there is a reasonable causal relationship between the 
investigational  product(s)  and  the  AE;  the  event  responds  to  withdrawal  of  the 
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investigational product(s) (de-challenge) and recurs with re-challenge when clinically 
feasible. 
 
 
Probable:   there is a reasonable causal relationship between the investigational 
product(s) and the AE; the event responds to de-challenge; re-challenge is not required. 
 
 
Possible: 
there is reasonable causal relationship between the investigational 
product(s) and the AE; de-challenge information is lacking or unclear. 
 
 
Not Likely:   There is a temporal relationship to study drug administration, but 
there is not a reasonable causal relationship between the study drug and the AE. 
 
 
Unrelated: there is not a temporal relationship to the investigational product(s) 
administration (too early, late, or the investigational product was not taken) or there is a 
reasonable causal relationship between another drug, concurrent disease, or circumstance 
and the AE. 
 
8.5 
Collection of safety information 
 
 
Pre-existing toxicities will be collected and noted on p
 medical record. 
 
 
 
Additionally, collection of AE information will be performed from the time the patient 
receives the initial infusion of the study drug(s), and must continue throughout the study 
until 30 days after the last dose, unless specified otherwise in the protocol. This includes 
pre-existing conditions or symptoms that worsened during the study, or whose 
relationship to the investigational product changed, but does not include pre-planned 
hospitalizations or procedures for pre-existing conditions. In addition, the investigator 
should notify Eli Lilly & Co. of any SAE or outcome that may occur after this time 
period that he/she believes to be related to IMC-A12 and/or cetuximab. An AE report 
must contain the following four basic elements: (1) an identifiable patient; (2) a suspect 
medicinal product; (3) an identifiable reporting source; and (4) an identifiable event or 
outcome. All identified AEs must be recorded and described in 
 medical record 
If known, the diagnosis of the underlying illness or disorder should be recorded in 
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addition to the presenting symptoms. The following information should be captured for 
all AEs: the date of the onset and resolution; the severity of the event as determined by 
PI or study collaborator (see definitions in NCI-CTCAE, Version 3.0); the 
 
opinion of the relationship of the event to the investigational drug/s (certainly/definitely, 
probably, possibly, unlikely, or not related); the treatment required for the AE; 
information regarding resolution/outcome; and if the AE is serious, a clear identification 
of the seriousness outcome. 
 
 
8.6 
Reporting Product Complaints 
 
 
ImClone collects product complaints on study drugs used in clinical trials in order to 
ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements. 
 
 
Complaints related to unblinded comparator drugs or concomitant drugs are reported 
directly to the manufacturers of those drugs in accordance with the package insert. 
The investigator or his/her designee is responsible for handling the following aspects of 
the product complaint process in accordance with the instructions provided for this study: 
 Recording a complete description of the product complaint reported and any 
associated AEs using the study-specific product complaint form provided by 
ImClone for this purpose 
 E-mailing the completed product complaint form within 24 hours to ImClone 
or its designee as listed on the product complaint form 
If the investigator is asked to return the product for investigation, he/she will return a 
copy of the product complaint form with the product. 
 
 
8.7 
Expectedness 
 
 
The IMC-A12 
 Brochure will be updated periodically to include new and 
relevant safety information. Until such time that an AE becomes identified in the 
 Brochure, it should be considered unexpected, regardless of whether the 
AE has been reported in a previous IND Safety Report. 
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8.8 
Clinical significance 
 
 
8.8.1 Pregnancy 
 
 
Women of childbearing potential (WOCBP) and fertile men with partners of childbearing 
potential must be using an adequate method of contraception to avoid pregnancy 
throughout the study and for up to 4 weeks after the study in such a manner that the risk 
of pregnancy is minimized. 
 
 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea 12 consecutive months 
or women on hormone replacement therapy with documented serum follicle stimulating 
hormone level 35 mIU/mL). Even women who are using oral, implanted, or injectable 
contraceptive hormones or mechanical products, such as an intrauterine device or barrier 
methods (e.g., diaphragm, condoms, spermicides), to prevent pregnancy, are practicing 
abstinence, or whose partner is sterile (e.g., vasectomy), should be considered to be of 
childbearing potential. 
 
 
WOCBP must have a negative serum or urine pregnancy test at baseline. 
 
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in a manner such that the risk of failure is minimized. 
 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. This discussion will be documented on the informed consent form required 
for study participation. 
 
 
In addition, all WOCBP or fertile men with partners of childbearing potential should be 
instructed to contact the investigator immediately if they suspect they or their partner 
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might be pregnant (eg, missed or late menstrual period) at any time during study 
participation. 
 
 
If following initiation of study treatment, it is subsequently discovered that a trial patient 
is pregnant or may have been pregnant at the time of exposure to IMC-A12 and/or 
cetuximab, including during at least 6 half-lives after product administration, IMC-A12 
and cetuximab will be permanently discontinued in an appropriate manner. 
 
 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the patient unless contraindicated by pregnancy (e.g., x-ray studies). Other 
appropriate pregnancy follow-up procedures should be considered if indicated. In 
addition, the investigator must report to Eli Lilly & Co. follow-up information regarding 
the course of the pregnancy, including perinatal and neonatal outcome. Infants should be 
followed for a minimum of 8 weeks. 
 
 
8.9 
Clinical laboratory adverse event 
 
 
All laboratory  test values  captured  as  part of the study  should be  recorded on  the 
appropriate source documents. 
 
Abnormal  laboratory  tests  will  be  considered  clinically  significant  and  will  be 
documented in the adverse event record only if any of the following are true: 
 
 Results in patient withdrawal from study participation 
 
 Requires treatment and/or medical intervention (such as a treatment hold or 
dose reduction) 
 Has clinical manifestations which are considered by the investigator as 
medically important 
 
 
 
It is expected that wherever possible, the clinical, rather than the laboratory term, will 
be used by the reporting investigator (e.g., 
m
 is preferable to 
 low hemoglobin 
 unless otherwise specified in this protocol. 
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8.10 Handling of serious adverse events 
 
 
In addition to the information provided above, adverse events classified as 
 must 
be recorded on the MDACC Internal Adverse Event Reporting Form and reported to the 
Sponsor (Safety Project Manager ORE&RM) and to Eli Lilly & Co. to comply with 
regulatory requirements. These SAEs will include deaths, regardless of their causal 
relationship to investigational product. All SAEs must be reported using the MDACC 
Internal Adverse Event Reporting Form. To the extent possible, the descriptive 
terminology and other SAE attributes entered on the MDACC Internal Adverse Event 
Reporting Form should approximate similar information in the 
 medical record. 
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) 
within 24 hours of investigator awareness of the event via a Sponsor-approved method. 
Alerts issued via telephone are to be immediately followed with official notification on 
study-specific MDACC Internal Adverse Event Reporting Form. The completed  
MDACC Internal Adverse Event Reporting Form must be faxed to 
 Global Product 
Safety Fax Number for all SAEs for Cetuximab and IMC-A12 at 866-644-1697 or 317- 
453-3402 within 24 hours of the study site pers
 initial notification/awareness of  
the event. Duly authorized study site personnel may sign completed forms; however, it is 
recommended that the investigator sign each final SAE report. 
 
 
Collection of complete information concerning SAEs is extremely important. Thus, 
follow-up information that becomes available as the SAE evolves, as well as supporting 
documentation (e.g., hospital discharge summaries, additional lab and test results, 
autopsy reports, etc), should be collected subsequently, if not available at the time of the 
initial report, and immediately sent to Eli Lilly & Co. using the same procedure as the 
initial SAE report. 
 
 
For ease of analysis, worldwide standardization, and regulatory reporting, Eli Lilly & Co. 
will code each reported adverse event or symptom to its corresponding preferred term  
and body system/organ class in the Medical Dictionary for Regulatory Activities version 
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adopted for the study. The NCI-CTCAE, Version 3.0, will serve as the reference 
document for determining/grading the severity or toxicity grade of all adverse events and 
other symptoms, with the exception of grade 4 infusion reaction (see Section 9.1.1 and 
9.2.1). For AEs whose toxicity grading is not contained within the NCI-CTCAE Version 
3.0 toxicity criteria, the principal investigator will be responsible for assessing severity 
based on the intensity of the event as it presented. Severity will be graded as mild (grade 
1), moderate (grade 2), severe (grade 3), or very severe (life threatening  grade 4). Eli 
Lilly & Co. recommends that investigators and study site personnel enter the adverse 
event term on the 
 medical record and MDACC Internal Adverse Event 
Reporting Form as accurately as possible, regardless of the NCI-CTCAE Version 3.0 
terminology for the event. The NCI-CTCAE Version 3.0 should only be used to assign 
the intensity/severity of the event as described above. 
9 Treatment emergent adverse events 
 
 
Patients will be closely monitored for treatment-related adverse events, especially 
infusion reactions. Adverse event monitoring will occur on a continuous basis for the 
duration that patients are on study therapy. In addition to the planned evaluations during 
follow-up visits, patients will be instructed to call their physician to report any adverse 
events between visits. 
 
 
9.1 
Cetuximab 
 
 
The two significant adverse events occurring most commonly in cetuximab-treated 
patients are infusion reactions and acneiform rash. Other adverse events associated with 
cetuximab include asthenia, nausea, vomiting, diarrhea, hypomagnesemia, and fever. 
 
 
9.1.1 Cetuximab infusion reactions 
 
 
Infusion reactions may occur during a cetuximab infusion or may be delayed until any 
time after the infusion. Infusion reactions will be defined according to the NCI-CTCAE, 
Version 3.0, definition of allergic reaction/hypersensitivity, as follows: 
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 NCI-CTCAE Grade 1: transient flushing or rash, drug fever <38oC 
 
 
 Treatment: decrease the cetuximab infusion rate by 50% and monitor closely 
for any worsening. 
 
 NCI-CTCAE Grade 2: rash, flushing, urticaria, dyspnea, drug fever 38oC 
 
 
 Treatment: stop the cetuximab infusion, administer appropriate therapy, and 
then restart the cetuximab infusion with a decrease in the infusion rate of 50% 
and monitor closely for any worsening. 
 
 NCI-CTCAE Grade 1 or 2 Infusion Reaction manifesting only as a delayed drug 
fever (starting after the end of cetuximab infusion) 
 
 Treatment: maintain the cetuximab dose and infusion rate and consider 
administering acetaminophen or cyclooxygenase-2 inhibitors (at the dose and 
schedule of the investigator s discretion) prior to the subsequent cetuximab 
infusion, if not otherwise contraindicated in the patient. 
 
 NCI-CTCAE Grade 3 or 4 Infusion Reaction 
 
 
 A grade 3 reaction consists of: symptomatic bronchospasm with or without 
urticaria, 
requiring 
parenteral 
medication(s); 
allergy-related 
edema/angioedema; hypotension. 
 
 A grade 4 reaction (anaphylaxis) is a life-threatening event characterized by 
rapid onset (often within minutes) of airway obstruction (bronchospasm, 
stridor, hoarseness), urticaria, and/or hypotension. 
 
Treatment of a Grade 3 or 4 Infusion Reaction: 
 
 
 Stop the cetuximab infusion immediately and disconnect infusion tubing from the 
patient. 
 
 Administer 
epinephrine, 
bronchodilators, 
antihistamines, 
glucocorticoids, 
intravenous fluids, vasopressor agents, oxygen, etc, as medically indicated. 
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Following a grade 3 or 4 infusion reaction, the patient is to receive no further cetuximab 
or IMC-A12 treatment. In the event of a grade 1 or 2 infusion reaction, the cetuximab 
infusion rate should be permanently reduced by 50%. 
If there is any question as to whether an observed reaction is an infusion reaction of 
grades 1 to 4, the Eli Lilly & Co. Medical Monitor should be contacted immediately to 
discuss and grade the reaction. 
 
 
9.1.2 Acneiform rash 
 
 
The severity of acneiform rash is graded according to the NCI-CTCAE, Version 3.0, 
definition of rash/desquamation. 
 
 
Based on emerging data, there appears to be a correlation between acneiform rash and 
various efficacy outcomes.67-71  Therefore, if a patient experiences a grade 1 - 3 
acneiform rash, cetuximab therapy may continue without dose modification or delay. 
The investigator could consider concomitant treatment with topical and/or oral 
antibiotics. 
 
 
9.1.3 Hematologic toxicities 
 
 
Hematologic toxicity is not an expected toxicity associated with cetuximab. 
 
 
 
9.1.4 Nonhematologic toxicities 
 
 
Guidelines for cetuximab dose modification related to nonhematologic toxicity may be 
found in Section 10.1. 
 
 
9.1.5 Electrolyte monitoring 
 
 
In 244 patients evaluated in ongoing, controlled clinical trials, the incidence of 
hypomagnesemia, both overall and severe (NCI-CTCAE Version 3.0 grades 3 and 4), 
was increased in patients receiving cetuximab alone or in combination with 
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chemotherapy as compared to those receiving best supportive care or chemotherapy 
alone. Approximately one-half of these patients receiving cetuximab experienced 
hypomagnesemia and 10-15% experienced severe hypomagnesemia. The onset of 
electrolyte abnormalities has been reported to occur from days to months after initiation 
of cetuximab. Electrolyte repletion was necessary in some patients and in severe cases, 
intravenous replacement was required. The time to resolution of electrolyte 
abnormalities is not well known. 
 
 
9.2 
IMC-A12 
 
 
Adverse events of concern, which may or may not be associated with IMC-A12 therapy, 
include infusion reactions, hyperglycemia, and peri-operative complications. 
 
 
9.2.1 IMC-A12 infusion reactions 
 
 
IMC-A12 infusion reactions will be defined according to the NCI-CTCAE Version 3.0 
definition of allergic reaction/hypersensitivity, as detailed below. Consistent with usual 
medical practice, selected parenteral medications may be utilized for grade 2 
allergic/hypersensitivity reaction as detailed below. The Eli Lilly & Co. Medical Monitor 
should be contacted immediately if questions arise concerning the grade of the reaction. 
 
 
 
Grade 1: transient flushing or rash, drug fever <38°C 
 
 
 
Treatment: Slow infusion rate by 50% and monitor patient for worsening of 
condition. 
 
 
Grade 2: rash, flushing, urticaria, dyspnea, drug fever 38°C 
 
 
 
Treatment: Stop the infusion, administer diphenhydramine hydrochloride 50 
mg i.v., acetaminophen 650 mg orally for fever, and oxygen. Resume infusion at 50% of 
the prior rate once the infusion reaction has resolved or decreased to grade 1; infusion 
duration should not exceed 2 hours. Monitor patient for worsening condition, and 
premedicate with diphenhydramine hydrochloride 50 mg i.v. for subsequent infusions. 
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For a second grade 1 or 2 infusion reaction, administer dexamethasone 
10 mg i.v.; for subsequent infusions, premedicate with diphenhydramine hydrochloride 
50 mg i.v., acetaminophen 650 mg orally, and dexamethasone 10 mg i.v. (or equivalent). 
 
 
Grade 3: symptomatic bronchospasm, requiring parenteral medication(s), with or 
without urticaria; allergy-related edema/angioedema, hypotension 
 
 
Treatment: Stop the infusion and disconnect infusion tubing from the 
patient. Administer diphenhydramine hydrochloride 50 mg i.v., dexamethasone 10 mg 
i.v. (or equivalent), bronchodilators for bronchospasms, and other medications/treatment 
as medically indicated. Patients who have a grade 3 infusion reaction will not receive 
further IMC-A12 or cetuximab treatment, but will continue to be followed on the protocol. 
 
 
Grade 4: anaphylaxis (a life-threatening event characterized by the rapid onset 
[often within minutes] of airway obstruction [bronchospasm, stridor, hoarseness], 
urticaria, and/or hypotension) 
 
 
Treatment: stop the infusion and disconnect the infusion tubing from the 
patient. Administer diphenhydramine hydrochloride 50 mg i.v., dexamethasone 10 mg 
i.v. (or equivalent), and other medications/treatment as medically indicated. Epinephrine 
or bronchodilators should be administered as indicated. Hospital admission for 
observation may be indicated. Patients who have a grade 4 infusion reaction will not 
receive further IMC-A12 or cetuximab treatment, but will continue to be followed on the 
protocol. 
 
9.2.2 Hyperglycemia (Diabetes) 
 
 
For the assessment of hyperglycemia (diabetes), both the NCI-CTCAE Version 3.0 
Endocrine (pancreatic endocrine: glucose intolerance / diabetes) and Metabolic / 
Laboratory (glucose, serum-high / hyperglycemia) terms should be used. 
If hyperglycemia/diabetes occurs during treatment with IMC-A12, treatment is dependent 
upon symptom severity. For grade 1 or 2 hyperglycemia (fasting glucose < 250 mg/dL), 
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IMC-A12 treatment should continue; oral agents or insulin may be used as clinically 
indicated. 
 
 
For grade 3 hyperglycemia (fasting glucose 250-500 mg/dL), IMC-A12 treatment may 
continue if the patient is asymptomatic and glucose < 300mg/dL; insulin may be initiated. 
IMC-A12 and cetuximab should be discontinued for grade 3 hyperglycemia if there are 
symptoms interfering with ADL or if glucose is  300mg/dL 
For grade 4 hyperglycemia (fasting glucose >500 mg/dL), IMC-A12 and cetuximab 
therapy should be discontinued. 
 
 
9.2.3 Peri-operative complications 
 
Cetuximab has not been studied pre-operatively in patients with HNSCC. However, 
preliminary reports of two studies of cetuximab in combination with chemotherapy prior 
to liver resection in patients with metastatic colorectal cancer did not raise post-operative 
toxicity concerns.72,73 IMC-A12 has never been studied in the pre-operative setting. 
Although there is no pre-clinical data that suggests an increased incidence of peri- 
operative complications with IMC-A12, patients will be closely monitored for these 
adverse events. In case a higher than expected incidence of peri-operative complications 
is seen, considerations will be given to terminating the study, or modifying the protocol, 
so as to increase the interval between the last dose of the study drug(s) and the surgical 
procedure. 
 
 
10 Dose modifications and study completion 
 
 
10.1 Dose modifications 
 
 
Dose reductions of either cetuximab or IMC-A12 are not permitted. However, treatment 
with both drugs may be delayed according to the following guidelines: 
 
For grade 1, no dose delay is required. 
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Patients with any grade 2 adverse event may, at the investi
s discretion, 
continue to receive study drugs(s) per protocol provided that the event does not pose a 
serious health risk or is easily treated. 
 
 
For a grade 3 clinically significant toxicity (excluding fatigue, skin rash and 
hyperglycemia/diabetes) not adequately controlled with appropriate supportive care, 
discontinue treatment. For grade 3 toxicity not considered to be clinically significant by 
the investigator, withhold dose until toxicity is  grade 1 or has returned to pretreatment 
baseline, then resume treatment with the protocol-planned dose. 
 
 
For a grade 4 possible, probable or definite treatment-related toxicity, discontinue 
treatment. 
 
The above are considered general guidelines. The investigator should use his or her best 
judgment when determining treatment interruptions. For example, some grade 2 non- 
hematologic toxicities may require treatment delays, and some grade 3 or 4 organ 
toxicities (e.g., hepatic, renal, cardiac, central nervous system) may require a permanent 
discontinuation from the investigational treatment. 
 
 
If cetuximab administration is interrupted, no re-bolus dose should be administered at the 
time of treatment resumption (i.e., subsequent dose of cetuximab will be 250 mg/m2). 
In arm C, if cetuximab treatment needs to be delayed or discontinued due to toxicity, so 
will treatment with A-12. Similarly, in arm C, if IMC-A12 treatment needs to be delayed 
or discontinued due to toxicity, so will treatment with cetuximab. 
 
 
10.2 Removal of patients from therapy 
 
 
A patient should be withdrawn from therapy if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient. If the patient does not return for a 
scheduled visit, every effort should be made to contact the patient; in any circumstance, 
patient outcome should be documented whenever possible. 
 
 
A patient should be removed from therapy if: 
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Tumor progression occurs, and is confirmed by radiographic progression (not 
solely based on clinical and/or tumor marker suggestions of progression, unless global 
deterioration of health status (symptomatic deterioration) requiring discontinuation 
occurs); 
 
 
A grade 4 possible, probable or definite treatment-related toxicity occurs; 
 
 
 
There is toxicity requiring more than 7 days delay of the second treatment dose; 
 
 
 
Other unacceptable toxicity necessitates cessation of treatment; 
 
 
 
The physician feels it is in the best interest of the patient to stop the treatment; 
 
 
 
The patient requests to be removed from the study; 
 
 
 
The patient is lost to follow-up; 
 
 
 
The patient becomes pregnant, or 
 
 
 
The sponsor (MDACC), supporting drug companies (Eli Lilly & Co. and ImClone 
Systems) or investigator terminates the study. 
 
10.3 Study completion 
 
 
This study will be considered complete when one or more of the following conditions is 
met: 
 
All patients have completed all required study visits. 
 
 
 
All patients have discontinued from the study. 
 
 
 
The IRB, Eli Lilly & Co., or ImClone Systems discontinues the study because of 
safety considerations. 
 
Long-term efficacy and toxicity data may continue to be collected after the study has 
been completed. 
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11 Criteria for tumor response evaluation 
 
 
11.1 Clinical response 
 
 
Patients will be evaluated for response according to the Response Evaluation Criteria in 
Solid Tumors (RECIST) guidelines.74  Additionally, waterfall plots will be used to depict 
changes in post-treatment tumor size from baseline. There will be no confirmatory scans 
after a response has been documented, since patients are expected to have the tumor 
resected shortly after the imaging studies. 
 
 
11.1.1 Baseline tumor assessment 
 
 
The baseline tumor burden (unidimensionally-measurable and nonmeasurable disease) 
will be assessed as closely as possible to the beginning of treatment. The investigator 
will prospectively identify the lesions to be followed to evaluate the 
 response to 
therapy (see Section 11.1.4, Definitions of Response). 
 
 
 
 
11.1.2 Method of tumor response assessment 
 
 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers according to RECIST guidelines and documented on 
 medical record. 
Tumor measurements will be done by PI or collaborator. 
 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and at reassessment during treatment. 
Imaging-based evaluation will be preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. Lesions 
evaluated clinically will only be considered measurable when they are superficial (eg, 
skin nodules, palpable lymph nodes). CT and MRI will be considered the best currently 
available and reproducible methods to measure target lesions (as defined in Section 
11.1.4). 
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11.1.3 Definitions 
 
 
Measurable lesions: 
 
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as > 2 cm with conventional techniques or as > 1 cm with spiral CT scan. 
A lesion located in a previously irradiated area will be considered measurable only if 
there has been a documented increase in its size subsequent to irradiation but prior to 
study entry. 
 
 
Non-measurable lesions: 
 
All other lesions including small lesions (longest diameter < 2 cm with conventional 
techniques or < 1 cm with spiral CT scan) and truly non-measurable lesions.  
Lesions considered to be truly non-measurable include the following: bone lesions; 
ascites; pleural/pericardial effusion; inflammatory breast disease; lymphangitis 
cutis/pulmonis; abdominal masses that are not confirmed and followed by imaging 
techniques; and cystic lesions.. 
 
 
11.1.4 
Definitions of response 
 
 
Overall tumor response, as defined in the Criteria for Overall Response Table, will be 
based on an integration of the evaluation of target, non-target, and new lesions, as 
described below: 
 
 
Target lesions: 
 
Target lesions are all measurable lesions up to a maximum of five lesions per organ and 
10 lesions in total, representative of all involved organs. Target lesions should be 
selected on the basis of their size (those with the longest diameters) and their suitability 
for accurate repeated measurements. 
 
 
The sum of the longest diameters of all target lesions will be calculated at baseline and 
reported as the baseline sum longest diameter (LD). This baseline sum LD will be used 
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as the reference by which to characterize the objective tumor response. For lesions 
measurable in two or three dimensions, always report the longest diameter at the time of 
each assessment. 
 
 
Complete Response (CR): The disappearance of all target lesions. 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of 
target lesions, taking as reference the baseline sum LD. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify progressive disease, taking as reference the smallest sum LD 
since the treatment started. 
 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum longest diameter recorded since the treatment started 
or the appearance of one or more new lesion(s). 
 
 
Non-target lesions 
 
All lesions (or sites of disease) not characterized as target lesions, both measurable and 
nonmeasurable, will be identified as non-target lesions and will be recorded at baseline. 
Measurements will not be required, and these lesions will be followed as 
n  or 
.  
 
 
Complete Response (CR): The disappearance of all non-target lesions and the 
normalization of the tumor marker level (if tumor markers are measured and are initially 
above the upper limit of normal, those must normalize for a patient to be considered in 
complete clinical response). 
 
 
Stable Disease (SD): The persistence of one or more non-target lesions and/or the 
maintenance of the tumor marker level above normal limits. 
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Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Because the clear isolated 
progression of non-target lesions is exceptional, in such circumstances, the opinion of the 
treating physician should prevail. 
 
 
11.1.5 Determination of overall clinical response 
 
 
Each response parameter (target, non-target, and new lesions) will be reported 
independently at each radiologic read. The investigator will make a determination of 
overall response based on the evaluation of target, non-target, and new lesions, as shown 
in the Criteria for Overall Response Table below. 
 
 
Criteria for Overall Response Table 
 
 
Target Lesions 
Non-Target 
 
Lesions 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
11.2 Histopathological changes 
 
 
Changes in histologic parameters in the post-treatment surgical specimen will be 
evaluated both in the tumor and in the host tissue, using a scoring system of 0, 1, 2, and 3 
(0, 0-25%, 26-50%, more than 50% of the tissue showing the feature, respectively), or a 
binary system (positive or negative). 
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11.2.1 Tumor tissue 
 
 
The features to be evaluated in the tumor tissue include: necrosis, dyskeratosis, 
keratinization, and apoptosis (all using the 0-3 scoring system). 
 
 
11.2.2 Host tissue 
 
 
The features to be evaluated in the host tissue include: fibrosis (using the 0-3 scoring 
system), immune response (binary system, accompanied by a description of the types of 
inflammatory cells involved), granulomatous inflammation (binary system), dystrophic 
features (binary system), and angiogenesis (binary system classifying as high or low). 
 
12 Planned statistical method 
 
 
12.1 Primary endpoint 
 
 
The primary endpoint of this trial is the modulation of phospho-Akt in the post-treatment, 
surgical tumor specimen as compared to the baseline tumor specimen in the different 
treatment groups. Levels of phospho-Akt will be determined by IHC as described in 
section 6.9.1. 
12.2 Secondary endpoints 
 
 
12.2.1 Tissue- and blood-based biomarkers 
 
 
Since there is no standard for determination of molecular activity of either cetuximab or 
IMC-A12, biomarkers in tumor tissue specimens and blood will be evaluated in an 
exploratory fashion so as to identify changes from baseline and differences between the 
two study arms and correlate them with other efficacy and toxicity outcomes. Biomarkers 
involved in intermediary metabolism will be evaluated in the blood and in the post- 
treatment specimens of skeletal muscle and adipose tissue in an exploratory fashion so as 
to identify differences between the two study arms and correlate them with toxicity 
outcomes. 
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Blood-based biomarkers will be evaluated in Dr. Hai 
 laboratory. Tumor tissue- 
based biomarkers will be evaluated in the laboratories of Drs. Adel K. El-Naggar , Ho- 
Young Lee and Jeffrey Myers. 
 
 
Tumor-tissue based biomarkers will include (but are not restricted to): IGF-1R, phospho- 
IGF-1R, IGF-2R, IGF-1, IGF-2, IGFBP-3, EGFR, phospho-EGFR, survivin, Ki-67, 
caspase-3, HIF-1 alpha, CD31, MMP-2, MMP-9, phosphorylation status of multiple 
kinases (using antibody arrays), micro-RNA and messenger-RNA expression levels 
(using high-throughput microarray chips), high-throughput proteomic analysis, genomic 
analysis and other biomarkers that may emerge to be important related to the use of 
EGFR and/or IGF-1R-targeted therapy. 
 
 
Skeletal muscle and adipose tissue-based biomarkers will include (but are not restricted 
to): insulin receptor, phosphorylated insulin receptor (phospho-tyrosine and phospho- 
serine), insulin receptor substrate-1 (phospho-tyrosine and phospho-serine) and its 
downstream effectors, glucose transporter-1, glucose transporter-4, hexokinase, PPAR- 
alpha, PPAR-gamma, phosphorylation status of multiple kinases (using antibody arrays), 
micro-RNA and messenger-RNA expression levels (using high-throughput microarray 
chips), high-throughput proteomic analysis, genomic analysis and other biomarkers that 
may emerge to be important for anti-IGF-1R therapy-induced toxicity. 
 
 
Blood-based biomarkers will include (but are not restricted to): free and total IGF-1 and 
IGF-2, IGFBP-3, insulin, peptide C, free fatty acids, triglycerides, fructosamine, a panel 
of 59 cytokine and angiogenic factors measured by available luminex multiplex beads  
kits (Bio-Plex 27-Plex & 23-Plex Kits [Bio-Rad, Hercules, CA] and Human CVD 
Biomarker Panel 1 kit [Linco Research, Inc., St, Charles, MO]), VEGF, solubleVEGFR- 
1, soluble VEGFR-2, osteopontin, high-throughput proteomic analysis, genomic analysis 
and other biomarkers that may emerge to be important for characterization of cetuximab 
and/or IMC-A12 activity and/or toxicity. 
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12.2.2 Objective response to treatment 
 
 
RECIST guidelines and waterfall plots will be used to describe the objective response to 
treatment in each arm. 
 
 
12.2.3 Histopathological changes after treatment 
 
 
Tumor tissue changes: necrosis, dyskeratosis, keratinization, and apoptosis 
 
Host tissue changes: fibrosis, immune response, granulomatous inflammation, dystrophic 
features, and angiogenesis. 
 
 
12.2.4 Safety 
 
 
The toxicity associated with each treatment arm will be observed and characterized; 
toxicity will be reported by type, frequency, and severity, as determined in section 8. 
 
 
12.3 Analysis population 
 
 
Analysis of the primary endpoint will be performed only in the evaluable population. 
Toxicity endpoints will be analyzed in the safety population. 
Populations: 
 
 
Evaluable population: will comprise all randomized patients who receive at least 
one dose of the study drug(s) in this trial, based on the arm to which they were randomized. 
Additionally, the last treatment dose should have been administered within 10 days of 
the surgical resection. The evaluable population will only include patients whose both 
baseline and post-treatment tumor tissue samples are successfully analyzed for phospho-
Akt levels. The reasons for non-evaluability in each arm will be assessed, at the time of 
the final analysis. 
 
 
Safety  population: 
will include all patients who received any dose of an 
investigational product. The patients will be analyzed for product safety as part of the 
treatment actually received, regardless of which treatment they were randomized to 
receive. 
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For the studies involving assessment of intermediary metabolism parameters, arms B and 
C may be combined and compared / contrasted to arm A. 
 
12.4 Sample size 
 
 
The number of patients planned to be enrolled in this study is 60 (20 per arm). The 
sample size will provide 90% power to detect the modulation between phospho-Akt 
levels between any two of the three groups with a 5% two-sided type I error rate 
(applying Bonf
 correction for multiple comparisons). After the samples have been 
analyzed for the primary endpoint, additional subjects may be enrolled to the study so 
that at least 18 evaluable patients (based on the aforementioned definition of evaluable 
population) are treated in each arm. 
 
The sample size calculation is based on the following assumptions: (1) the standard 
deviation (SD) of phospho-Akt levels will be 68 arbitrary units in both arms (this value is 
derived from the standard deviation of phospho-Akt observed in 106 samples of 
squamous cell carcinomas of the lung using the same IHC assay, personal 
communication, Dr. I. I. Wistuba, Houston, Texas). (2) The difference in means between 
arms will be equal to 1.5 SD. Since this trial is the first of its kind, the estimated 
treatment effect is somewhat arbitrary. However, in 106 squamous cell carcinomas of the 
lung, the median phospho-Akt score was 200 arbitrary units (personal communication, 
Dr. I. I. Wistuba, Houston, Texas), which would theoretically allow for detection of a 
possible 1.5 SD treatment-induced modulation; and (3) the distribution of phospho-Akt 
levels is approximately normal. Under these assumptions, the probability of a single 
reduction in one arm being greater than a single reduction in one of the other two arms is 
0.856, and consequently the Wilcoxon test has 90% power with 18 evaluable subjects per 
arm. Allowing for a small fraction of inevaluable patients yields an N of 20 per arm. 
 
12.5 Statistical analysis 
 
 
Modulation of phospho-Akt (difference in IHC score between the surgical specimen and 
the baseline biopsy) and other biomarkers will be compared between any two of the three 
treatment arms with the use of Wilcoxon rank sum test. Further evaluations will adjust 
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comparisons of follow-up marker values for baseline values, when available, using analysis 
of covariance. Prior to analysis by parametric methods (such as analysis of covariance), 
we will assess the data for the need for transformation to normality, transforming where 
appropriate. We will use repeated measures analysis of variance to analyze endpoints that 
are observed at multiple time points (e.g. serum glucose). Spearm
 rank correlation 
test will be used to investigate the relationship between different biomarkers and 
between biomarkers and toxicity. Correlations of categorical variables will be assessed 
by 
 exact test. A type I error rate of 0.05 (two-sided test) will be used for all 
comparisons. 
 
12.6 Interim analysis 
 
 
12.6.1 
Interim efficacy analysis 
 
 
No formal interim analysis of efficacy is planned. 
 
 
 
12.6.2 
Interim safety analysis 
 
 
The combination of cetuximab and IMC-A12 has not been extensively assessed in human 
subjects. Because of the different anticancer mechanisms and non-overlapping clinical 
toxicities of these agents, it is not anticipated that the toxicity of this combination therapy 
will significantly exceed that observed with IMC-A12 or cetuximab monotherapy or 
present an undue risk to patients. Additionally, the combination of cetuximab and IMC- 
A12 was not associated with enhanced toxicity in preclinical in vivo studies.  
Nonetheless, the potential for unforeseen or additional toxicity exists with any novel 
combination. Hence, as added precautions, in the event that new safety signals are 
detected, or the incidence of serious adverse events exceeds that expected of the 
component drugs within the combination therapy, consideration will be given to protocol 
modification, termination, or additional safety review at specified time-points before 
accrual is completed. 
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A Bayesian toxicity monitoring rule will be applied in each arm separately to ensure 
patient safety. However, all toxicities across all arms will be examined together as well 
for identifying the patterns of toxicity to provide further protection of patient safety. It is 
defined that an acceptable target toxicity level is no more than 30% of the patients 
experiencing dose limiting toxicity (DLT, defined as grade 3 4 toxicities, except for 
hypersensitivity reactions and grade 3 skin toxicity and fatigue). If at any given time, the 
probability that the DLT rate exceeds the 30% target is high (probability > 0.8), 
consideration will be given to modifying the protocol accordingly. Assuming that the 
probability of DLT has a vague prior of beta (0.3, 0.7), the posterior distribution of the 
DLT rate is also a beta. The 
ing 
 (i.e., holding for new patients 
randomization) are 3/6, 4/8, 5/11, 6/14, 7/17, and 8/20 where 
 indicates 
 
patients experiencing a DLT among the first 
 patients. In other words, in each given arm 
we will hold randomization for new patients if the number of DLTs given the number of patients 
treated is greater than or equal to the boundaries indicated above. 
 
 
13 Administrative considerations 
 
 
13.1 Institutional review board approval 
 
 
The IRB must operate in accordance with 21 Code of Federal Regulations Part 56 and 
other appropriate governmental regulations. Before study initiation, the investigator must 
have specified written and dated approval from the IRB/aEC for the protocol, consent 
form, and patient recruitment materials/process (e.g., advertisements). 
The investigator should provide the IRB/aEC with reports, updates, and other information 
(e.g., safety updates, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
 
13.2 Ethical conduct of the study 
 
 
This study will be conducted under a United States (US) IND, and the findings of this 
study are expected to significantly contribute to subsequent regulatory submissions. 
Therefore, US FDA regulations (21 Code of Federal Regulations [CFR] Part 56 and Part 
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312), International Conference on Harmonization (ICH) guidelines, Eli Lilly & Co. and 
ImClone Systems policies require the investigator to be aware of his/her obligations in 
the conduct of this study. 
 
This study will also be conducted in accordance with the ethical principles included in the 
"Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects" adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964,  
and amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975; the 35th 
World Medical Assembly, Venice, Italy, October 1983; the 41st World Medical  
Assembly, Hong Kong, September 1989; the 48th General Assembly, Somerset West, 
Republic of South Africa, October 1996; and the 52nd World Medical Assembly, 
Edinburgh, Scotland, October 2000 and will conform to any more current revisions to 
these principles. 
 
 
 
13.3 Compliance with the protocol and protocol revisions 
 
 
The investigator must comply with all requirements of the protocol. When a situation 
occurs that requires a temporary departure from the protocol, the investigator will 
describe the departure from the protocol and the circumstances requiring it on the 
patien
 medical record and will notify the IRB/aEC as appropriate. 
Patients may not be enrolled in an amended protocol until that amendment has been 
IRB/aEC approved. 
 
 
13.4 Patient information and consent 
 
 
Written informed consent will be given by each patient before entering the study, in 
accordance with US Title 21 CFR Parts 50.20 through 50.27 and the current edition of 
the Declaration of Helsinki, as well as Good Clinical Practices (GCPs). 
Investigators must ensure that patients are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical trials in which they volunteer to 
participate. 
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13.4.1 Informed consent procedures 
 
 
Preparation of the consent form is the responsibility of the investigator and must include 
all elements required by the ICH, GCP, and applicable regulatory requirements and must 
adhere to GCP and the ethical principles that have their origin in the Declaration of 
Helsinki. Prior to the beginning of the study, the investigator must have the 
 
written approval/favorable opinion of the written informed consent form and any other 
information to be provided to the patients. 
 
 
The investigator must provide the patient or legally acceptable representative with a copy 
of the consent form and written information about the study in the language in which the 
patient is most proficient. The language must be nontechnical and easily understood.  
The investigator should allow time necessary for patient or patien
 legally acceptable 
representative to inquire about the details of the study, informed consent must be signed 
and personally dated by the patient or the patient s legally acceptable representative and 
by the person who conducted the informed consent discussion. The patient or legally 
acceptable representative should receive a copy of the signed informed consent form and 
any other written information provided to study patients prior to the 
  
participation in the trial. 
 
 
13.4.2 Update of the informed consent 
 
 
The informed consent and any other information provided to patients or the 
 
legally acceptable representative should be revised whenever important new information 
becomes available that is relevant to the 
 consent and should receive IRB/aEC 
approval/favorable opinion prior to use. The investigator, or a person designated by the 
investigator, should fully inform the patient or the patient s legally acceptable 
representative of all pertinent aspects of the study and of any new information relevant to 
the 
 willingness to continue participation in the study. This communication 
should be documented. During a 
 participation in the trial, any updates to the 
consent form and any updates to the written information will be provided to the patient. 
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If a protocol amendment substantially alters the study design or increases the potential 
risk to the patient: (1) the consent form must be revised and submitted to the IRB/aEC 
for review and approval, (2) the revised consent form must be used to obtain consent 
from patients currently enrolled in the study, and (3) the new consent form must be used 
to obtain consent from new patients prior to enrollment. 
 
 
13.5 Study monitoring 
 
 
Representatives of Eli Lilly & Co and ImClone Systems must be allowed to visit all study 
site locations periodically to assess the data, quality, and study integrity. On site, they  
will review study records and directly compare them with source documents, discuss the 
conduct of the study with the investigator, and verify that the facilities remain acceptable. 
 
 
13.6 Case report forms and study records 
 
 
An investigator will be required to prepare and maintain adequate case histories designed 
to record all observations and other data pertinent to the investigation on each individual 
treated with IMC-A12 and/or cetuximab. All data reported on the PDMS and/or CORE 
databases must be derived from source documents and be consistent with the source 
documents, or the discrepancies must be explained. 
 
 
The confidentiality of records and information that could identify patients must be 
protected, respecting the privacy and confidentiality rules in accordance with applicable 
regulatory requirements. 
 
 
The investigator will maintain, in confidence, all information furnished by Eli Lilly & 
Co. and/or ImClone Systems and all data generated in the study, except as provided or 
required by law, and will divulge such information to the IRB/aEC with the 
understanding that confidentiality will be maintained by the committee. 
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13.7 Access to source documentation 
 
 
The study may be evaluated by auditors designated by Eli Lilly & Co. and/or ImClone 
Systems and by government inspectors who must be allowed access to source documents, 
and all other study files. Eli Lilly & Co. and/or ImClone Systems audit reports will be 
kept confidential. 
 
13.8 Retention of data 
 
The investigator must retain cetuximab and IMC-A12 disposition records, copies of 
PDMS and/or CORE databases (or electronic files), and source documents (including 
scans) for the maximum period required by applicable regulations and guidelines, or 
institution procedures, whichever is longer. 
Eli Lilly & Co. and ImClone Systems will 
notify the investigator when the trial records are no longer needed. If the investigator 
withdraws from the study (e.g., relocation, retirement), all records will be transferred to a 
designee (e.g., another investigator, IRB) who will assume responsibility for the study 
and 
 conduct. 
 
 
13.9 Publication and disclosure policy 
 
 
The results of the study may be published as an original article in an appropriate medical 
journal and/or presented in a medical meeting. The choice of the journal will be made by 
the co-authors. 
 
 
 
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