Conditions: Head and Neck Basaloid Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma Recurrent Oropharyngeal Squamous Cell Carcinoma Squamous Cell Carcinoma of Unknown Primary Origin Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma Stage IV Oropharyngeal Squamous Cell Carcinoma Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma Stage IVA Nasopharyngeal Keratinizing Squamous Cell Carcinoma Stage IVA Oropharyngeal Squamous Cell Carcinoma Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma Stage IVB Nasopharyngeal Keratinizing Squamous Cell Carcinoma Stage IVB Oropharyngeal Squamous Cell Carcinoma Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma Stage IVC Nasopharyngeal Keratinizing Squamous Cell Carcinoma Stage IVC Oropharyngeal Squamous Cell Carcinoma Head and Neck Cancer Oropharyngeal Cancer HNSCC Stage IV Lip and Oral Cavity Squamous Cell Carcinoma
Keywords: Head and Neck Cancer Oropharyngeal Cancer Squamous Cell Carcinoma lip carcinoma oral cavity carcinoma HNSCC Head and Neck Squamous Cell Carcinoma AVEO
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 78
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well ficlatuzumab with or without cetuximab works in treating patients with head and neck squamous cell carcinoma that has come back or spread to other places in the body and resistant to cetuximab treatment. Monoclonal antibodies, such as ficlatuzumab and cetuximab, may block growth signals that lets a tumor cell survive and reproduce, and helps the immune system recognize and fight head and neck squamous cell carcinoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy of ficlatuzumab, with or without concurrent cetuximab, in patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) as measured by progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. To describe toxicity. II. To evaluate response rate and overall survival in both treatment arms.

EXPLORATORY OBJECTIVES I. To describe patient reported quality of life

II. To evaluate the relationship between clinical outcomes (Progression-Free Survival and Response Rate) and candidate tumoral, genomic, peripheral, and immune biomarkers, potentially including but not limited to:

* Tumor Hepatocyte Growth Factor (HGF) and tyrosine-protein kinase Met (cMet) expression
* mutations in PIK3CA, phosphatase and tensin homolog (PTEN), and HumanRAS proto-oncogene (HRAS);
* peripheral serum biomarkers including HGF, soluble HGF, and interleukin 6 (IL6);
* peripheral lymphocyte populations;
* archived and baseline immune infiltrate;
* tumor Human Papilloma Virus (HPV) status.

OUTLINE: Patients are randomized into 1 of 2 arms.

Arm I: Patients receive ficlatuzumab intravenously (IV) over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive cetuximab IV over 60 -120 minutes and ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms:
arm 1: Patients receive ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cetuximab IV over 60 -120 minutes and ficlatuzumab IV over 30-60 minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cetuximab intervention 2: Ficlatuzumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol document:
Prot_SAP_003.pdf: 
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Title: A Randomized, Phase II Study of Ficlatuzumab with or without Cetuximab in 
Patients with Cetuximab-Resistant, Recurrent/Metastatic Head and Neck 
Squamous Cell Carcinoma  
 
 
 
UA IRB Protocol #: 
1710965268 
IND#: 
136947 (Research IND) 
Phase: 
II 
Version: 
V. 10 
Investigational Agent: 
Ficlatuzumab 
Commercial Agent: 
Cetuximab 
 
 
CO-PRINICPAL INVESTIGATOR: 
Ricklie Julian, MD 
University of Arizona Cancer Center 
1515 N. Campbell Ave. 
Tucson, AZ 85724 
Phone: 520-694-2873 
Email:  rickliej@arizona.edu 
 
 
CO-PRINICPAL INVESTIGATOR & SPONSOR-INVESTIGATOR: 
 
Julie E. Bauman, MD, MPH 
University of Arizona Cancer Center 
1515 N. Campbell Ave. 
Tucson, AZ 85724 
Email: jebauman@email.arizona.edu 
 
 
Source(s) of Support: 
Aveo Oncology 
 
Aveo Oncology Protocol ID #: AV-299-17-117i 
 
Study Safety Oversight: 
University of Arizona Cancer Center  
 
Data Safety and Monitoring Board 
 


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TRIAL SCHEMA 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. 
BACKGROUND & RATIONALE ....................................................................................................................... 6 
1.1 
Background .................................................................................................................................................................. 6 
1.2 
Epidermal Growth Factor Receptor in HNSCC ............................................................................................... 6 
1.3 
HGF/c-Met in Head and Neck Squamous Cell Carcinoma ........................................................................ 7 
1.4 
Phase Ib Study of the Combination of Ficlatuzumab and Cetuximab .................................................. 8 
1.5 
Study Rationale .......................................................................................................................................................... 9 
1.6 
Ficlatuzumab (AV-299) ............................................................................................................................................ 9 
1.6.1 
Introduction ......................................................................................................................................................... 9 
1.6.2 
Ficlatuzumab clinical experience .............................................................................................................. 10 
1.6.3 
Ficlatuzumab Safety Experience ................................................................................................................ 11 
1.7 
Cetuximab ................................................................................................................................................................. 14 
1.7.1 
FDA Indications in HNSCC .......................................................................................................................... 14 
1.7.2 
Rationale for Every Two Week Dosing Schedule of Cetuximab ................................................... 14 
1.8 
Correlative Studies Background ........................................................................................................................ 15 
1.8.1 
Tumoral Activation of HGF/cMet Pathway ........................................................................................... 15 
1.8.2 
Peripheral Biomarkers of HGF/cMet Pathway Activation ................................................................ 16 
1.8.3 
Genomic Alterations: PIK3CA, PTEN, and HRAS ................................................................................. 17 
1.8.4 
Immune Biomarkers ....................................................................................................................................... 17 
1.8.5 
Patient-Reported Outcomes ...................................................................................................................... 17 
2. 
STUDY OBJECTIVES ......................................................................................................................................... 18 
2.1 
Primary ........................................................................................................................................................................ 18 
2.2 
Secondary .................................................................................................................................................................. 18 
2.3 
Exploratory ................................................................................................................................................................ 18 
3. 
PATIENT SELECTION ....................................................................................................................................... 18 
3.1 
Inclusion Criteria ..................................................................................................................................................... 18 
3.2 
Exclusion Criteria ..................................................................................................................................................... 21 
4. 
PATIENT REGISTRATION AND RANDOMIZATION ................................................................................. 23 
4.1 
Registration ............................................................................................................................................................... 23 
4.2 
Randomization ......................................................................................................................................................... 23 
5. 
TREATMENT PLAN ........................................................................................................................................... 24 
5.1 
Ficlatuzumab ............................................................................................................................................................ 24 
5.1.1 
Route of Administration ............................................................................................................................... 25 
5.1.2 
Dose and Schedule ........................................................................................................................................ 25 
5.1.3 
Order of Administration for Arm B (Combination Arm) .................................................................. 25 
5.2 
Cetuximab ................................................................................................................................................................. 25 
5.2.1 
Route of Administration ............................................................................................................................... 25 
5.2.2 
Dose and Schedule ........................................................................................................................................ 25 
5.2.3 
Order of Administration for Arm B (Combination Arm) .................................................................. 26 
5.2.4 
Premedications ................................................................................................................................................ 26 
5.3 
General Concomitant Medication and Supportive Care Guidelines ................................................... 26 


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5.4 
Duration of Treatment and Follow-up ........................................................................................................... 26 
5.4.1 
Treatment Duration: ...................................................................................................................................... 26 
5.4.2 
Follow up duration - WITHOUT progressive disease: ....................................................................... 26 
5.4.3 
Follow up duration - WITH progressive disease: ................................................................................ 26 
5.4.4 
Follow up for unacceptable adverse events ......................................................................................... 27 
5.5 
Dose Delays and Modifications......................................................................................................................... 27 
5.5.1 
Treatment Plan Interruptions and Delays.............................................................................................. 27 
5.5.2 
Dose Reduction Levels .................................................................................................................................. 27 
5.5.3 
Treatment Stoppage Rules For Toxicity ................................................................................................. 28 
5.5.4 
Treatment Interruption for Interstitial Lung Disease ........................................................................ 28 
5.5.5 
Dose Modification for Hematologic Toxicity ....................................................................................... 28 
5.5.6 
Dose Modification for Non-Hematologic Toxicity............................................................................. 29 
5.5.7 
Dermatologic Toxicity ................................................................................................................................... 35 
5.5.8 
Cetuximab Infusion Reaction ..................................................................................................................... 37 
6. 
RESPONSE ASSESSMENT............................................................................................................................... 39 
6.1 
Malignant Disease Evaluation ............................................................................................................................ 39 
6.1.1 
Measurable Disease ....................................................................................................................................... 40 
6.1.2 
Non-measurable disease ............................................................................................................................. 40 
6.1.3 
Target Lesions .................................................................................................................................................. 40 
6.1.4 
Non-target Lesions ........................................................................................................................................ 41 
6.2 
Response Criteria .................................................................................................................................................... 41 
6.2.1 
Evaluation of Target Lesions ...................................................................................................................... 41 
6.2.2 
Evaluation of Non-target Lesions ............................................................................................................. 41 
6.2.3 
Evaluation of Patient's Best Overall Response .................................................................................... 42 
6.3 
Methods of Measurement .................................................................................................................................. 44 
7. 
DRUG INFORMATION .................................................................................................................................... 46 
7.1 
Ficlatuzumab ............................................................................................................................................................ 46 
7.1.1 
Study Drug Materials .................................................................................................................................... 46 
7.1.2 
Ficlatuzumab Study Drug Storage ........................................................................................................... 46 
7.1.3 
Study Drug Accountability .......................................................................................................................... 47 
7.2 
Cetuximab ................................................................................................................................................................. 47 
8. 
STUDY PROCEDURES/EVALUATIONS ........................................................................................................ 49 
8.1 
Screening/Pre-treatment evaluations ............................................................................................................. 49 
8.2 
Registration & Randomization .......................................................................................................................... 50 
8.3 
Evaluations during study treatment ................................................................................................................ 51 
8.3.1 
Every Two Weeks – Day 1 and Day 15 of each cycle (+/- 3 days) ............................................... 51 
8.3.2 
Every 8 Weeks (the end of even cycles – “Day 28”/8 weeks, 16 weeks, etc.)........................... 51 
8.3.3 
OPTIONAL:  Every 12 Weeks Cycle 13+ (“Day 28” of every 3rd cycle after Cycle 12) ........... 52 
8.4 
End-of-treatment (EOT) evaluations ............................................................................................................... 53 
8.5 
Post-treatment follow-up .................................................................................................................................... 53 
8.5.1 
Adverse Event and Concomitant Medication Follow-up ................................................................. 53 
8.5.2 
Discontinuation of treatment WITHOUT progressive disease ...................................................... 54 


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8.5.3 
Progressive disease follow-up ................................................................................................................... 55 
9. 
BIOMARKER, CORRELATIVE, OR SPECIAL STUDIES ............................................................................... 55 
9.1 
Submission of archived diagnostic tissue ..................................................................................................... 55 
9.2 
Research biopsy ...................................................................................................................................................... 55 
9.2.1 
Research Biopsy Methodology .................................................................................................................. 56 
9.3 
Research Blood ........................................................................................................................................................ 56 
10. 
STATISTICAL METHODS ................................................................................................................................. 56 
10.1 
Study Design ............................................................................................................................................................ 56 
10.2 
Primary Objective ................................................................................................................................................... 56 
10.3 
Sample Size Determination ................................................................................................................................ 57 
10.4 
Secondary Objectives ............................................................................................................................................ 57 
10.4.1 Toxicity ................................................................................................................................................................ 57 
10.4.2 Other Efficacy Endpoints .............................................................................................................................. 57 
10.5 
Exploratory Objectives .......................................................................................................................................... 58 
10.5.1 Patient-Reported Outcomes ...................................................................................................................... 58 
10.5.2 Biomarker endpoints ..................................................................................................................................... 58 
10.6 
Statistical Analysis Plan ........................................................................................................................................ 58 
10.7 
Continuous Monitoring Rule for Futility ........................................................................................................ 58 
11. 
DATA SAFETY MONITORING PLAN ............................................................................................................ 59 
12. 
ADVERSE EVENT REPORTING ...................................................................................................................... 62 
12.1 
Definitions ................................................................................................................................................................. 62 
12.2 
Description of Adverse Event Reporting Procedures ............................................................................... 63 
12.3 
Reporting of Serious Adverse Events .............................................................................................................. 64 
12.4 
Review of Safety Information: Sponsor-Investigator Responsibilities ............................................... 64 
12.5 
IND safety reports for ficlatuzumab ................................................................................................................ 64 
13. 
DATA HANDLING AND RECORD-KEEPING .............................................................................................. 65 
14. 
ETHICS AND REGULATORY COMPLIANCE ............................................................................................... 65 
14.1 
Institutional Review Board (IRB) approval ..................................................................................................... 65 
14.2 
Ethical and scientific conduct of the clinical research study .................................................................. 66 
14.3 
Subject informed consent ................................................................................................................................... 66 
14.4 
Confidentiality .......................................................................................................................................................... 67 
FiclaYCetux Protocol Signature Page ........................................................................................................................ 68 
15. 
APPENDICES ...................................................................................................................................................... 69 
15.1 
Appendix A: FACT-H&N Symptom index (FHNSI) ..................................................................................... 69 
15.2 
Appendix B: Performance Status Criteria ...................................................................................................... 70 
15.3 
Appendix C: Study Calendar (Also see Section 8) ...................................................................................... 71 
15.4 
Appendix D: Tobacco Use Assessment Form .............................................................................................. 73 
16. 
REFERENCES ...................................................................................................................................................... 74 
 


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1. BACKGROUND & RATIONALE 
1.1 Background 
Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the 
upper aerodigestive tract. HNSCC is the sixth leading incident cancer worldwide with 600,000 
cases anticipated in 2012.1  Despite advances in multimodality therapy, 5-year overall survival 
(OS) is 40-50%, and has increased only incrementally in the past two decades.2  Patients with 
recurrent or metastatic (R/M) HNSCC have particularly poor prognosis, with median overall 
survival of 6-10 months. Options for palliative management are limited. For nearly three 
decades, the cornerstone of first line chemotherapy has been cisplatin,3  frequently combined 
with fluorouracil or a taxane derivative due to increased response rate (RR) albeit no conclusive 
evidence of superior survival compared to cisplatin monotherapy.4   
Ubiquitous expression of EGFR compelled the development of EGFR inhibitors for HNSCC 
treatment 5, 6. The EGFR-directed monoclonal antibody, cetuximab, is the only targeted therapy 
to date FDA-approved for the treatment of HNSCC, and improves survival when added to front 
line platinum 7. Despite aberrant EGFR signaling in the majority of HNSCC cases, the modest 
clinical activity of cetuximab has been disappointing; either primary or acquired resistance is 
inevitable. Co-targeting EGFR and a parallel or compensatory oncogenic pathway may overcome 
cetuximab resistance.  
While immunotherapeutic antibodies inhibiting programmed death receptor 1 (PD-1) recently 
gained FDA approval in patients with platinum-refractory HNSCC, the OS benefit appears to be 
limited to approximately 20% 8, 9. Currently, there is no standard therapy for patients after failure 
of platinum, cetuximab, and anti-PD1 therapy; all such patients will succumb with a median 
survival of less than 6 months. The lack of therapeutic options for patients with pan-refractory, 
recurrent and/or metastatic HNSCC represents a major unmet clinical need. 
1.2 Epidermal Growth Factor Receptor in HNSCC 
EGFR is a member of the ErbB/HER family of transmembrane glycoprotein receptor tyrosine 
kinases (RTK). Activated EGFR initiates a pleiotropic network of downstream signaling cascades 
including Ras/Raf/MAPK, PI3K/Akt, STAT, and Src Kinase effecting cellular proliferation, invasion, 
angiogenesis and metastasis.10  In vitro, forced overexpression of EGFR causes malignant 
transformation of oral epithelial cells, suggesting its role as an oncogene in HNSCC. EGFR 
overexpression as measured by immunohistochemistry (IHC) and increased EGFR gene copy 
number as measured by fluorescence in situ hybridization occur in the majority of HNSCC, and 
associate with increased stage as well as reduced relapse-free and overall survival (OS).6, 11-13   
Thus, EGFR is both oncogene and prognostic biomarker in HNSCC. 


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EGFR’s functional importance in HNSCC resulted in successful development of the first 
molecularly targeted strategy, the murine anti-EGFR monoclonal antibody cetuximab. Despite 
clear clinical importance, intrinsic or acquired resistance to EGFR inhibition is the rule rather than 
the exception. Currently, there is no predictive molecular marker for resistance or sensitivity to 
anti-EGFR therapy in HNSCC, including EGFR gene copy number as assessed in the EXTREME 
study.14  Given the poor prognosis and desperate lack of therapeutic options for patients with 
recurrent and/or metastatic HNSCC after failure of cetuximab, there is heightened interest in 
understanding resistance mechanisms in order to drive novel therapies for this population. 
1.3 HGF/c-Met in Head and Neck Squamous Cell Carcinoma 
An established intrinsic or acquired resistance mechanism to anti-EGFR therapy in HNSCC is 
primary or compensatory activation of alternate RTKs including c-Met. The MET oncogene 
encodes c-Met, an RTK bound exclusively by the ligand, hepatocyte growth factor (HGF). HGF is 
also known as “scatter factor;” this designation arose from early observations that HGF 
stimulates cellular decoupling and motogenesis. Overexpression of c-Met is transformative for 
normal cells and enhances motility, invasion/metastasis and angiogenesis.15  MET is an 
established driver of epithelial-to-mesenchymal transition, a phenotype associated with 
cetuximab resistance in HNSCC.16, 17  
c-Met and/or HGF are overexpressed in ~80% of HNSCC,18  and MET amplification has been 
reported in 13% of HNSCC tumors.19  Moreover, several mutations have been identified in the 
MET oncogene in HNSCC, including alterations in the semaphorin ligand-binding, 
juxtamembrane, and RTK domains.19  An activating point mutation (Y1253D) was described in 
14% of patients in a Swiss chemoradiotherapy trial for locally advanced disease and predicted 
decreased metastasis-free survival, although the presence of this mutation in HNSCC was not 
confirmed in two whole-exome sequencing projects.20-22 
  Although validation and functional characterization of MET mutations in HNSCC is ongoing, the 
presence of MET overexpression, amplification, and mutation events suggests strong biologic 
relevance of this pathway. Furthermore, the current feasibility of measuring these events holds 
the promise that the clinical development of c-Met targeting in HNSCC may be accompanied by 
rational development of a predictive biomarker. 
Of unique interest to the proposed study, the HGF/c-Met signaling pathway converges with the 
EGFR network at both the PI3K/Akt and MAPK nodes, suggesting the ability for reciprocal 
compensation. Several lines of evidence developed in our laboratories indicate that c-Met has 
an important role in resistance to EGFR based therapies. In vitro, the EGFR ligand TGF-α 
stimulated activation of c-Met in HNSCC cell lines, through prolonged tyrosine phosphorylation 


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and increased c-Met protein expression. Moreover, dual inhibition of EGFR (gefitinib) and c-Met 
(crizotinib) maximally inhibited phosphorylation of MAPK and Akt compared to single inhibition 
of either RTK, effectively abrogating crosstalk. Similarly, dual inhibition significantly reduced cell 
proliferation, invasion and wound healing, compared to mono- inhibition of either RTK. In vivo, 
dual inhibition of EGFR and c-Met retarded tumor growth, decreased the proliferative index, and 
enhanced apoptosis compared to either single agent.23  A second laboratory found that dual 
blockade of c-Met (SU11274) and EGFR (erlotinib) in erlotinib-sensitive HNSCC cell lines 
decreased viability significantly more than exposure to either single agent, and isobologram 
indicated synergism.19  Finally, growth factors have recognized potential to drive resistance to 
anticancer kinase inhibitors; in kinase addicted cell line models, the HGF ligand had broad 
potential to rescue kinase-addicted cancer cells dependent upon HER2 amplification, NRG1 
autocrine stimulation, EGFR mutation, and BRAF mutation.24 Finally, serum levels of HGF have 
been associated with resistance to EGFR inhibitors in KRAS wild-type metastatic colorectal 
cancer 25 and lung cancer 25-27. 
Above, convergent data suggest that HGF/c-Met pathway inhibition may overcome resistance to 
anti-EGFR therapy in R/M HNSCC, such as in patients with clinical cetuximab resistance. In 
theory, targeting HGF/cMet may have independent activity when administered as monotherapy 
in this setting, although this hypothesis has not been clinically tested. However, the cross talk 
and mutual compensation between c-Met and EGFR suggest that optimal benefit may be 
achieved by continuing cetuximab concurrent with HGF/c-Met pathway inhibition, in spite of 
established clinical resistance.  
Ficlatuzumab (AV-299) is a humanized HGF-inhibitory immunoglobulin G1 (IgG1) monoclonal 
antibody that exhibits anti-tumor effects in vitro and in animal tumor models by 1) binding and 
neutralization of free HGF, 2) inhibition of c-Met phosphorylation, 3) inhibition of proliferation, 
4) induction of apoptosis, and 5) inhibition of invasion and motility.  Ficlatuzumab in 
combination with cetuximab resulted in prolonged tumor stasis/regression in 3 HNSCC 
xenograft models tested with increased activity compared to cetuximab alone in two of the 
three models tested.  The recommended phase II dose (RP2D) for ficlatuzumab monotherapy 
has been established as 20 mg/kg IV every 2 weeks. 
1.4 Phase Ib Study of the Combination of Ficlatuzumab and Cetuximab 
We recently completed a phase Ib study of the combination of ficlatuzumab and cetuximab in 
patients with cetuximab-resistant, recurrent and/or metastatic HNSCC (NCT 02277197; Bauman 
JE et al, ASCO 2017). In this Narayana k-in-a-row phase I design, fixed-dose cetuximab was 
administered at 500 mg/m2 IV every 2 weeks. Ficlatuzumab dose tiers were 10 mg/kg (starting 


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dose) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based 
on cumulative dose-limiting toxicities (DLT). The RP2D was set at dose tier 2 if no DLTs were 
observed after 8 enrolled patients, with expansion planned to n=12. Key eligibility criteria 
included: R/M HNSCC, cetuximab resistance (recurrence within 6 months of cetuximab-radiation 
or progression during/within 6 months of palliative cetuximab); ECOG performance status 0-1; 
mandatory baseline research biopsy. Candidate biomarkers included serum VeriStrat 
classification and tumor expression of pMet and HGF/cMet dimers. 
From Sept 2015-June 2016, 12 pts were enrolled and treated. Primary site: 1 oral cavity; 3 
oropharynx (1 p16+); 2 hypopharynx; 5 larynx; 1 external auditory canal. Platinum-refractory: 
11/12. VeriStrat: 8 poor; 4 good. Three were treated at tier 1 and 9 at tier 2. No DLTs were 
observed. Grade 3 adverse events included: edema (1), hypoalbuminemia (1), infection (2), and 
thromboembolic event (2). Median PFS and OS at RP2D were 6.0 mos (90% CI = 2 mos – not 
reached) and 8.2 mos (90% CI = 2.7 mos – not reached), respectively. Response rate was 17% 
(90% CI = 0-28%): 2/12 partial response (PR); 1/3 at 10 mg/kg; 1/9 at 20mg/kg. Clinical benefit 
rate (PR + stable disease) was 67%. VeriStrat was not associated with PFS. 
1.5 Study Rationale 
Above, convergent data suggest that HGF/c-Met pathway inhibition may overcome resistance to 
anti-EGFR therapy in recurrent and/or metastatic HNSCC. The promising clinical activity 
observed in patients with cetuximab-resistant, recurrent and/or metastatic HNSCC during phase 
Ib compels further study in the same poor prognosis population. In theory, targeting HGF/cMet 
may have independent activity when administered as monotherapy in this setting, although this 
hypothesis has not been clinically tested. We also hypothesize that the cross talk and mutual 
compensation between c-Met and EGFR may necessitate the continuation of cetuximab with 
HGF/c-Met pathway inhibition, to optimize benefit. Thus we proposed a randomized, phase II 
study evaluating the efficacy of ficlatuzumab, with or without cetuximab, in patients with 
cetuximab-resistant, recurrent and/or metastatic HNSCC. 
1.6 Ficlatuzumab (AV-299) 
1.6.1 
Introduction 
Ficlatuzumab (AV-299) is a humanized HGF inhibitory immunoglobulin G1 (IgG1) monoclonal 
antibody that exhibits anti-tumor effects in vitro and in animal tumor models by 1) binding and 
neutralization of free HGF, 2) inhibition of c-Met phosphorylation, 3) inhibition of proliferation, 
4) induction of apoptosis, and 5) inhibition of invasion and motility. 
Hepatocyte growth factor is the soluble ligand for the c-Met tyrosine kinase receptor. 
Hepatocyte growth factor/c-Met pathway dysregulation by over-expression or genetic alteration 


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is frequently observed in many types of cancer. Ficlatuzumab exhibited potent in vivo inhibitory 
activity in autocrine and paracrine xenograft models as single agents in GBM, multiple myeloma 
and RCC. Ficlatuzumab demonstrated enhanced antitumor activity when combined with 
targeted therapy or chemotherapy, such as erlotinib, cetuximab, tivozanib or temozolomide in a 
panel of xenograft models, suggesting ficlatuzumab may have anti-tumor activity in multiple 
tumor indications.  Ficlatuzumab in combination with cetuximab resulted in prolonged tumor 
stasis/regression in all 3 HNSCC xenograft models tested with increased activity compared to 
cetuximab alone in two of the three models tested 
A summary of ficlatuzumab’s pertinent efficacy results and safety data follow. Please refer to the 
ficlatuzumab Investigator Brochure (IB) for descriptions of all available data. 
1.6.2 
Ficlatuzumab clinical experience 
An overview of the clinical data available for ficlatuzumab clinical studies; protocols P05538 
(phase I), P05670 (pharmacodynamic study) and P06162 (phase Ib/II in NSCLC) is provided 
below. Final data for Protocols P05538 (with the exception of the 1 ongoing subject) and P05670 
and preliminary data for Protocol P06162 are included in the Ficlatuzumab Investigator 
Brochure. 
Protocol P05538 includes data for 41 subjects diagnosed with relapsed or refractory solid 
tumors that were metastatic or unresectable, or symptomatic relapsed or refractory multiple 
myeloma. There were 7 cohorts in total. The dose-escalation cohorts included subjects 
diagnosed with relapsed or refractory solid tumors that were metastatic or unresectable that 
were treated at the following dose levels: Cohort 1 (2 mg/kg), Cohort 2 (5 mg/kg), Cohort 3 (10 
mg/kg), and Cohort 4 (20 mg/kg); safety expansion Cohort 5 (20 mg/kg, which was the RP2D). 
The additional cohorts were the Erlotinib Combination Cohort (ficlatuzumab 20 mg/kg and 
erlotinib 150 mg) and Multiple Myeloma Cohort (ficlatuzumab 20 mg/kg). There were 24 
subjects enrolled in the dose escalation/safety expansion cohorts, 13 subjects enrolled in the 
Erlotinib Combination Cohort, and 4 subjects enrolled in the Multiple Myeloma Cohort. After an 
interim review of the data, there was no signal of clinical benefit to subjects with multiple 
myeloma; therefore, enrollment into this cohort was terminated.  
Protocol P05670 was a pharmacodynamic study including data for 19 subjects with advanced 
solid tumors and liver metastases. There were 3 dose cohorts of ficlatuzumab (2, 10, and 
20 mg/kg). Six subjects were enrolled in the Dose Level 1 Cohort (2 mg/kg), 7 subjects were 
enrolled in the Dose Level 2 Cohort (10 mg/kg), and 6 subjects were enrolled in the Dose Level 3 
Cohort (20 mg/kg). The best responses in the study were stable disease seen 5/18 patients and 
the median duration of treatment was 6 weeks. The Pk of ficlatuzumab was characterized by low 


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clearance and a half-life of 7-10 days. Ficlatuzumab treatment at 20 mg/kg, but not at 2 and 10 
mg/kg, demonstrated pharmacodynamic modulation in the tumor by inhibiting HGF/c-Met 
pathway and downstream signaling for cell proliferation, survival, and angiogenesis in majority 
of the patients treated. 
Protocol P06162 is a Phase 1b/2 study including preliminary data for 199 subjects. Phase 1b 
enrolled Asian subjects with NSCLC or other advanced solid tumors. Phase 2 enrolled Asian 
subjects (nonsmokers or light ex-smokers) with previously untreated lung adenocarcinoma. 
Subjects in Phase 1b are treated with a dose of ficlatuzumab 10 mg/kg or 20 mg/kg in 
combination with gefitinib 250 mg. Subjects in Phase 2 are treated with a combination of 
ficlatuzumab 20 mg/kg and gefitinib 250 mg or gefitinib 250 mg monotherapy. Upon 
progression in the gefitinib monotherapy arm, subjects who initially demonstrated disease 
control with single agent gefitinib were offered to receive the combination of ficlatuzumab 
20 mg/kg and gefitinib 250 mg, provided that safety was maintained and the subject continued 
to meet eligibility criteria. There were 15 subjects enrolled in Phase 1b (3 subjects enrolled in the 
10 mg/kg cohort and 12 subjects enrolled in the 20 mg/kg) and 184 subjects enrolled in Phase 2 
(90 subjects enrolled in the Combination Cohort and 94 subjects enrolled in the Gefitinib 
Monotherapy Cohort). Of the subjects enrolled in the Phase 2 Gefitinib Monotherapy Cohort, 20 
were crossed over to receive the combination of ficlatuzumab 20 mg/kg and gefitinib 250 mg. 
The addition of ficlatuzumab to gefitinib did not result in a significant improvement in ORR 
(primary endpoint) or PFS in the intent to treat population. The ficlatuzumab/gefitinib 
combination demonstrated a trend for increased ORR and OS in a subset of patients without 
EGFR sensitizing mutations and increased PFS, OS and ORR in a subset of patients with high 
stromal HGF. Overall survival data continues to mature and are being analyzed in the intent to 
treat group as well as other biomarker subsets. The combination of ficlatuzumab and gefitinib 
was well tolerated in this patient population.
1.6.3 
Ficlatuzumab Safety Experience 
Refer to the Aveo Pharmaceuticals Investigator Brochure for the most up-to-date information. 
Data from the first-in-human dose-escalation study (Study P05538) in 41 subjects diagnosed 
with relapsed or refractory solid tumors or lymphoma that was metastatic or unresectable, or 
symptomatic relapsed or refractory multiple myeloma showed ficlatuzumab to be well-tolerated 
as monotherapy at the 4 dose levels tested (2, 5, 10 or 20 mg/kg) and in combination with 
erlotinib (20 mg/kg ficlatuzumab and 150 mg/day erlotinib). The maximum administered dose 
of 20 mg/kg intravenous (IV) ficlatuzumab every 2 weeks as monotherapy and in combination 
with erlotinib (150 mg/day) was determined to be the RP2D. 


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There were no DLTs observed with single-agent ficlatuzumab. One subject in the ficlatuzumab 
plus erlotinib combination cohort experienced a Grade 3 mucositis which the investigator 
determined was possibly related to ficlatuzumab and related to erlotinib. The most common 
treatment-emergent adverse events (TEAEs) were fatigue (18 subjects, 44%), peripheral edema 
(13 subjects, 32%), hypokalemia (11 subjects, 27%), and nausea (10 subjects, 24%). The most 
frequently reported related TEAEs were fatigue (12 subjects [29%]; 9 subjects monotherapy 
[22%], 3 subjects erlotinib combination [7%]); peripheral edema (6 subjects [15%]; 5 subjects 
monotherapy [12%], 1 subjects erlotinib combination [2%])); headache (5 subjects [12%]; 4 
subjects monotherapy [10%], 1 subjects erlotinib combination [2%]), pruritus (5 subjects [12%]; 3 
subjects monotherapy [7%], 2 subjects erlotinib combination [5%]), and rash maculo-papular (5 
subjects [12%]; 5 subjects erlotinib combination [12%]). 
Serious adverse events (SAEs) considered at least possibly related to ficlatuzumab included 
Grade 1 blindness transient, Grade 4 hyperkalemia, and Grade 1 hypokalemia, one case each.  
Data from a Phase 1 pharmacodynamic study (Study P05670) in 19 subjects with advanced solid 
tumors and liver metastases showed ficlatuzumab to be well-tolerated as monotherapy at the 2 
to 20 mg/kg dose range tested. There were no DLTs in this study. The most frequently reported 
TEAEs were asthenia, peripheral edema, and hepatic pain (each reported by 6 subjects [32%]), 
and cough (5 subjects [26%]). The only related adverse event (AE) was pyrexia, which occurred in 
1 subject in the 2 mg/kg treatment group (5%). There were no SAEs considered at least possibly 
related to ficlatuzumab. 
The safety profile of ficlatuzumab was acceptable and similar to the drugs in its class. Serum 
albumin decreased to below the lower limit of normal at end of study for all exposed subjects. 
Serum albumin levels began to recover at the follow up visit. 
Data from the Phase 1b portion of the Study P06162 in 15 subjects with non-small cell lung 
cancer (NSCLC) showed ficlatuzumab to be well-tolerated in combination with gefitinib. 
Ficlatuzumab at 20 mg/kg plus gefitinib at 250 mg/day was determined to be the RP2D. 
Of the 12 Phase 1b subjects who received the RP2D, 2 subjects (17%) had DLTs: an SAE of 
diffuse alveolar damage in 1 subject that resulted in death, and Grade 3 acneiform dermatitis in 
1 subject. Both of these events were assessed by the investigator as probably related to gefitinib 
and/or ficlatuzumab. 
The most common TEAEs were dermatitis acneiform (in 10 subjects [67%]), decreased appetite 
(7 subjects [47%]), diarrhea (6 subjects [40%]), and cough, fatigue, and paronychia (each in 5 


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subjects [33%]). The most frequently reported study drug-related TEAEs were dermatitis 
acneiform (10 subjects [67%]), paronychia (5 subjects [33%]), and diarrhea (4 subjects [27%]).  
Ficlatuzumab monotherapy has been generally well tolerated. Table 1 lists the TEAEs that, based 
upon preliminary monotherapy safety data, could be reasonably assumed to be associated with 
ficlatuzumab. 
Data from the Phase 2 portion of the Study P06162 in 184 subjects with non-small cell lung 
cancer (NSCLC) showed ficlatuzumab to be well tolerated in combination with gefitinib. Table 2 
lists the preliminary data on TEAEs with a ≥ 10% difference between the two treatment groups 
(ficlatuzumab+gefitinib vs gefitinib monotherapy). 
Table 1:  Adverse Events Expected to Occur with Ficlatuzumab Monotherapy 
MedDRA Preferred Term 
Decreased appetite 
Diarrhea 
Dry skin 
Edema peripheral 
Fatigue 
Headache 
Hypoalbuminemia 
Hypokalemia 
Hypomagnesemia 
Myalgia 
Nausea 
Pruritus 
Rash  
Chills  
Dizziness 
Muscle Spasms 
Bacterial skin infection, which may cause swelling, redness, and sensitivity 
Vomiting 
MedDRA = Medical Dictionary for Regulatory Activities 
 


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Table 2: TEAEs w/ ≥ 10% Difference between Treatment Groups (Study P06162) 
 
Ficlatuzumab has not been found to be immunogenic in any patients treated to date; no post-
treatment anti-drug antibodies have developed. 
1.7 Cetuximab 
1.7.1 
FDA Indications in HNSCC 
Cetuximab is an IgG1, chimeric murine-human antibody against EGFR that was first approved by 
the U.S. Food and Drug Administration for the treatment of patients with recurrent and/or 
metastatic HNSCC in 2006. As cetuximab is a common and accepted standard of care, 
commercial cetuximab will be used in this study. Please see the cetuximab package insert for 
complete prescribing information (http://pi.lilly.com/us/erbitux-uspi.pdf).  
The most common adverse events (≥25%) associated with cetuximab in clinical trials include: 
cutaneous adverse reactions (acneiform rash, pruritus, and nail changes), headache, diarrhea, 
hypomagnesemia/accompanying electrolyte abnormalities, and infection. 
The  most serious adverse reactions associated with cetuximab are: infusion reactions, 
cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, 
interstitial lung disease, and pulmonary embolus. 
1.7.2 
Rationale for Every Two Week Dosing Schedule of Cetuximab 
The early studies that established weekly dosing of cetuximab did not establish an MTD.28, 29  
Subsequent pharmacokinetic studies were conducted in patients with advanced colorectal 
cancer, exploring other doses and schedules.  In studies of q2week dosing, cetuximab doses of 
400 to 700 mg/m2 q2weeks were well tolerated and the MTD was not reached.30 
Pharmacokinetic analysis showed that trough cetuximab levels for the 500 mg/m2 q2weeks, 600 
mg/m2 q2weeks, and 250 mg/m2 weekly regimens were comparable.30, 31 Pharmacodynamic 
 
 


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studies, in which subjects underwent skin biopsies at baseline and at week 4 showed that all 
cetuximab dose levels yielded comparable changes in the expression of pEGFR, pMAPK, Ki67, 
p27, and pSTAT3 as detected with immunohistochemistry.32  Cetuximab at 500 mg/m2 q2weeks 
was identified as a convenient and feasible dose. 
In recurrent and/or metastatic HNSCC, a randomized phase II study compared two q2week 
cetuximab doses and found that the dose of 500 mg/m2/q2weeks resulted in similar efficacy to 
weekly dosing at 250 mg/m2/week, with no therapeutic advantage for 750 mg/m2 q2weeks. Due 
to convenience and comparable efficacy, clinical trials in HNSCC are now integrating the q2week 
dosing schedule.33  
1.8 Correlative Studies Background 
1.8.1 
Tumoral Activation of HGF/cMet Pathway 
We have published a report of a cohort of 56 HNSCC patients with tumor protein levels of HGF 
and cMet calculated by the H score (intensity weighted by percent tumor).18   We found that 
HNSCC tumors overexpress both HGF and c-Met as compared to adjacent tissue, as 
demonstrated below in Figure 1. Ongoing work indicates a bidirectional positive feedback loop 
between tumor-associated fibroblasts (TAF) which secrete HGF, and HNSCC tumor cells whose 
conditioned media stimulate HGF secretion from TAFs.34 In a preclinical HNSCC-TAF co-culture 
model, ficlatuzumab inhibited HNSCC progression via reduced cMet and mitogen-activated 
protein kinase (MAPK) signaling.35 
During the phase Ib trial evaluating the combination of ficlatuzumab and cetuximab in patients 
with cetuximab-resistant, recurrent and/or metastatic HNSCC, we evaluated three candidate 
baseline biomarkers for feasibility and relationship to response: VeriStrat; tumoral expression of 
pMet; and tumoral expression of HGF/cMet dimers. There was no relationship between VeriStrat 
status and PFS. pMet and HGF/cMet dimer analyses are pending. 


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Figure 1: HGF and c-Met are overexpressed in head and neck cancer. HGF and c-Met protein 
levels were assessed by immunohistochemistry in HNSCC tumors and paired adjacent mucosa (n 
= 26). Intensity (integer scale 0 to +3) and percent of tumor stained were evaluated. A weighted 
score of intensity times percent of tumor stained was calculated. A, tumor tissues showed 
increased HGF and c-Met staining compared with paired adjacent mucosal tissues. B, two-tailed 
Wilcoxon signed-rank test for paired samples indicated significant differences in weighted HGF 
and c-Met intensity in tumor versus paired adjacent mucosa (HGF; P < 0.001; c-Met; P = 0.04). C, 
HGF and c-Met immunohistochemistry score frequency distributions indicate that higher levels 
of HGF are more frequently present in HNSCC tumors than c-Met.18 
 
In this clinical trial, patients will undergo a research biopsy at baseline. We will investigate the 
relationship between candidate biomarkers and clinical outcomes on each arm, including the 
following:  
• 
Dimers (Monogram assay): HGF/cMet, EGFR/EGFR, EGFR/HER2 
• 
Signaling proteins: pMet, bFGF, pMAPK, pAkt 
We will also analyze HGF and cMet in archived diagnostic biopsies which took place before 
clinical cetuximab exposure, as available.   
1.8.2 
Peripheral Biomarkers of HGF/cMet Pathway Activation 
We will also assess candidate peripheral biomarkers for relationship to clinical outcomes. In the 
present study, we will evaluate candidate peripheral biomarkers related to HGF/c-Met pathway 


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activation, including: 
• 
HGF 
• 
Soluble HGF 
• 
IL6 
1.8.3 
Genomic Alterations: PIK3CA, PTEN, and HRAS 
The mutational landscape of HNSCC was assessed by whole exome sequencing of 74 tumor-
normal pairs.37  Several mutations in HNSCC interact with the EGFR and HGF/c-Met signaling 
pathways and may modulate the impact of pathway antagonism. These include PIK3CA (8%), 
PTEN (8%), and HRAS (4%) mutations. As we did not confirm the presence of activating MET 
mutations or amplification described by others, and the TCGA has demonstrated less than 1% 
prevalence  in >300 case of MET mutation or MET amplification, we will not assess MET mutation 
or amplification status.19.38 
1.8.4 
Immune Biomarkers 
HNSCC is an immunosuppressive disease. Patients demonstrate lower absolute lymphocyte 
counts than healthy subjects 39, impaired natural killer (NK) cell activity 40, 41, and poor antigen-
presenting function 42, 43. Mechanistically, HGF inhibits dendritic cell activation by blocking IκB 
kinase activity and subsequent nuclear factor-κB activation. Inhibition of IκB kinase is mediated 
by HGF-induced activation of c-Src.44  Bruton’s tyrosine kinase is also necessary for the 
association of c-Src with c-Met.45 
We will evaluate and describe the immune infiltrate in both archived biopsies (prior to 
cetuximab exposure) and the baseline research biopsies (after cetuximab resistance) from 
patients enrolled in this study. We will relate immunoscores to clinical outcomes.  
1.8.5 
Patient-Reported Outcomes 
Quality of Life (QOL). The Functional Assessment of Cancer Therapy-Head and Neck Symptom 
Index (FACT-H&N SI) will be used to measure global quality of life and functional decline from 
the patient’s perspective. The FACT-H&N SI is an internationally validated QOL tool. It is a 
multidimensional, patient-self report QOL instrument that has been specifically designed and 
validated for this patient population.46  The questionnaire consists of 10 core items that assess 
patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being. 
Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores 
for each domain, as well as a global QOL score; higher scores represent better QOL. The FACT-
H&N SI can be completed by the patient in about 5 minutes, is available in 26 languages, and 
will be completed at baseline, end of cycle 2, and end of cycle 6.  See Appendix A for FACT-
H&N-SI. 


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2. STUDY OBJECTIVES 
 
2.1 Primary 
To assess the efficacy of ficlatuzumab, with or without concurrent cetuximab, in patients with 
cetuximab-resistant, recurrent and/or metastatic HNSCC as measured by Progression-Free 
Survival (PFS). 
2.2 Secondary 
• 
To describe toxicity 
• 
To evaluate response rate and overall survival in both treatment arms. 
2.3 Exploratory 
• 
To describe patient-reported quality of life. 
• 
To evaluate the relationship between clinical outcomes (Progression-Free Survival and 
Response Rate) and candidate tumoral, genomic, peripheral, and immune biomarkers, 
potentially including but not limited to:  
o Tumor HGF and cMet expression 
o mutations in PIK3CA, PTEN, and HRAS;  
o peripheral serum biomarkers including HGF, soluble HGF, and IL6;  
o peripheral lymphocyte populations;  
o archived and baseline immune infiltrate; 
o tumor HPV status. 
 
3. PATIENT SELECTION 
 
3.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
• 
Patients must have histologically confirmed HNSCC from any primary site, except 
nasopharyngeal if WHO Type III (non-keratinizing and EBV-positive).   
ο 
Eligible histologies include: 
 
Basaloid, poorly differentiated, and undifferentiated carcinoma 
histologies. 
 
Nasopharyngeal carcinoma, WHO Type I and II (keratinizing, non-EBV 
positive). 
 
Paranasal sinus, lip, and external auditory canal sites.  


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 
Squamous cell carcinoma of unknown primary, clearly related to the head 
and neck. 
Note:  Documentation of primary site diagnosis must be submitted with the 
registration request. 
• 
Patients must have recurrent and/or metastatic disease, fulfilling at least one of the 
criteria defined below: 
o Incurable disease as assessed by surgical or radiation oncology; 
o Metastatic (M1) disease; 
o Persistent or progressive disease following curative-intent radiation, and not a 
candidate for surgical salvage due to incurability or morbidity. Note: Patients who 
decline radical surgery are eligible. 
• 
For patients with oropharyngeal primary site or unknown primary site only: Patients 
must have known tumoral HPV status (p16). (Acceptable standards include p16 
immunohistochemistry (where a tumor is classified as p16-positive when showing diffuse 
nuclear and cytoplasmic staining in at least 70% of tumor cells) and/or assessment of 
HPV DNA.) 
Note:  For these subjects, documentation of p16 status must be submitted with the 
registration packet. 
• 
Patients must be cetuximab-resistant by fulfilling at least one of the two criteria defined 
below: 
o Disease persistence or recurrence within 6 months of completing definitive 
radiotherapy with concurrent cetuximab for locally advanced disease. Induction 
chemotherapy, if given, may or may not have included cetuximab. 
o Disease progression during, or within 6 months, of cetuximab treatment in the 
recurrent and/or metastatic setting.  
Note:   Prior cetuximab exposure may have occurred in any line of therapy (first line, 
second line, etc.) and is not required to be the most recent therapy received. 
• 
Patients must be platinum-resistant or platinum-ineligible by fulfilling at least one of the 
three criteria defined below: 
o Disease persistence or recurrence within 6 months of completing definitive 
radiotherapy for locally advanced disease, where platinum chemotherapy was 
administered as a component of induction and/or concurrent systemic treatment. 
o Disease progression during, or within 6 months, of treatment with platinum 
chemotherapy (e.g., carboplatin or cisplatin) in the recurrent and/or metastatic 
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o The patient is not an acceptable candidate for platinum chemotherapy due to 
medical comorbidities, in the judgment of the local investigator.  
Note:  Prior platinum exposure may have occurred in any line of therapy (first line, 
second line, etc.) and is not required to be the most recent therapy received. 
• 
Patients must have prior exposure to an anti-PD1 or anti-PDL1 mAb, if eligible for 
immunotherapy in the judgment of the local investigator. 
Note:  Prior exposure to investigational immunotherapies, including anti-CTLA4, anti-
OX40, anti-CD40, anti-CD27, anti-TNFR antibodies or other investigational 
immunotherapies, is acceptable.  
• 
Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 
at time of informed consent (see Appendix B). 
• 
Patients must be age ≥ 18 years. 
• 
Patients must consent to a research biopsy of tumor tissue at baseline, for conduct of 
correlative studies. In cases where a fresh biopsy is not feasible (i.e., if an accessible 
tumor site cannot be biopsied with acceptable clinical risk), archival tissue may be 
submitted instead, after discussion with and approval by the Sponsor-Investigator.  
• 
Patients must have measurable disease per RECIST criteria, version 1.1 (see Section 6) per 
scan within 28 days prior to registration. 
• 
Patients must have adequate electrolytes, liver, renal, and hematology function as 
defined below within 28 days of registration: 
o Absolute neutrophil count (ANC) ≥ 1500/mm3 
o Platelet count (PLT) ≥ 75,000/mm3 
o Creatinine clearance ≥ 30 mL/min per estimated by the Cockraft-Gault formula: 
 
Calculated Creatinine Clearance = [(140-age) X (actual body weight in kg) X 
(0.85 if female)]/(72 X serum creatinine) 
o Total bilirubin ≤ 1.5 times upper-limit of normal (ULN) 
o AST (aspartate aminotransferase) ≤ 3 times ULN  
o ALT (alanine aminotransferase) ≤ 3 times ULN  
o Magnesium ≥ 1.2 mg/dL or 0.5 mmol/L* 
o Corrected Calcium ≥ 8.0 mg/dL or 2.0 mmol/L* 
o Potassium ≥ 3.0 mmol/L*  
o Serum albumin ≥ 25 g/L (≥ 2.5 g/dL) 
(*Note: Patients may be supplemented to achieve acceptable electrolyte values.) 


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• 
Patients must sign written informed consent prior to beginning study screening 
procedures. Patients must have the ability to understand and the willingness to sign a 
written informed consent document. 
• 
Women of child-bearing potential (WOCBP) must agree to have a pregnancy test within 
14 days prior to registration and a repeated test within 3 days of the first dose of 
ficlatuzumab.   
• 
Patients must agree to use highly effective contraceptive measures while on study and 
for 60 days after the last dose of study drug.  This includes: Men of reproductive 
potential AND women of childbearing potential. 
ο 
Effective birth control includes (a) intrauterine device (IUD) plus one barrier 
method; or (b) 2 barrier methods. Effective barrier methods are male or female 
condoms, diaphragms, and spermicides (creams or gels that contain a chemical to 
kill sperm).  
3.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
• 
Nasopharyngeal primary site if WHO Type III (non-keratinizing and EBV-positive as 
established at the local site). 
• 
History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational agent. 
• 
Prior treatment with an HGF/cMet inhibitor such as rilotumumab, crizotinib, MetMAb, or 
ARQ197. 
• 
Uncontrolled central nervous system (CNS) metastases, including leptomeningeal 
metastases, are not allowed.  
Note:  Subjects with previously treated brain metastases will be allowed if the brain 
metastases have been stable without steroid treatment for at least 2 weeks 
(radiotherapy or surgery). 
• 
Failure to recover to Grade 1 or baseline from all toxic effects of previous chemotherapy, 
radiation therapy, biologic therapy, immunotherapy, and/or experimental therapy, with 
the exception of:  
o Alopecia,  
o Grade ≤ 2 peripheral neuropathy,  
o Grade ≤ 2 cetuximab-related rash or other skin changes,  
o Hypomagnesemia (acceptable values detailed in the exclusion criteria below),  
o Hypokalemia (acceptable values detailed in the exclusion criteria below), and  


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o The acceptable ANC and PLT inclusion criteria values above.   
• 
Treatment with cetuximab 2 weeks prior to the first dose of study drug.  A washout 
period of 2 weeks from prior cetuximab is required if applicable.  
• 
Treatment with cytotoxic chemotherapy, targeted therapy, immunotherapy or 
investigational drug 3 weeks prior to the first dose of study drug.  A washout period of 3 
weeks from any prior cytotoxic chemotherapy, targeted therapy, immunotherapy or 
investigational drug is required, if applicable. 
• 
Significant underlying pulmonary disease, including pulmonary hypertension or 
interstitial pneumonitis. 
• 
Peripheral edema ≥ Grade 2 per NCI-CTCAE version 4.0. 
• 
Significant cardiovascular disease, including: 
o Cardiac failure New York Heart Association (NYHA) class III or IV. 
o Myocardial infarction within 6 months prior to registration.  
o Severe or unstable angina within 6 months prior to registration. 
o History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation). 
o Cardiac arrhythmia requiring anti-arrhythmic medication(s). (Beta-blockers, calcium 
channel blockers, and digoxin administered for the purpose of rate control of 
supraventricular tachycardia, including atrial fibrillation and atrial flutter, are not 
classified as anti-arrhythmic medications for purposes of trial eligibility.) 
• 
Significant thrombotic or embolic events within 28 days prior to registration. (Significant 
thrombotic or embolic events include but are not limited to stroke or transient ischemic 
attack (TIA). Catheter-related thrombosis is not a cause for exclusion. Diagnosis of deep 
vein thrombosis or pulmonary embolism is allowed if it occurred > 28 days prior to 
registration and the patient is asymptomatic and stable on anti-coagulation therapy.) 
• 
Any other medical condition (e.g., alcohol abuse) or psychiatric condition that, in the 
opinion of the local Investigator, might interfere with the subject’s participation in the 
trial or interfere with the interpretation of trial results. 
• 
History of second malignancy within 2 years prior to registration except:  
o Excised and cured non-melanoma skin cancer,  
o Carcinoma in situ of breast or cervix,  
o Superficial bladder cancer,  
o Stage I differentiated thyroid cancer that is resected or observed,  
o pT1a /pT1b prostate cancer comprising < 5% of resected tissue with normal prostate 
specific antigen (PSA) since resection, or  


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o cT1a/cT1b prostate cancer treated with brachytherapy or external beam radiation 
therapy with normal PSA since radiation.  
• 
Not completely recovered from any previous surgery. 
Note:  Complete recovery is in the opinion of the treating investigator. Consult the 
Sponsor-Investigator, if needed.  
• 
Active systemic infection requiring systemic antibiotics or antifungals within 7 days prior 
to first dose of study drug, except tetracycline family antibiotics (tetracycline, 
doxycycline, minocycline) administered for the management of cetuximab-related rash 
may be continued per the Investigator’s judgment. 
Note:  Active topical infections (for example oral thrush) do not exclude a subject even 
if treated with systemic antibiotics or systemic antifungals. 
• 
History of severe infusion reaction to cetuximab or a monoclonal antibody. 
• 
Known to be HIV positive.  Note: HIV testing is not required for entry into this protocol. 
• 
Women who are pregnant or breastfeeding. (A negative urine pregnancy test must be 
confirmed within 14 days of registration and repeated within 3 days of the first dose of 
study drug.) 
 
4. PATIENT REGISTRATION AND RANDOMIZATION 
4.1 Registration 
After eligibility has been confirmed, registration will be submitted to the University of Arizona 
Cancer Center using the Registration Form. The study Eligibility Checklist and Registration Form, 
with required source documentation must be provided for the randomization.  The following 
source documentation must be submitted and other documentation may be requested: 
• 
Confirmation of primary site diagnosis. 
• 
For oropharyngeal primary site or unknown primary site, confirmation of p16 (HPV) 
status. 
• 
Signed consent page with Subject ID added, and PHI redacted. 
4.2 Randomization 
Subjects will be randomized to one of the following two arms: 
• 
Arm A:  Ficlatuzumab monotherapy, or 
• 
Arm B:  Ficlatuzumab + cetuximab combination therapy. 
Randomization will be performed by the UACC Biostatistics Shared Resource.  


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Stratification Factors:  
Patients will be stratified by HPV status, a known prognostic factor in recurrent and/or 
metastatic HNSCC, and study center. 
• 
HPV-positive vs. HPV-negative as assessed by p16 status.  
o To be classified as HPV-positive, patients must meet BOTH of the following 
criteria:  
 
1) either oropharynx or unknown primary site; AND  
 
2) p16+ by immunohistochemistry, where ≥ 70% of tumor cells 
demonstrate diffuse nuclear and cytoplasmic staining with p16 antibody.   
o For purposes of stratification, the remainder of patients will be classified as HPV-
negative. 
• 
Study Center 
 
5. TREATMENT PLAN 
Note: One cycle consists of 28 days (with a window of +7 days, that is 35 days maximum), and 
includes two doses of study drug(s), on Day 1 and Day 15 (+/- 3 days unless there is a delay as 
described in Section 5.5). 
The doses of both ficlatuzumab and cetuximab will be recalculated only if there is a ≥ 10% 
change in weight.  Exception:  If, in the opinion of the treating investigator, weight change of ≥ 
10% is due to edema, recalculation of the ficlatuzumab dose is not required.  This decision must 
be clearly documented. 
Refer to Section 5.5 for additional information on dose modifications, delays and skipped 
treatments, and treatment stoppage rules. 
Treatment holidays are allowed, per investigator judgement.  For the purposes of the study 
schedule, treatment holidays will be considered skipped doses. 
5.1 Ficlatuzumab 
The ficlatuzumab Pharmacy Manual provided by Aveo can be referenced for drug preparation 
and administration information. 
The lot of ficlatuzumab will expire on March 31, 2021. The latest administration of ficlatuzumab 
will be on or before that date.  Subjects on the treatment portion of the trial at that time will 
stop the study treatment and be censored for progression. Subjects will be followed for AEs per 


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Section 8.5.1, then enter the progressive disease follow-up as described in Section 5.4.1 and 
Section 8.5.3. Investigators will discuss the transition with their subjects in a timely manner prior 
to the expiration. 
5.1.1 
Route of Administration 
Ficlatuzumab will be administered as an IV infusion.  
5.1.2 
Dose and Schedule 
Ficlatuzumab will be administered at the dose of 20 mg/kg IV every 2 weeks (+/- 3 days). 
Ficlatuzumab will be administered over 30-60 minutes.  
Ficlatuzumab dose must be recalculated if there is a ≥ 10% change in weight.  Exception:  If, in 
the opinion of the treating investigator, weight change of ≥ 10% is due to edema, recalculation 
of the ficlatuzumab dose is not required.  This decision must be clearly documented.   
Protocol-specified dose modifications are permitted. See Table 3 below for dose reduction 
levels. 
5.1.3 
Order of Administration for Arm B (Combination Arm) 
Subjects randomized to the combination arm will receive cetuximab and ficlatuzumab on the 
same day.  Cetuximab will be administered first per the dose and schedule described in Section 
5.2.2. Ficlatuzumab will be administered 30-60 minutes after the completion of the cetuximab 
infusion, per the dose and schedule described in Section 5.1.2. 
5.2 Cetuximab 
5.2.1 
Route of Administration 
Cetuximab will be administered as an IV infusion. 
5.2.2 
Dose and Schedule 
Cetuximab will be administered at the dose of 500 mg/m2 IV every 2 weeks (+/- 3 days), on the 
same day as ficlatuzumab. Suggested schedule:   
• 
The first dose will be administered over 120 minutes (+/- 15 minutes) and at a rate 
no faster than 10 mg/minute.  
• 
Subsequent doses will be infused at a rate no faster than 10 mg/minute.  
Local standard of care can be followed if it is different than this suggested schedule. 
Cetuximab dose must be recalculated if there is a ≥ 10% change in weight.  Exception:  If, in the 
opinion of the treating investigator, weight change of ≥ 10% is due to edema, recalculation of 
the ficlatuzumab dose is not required.  This decision must be clearly documented. 
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levels. 
5.2.3 
Order of Administration for Arm B (Combination Arm) 
See Section 5.1.3. 
5.2.4 
Premedications 
Prior to the first dose of cetuximab, 50 mg of diphenhydramine will be administered PO or IV. If 
the patient shows no evidence of hypersensitivity, the dose of diphenhydramine may be 
reduced to 25 mg PO or IV, or eliminated, per investigator judgment. In patients intolerant of 
diphenhydramine, a non-sedating antihistamine (eg. cetirizine 10 mg) may be substituted per 
local preference. Alternately or in addition, a dose of IV steroids (eg. dexamethasone 10 mg; 
hydrocortisone 50 mg) may be substituted per local preference.  
5.3 General Concomitant Medication and Supportive Care Guidelines 
Colony-Stimulating Factors:  Colony stimulating factors, including G-CSF, pegylated G-CSF, and 
erythropoietin analogs may be used in accordance with local and national practice guidelines. 
5.4 Duration of Treatment and Follow-up 
5.4.1 
Treatment Duration: 
Treatment will continue until one of the following criteria applies: 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient elects to withdraw from the study for any reason, 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, including 
pregnancy. 
• 
March 31, 2021 (expiration date of ficlatuzumab) 
5.4.2 
Follow up duration - WITHOUT progressive disease: 
Patients who stop treatment without progressive disease will be followed approximately every 8 
weeks (+/- 2 weeks) until progression of disease, then every 12 weeks (+/- 2 weeks) for 2 years 
after disease progression. Patients who begin a new line of therapy will be censored for 
progression and be followed per the progressive disease schedule. Refer to Section 8.5 for post-
treatment protocol-required evaluations. 
5.4.3 
Follow up duration - WITH progressive disease: 
Patients who stop treatment with progressive disease will be followed for survival every 12 
weeks (+/- 2 weeks) for two years after disease progression, or until death, whichever occurs 
first. Refer to Section 8.5 for post-treatment protocol-required evaluations. 


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5.4.4 
Follow up for unacceptable adverse events 
Patients who stop the study treatment for unacceptable adverse event(s) will be followed for 60 
days after the last dose of study drug or until resolution or stabilization of the unacceptable 
adverse event.  Patients will then be followed per the schedule described in Section 5.4.2 (also 
see Section 8.5). 
5.5 Dose Delays and Modifications 
5.5.1 
Treatment Plan Interruptions and Delays  
Treatment delays and/or skipped visits must be implemented as follows. 
These definitions are independent of the +/- 3-day window for treatment visits. 
• 
Treatment delays:  Treatment delayed 7 or less days will be considered a delay.  
• 
Skipped/missed treatments:  For a treatment delay that is more than 7 days, the 
treatment will be considered a missed/skipped visit and the next treatment should occur 
at the next regularly scheduled visit. 
Note regarding multiple delays within 2 cycles:  Two or more delays within 2 cycles may result in 
the every-8-week scan occurring out of window.  Contact the Sponsor-Investigator team for 
consensus on subsequent scheduling. 
5.5.2 
Dose Reduction Levels 
The following table summarizes dose levels available for protocol-specified dose reductions of 
ficlatuzumab and/or cetuximab (Table 3).  
Table 3: Dose Reduction Levels 
Dose Level 
Ficlatuzumab 
Cetuximab 
-1 
15 mg/kg q2weeks 
400 mg/m2 q2weeks 
-2 
10 mg/kg q2weeks 
300 mg/m2 q2weeks 
 
Subjects may have up to two dose reductions. Subjects at the lowest ficlatuzumab dose level 
(10mg/kg) who experience an attributable Grade 3 or 4 toxicity will be discontinued from 
ficlatuzumab. However, if in the investigator’s opinion there is evidence of clinical benefit, a 
subject may resume treatment at 10 mg/kg after the AE has resolved or ameliorated to ≤ Grade 
2 or baseline. Contact the Sponsor-Investigator for consensus on subsequent treatment. 
If a cetuximab-related toxicity results in discontinuation of cetuximab permanently, treatment 
with ficlatuzumab can continue. 
If a ficlatuzumab-related toxicity results in discontinuation of ficlatuzumab permanently, per 


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discretion of the treating investigator, treatment with cetuximab can continue. 
5.5.3 
Treatment Stoppage Rules For Toxicity 
If any observed toxicity at least possibly related to ficlatuzumab and/or cetuximab prevents 
dosing within the scheduled study visit window, the dose for that study visit will be skipped and 
the next study drug administration will occur at the next scheduled dose. If a ficlatuzumab-
related toxicity results in 2 consecutive missed doses, the ficlatuzumab will be discontinued 
permanently. However, if in the investigator’s opinion there is evidence of clinical benefit, a 
subject with 2 consecutive missed doses may resume treatment after the AE has resolved to the 
minimum specifications in Table 4A or Table 4B. Contact the Sponsor-Investigator for consensus 
on subsequent treatment. 
5.5.4 
Treatment Interruption for Interstitial Lung Disease 
In the event of acute onset (grade ≥ 2) or worsening pulmonary symptoms which are not 
thought to be related to underlying cancer, both cetuximab and ficlatuzumab should be 
interrupted and a prompt investigation of these symptoms should occur. Neither ficlatuzumab 
nor cetuximab retreatment should occur until these symptoms have resolved to grade 1. If 
interstitial lung disease is confirmed, both cetuximab and ficlatuzumab should be discontinued 
permanently and the patient should be treated appropriately. 
5.5.5 
Dose Modification for Hematologic Toxicity 
While serious (Grade 3-4) myelosuppression has not been observed with ficlatuzumab 
monotherapy or the combination of ficlatuzumab with EGFR-inhibitors during phase I 
development, dose modifications are specified in Table 4A for neutropenia or 
thrombocytopenia, should either be observed during the course of this phase II study. As 
cetuximab does not cause myelosuppression, the cetuximab dose will not be affected by 
observed neutropenia or thrombocytopenia.  
Table 4A. Ficlatuzumab and Cetuximab Dose Modifications for Hematologic Toxicity 
Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
Ficlatuzumab Dose 
Cetuximab Dose 
Neutropenia 
Grade 1-2 
1 (1,500-1,999/mm3) 
2 (1,000-1,499/mm3) 
Maintain dose level 
Maintain dose level 
Grade ≥3: 
3 (500-999/mm3) 
4 (<500/mm3) 
Hold dose. When 
recovered to Grade 2 or 
Maintain dose level 


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better, decrease by 1 dose 
level.  
Thrombocytopenia 
Grade 1 (75,000/mm3-LLN) 
Maintain dose level 
Maintain dose level 
Grade ≥ 2: 
2 (50,000-74,999/mm3) 
3 (25,000-49,999/mm3) 
4 (<25,000/mm3) 
Hold dose. Re-assess prior 
to next scheduled dose. 
When recovered to Grade 
1 or better, decrease by 1 
dose level. 
Maintain dose level 
 
5.5.6 
Dose Modification for Non-Hematologic Toxicity 
Adverse events observed and deemed to be at least possibly related to study drug(s) will be 
managed according to the guidelines for dose interruption, delay, or reduction. 
If the non-hematologic toxicity can be clearly and solely attributed to ficlatuzumab, the 
ficlatuzumab should be withheld or reduced as described below in Table 4B. If the non-
hematologic toxicity is at least possibly related to both ficlatuzumab and cetuximab, then both 
study drugs should be modified as described below. If the non-hematologic toxicity can be 
clearly and solely attributed to cetuximab, the cetuximab should be withheld or reduced as 
described below in Table 4B. 
Table 4B. Ficlatuzumab and Cetuximab Dose Reductions for Non-Hematologic Toxicity  
Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
Metabolic a 
Hypomagnesemia, 
Hypokalemia, 
Hypophosphatemia, or 
Hyponatremia 
 
Grade ≥ 3, Asymptomatic 
 
 
 
 
 
 
 
 
Grade ≥ 3, Symptomatic 
 
 
 
 
 
 
 
Administer PO or IV 
replacement and reassess. If 
Grade ≤2, continue drug at 
same dose level. (Same day 
re-assessment and dosing is 
permissible.) If AE does not 
recover to Grade ≤2, hold 
drug. 
 
Administer PO or IV 
replacement and reassess.  If 
 
 
 
 
 
 
Administer PO or IV 
replacement and reassess. If 
Grade ≤2, continue drug at 
same dose level. (Same day 
re-assessment and dosing is 
permissible.) If AE does not 
recover to Grade ≤2, hold 
drug. 
 
Administer PO or IV 
replacement and reassess.  If 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
≤ Grade 2 and asymptomatic, 
then reduce by one dose 
level. (Same day re-
assessment and dosing is 
permissible.) If AE does not 
recover to Grade ≤2 and 
asymptomatic, hold drug. 
 
≤ Grade 2 and 
asymptomatic, then reduce 
by one dose level. (Same day 
re-assessment and dosing is 
permissible.) If AE does not 
recover to Grade ≤2 and 
asymptomatic, hold drug. 
Hepatic Function 
 
AST and/or ALT Elevation 
 
Grade 2 
 
Grade ≥ 3 
 
 
 
AST or ALT elevation >3x ULN 
and concomitant elevation of 
bilirubin >2x ULN 
 
 
Low Albumin 
 
Grade 3 
 
Grade 4 
 
 
 
 
 
Reduce by one dose level 
 
Hold drug until ≤ grade 2 
then reduce by one dose level 
 
 
Discontinue ficlatuzumab 
 
 
 
 
 
 
No dose reduction 
 
Reduce by one dose level 
 
 
 
 
 
Reduce by one dose level 
 
Hold drug until ≤ grade 2 
then reduce by one dose 
level 
 
Discontinue cetuximab 
 
 
 
 
 
 
No dose reduction 
 
No dose reduction 
Edema:  Head/Facial/Neck edema 
and peripheral edema are to be 
managed individually. 
 
Head/Facial/Neck Edema 
 
Tolerable Grade ≤ 2 
 
 
 
 
 
 
 
 
 
No dose reduction. Treat with 
PO diuretics as clinically 
indicated. 
 
Hold drug. Administer 
steroids c and/or PO or IV 
 
 
 
 
 
 
No dose reduction  
 
 
 
No dose reduction 
 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
Intolerable b Grade 2 (per opinion 
of treating investigator) or Grade 
≥ 3 
 
 
 
 
 
 
Peripheral Edema 
 
Tolerable Grade ≤ 2 
 
 
 
Intolerable b Grade 2 (per the 
opinion of treating investigator) 
or Grade ≥ 3 
 
 
 
 
diuretics as clinically 
indicated. Resume drug when 
≤ tolerable grade 2 and 
reduce by one dose level. 
 
 
 
 
 
No dose reduction. Treat with 
PO diuretics as clinically 
indicated. 
 
Hold drug. Administer 
steroids c and/or PO or IV 
diuretics as clinically 
indicated. Resume drug when 
≤ tolerable grade 2 and 
reduce by one dose level. 
 
 
 
 
 
 
 
 
 
No dose reduction 
 
 
 
No dose reduction 
 
 
 
 
 
Fatigue  
 
Grade ≥ 3, lasting more than 7 
days 
 
 
Hold drug until ≤ grade 2 
then reduce by one dose level 
 
 
Hold drug until ≤ grade 2 
then reduce by one dose 
level 
Nausea/Vomiting 
 
≥ Grade 3 with maximal  
medical management 
 
 
 
Hold drug until ≤ grade 2 
then reduce by one dose level 
 
 
Hold drug until ≤ grade 2 
then reduce by one dose 
level 
 
Dermatologic events 
 
 
 
 
 
 
 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
Rash, Acneiform 
(Grade per Table 5 below.) 
 
≥ Grade 3 
 
 
 
Maintain dose level 
 
 
 
First Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at same dose 
level. If rash remains ≥ Grade 
3 then discontinue 
cetuximab. 
 
Second Occurrence: Hold 
drug for two weeks. If 
improved to ≤ grade 2 then 
restart cetuximab at dose 
level -1. If rash remains ≥ 
Grade 3 then discontinue 
cetuximab. 
 
Third Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at dose level -2. If 
rash remains ≥ Grade 3 then 
discontinue cetuximab. 
 
Fourth occurrence: 
discontinue cetuximab. 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
Paronychia 
(Grade per Table 5 below.) 
 
≥ Grade 3 
 
 
 
Maintain dose level 
 
 
 
First Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at same dose 
level. If paronychia remains ≥ 
Grade 3 then discontinue 
cetuximab. 
 
Second Occurrence: Hold 
drug for two weeks. If 
improved to ≤ grade 2 then 
restart cetuximab at dose 
level -1. If paronychia 
remains ≥ Grade 3 then 
discontinue cetuximab. 
 
Third Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at dose level -2. If 
paronychia remains ≥ Grade 
3 then discontinue 
cetuximab. 
 
Fourth occurrence: 
discontinue cetuximab. 
Pruritus 
(Grade per Table 5 below.) 
 
≥ Grade 3 
 
 
 
 
 
Maintain dose level 
 
 
 
First Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at same dose 
level. If pruritus remains ≥ 
Grade 3 then discontinue 
cetuximab. 
 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
Second Occurrence: Hold 
drug for two weeks. If 
improved to ≤ grade 2 then 
restart cetuximab at dose 
level -1. If pruritus remains ≥ 
Grade 3 then discontinue 
cetuximab. 
 
Third Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at dose level -2. If 
pruritus remains ≥ Grade 3 
then discontinue cetuximab. 
 
Fourth occurrence: 
discontinue cetuximab. 
Rash, other 
(Grade per Table 5 below.) 
 
≥ Grade 3 
 
 
 
Maintain dose level 
 
 
 
First Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at same dose 
level. If rash remains ≥ Grade 
3 then discontinue 
cetuximab. 
 
Second Occurrence: Hold 
drug for two weeks. If 
improved to ≤ grade 2 then 
restart cetuximab at dose 
level -1. If rash remains ≥ 
Grade 3 then discontinue 
cetuximab. 
 
Third Occurrence: Hold drug 
for two weeks. If improved to 
≤ grade 2 then restart 
cetuximab at dose level -2. If 


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Adverse Event 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
 
Ficlatuzumab Dose 
Cetuximab Dose 
rash remains ≥ Grade 3 then 
discontinue cetuximab. 
 
Fourth occurrence: 
discontinue cetuximab. 
Other, Grade ≥ 3 
Events at least possibly related to 
ONLY ficlatuzumab 
 
Hold drug until ≤ grade 1 or 
baseline, then reduce by one 
dose level. 
Maintain dose level. 
 
Other, Grade ≥ 3 
Events at least possibly related to 
ONLY cetuximab 
 
Maintain dose level. 
Hold drug until ≤ grade 1 or 
baseline, then reduce by one 
dose level. 
 
Other, Grade ≥ 3 
Events at least possibly related to 
both ficlatuzumab and 
cetuximab 
 
Hold drug until ≤ grade 1 or 
baseline, then reduce by one 
dose level. 
Hold drug until ≤ grade 1 or 
baseline, then reduce by one 
dose level. 
 
Other, Grade ≥ 3 
Events that are NOT related to or 
expected from either 
ficlatuzumab or cetuximab 
If determined to be clinically significant, in the judgement of 
the treating investigator, hold until resolved to ≤ grade 1 or 
baseline and restart at same dose. 
a. 
Sustained deficiency may require both chronic oral and IV replacement.  An EKG is strongly 
recommended in the event of: 1) symptomatic Grade ≥ 3 hypomagnesemia or hypokalemia or 2) 
asymptomatic Grade 4 hypomagnesemia or hypokalemia.  Interventions, including hospitalization 
as necessary for correction of electrolyte derangement, should occur in accordance with clinical 
severity and investigator judgment.  
b. “Intolerable” is to be determined by treating investigator opinion. 
c. Suggested steroid pulse of Prednisone 40 mg/daily for 5 days.  
 
5.5.7 
Dermatologic Toxicity 
Cetuximab-related dermatologic toxicity should be graded according to the criteria outlined in 
Table 5 below. According to physician judgment, if a patient experiences ≥ grade 3 rash, 
cetuximab treatment adjustments should be made according to Table 4B above. In patients with 
mild and moderate skin adverse events, cetuximab should continue without adjustment. 
 
 


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Table 5: Grading of Cetuximab-Related Skin Changes 
 
1 
2 
3 
4 
Pruritus* 
Mild or localized 
Intense or 
widespread 
Intense or 
widespread and 
interfering with 
ADL 
- 
Rash/acneiform* 
Papules and/or 
pustules 
covering <10% 
BSA, which may 
or may not be 
associated with 
symptoms of 
pruritus or 
tenderness 
Papules and/or 
pustules covering 10-
30% BSA, which may 
or may not be 
associated with 
symptoms of pruritus 
or 
tenderness; 
associated with 
psychosocial impact; 
limiting 
instrumental ADLI; 
Responds promptly 
to symptomatic 
treatment 
Papules and/or 
pustules covering 
>30% BSA, which 
may or may not be 
associated with 
symptoms of 
pruritus or 
tenderness; limiting 
self-care ADL; 
associated with 
local superinfection 
with oral antibiotics 
indicated; 
Prolonged. 
Papules 
and/or 
pustules 
covering any 
% BSA, which 
may or may 
not be 
associated 
with 
symptoms of 
pruritus or 
tenderness 
and are 
associated 
with extensive 
superinfection 
with IV 
antibiotics 
indicated; life 
threatening 
consequences 
 
Paronychia 
Onset of grade 3 
will require dose 
modification for 
cetuximab. See 
Table 4B above. 
Nail fold edema 
or erythema; 
disruption of the 
cuticle 
Localized 
intervention 
indicated; oral 
intervention 
indicated (e.g., 
antibiotic, antifungal, 
antiviral); 
nail fold edema or 
erythema with pain; 
associated with 
discharge or nail 
plate 
separation; limiting 
instrumental ADL 
 
Surgical 
intervention or IV 
antibiotics 
indicated; limiting 
self 
care ADL 
- 
 
 
 


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Cetuximab-Related Rash Management  
Skin rash, ranging from dry skin and erythema to a pustular eruption is extremely common 
during cetuximab therapy. Biopsy of the papulopustular rash demonstrates histopathologic 
suppurative inflammation and not acne vulgaris. Although the initial rash is sterile, 
superinfection may occur.   
Patients developing dermatologic AEs while receiving cetuximab should be monitored for the 
development of inflammatory or infectious sequelae, and appropriate treatment of these 
symptoms initiated. Below are suggestions for managing cetuximab-induced rash, adapted from 
the NCCN Task Force for the Management of Dermatologic Toxicities Associated with EGFR 
Inhibition in Patients with Cancer.47 In the event of severe rash not responsive to topical 
treatments or oral antibiotics, dose modification per Table 4B is indicated.  
• 
Moisturizers: Use of topical emollients to prevent and alleviate skin dryness is strongly 
advised.  Examples include Aquaphor Ointment, Cetaphil Cream, Neutrogena Norwegian 
Formula Hand Cream, and Vaseline Intensive Care Advanced Healing Lotion. 
• 
Soap: A mild, neutral pH soap is recommended. 
• 
Antibiotics: Topical clindamycin or erythromycin, or an oral tetracycline family antibiotic 
(e.g. tetracycline, minocycline, doxycycline) should be considered in the case of 
superinfection or suspected superinfection. Oral minocycline, tetracycline or doxycycline 
may be given prophylactically to patients with a history of severe acneiform eruption 
during prior cetuximab therapy.   
• 
Antihistamines: Diphenhydramine or hydroxyzine may be helpful to control itching. 
• 
Topical Steroids: Topical therapy with a low potency steroid to the face (e.g. 
hydrocortisone valerate 0.2%) or a mid-potency steroid to the body (e.g. triamcinolone 
acetonide 0.1%) may be used for management of cetuximab rash.   
• 
Sunlight: It is recommended that patients wear sunscreen (at least SPF 40) and hats and 
limit sun exposure while receiving cetuximab as sunlight can exacerbate any skin 
reactions that may occur. 
• 
Over-the-counter medications: Over-the-counter acne vulgaris medications (e.g. 
benzoyl peroxide) are not advised.  
• 
Retinoids: Use is not advised. 
5.5.8 
Cetuximab Infusion Reaction 
A cetuximab infusion reaction will be managed as described in Table 6 below. If there is any 
question as to whether an observed reaction is an infusion reaction of Grades 1-4, Dr. Julie 
Bauman should be contacted immediately to discuss and grade the reaction. 


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Should an infusion reaction occur, retreatment will be managed as follows: Once a cetuximab 
infusion rate has been decreased due to an infusion reaction, it will remain decreased for all 
subsequent infusions. If the subject has a second infusion reaction with the slower infusion rate, 
the infusion should be stopped, and the subject should receive no further cetuximab treatment. 
If a subject that experienced an initial cetuximab infusion reaction experiences a Grade 3 or 4 
infusion reaction at any time, the subject should receive no further cetuximab treatment.  
 
Table 6: Management of Cetuximab Infusion Reaction 
Grade 
Management 
Grade 1: 
Transient flushing or 
rash; drug fever 
< 38º C (< 100.4º F) 
For mild infusion reactions manifesting only as delayed drug fever, 
consider administering prophylactic antihistamine medications for 
subsequent doses. Maintain the cetuximab dose but slow the infusion 
rate by 50%. Acetaminophen or a non-steroidal anti-inflammatory drug 
(NSAID) may be administered prior to subsequent cetuximab infusions, 
if not otherwise contraindicated in subjects. 
Grade 2 : 
Rash; flushing; 
urticaria; dyspnea; 
drug fever 
≥ 38º C (≥ 100.4º F) 
For moderate infusion reactions manifesting only as delayed drug 
fever, slow the infusion rate for cetuximab by 50%, and consider 
administration of antihistamine medications and/or steroidal 
medications. Maintain the cetuximab dose. Acetaminophen or a non-
steroidal anti-inflammatory drug (NSAID) may be administered prior to 
subsequent cetuximab infusions, if not otherwise contraindicated in 
subjects. 
Grade 3: 
Symptomatic 
bronchospasm with 
or without urticaria; 
parenteral 
medication(s) 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Severe infusion reactions requires immediate interruption of 
cetuximab infusion and permanent discontinuation from further 
treatment with cetuximab. Appropriate medical therapy including 
epinephrine, corticosteroids, diphenhydramine, bronchodilators, and 
oxygen should be available for use in the treatment of such reactions. 
Subjects should be carefully observed until the complete resolution of 
all signs and symptoms. 


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Grade 4: 
Anaphylaxis 
NO FURTHER CETUXIMAB 
Life-threatening infusion reactions require immediate interruption of 
cetuximab infusion and permanent discontinuation from further 
treatment with cetuximab. Appropriate medical therapy including 
epinephrine, corticosteroids, diphenhydramine, bronchodilators, and 
oxygen should be available for use in the treatment of such reactions. 
Subjects should be carefully observed until the complete resolution of 
all signs and symptoms. 
 
 
6. RESPONSE ASSESSMENT 
Patients are to be re-evaluated for response every 8 weeks, +/- 7 days during at least Cycle 1 
through Cycle 12. Disease assessment is performed per standard of care and per physician’s 
determination of clinical indication. 
Consistent with standard of care, subjects who remain on treatment after cycle 12 can be 
transitioned to re-evaluation for response every 12 weeks, +/- 14 days.  Refer to Section 8.3.3. 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).48  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used. 
The objective malignant disease evaluation will determine the subject’s response, except when 
the subject presents with symptomatic deterioration (“clinical progression”).  Patients with a 
global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having symptomatic 
deterioration. 
6.1 Malignant Disease Evaluation 
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to 
which subsequent measurements will be compared. Measurable disease is defined by the 
presence of at least one measurable lesion. 
All measurements should be recorded in metric notation by use of a ruler or calipers. The same 
method of assessment and the same technique should be used to characterize each identified 
lesion at baseline and during follow-up. All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 28 days before registration. 


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Refer to Section 8.1 Screening/Pre-treatment Evaluations. 
The term unevaluable in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
At baseline, the primary tumor and pathologic neck lymph nodes will be characterized as either 
measurable or non-measurable. 
6.1.1 
Measurable Disease 
Primary and/or Metastatic HNSCC Tumors (non-Lymph node):  
• 
Lesions that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥ 20 mm (2.0 cm) with conventional techniques or as ≥ 10 mm (1.0 cm) 
with spiral CT scan. 
Lymph Nodes: 
• 
Lymph nodes are considered pathologic and measurable if short axis ≥ 15 mm. 
• 
Lymph nodes are considered pathologic but non-measurable if short axis ≥ 10 mm but < 
15 mm. 
• 
Lymph nodes are considered non-pathologic and non-measurable if short axis < 10 mm. 
6.1.2 
Non-measurable disease 
All other lesions, including small lesions [longest diameter < 20 mm (2.0 cm) with conventional 
techniques or < 10 mm (1.0 cm) with spiral CT scan] are truly non-measurable lesions. 
Lesions considered to be truly non-measurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging 
techniques, and cystic lesions. 
6.1.3 
Target Lesions 
Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 


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sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
6.1.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
6.2 Response Criteria 
6.2.1 
Evaluation of Target Lesions 
 
Complete Response (CR) of Target Lesions 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm. 
Partial Response (PR) of Target Lesions 
At least a 30% decrease in the sum of target lesion diameters (longest diameter of non-nodal 
lesions; short axis diameter of the target lymph nodes), taking as reference the baseline sum 
diameter. 
Stable Disease (SD) of Target Lesions 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
Progressive Disease (PD) of Target Lesions 
At least a 20% increase in the sum of target lesion diameters (longest diameter of non-nodal 
lesions; short axis diameter of the target lymph nodes), taking as reference the smallest sum 
diameter recorded since the baseline sum diameter measurements. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: 
the appearance of one or more new lesions is also considered progressions. 
6.2.2 
Evaluation of Non-target Lesions 
All other lesions or sites of disease. Measurements of these lesions are not required, but the 
presence, absence, stable, or progression of each must be noted throughout follow-up. 
Complete Response (CR) of Non-target Lesions 
The disappearance of all nontarget lesions. 
Partial Response/Stable Disease (SD) of Non-target Lesions 


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The persistence of one or more nontarget lesion(s). 
Progressive Disease (PD) of Non-target Lesions 
The appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. Unequivocal progression should not normally trump target lesion status. It must 
be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.2.3 
Evaluation of Patient's Best Overall Response 
The best overall response is the best response recorded from registration until disease 
progression/recurrence, taking as reference for progressive disease the smallest measurements 
recorded since registration. Table 7 below provides overall responses for all possible 
combinations of tumor responses in target and nontarget lesions, with or without new lesions. 
To be assigned a status of stable disease, measurements must have met the stable disease 
criteria at least once after study entry at a minimum interval of eight weeks (+/- 1 week). 
Table 7: Evaluation for Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required*  
CR  
CR  
No  
CR  
>4 wks. Confirmation**  
CR  
Non-CR/Non-PD  
No  
PR  
>4 wks. Confirmation**  
CR  
Not evaluated  
No  
PR  
PR  
Non-CR/Non-PD/not evaluated  
No  
PR  
SD  
Non-CR/Non-PD/not evaluated  
No  
SD  
Documented at least once 
>4 wks. from baseline**  
PD  
Any  
Yes or No 
PD  
No prior SD, PR or CR  
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  
** Only for non-randomized trials with response as primary endpoint.  
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 


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deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 
 
 
First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must 
be confirmed by repeat assessments performed no less than four weeks after the criteria for 
response are first met. 
Duration of Response 
Duration of overall response - the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the first date that 
recurrent or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded since treatment started. 
Duration of Overall Complete Response 
The period measured from the time measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
A measurement from registration until the criteria for disease progression is met, taking as 
reference the smallest measurements recorded since registration. To be assigned a status of 
stable disease, measurements must have met the stable disease criteria at least once after study 
entry at a minimum interval of eight weeks (+/- 1 week). 
Survival 
Survival will be measured from the date of entry on study. 
Time to Progression and Progression-free survival 
This interval will be measured from the date of entry on the study to the appearance of new 
metastatic lesions or objective tumor progression. 
Progression-free survival (PFS) will be calculated from treatment initiation to disease progression 
or death from any cause.  


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6.3 Methods of Measurement 
Disease assessment is performed per standard of care. 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 28 days before registration. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam and measureable by ruler or caliper (clinical lesions). 
Diagnostic CT scan is the preferred modality.  
MRI may be substituted per investigator judgment (e.g., MRI of the neck with contrast, in cases 
where patient has an iodinated contrast allergy despite premedication).  
PET/CT may only be used for tumor measurements if the CT component is of diagnostic quality. 
PET/CT where CT is performed only for attenuation correction is not of sufficient quality for 
RECIST measurements. 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using a ruler or 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact 
image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
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should be performed with breath-hold scanning techniques, if possible. 
PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Cytology, Histology These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 


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• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image.  
 
7. DRUG INFORMATION 
7.1 Ficlatuzumab 
7.1.1 
Study Drug Materials 
The Aveo Pharmacy Manual should be referenced for drug preparation and administration 
information.  
Ficlatuzumab Concentrate for Injection, 50 mg/mL, is formulated in 10 mM histidine buffer pH 
5.8. The formulation also includes 142 mM arginine (for isotonicity) and 0.01% polysorbate-80. 
The product is sterile filtered and aseptically filled into washed and depyrogenated 4-mL and 20 
mL glass vials. An excess fill is provided in the vial to ensure that the label fill of 4.0 mL can be 
withdrawn. The product is a clear to slightly opalescent, colorless to slightly yellow, solution. 
Ficlatuzumab Concentrate for Injection is to be administered by IV infusion as an admixture with 
normal saline solution. The admixture solution in an IV bag is connected to an infusion set 
containing a 0.22 µm low protein-binding in-line filter. The IV bag and the infusion set 
containing the in-line filter have been shown to be compatible with the admixture. The filtered 
admixture solution is clear to slightly opalescent. 
7.1.2 
Ficlatuzumab Study Drug Storage 
Ficlatuzumab is to be stored under refrigerated conditions (2o C – 8oC) and in a secure location.  
Note:  No other use of ficlatuzumab study drug intended for use in this trial is authorized by the 


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sponsor. The investigator (or designee) will be responsible for the appropriate handling and 
disposition of residual study drug in partially used vials.  
Vial Labels: Ficlatuzumab vial labels will bear the appropriate label text for investigational 
agents, as required by governing regulatory agencies. 
Complete study drug information (including packaging, labeling, storage and disposition) is 
provided in the Ficlatuzumab Investigator’s Brochure (IB). 
7.1.3 
Study Drug Accountability 
The local Investigator will be responsible for the supplied study drug, its administration, and 
accountability.  The investigational product must only be used for this protocol and must be 
stored and accounted for consistent with regulatory requirements, the Aveo Pharmacy Manual, 
and this protocol.  An accurate record of all study drugs received, dispensed, returned, and 
destroyed must be maintained. 
7.2 Cetuximab 
Refer to the package insert for additional information. 
Formulation:  Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal antibody. 
Cetuximab is expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors, 
and purified to a high level purity using several purification steps including protein A 
chromatography, ion exchange chromatography, low pH treatment, and nanofiltration. 
Cetuximab is not known to be a vesicant.  
Safety Precautions:  Appropriate mask, protective clothing, eye protection, gloves and Class II 
vertical-laminar-airflow safety cabinets are recommended during preparation and handling.  
Preparation and Administration:  Cetuximab must not be administered as an IV push or bolus. 
Cetuximab must be administered with the use of a low protein binding 0.22-micrometer in-line 
filter.  
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a 
concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and 
colorless and may contain a small amount of easily visible white amorphous cetuximab 
particulates. DO NOT SHAKE OR DILUTE. 
Cetuximab can be administered via infusion pump or syringe pump. 
Infusion Pump: 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike or other appropriate transfer device may be used). 


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2. Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), 
DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags. 
3. Repeat procedure until the calculated volume has been put in to the container. Use a 
new needle for each vial. 
4. Administration must be through a low protein binding 0.22-micrometer in-line filter 
(placed as proximal to the patient as practical). 
5. Affix the infusion line and prime it with cetuximab before starting the infusion. 
6. Maximum infusion rate should not exceed 5 mL/min (10 mg/min). 
7. Use 0.9% saline solution to flush line at the end of infusion. 
 
Syringe Pump: 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike may be used). 
2. Place the syringe into the syringe driver of a syringe pump and set the rate. 
3. Administration must be through a low protein binding 0.22-micrometer in-line filter 
rated for syringe pump use (placed as proximal to the patient as practical). 
4. Connect up the infusion line and start the infusion after priming the line with 
cetuximab. 
5. Repeat procedure until the calculated volume has been infused. 
6. Use a new needle and filter for each vial. 
7. Maximum infusion rate should not exceed 5 mL/min (10 mg/min). 
8. Use 0.9% saline solution to flush line at the end of infusion. 
Cetuximab should be piggybacked to the patient’s infusion line. 
Following the cetuximab infusion, a one-hour observation period is recommended. 
Storage Requirements/Stability 
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). DO NOT FREEZE. Increased 
particulate formation may occur at temperatures at or below 0°C. This product contains 
no preservatives. Preparations of cetuximab in infusion containers are chemically and 
physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at 


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controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining 
solution in the infusion container after 8 hours at controlled room temperature or after 
12 hours at 2° to 8° C. Discard any unused portion of the vial. 
Supply 
Cetuximab is commercially available in the U.S. 
  
 
8. STUDY PROCEDURES/EVALUATIONS 
 
Schedule of Assessments. See Appendix C for Study Calendar.  
 
Coronavirus/COVID-19 Considerations 
As of March 2020, special considerations were implemented in the conduct of clinical trials 
during the COVID-19 public health emergency.  Investigators must determine if changes are 
needed prior to IRB approval in order to eliminate apparent immediate hazard as allowed by 
regulations.  The safety of subjects and others is priority, and the integrity of the study/study 
data must also be considered.  Any changes/deviations related to the COVID-19 pandemic must 
be clearly documented as such and particular attention made to account for any missing data. 
Should an in-person visit not be feasible or present immediate hazard to the subject, a phone 
contact should be performed to assess adverse events, concomitant medications, and ECOG 
performance status, as applicable for the specific visit.  Additionally, the study questionnaires, 
Tobacco Use Assessment and FACT-H&N, can be done by phone or other method as 
appropriate. 
Other potential changes and specific situations can be discussed with the Sponsor-Investigator 
as applicable/needed. 
 
8.1 Screening/Pre-treatment evaluations 
NOTE: All baseline evaluations should be performed as closely as possible to the 
beginning of treatment but must be performed within 28 days prior to registration 
unless otherwise indicated.  
• 
Written informed consent (prior to screening procedures) 


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• 
History and physical examination, including vital signs, weight, height, and ECOG 
performance status determination 
• 
Documentation of medications subject is currently taking 
• 
Complete blood count, including platelets, and differential  
• 
Blood chemistry studies: 
o BUN, creatinine, electrolytes (K+, Na+, CI-, CO2), glucose, calcium, magnesium 
 
Note: Patients may be supplemented to achieve acceptable electrolyte 
values 
• 
Liver function tests: 
o Total protein, albumin, total bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase 
• 
Documentation of calculation of corrected calcium for eligibility criterion  
• 
For women of child bearing potential: Urine pregnancy test within 14 days prior to 
registration to rule out pregnancy. (Note, negative pregnancy test must be confirmed 
again within 3 days prior to first study treatment.) 
• 
Baseline tumor measurements within 28 days prior to registration.   
• 
For oropharyngeal cases and unknown primary: HPV status (p16) status must be 
known or established and recorded at baseline (randomization is stratified by HPV 
status and documentation must be sent with the registration; see Section 4). 
• 
Tobacco history assessment form (See Appendix D) (may be performed at screening 
or prior to study treatment on day 1; the assessment can be performed by method 
other than in-person, if needed, and the method used must be documented) 
• 
Quality of life assessment (FACT-H&N Symptom Index) (may be performed at 
screening or prior to study treatment on day 1; the assessment can be performed by 
method other than in-person, if needed, and the method used must be documented) 
• 
Research blood samples for correlative studies (may be performed at screening or 
prior to study treatment on day 1) 
• 
Research biopsy of tumor tissue before first study drug administration (See Section 
9.2 for more information.) 
• 
Confirm archived tumor specimens prior to cetuximab exposure are available for 
correlative research as outlined in Section 9.1.  (Note:  This is not an eligibility 
requirement and subjects can be randomized without this confirmation.) 
 
8.2 Registration & Randomization 
Once deemed eligible, subject registration will be emailed to the sponsor.  The randomization 
assignment will be returned to the site via email, typically within the day, or the following day 


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(including weekends). 
 
8.3 Evaluations during study treatment 
 
8.3.1 
Every Two Weeks – Day 1 and Day 15 of each cycle (+/- 3 days) 
 
Note: The following may be performed on the day of or within the 3 days prior to study 
drug administration.  If the subject is deemed not acceptable for drug administration, 
refer to the visit delay and skipped visit description in Section 5.5.  Subjects can return 
within the +3-day window, in 1 week, or for the next regularly scheduled treatment.  If 
appropriate, the visit can be skipped and treatment can occur on schedule with the next 
regularly scheduled treatment (i.e., 2 weeks later). 
• 
Physical examination, including vital signs, weight and ECOG performance status 
• 
Adverse Event/Toxicity assessment with attribution 
• 
Update of concomitant medications 
• 
Complete blood count, including platelets and differential 
• 
Blood chemistries: 
o BUN, creatinine, electrolytes (K+, Na+, CI-, CO2), glucose, calcium, magnesium 
 
Note: Refer to Table 4B regarding grading, repletion, holding treatment, 
and/or dose reductions. 
• 
Liver function tests: 
o total protein, albumin, total bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase 
• 
Study drug administration 
o For both agents: Recalculate the doses of both ficlatuzumab and cetuximab only 
if there is a ≥ 10% change in weight.  Exception:  If, in the opinion of the treating 
investigator, weight change of ≥ 10% is due to edema, recalculation of the 
ficlatuzumab dose is not required.  This decision must be clearly documented.  
8.3.2 
Every 8 Weeks (the end of even cycles – “Day 28”/8 weeks, 16 weeks, 
etc.) 
 
• 
Quality of life assessment (FACT-H&N) – end of cycle 2 and cycle 6 only.  
o The FACT-H&N may be done cycle 3, day 1/cycle 7, day 1 for subjects who 
remain on treatment. 
o If a subject stops treatment per the cycle 2 or cycle 6 scan, the FACT-H&N 
scheduled for C2D28 or C6D28 can be done at the End of Treatment visit. 


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• 
Tumor measurements according to RECIST 1.1 may be done during the last week of 
an even cycle, by CT scan or MRI. 
o Tumor measurements must be performed every 8 weeks, +/- 7 days for (at least) 
the first 12 cycles.  (See Section 8.3.3 regarding an optional tumor measurements 
schedule for subjects on treatment longer than 12 cycles.)   
o The schedule is independent of any treatment delays within the 2 cycles since the 
prior response assessment.  (See Section 5.5.1 regarding missed and/or skipped 
visits.) 
o The Response Assessment must be completed prior to drug administration at day 
1 of the following cycle. 
• 
Research blood samples for correlative studies (these may be drawn simultaneously 
with the pre-treatment labs for the following cycle). 
 
8.3.3 
OPTIONAL:  Every 12 Weeks Cycle 13+ (“Day 28” of every 3rd cycle 
after Cycle 12) 
Tumor assessments for this trial are performed per standard of care.  This optional transition to 
an every-12-week assessment is consistent with standard of care. This transition is optional and 
can occur only if it is appropriate as assessed on a patient-by-patient basis. 
Transition to every-12-week tumor assessment will not affect the every-2-week drug 
administration treatment plan described in Section 5 of this protocol.  
 
• 
Subjects who remain on treatment past Cycle 12 (Cycle 13+) can be transitioned from 
every-8-week (+/- 7 days) tumor assessment to every-12-week (+/- 14 days) tumor 
assessment.  
o For example, a subject who has stable disease, partial response, or complete 
response per the Cycle 12, Day 28 scan can have their next scan performed on 
Cycle 15, Day 28, then Cycle 18, Day 28, Cycle 21, Day 28, and so forth. 
o The tumor assessment will be scheduled for Day 28 of every 3rd cycle (+/- 14 
days). 
o The schedule is independent of any treatment delays within the 3 cycles since the 
prior assessment.  (See Section 5.5.1 regarding missed and/or skipped visits.) 
o The Response Assessment must be completed prior to drug administration on 
day 1 of the following cycle. 
• 
Research blood samples for correlative studies will be drawn (blood may be drawn 
simultaneously with the pre-treatment labs for the following cycle). 


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8.4 End-of-treatment (EOT) evaluations 
• 
Patients who discontinue treatment for any reason will have an evaluation with the 
following tests, if possible unless performed within the previous 2 weeks (except as 
noted below) and unless otherwise indicated below.  The EOT evaluations should be 
performed as soon as possible but within 30 days after the off-treatment decision 
date. 
• 
Physical examination, including vital signs, weight and ECOG performance status 
• 
Adverse Event/Toxicity assessment with attribution 
• 
Update of concomitant medications 
• 
Complete blood count, including platelets and differential 
• 
Blood chemistries:  
o BUN, creatinine, electrolytes (K+, Na+,  CI-, CO2), glucose, calcium, magnesium 
• 
Liver function tests: 
o Total protein, albumin, total bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase  
• 
Research blood for correlative studies 
• 
For subjects that end treatment at C2D28 or C6D28, Quality of life (QoL) assessment 
(FACT-H&N) 
o Subjects that end treatment after C4D28 but prior to C6D28 due to expiration of 
the study drug will complete the QoL assessment at the EOT visit  
• 
Tumor measurements according to RECIST 1.1 (unless performed within the previous 
28 days if it is an appropriate standard of care procedure – the EOT tumor 
measurement will not be performed only for the research) 
 
8.5 Post-treatment follow-up 
  
8.5.1 
Adverse Event and Concomitant Medication Follow-up  
AEs and SAEs will be followed per the details below regardless of the reason the subject ended 
treatment. 
• 
Subjects will be followed for AEs (including SAEs) and pregnancy for at least 60 days 
after last dose of study drug(s) or until the initiation of subsequent antineoplastic 
therapy, whichever is earlier.   
• 
Only new AEs that are considered related to the drug and pregnancy need to be 
documented during the 60 days.   


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o Any of related AEs that are SAEs must be reported as an SAE to the sponsor.   
• 
AEs that are determined to be related to the study drug, whether documented during 
treatment or during follow-up, will be followed until resolution or stabilization. 
• 
New concomitant medications do not need to be documented. 
If a subject starts any new antineoplastic therapy, collection and follow up of AEs will stop, 
including AEs considered related/possibly related to the study drug, but SAEs that are 
considered related/possibly related may require continued assessment.  Contact the Sponsor-
Investigator for guidance. 
 
8.5.2 
Discontinuation of treatment WITHOUT progressive disease 
If a patient discontinues treatment without progressive disease (clinical progression or 
radiologically assessed progression), he/she will be followed every 8 weeks (+/- 2 weeks) until 
progression of disease. 
• 
AE/SAE assessment, per Section 8.5.1, must be done at the first follow-up visit after 
discontinuation at the latest.  
• 
Research blood will be drawn at the time of disease progression.  
• 
If a patient discontinues treatment without progressive disease and a new line of 
antineoplastic therapy is initiated, he/she will be censored for progression at that time 
point, research blood should be drawn, and AE/SAE follow up will cease. 
• 
Upon disease progression or censoring for progression, the patient will be followed for 
survival per the progressive disease follow-up schedule in Section 8.5.3.   
Follow-up will include collection of data of the following procedures.  The procedures are not 
required every 8 weeks, but information from such procedures that are done per standard of 
care procedures will be collected if performed: 
• 
Physical examination, including vital signs, weight and ECOG performance status 
• 
Complete blood count, including platelets and differential 
• 
Blood chemistries:  
o BUN, creatinine, electrolytes (K+, Na+,  CI-, CO2), glucose, calcium, magnesium 
• 
Liver function tests: 
o Total protein, albumin, total bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase  


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• 
Adverse event follow-up per Section 8.5.1. 
• 
Survival Assessment 
• 
Research blood for correlative studies at the time of disease progression as noted 
above. 
• 
Tumor measurements according to RECIST 1.1 
 
8.5.3 
Progressive disease follow-up 
Patients who discontinue treatment with progressive disease, experience progression during 
non-progressive disease follow up, or are censored for progression, will be followed for survival 
every 12 weeks (+/- 2 weeks) for 2 years.   
AE/SAE assessment will be performed by phone contact or per a standard of care visit at least 60 
days after the last dose of study drug, and per the requirements in Section 8.5.1.   
 
9. BIOMARKER, CORRELATIVE, OR SPECIAL STUDIES 
Any remaining biospecimens collected for the research will be placed in a biorepository if 
subjects agree and consent to future use of their samples. 
9.1 Submission of archived diagnostic tissue  
For randomized subjects, submission of primary tumor tissue blocks (or slides, if blocks are not 
available) from procedures prior to clinical cetuximab exposure should be submitted for 
biomarker correlatives.  This includes: A representative paraffin block of the original diagnosis 
and/or any repeat diagnostic biopsies, if available. Include a copy of the corresponding 
pathology report with the archived tissue. Collection, preparation, and shipping information for 
the archived tissue is in the Lab Manual. All efforts must be made to obtain paraffin blocks. If 
paraffin blocks are not available or the pathology department will only release slides, please 
contact the Sponsor-Investigator prior to requesting slides. A 3 mm core, punched from the 
tissue block with a punch tool, and 5-10 unstained slides of 5 micron thickness mounted on 
positively-charged glass slides may be acceptable.  
9.2 Research biopsy 
All patients will be evaluated for a research biopsy at the time of enrollment. The biopsy is to be 
done prior to initiation of protocol treatment. Biopsies of primary tumor, accessible metastatic 
tumor, cutaneous lesion, or lymph node can occur in the outpatient office of the head and neck 
surgeon, with local anesthetic per standard of care. Biopsies of lymph nodes requiring imaging 


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guidance or distant metastases will occur under the care of an interventional radiologist, with 
ultrasound or CT guidance and local anesthetic per standard of care. 
Omission of the research biopsy is allowed if performing the biopsy is not safe and/or feasible, 
and/or would present unacceptable clinical risk.  Contact the Sponsor-Investigator for approval 
to omit the research biopsy.  If the research biopsy is omitted, archived tumor tissue should be 
collected to substitute for the lack of baseline tissue. The archived tissue substituted for the 
Research Biopsy should be the most recent biopsy available and the corresponding pathology 
report must be obtained.  (Substitution of archived tumor tissue for the research biopsy is 
independent of the archived tissue submission described above in Section 9.1.) 
9.2.1 
Research Biopsy Methodology 
Research biopsies will consist of a cup forceps biopsy, a core needle biopsy, or a punch biopsy 
that can be safely performed in the outpatient setting with only local anesthesia. During the 
biopsy procedure, at least two cores of tissue 1-cm in length should be obtained with an 18-
guage core biopsy needle (18-gauge or greater is preferred; 20-gauge is acceptable) – or the 
equivalent with cup forceps biopsy.  
Collection, preparation, and shipping information for the research biopsy is in the Lab Manual.  
9.3 Research Blood 
Blood for research purposes will be collected at the following time points:  
• 
baseline 
• 
end of cycles when a tumor assessment is due (Refer to Section 8.3.2 and Section 8.3.3) 
• 
at the end of treatment if not collected within the prior 14 days 
• 
at disease progression if not collected within the prior 14 days 
Peripheral blood obtained by venipuncture will serve as the source for laboratory testing. Up to 
70 mL of blood may be obtained at each draw. See the Lab Manual for collection information. 
Research blood will be used for correlative research and will be batch processed. 
 
10. STATISTICAL METHODS 
10.1  Study Design 
This is an open-label phase II trial with a randomized, non-comparative, two-arm design (Arm A: 
ficlatuzumab vs. Arm B: ficlatuzumab + cetuximab) in patients with recurrent and/or metastatic 
head and neck squamous cell carcinoma after failure of anti-EGFR therapy.  
10.2  Primary Objective 


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The primary objective is to estimate the efficacy of ficlatuzumab, with or without cetuximab, as 
measured by the endpoint of PFS. Patients will be evaluable for PFS from the time of their first 
treatment with ficlatuzumab. PFS will be measured from the date of randomization until the date 
of progression or death. Patients without progression will be censored at the date of last follow 
up. 
10.3  Sample Size Determination 
The primary objective of this study is to estimate PFS in both arms. The sample size calculation 
thus is based on the primary endpoint of PFS. Given no data are available for single-agent 
ficlatuzumab in patients with recurrent and/or metastatic HNSCC refractory to platinum, 
cetuximab, and PD-1 inhibition, the historical control will be represented by dealer’s choice 
chemotherapy in the phase III trial of nivolumab in platinum-refractory HNSCC: 2 months. This 
median PFS is very similar to single-agent data in the refractory, recurrent and/or metastatic 
setting for cetuximab, afatinib, and methotrexate 49, 50.  We would like to investigate whether the 
new regimen in either arm can improve the median PFS from 2 months to 3.33 months (i.e. 60% 
improvement in median PFS). To detect such an improvement, the study design requires 66 
eligible patients (33 eligible patients on each arm) over 24 months with an additional follow-up 
of 6 months (making the study duration of approximately 2.5 years in total), using a log-rank 
test with 90% power while assuming a 0.10 one-sided type 1 error rate.  Full information for the 
primary endpoint of PFS will occur at 33 events per arm. To account for an assumed 10% 
ineligibility/drop-out rate, 74 patients in total will be accrued to obtain the necessary 66 
eligible randomized patients.  If one arm achieves the hypothesized median PFS, that arm will 
be advanced to phase III testing.  If both arms achieve the hypothesized PFS, the numerically 
superior arm will be advanced to phase III testing. 
Definition of Evaluable: 
Subjects who receive at least one dose of ficlatuzumab will be considered evaluable.   
10.4  Secondary Objectives 
The secondary objectives of this trial are to describe toxicity  and, to obtain additional measures 
of efficacy including response rate and overall survival.  
10.4.1 Toxicity 
Patients will be evaluable for toxicity from the time of their first treatment with ficlatuzumab. The 
proportion of AEs will be reported in accordance with NCI CTCAE v.4.0 grading criteria. 
 
10.4.2 Other Efficacy Endpoints 
Response rate will be assessed by modified RECIST criteria, version 1.1. Overall survival will be 
measured from the date of randomization until the date of death. 


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10.5 Exploratory Objectives 
The exploratory objectives of this trial are to describe patient reported quality of life and to 
evaluate whether candidate biomarkers are prognostic in the context of treatment with 
ficlatuzumab.  
10.5.1 Patient-Reported Outcomes 
Quality of life will be described according to FACT-H&N Symptom Index scores obtained at 
baseline and after two cycles of study treatment.  
10.5.2 Biomarker endpoints  
We will evaluate the relationship between clinical outcomes (PFS, RR) and candidate tumoral, 
genomic, peripheral, and immune biomarkers, potentially including but not limited to: tumor 
HGF and cMet expression; mutations in PIK3CA, PTEN, and HRAS; peripheral serum biomarkers 
including HGF, soluble HGF, and IL6; peripheral lymphocyte populations; archived and baseline 
immune infiltrate. 
Two candidate mechanistic biomarkers will be prioritized for specialized alpha spending: 1) 
baseline HGF expression; 2) baseline cMet expression. Testing two biomarkers each at α = .05 
guarantees a maximum 10% false discovery rate for this exploratory objective.  
Other candidate biomarkers in tumor and blood described above will be quantitatively 
measured and will be evaluated as predictors of PFS and/or tumor response in appropriate 
generalized linear models. Calculated p values for testing the significance of the prediction 
models will be adjusted for false discovery by the method of Benjamini and Hochberg.51  
10.6 Statistical Analysis Plan 
Progression-free and overall survival will be estimated for each arm using a Kaplan-Meier curve. 
Toxicities and the response rate will be tabulated and reported with 95% exact confidence 
intervals. The relationship between progression-free survival and the candidate biomarkers will 
be assessed using Cox proportional hazards models. The relationship with clinical response will 
be assessed using logistic regression models. 
10.7  Continuous Monitoring Rule for Futility  
The study will include a continuous Bayesian monitoring rule for futility. We will accrue and 
observe the first 8 evaluable patients on each arm, then continuously observe the proportion of 
patients who are without progression at 16-weeks.  Based on the hypothesized increase in 
median progression-free survival from the historical rate of 2 months to 3.33 months in either 
the ficlatuzumab arm or the ficlatuzumab plus cetuximab arm, the expected proportion 


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progression-free at 16 weeks would be 0.46 under the alternative hypothesis.  A Bayesian 
predictive probability design was used to estimate the rejection regions to stop an arm for 
futility.52  The rejection regions to stop an arm for futility are: 0/8, 1/9, 2/13, 3/16, 4/19, 5/21, 
6/24, 7/26, 8/28, 9/29, 10/31, 11/32, 12/33.  Thus, if none of the first 8 patients is progression-
free at 16 weeks, that arm will be stopped, or if only 1 of the first 9 patients is progression-free, 
that arm will be stopped, etc.  This design has 80% power at α = 0.10 with an expected sample 
size of 21.3 under the null hypothesis and 31.4 under the alternative hypothesis.  The probability 
of early termination under the null hypothesis is 0.86.  The rejection regions were derived to 
maximize power under the alternative hypothesis.  There was no Bayesian predictive probability 
design with 90% statistical power given the proposed median survival times and sample size 
with α = 0.10.  
 
11. DATA SAFETY MONITORING PLAN 
11.1 Identification of the DSMB obligated for oversight responsibilities 
Dr. Julie Bauman at the University of Arizona Cancer Center (UACC) will assume the role of the 
Sponsor.  The UACC Data and Safety Monitoring Board (DSMB) will assume responsibility for 
oversight of safety monitoring. Based on the UACC DSMB Charter this is a high risk study.  
11.2 Identification of the entity obligated and requirements for routine monitoring duties 
Affiliate sites that participate in this trial will choose, through a reciprocal agreement with UACC, 
either to: 
1) Perform monitoring per the sites’ Data and Safety Monitoring Plan, only if the site has 
fully approved NCI Data and Safety Monitoring Plan.  
2) Allow UACC to conduct remote and on-site monitoring for this trial in accordance with 
the UACC’s approved NCI Data and Safety Monitoring Charter/Monitoring Plan. 
3) Perform monitoring per the UACC’s Data and Safety Monitoring Charter/Plan.  
If a site-specific monitoring plan will be used, the UACC DSMB must review the sites’ Data and 
Safety Monitoring Plan and approve that the plan is acceptable.  If the UACC DSMB finds that a 
plan is not acceptable, the UACC or the site’s internal monitors will perform monitoring per the 
UACC Data and Safety Monitoring Plan.  
Elements that are required to be included within each site-specific DSM plan are: 
• 
A process to verify eligibility by the local monitoring team. 
• 
Frequency and extent of monitoring activities for this trial at the site 


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11.3 Monitoring progress, assuring data accuracy and protocol compliance 
Frequency and methodology of routine monitoring may vary slightly from institution to 
institution.  
Regardless of monitoring entity, all monitoring reports must be completed and submitted to the 
local site PI, the Sponsor-Investigator, and UACC DSMB. 
All submitted serious adverse events will be submitted to the UACC DSMB Coordinator monthly 
and then reviewed by the DSMB Chair.  
Any identified SAE trends will be made available for review at the investigator teleconferences. 
A teleconference will occur on a regular schedule to review study progress and any safety, or 
other, issues. Minutes of these teleconference meetings will be submitted to UACC DSMB for 
review.   
At each site, the Principal Investigator will ensure the accuracy, completeness, legibility and 
timeliness of the data reported in the OnCore electronic Case Report Form (eCRF), and other 
data formats. Source documentation supporting the study data should indicate the subject’s 
participation in the trial and should document the dates and details of study procedures, 
adverse events, and patient status.  
Case report forms, which include adverse event forms, serious adverse event forms, and protocol 
or patient deviations must be completed via the UACC OnCore CRM database. 
11.4 Oversight Activities by the UACC DSMB 
Any identified safety issue will be submitted to the UA IRB, DSMB or other oversight entity as 
applicable.  In addition to review of site specific monitoring, the convened UACC DSMB will 
review all monitoring reports and findings every 6 months.  Every 6 months, the UACC convened 
DSMB will perform a review of all study data which will include the following: 
• 
SAEs 
• 
AEs 
• 
Protocol Deviations 
• 
Any pending action items (i.e., responses to DSMB reports; pending items from routine 
monitoring reports). 
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In addition to site specific monitoring, the local PI will complete a status report for each UACC 
DSMB review.  These reports should include summaries of: 
• 
Study activity, cumulative and for the period under review; 
• 
Safety information (non-serious and serious adverse events); 
• 
Status of study in relationship to stopping rules;   
• 
Routine monitoring and protocol compliance (describe the monitoring process and 
identify the status of the monitoring); 
• 
Attachments (AE data reviewed by the PI to compile the report, SAE reports, results of 
any review(s), applicable correspondence with the IRB or other regulatory agencies.  
Data and Safety Monitoring Board determinations will be reported to the University of Arizona 
IRB at least annually.  DSMB determinations will be distributed to the sites contemporaneously.  
11.5 Process to implement study closure when significant risks or benefits are 
identified 
This study may be prematurely terminated, if in the opinion of the investigator or Aveo, there is 
sufficient reasonable cause.  Written notification documenting the reason for study termination 
will be provided to the investigator or Aveo by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Failure to enter patients at an acceptable rate 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient complete and/or evaluable data 
• 
Plans to modify, suspend or discontinue the development of the drug 
Should the study be closed prematurely, remaining study drug must be returned to Aveo or 
destroyed. 
 
11.6 Identification of the sponsor or funding agency, as applicable 
Dr. Julie E. Bauman is the sponsor-investigator responsible for all requirements as set out in 21 
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The sponsor-investigator will immediately notify applicable entities of any action resulting in a 
temporary or permanent suspension of the study.  
 
12. ADVERSE EVENT REPORTING 
12.1  Definitions 
The following definitions of terms apply to this section: 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  The term “Adverse Event” is inclusive of SAEs. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Serious adverse event: An adverse event is considered "serious" if it results in any of the following 
outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• 
a congenital anomaly/birth defect.  
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious 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. 
• 
Pregnancy  
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 


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investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
12.2  Description of Adverse Event Reporting Procedures  
Adverse events will be recorded in the adverse events record form in the UACC OnCore CRM 
and reviewed by the local Principal Investigator. All Adverse Events as defined in this section will 
be collected starting on Cycle 1, Day 1 must be recorded.  AEs will be followed per the details 
indicated in protocol Section 8.5.1.  Only AEs meeting one of the following criteria will be 
entered into the OnCore CRM study database: 
• 
Any AE that is Grade 3 or higher, regardless of relationship to the study drug 
• 
Any AE that results in submission of a Serious Adverse Event (i.e., hospitalization for a 
non-serious grade AE) 
• 
Any intolerable (per the opinion of the treating investigator) Grade 2 AE 
• 
Any Grade AE resulting in a dose reduction of ficlatuzumab or cetuximab 
• 
Any Grade 2 laboratory or vital sign values that are deemed clinically significant by the 
treating investigator 
• 
Any Grade AE in the following categories of interest: 
o Rash 
o Diarrhea 
o Edema, peripheral 
o Edema, head, face and neck 
o Hypoalbuminemia 
 
All adverse events will be classified using either the MedDRA term or NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 and will address: 
• 
Grade 
• 
Relationship to ficlatuzumab (not related, unlikely, possible, probable, definitely) 
• 
Relationship to cetuximab (not related, unlikely, possible, probable, definitely)  


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• 
Causality other than study drug (disease related, concomitant medication related, 
intercurrent illness, other)   
• 
Date of onset 
• 
Date of resolution 
• 
Frequency of event (single, intermittent, continuous) 
• 
Event outcome (resolved, ongoing, death) 
• 
Action taken with ficlatuzumab (none, held, dose reduced, discontinued, medication 
given) 
• 
Action taken with cetuximab (none, held, dose reduced, discontinued, medication given) 
 
12.3 Reporting of Serious Adverse Events 
All Serious Adverse Events as defined in Section 12.1 will be collected starting Cycle 1, Day 1 and 
must be reported to the Sponsor. SAEs will be followed per the details indicated in protocol 
Section 8.5.1. SAEs must be reported to the IRB of Record per local procedure. 
Regardless of attribution, SAEs must be reported to the sponsor and the UACC DSMB within 24 
hours of notification of the event. SAEs will also be copied to the Aveo pharmacovigilance entity, 
Parexel. The FiclaYCetux Serious Adverse Event Report Form must be used to report SAEs and 
redacted, relevant medical records must be attached when available. Follow-up information that 
describes an increase in severity or risk must be submitted within 24 hours of notification of the 
information. Follow-up SAE reports must also be reported within 24 hours of notification of 
updated information related to the event. 
The Sponsor, UACC DSMB, and/or the Aveo pharmacovigilance entity, Parexel, may contact site 
personnel with queries to ensure all necessary information is obtained. 
SAEs must be recorded in the OnCore ”SAEs” tab. 
12.4 Review of Safety Information: Sponsor-Investigator Responsibilities 
The sponsor will review all SAEs and safety information received to determine if the events meet 
the reporting requirements for FDA.  Information will be reviewed and reported, if needed, by 
the Sponsor-Investigator consistent with 21 CFR 312.32 IND safety reporting. 
12.5 IND safety reports for ficlatuzumab 
Suspected, Unexpected, and Serious Adverse Drug Reaction (SUSAR)/IND Safety reports 
received from Aveo will be distributed to site investigators within 15 days of receipt.  Any 
updates to the ficlatuzumab Investigator Brochure will be distributed upon receipt from Aveo. 
 


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13. DATA HANDLING AND RECORD-KEEPING 
Local site PIs are responsible to maintain, archive, and retain research records according to local 
and Federal policy, and per the Clinical Trial Agreement. This includes, but is not limited to, 
accurate drug accountability and disposition records, case histories, and source documents.  
The Sponsor-Investigator will maintain records in accordance with Good Clinical Practice 
guidelines. 
The Sponsor-Investigator will retain the specified records and reports for up to 2 years after the 
marketing application is approved for the investigational drug; or, if a marketing application is 
not submitted or approved for the investigational drug, until 2 years after investigations under 
the IND have been discontinued and the FDA so notified. 
 
14. ETHICS AND REGULATORY COMPLIANCE 
14.1 Institutional Review Board (IRB) approval 
The Sponsor-Investigator will obtain, from the University of Arizona (UA) Institutional Review 
Board (IRB), prospective approval of the clinical protocol and corresponding informed consent 
form(s); modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research subjects) for study recruitment. Once UA IRB 
approval is secured, the revised materials will be distributed to each participating site. Each site 
participating in the trial must obtain IRB approval from the applicable IRB prior to initiating the 
research. 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). Per local procedure, 
investigators must promptly notify the applicable IRB of the deviation. 
The University of Arizona IRB operates in compliance with FDA regulations at 21 CFR Parts 50 
and 21 CFR 56, and in conformance with applicable International Conference on Harmonization 
(ICH) Guidelines on Good Clinical Practice (CGP). 
In the event that the University of Arizona IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of the Sponsor-Investigator’s decision to modify the previously accepted clinical protocol: 
• 
The Sponsor-Investigator will submit (i.e., in advance of implementing the change) a 
Protocol Amendment to the IND describing any change to a Phase 2 or Phase 3 protocol 
that significantly affects the safety of subjects, the scope of the investigation, or the 


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scientific quality of the study. Examples of Phase 2 and 3 clinical protocol changes 
requiring the submission of a Protocol Amendment include: 
ο 
Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any 
significant increase in the number of subjects under study. 
ο 
Any significant change in the design of the protocol (such as the addition or 
deletion of a control group). 
ο 
The addition of a new test or procedure that is intended to improve monitoring for, 
or reduce the risk of, a side effect or adverse event; or the dropping of a test 
intended to monitor the safety of the investigational drug. 
14.2  Ethical and scientific conduct of the clinical research study 
The clinical research study will be conducted in accordance with the current IRB-approved 
clinical protocol; ICH GCP Guidelines adopted by the FDA; and relevant policies, requirements, 
and regulations of the University of Arizona IRB and applicable federal agencies. 
14.3  Subject informed consent 
The Sponsor-Investigator and local site PIs will make certain that an appropriate informed 
consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The site 
PIs or a sub-investigator(s) designated appropriately, will obtain the written, signed informed 
consent of each subject, or the subject’s authorized representative, prior to performing any 
study-specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the issues 
discussed during the informed consent process will be documented in the subject’s case history. 
Each site will retain the original copy of the signed informed consent form, and a copy will be 
provided to the subject, or to the subject’s authorized representative. 
The site PIs/sub-investigators will make certain that appropriate processes and procedures are in 
place to ensure that ongoing questions and concerns of enrolled subjects are adequately 
addressed and that the subjects are informed of any new information that may affect their 
decision to continue participation in the clinical study. In the event of substantial changes to the 
clinical study or the risk-to-benefit ratio of study participation, a revised informed consent will 
be presented to each enroll subjects for their consideration regarding continued participation in 
the clinical study. A subject can withdraw from the study at any time. 


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14.4     Confidentiality 
All records identifying subjects must be kept confidential per local and Federal policy.  Minimum 
necessary standards must be followed. Information sent to the Sponsor must be redacted. Site 
PIs must maintain a list of subjects and assigned study ID numbers to enable identification of 
the patients. Subject identities will not be used in any results that are published. 
 
 


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FiclaYCetux Protocol Signature Page 
Protocol Version:  8 
 
Investigator Agreement 
 
STUDY TITLE: A Randomized, Phase II Study of Ficlatuzumab with or without Cetuximab in 
Patients with Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Squamous Cell 
Carcinoma 
 
By signing below I agree:  
1) That my staff and I have read, understand and will adhere to the protocol as written, and that 
any changes to the protocol will be agreed to and approved by the Principal Investigator and 
the Institutional Review Board (IRB) 
2) To abide by all obligations stated on the FDA Form 1572 and other documents required by 
regulation;  
3) To conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practices (GCP) guidance, the Declaration of 
Helsinki, US FDA regulations and local IRB and legal requirements; 
4) To obtain IRB approval of the protocol, any amendments to the protocol, and periodic re-
approval as required, and to keep the IRB informed of adverse events as required by their 
guidelines report the status of the study to them;  
5) To ensure that each individual enrolled into the trial, or legally authorized representative, has 
read, understands, and has signed the Informed Consent form;  
6) To ensure that I and all persons assisting me with the study are adequately informed and 
trained about the study and the possible adverse events associated with the study required 
medication 
7) To make prompt reports of SAEs and deaths to the Sponsor/FDA according to the 
regulations;  
8) To prepare and maintain adequate and accurate case histories to document all observations 
and other data pertinent to the study for each individual enrolled in the clinical trial.  
 
___________________________________________ 
 
 
_______________ 
Site Principal Investigator Signature   
 
 
Date  
 
___________________________________________ 
Investigator Name (Print) 
 


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15. APPENDICES 
15.1 Appendix A: FACT-H&N Symptom index (FHNSI) 
 
 
 
 


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15.2 Appendix B: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time. 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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15.3 Appendix C: Study Calendar (Also see Section 8) 
 
Screening 
Study Treatment 
End Of 
Treatment 1 
Follow Up 
Within 28 
days of 
registration 
(except 
pregnancy 
within 14 days 
of registration) 
28 Day Cycles 2 
Day 1 
+/- 3 days 
Day 15 
+/- 3 days 
Every 8 
weeks 13 
Day 28 
+/- 7 days 
(C12+ Optional 
q12wks +/- 14d)  
Non-PD 
Follow-
up 3  
PD 
Follow-
up 19 
q8wks 
+/- 2 
week 
q12wks 
+/- 2 
weeks 
Medical History 
X 
 
 
 
 
 
 
Physical Exam & Vital Signs 
X 
X 
X 
 
X 
Z 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 4 
X 4 
 
X 
Z 
 
ECOG Performance Status 
X 
X 
X 
 
X 
Z 
 
CBC with Differential 5 
X 
X 
X 
 
X 
Z 
 
Serum chemistries and Liver 
function tests 5 
X 
X 
X 
 
X 
Z 
 
Magnesium 5 
X 
X 
X 
 
X 
Z 
 
Documentation of Corrected 
Calcium  
X 
 
 
 
 
 
 
Research (correlatives) blood 
X 6 
 
 
X 7 
X 
X 8 
 
Pregnancy test 
X 9 
 
 
 
 
 
 
Research biopsy 10 
X 
 
 
 
 
 
 
Confirmation of availability of 
archived diagnostic specimens 
X 11 
 
 
 
 
 
 
Tumor measurements,  
RECIST 1.1 (CT or MRI) 12 
X  
 
 
X 13 
X 
Z 
 
FACT-H&N Symptom Index 
X 6 
 
 
X 14 
X  14 
 
 
Tobacco Assessment 
X 6 
 
 
 
 
 
 
Oropharyngeal & unknown 
primary cases, p16 Status 15 
X 
 
 
 
 
 
 
Registration/Randomization 
X 
 
 
 
 
 
 
Cetuximab 
 
X 
X 
 
 
 
 
Ficlatuzumab 
 
X 
X 
 
 
 
 
Concomitant medication review 
X 
X 
X 
 
X 
 
 
Adverse event evaluation 
 
X 
X 
 
X 16 
X 17 
X 18 
Survival assessment 
 
 
 
 
 
X 
X 19 


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1 The End of Treatment visit should be performed as soon as possible, but preferably within 30 days after the off-
treatment decision date.  Procedures will be performed if not performed in the previous 14 days, except tumor 
measurements should only be performed if not performed in the previous 28 days and only if it is an appropriate 
standard of care procedure.    
2 Refer to Section 5.5.1 which addresses scheduling when there are missed and/or skipped visits due to treatment 
delays or other. 
3 Procedures indicated with “Z” are not required to be performed for the research, but if they are performed for 
standard of care, the data will be collected. Patients who initiate a new line of antineoplastic therapy will be 
censored for progression at that time point; research blood will be drawn and they will be followed per the 
progressive disease follow-up schedule. 
4 For both agents: Recalculate the doses of both ficlatuzumab and cetuximab only if there is a ≥ 10% change in 
weight.  Exception:  If, in the opinion of the treating investigator, weight change of ≥ 10% is due to edema, 
recalculation of the ficlatuzumab dose is not required.  This decision must be clearly documented.  Refer to Section 
5. 
5 May be performed on the day of, or within the 3 days prior to study treatment. 
6 May be performed during screening, or prior to drug administration on Cycle 1, Day 1. 
7 For convenience, research blood may be drawn simultaneously with pre-treatment labs for the next cycle.  Subjects 
who transition to every-12-week tumor assessments will have the research blood drawn every 12 weeks, consistent 
with the tumor assessment schedule.  Refer to Section 8.3.3 
8 Research blood will be obtained at the time of disease progression or censored for progression (see footnote 3 
above, and Section 8.5.2) during the follow up period, then followed per the progressive disease follow up. 
9 A negative pregnancy test is required in women of child-bearing potential within 14 days prior to registration. 
Negative pregnancy test must be confirmed again within 3 days prior to first drug administration. 
10 Archived tumor tissue, preferably the most recent tissue available, may be substituted if the biopsy is not safe 
and/or feasible, and/or would present unacceptable clinical risk, and the Sponsor has approved omission of the 
baseline biopsy. See Section 9.2. 
11 Archived tissue, preferably primary tumor tissue blocks (or slides, if blocks are not available) from procedures 
prior to clinical cetuximab exposure. This is not an eligibility requirement and subjects can be randomized 
without this confirmation. 
12 For scheduling convenience, tumor measurements may occur on day 1 of the following cycle, so long as the scan 
is done and results are known prior to drug administration. 
13 Tumor measurements must be performed every 8 weeks, +/- 7 days, regardless of any delay that occurs within 
the prior 2 cycles.  Subjects who remain on treatment past Cycle 12 can transition to tumor assessments being 
performed every 12 weeks, +/- 14 days.  Refer to Section 8.3.3. 
14 FACT-H&N Symptom Index will be performed at baseline and at the end of cycle 2 and cycle 6 only, or when the 
subject is censored for progression after C4D28 but before C6D28 (see EOT procedures). For scheduling 
convenience, FACT-H&N Symptom Index may be completed on day 1 of the following cycle or at the EOT visit.   
15 For oropharyngeal & unknown primary, p16 status must be established, if not previously known, before 
randomization. 
16 Subject will be followed for AEs/SAEs for 60 days after last dose of study drug or until the initiation of 
subsequent antineoplastic therapy, whichever is earlier. (Refer to protocol Section 8.5.1 for important and specific 
details on collection and follow up of AEs.)  
17 Subjects who end treatment due to a reason other than progressive disease will have an AE assessment at the 
first follow-up visit. (Refer to protocol Section 8.5.1 for important and specific details on collection and follow up of 
AEs.) 
18 Subjects who end treatment due to progressive disease will have an AE assessment at least 60 days after last 
dose of study drug. (Refer to protocol Section 8.5.1 for important and specific details on collection and follow up 
of AEs.) 
19 Subjects will be followed for survival for 2 years after disease progression. 


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15.4 Appendix D: Tobacco Use Assessment Form 
 
 
 


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16. 
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33. Bossi P, Kornek G, Lanzetta G, et al. Safety and feasibility of every-other-week maintenance cetuximab 
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106. 
 
 

ICF_001.pdf: 
UACC Consent Version: 09/04/2020 
 
Page 1 of 19 
 
 
  
HSPP Use Only: 
B–UM/UA T503a v 2016-10 
Consent to Participate in Research 
 
Study Title: A Randomized, Phase II Study of Ficlatuzumab with or without Cetuximab in 
Patients with Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Squamous Cell 
Carcinoma 
 
Principal Investigator: Julie E. Bauman, MD, MPH 
 
Sponsor: University of Arizona Cancer Center 
 
 
This is a consent form for research participation.  It contains important information about 
this study and what to expect if you decide to participate.  Please consider the information 
carefully. Feel free to discuss the study with your friends and family and to ask questions before 
making your decision whether or not to participate. 
This is a clinical trial, a type of research study. Clinical trials include only people who choose to 
take part. You are being asked to take part in this study because you have Head and Neck 
Squamous Cell Carcinoma. This study will enroll both males and females, 18 years of age or 
older, for whom cetuximab did not or does not work. Your doctor will determine your ability and 
eligibility to participate in this study. 
Taking part in this study is entirely voluntary and up to you to decide. In order to decide whether 
or not you wish to take part, you should understand enough about its purpose, procedure, risks, 
benefits, and costs to make an informed decision. This process is known as Informed Consent. 
Before you agree to participate in this study, it is important for you to understand why the study 
is being done and what the requirements are for your participation. Please take time to read the 
following information carefully and ask questions if anything is not clear. This consent form 
describes the purpose, procedures, precautions, the possible benefits, risks (side effects), and 
discomforts that go along with your participation in this study. This consent form also outlines 
your rights as a subject involved in a study. If you agree to participate, you will be asked to sign 
this form. 
The consent form also describes the alternative procedures that are available to you, and your 
right to withdraw from the study at any time. Take as much time as you want to decide whether 
or not you wish to take part. 
The University receives compensation from the sponsor of this study for the conduct of this 
study.  If you have any questions, please discuss this with your study doctor. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by US 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
  
Why is this study being done? 
The main goal of this research study is to study the safety and effectiveness of ficlatuzumab 
with or without cetuximab to determine which will be more effective, as well as to learn the 
potential side effects of ficlatuzumab alone or in combination with cetuximab.  
 
It was recently determined that not enough patients were benefiting from receiving only 
ficlatuzumab. Although some patients benefited, there were not enough to continue adding 
patients to that group. Therefore, if you are eligible for the study, you will receive ficlatuzumab 
with cetuximab. 
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HSPP Use Only: 
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Ficlatuzumab is considered an “experimental” drug because it has not been approved for 
commercial use in the treatment of cancer by any authority that regulates new drugs, including 
the U.S. Food and Drug Administration (FDA). Ficlatuzumab is a monoclonal antibody, also 
referred to as a targeted therapy or an immunotherapy. Ficlatuzumab works by blocking growth 
signals that let a cancer cell survive and reproduce, and may also help the immune system 
recognize and fight cancer. 
 
Cetuximab is an approved chemotherapy drug by the Federal Drug Administration (FDA) for 
treating squamous cell carcinoma of the head and neck in which prior platinum-based therapy 
(chemotherapy) has failed. Cetuximab is a monoclonal antibody, also referred to as a targeted 
therapy or an immunotherapy. Cetuximab is given as an anti-cancer therapy because it blocks 
growth signals that lets a cancer cell survive and reproduce, and helps the immune system 
recognize and fight cancer. 
 
If you participate in this study we will also collect samples of blood and tissue to determine how 
your body processes the study drug combination of cetuximab and ficlatuzumab and the effects 
they have on the various biomarkers (a DNA sequence that causes disease or is associated 
with susceptibility to disease) related to your cancer. 
 
What will happen if I take part in this study?  
If you join this study, you will be asked to sign this consent form before you receive any study 
related tests or procedures.  
 
Screening Procedures 
After signing this consent form, you will need to have exams, tests or procedures to find out if 
you can be in the study. Some exams, tests or procedures are part of regular cancer care and 
may be done even if you do not join the study, such as medical history, review of your current 
medications, routine blood draws, and physical examination. If you have had some of them 
recently, within 28 days of the first dose of study drugs, they may not need to be repeated. This 
will be up to your study doctor. Some procedures may be done only for the purposes of the 
research.  This includes a blood draw and a pregnancy test if applicable. The tests will be done 
by your study doctor, or a nurse, physician assistant, nurse practitioner, or laboratory technician 
under your study doctor’s supervision, and will take about 2-4 hours to complete. If the results of 
these screening tests determine you are not eligible, you will be removed from the study and 
your doctor will discuss alternative treatments with you. 
 
Baseline Research Procedures 
After the screening procedures, if it is determined you are eligible to participate, you will 
undergo additional procedures that are only being performed because you have agreed to 
participate in this study. These will be referred to as research procedures and are described 
below. These will be done by your study doctor, a nurse, physician assistant, nurse practitioner, 
phlebotomist, pharmacist, or laboratory technician under your study doctor’s supervision and will 
take about 3-4 hours to complete. 
 
• 
Blood draw (about 5 Tablespoons) for various research blood tests may be performed 
after consent and before first study treatment.  This and all research blood may be 
drawn at the same time blood is drawn for your regular care. 
• 
Research Biopsy: You will also have a biopsy prior to the first study treatment so long 
as it is safe and/or feasible. This will be used for research testing only.  
o To be in the study, you must agree to have the research biopsy performed. A 
biopsy is a standard, commonly performed procedure in which a piece of tissue 
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UACC Consent Version: 09/04/2020 
 
 
Page 3 of 19 
 
 
 
 
  
HSPP Use Only: 
B–UM/UA T503a v 2016-10 
(tumor or mass) is taken and studied under the microscope. Details on the biopsy 
procedure are provided at the end of this document. 
• 
Quality of life assessment: The Functional Assessment of Cancer Therapy-Head and 
Neck (FACT H&N) Symptom Index Questionnaire will be completed to assess your 
symptoms related to your cancer. This may be performed any time after consent but 
prior to your first study treatment and takes about 5 minutes to complete. If any 
questions make you feel uncomfortable, you may skip those questions and not give an 
answer. This can be done during an in-person visit but can also be done by phone, or 
other method, if needed. 
o The questionnaire asks about your view of how your life has been affected by 
cancer and its treatment. There are 10 questions. This information will help 
doctors better understand how patients feel during treatments and what effects 
the medicines are having. 
• 
Tobacco Use Assessment: A questionnaire about your tobacco use history will be 
completed. This takes about 5-10 minutes to complete. This can be done during an in-
person visit but can also be done by phone, or other method, if needed. 
o The assessment has 13 questions about the type of tobacco and quantity you 
may have used. If any questions make you feel uncomfortable, you may skip 
those questions and not give an answer. 
 
Archival tumor tissue (tissue from a prior biopsy or tumor excision) will be requested to be 
used for research purposes to learn more about the makeup of tumor tissues and the 
development of cancer.  
 
If you are eligible to receive the study drug(s), you will receive ficlatuzumab in combination with 
cetuximab.  
 
Study procedures will occur on a regular schedule, known as a “cycle.” Each cycle is 4 weeks. 
 
Study Drug Administration 
You will receive the study drugs every 2 weeks. You will be evaluated periodically to determine 
if the study treatment is working. If it is, you will continue at the same dose and schedule for as 
long as the study treatment helps or until March 31, 2021, whichever is sooner.  (See the 
section below titled, How long will I be in this study?) 
 
• 
You will receive the study drugs on the same day.  
 
• 
The drugs will be administered intravenously (through the vein). You will receive 
cetuximab first, and then ficlatuzumab. 
 
• 
Before you receive cetuximab, you will receive pre-medications to prevent allergic 
reactions and to replace body fluids, if necessary. 
 
• 
You will receive cetuximab. The cetuximab infusion will last between 1 to 2 hours. 
 
• 
There will be 30-60 minutes between the cetuximab and ficlatuzumab infusions. 
 
• 
You will then receive ficlatuzumab. The ficlatuzumab infusion will last between 30 to 60 
minutes.  
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• 
The infusions will take about 4 hours total, including administration of pre-medications. 
 
Study Drug Doses 
 
• 
Ficlatuzumab will be administered at the dose of 20 mg/kg IV every 2 weeks (+/- 3 days).  
 
• 
Cetuximab will be administered at the dose of 500 mg/m2 IV every 2 weeks (+/- 3 days).  
 
• 
Dose modifications for ficlatuzumab and cetuximab are allowed if you experience certain 
side effects from the study medications.   
 
Every Two Weeks  
(The following may be performed on the day of or within the 3 days prior to the study drug 
infusion) 
• 
Toxicity/adverse event assessment to evaluate if the study drugs are having harmful 
effects on you. Note: if a toxicity occurs, this will be assessed at each visit and you may 
need to be seen more frequently until the issue is resolved. 
• 
Physical examination, including vital signs, weight and performance status 
• 
Update of concomitant medications 
• 
Blood draw (about 5 tablespoons) research purposes 
  
Every 8 Weeks (The end of even cycles)  
(The following may be performed on the day of or within the 3 days prior to the study drug 
infusion) 
• 
As part of your regular care, you will have a tumor assessment every 8 weeks (+/- 7 
days).  Information from this procedure, which is typically a CT Scan or MRI, will be used 
to assess your response to the study drug(s).   
• 
Quality of life assessment (FACT-H&N) – end of cycle 2 and cycle 6 only. 
o This questionnaire can be done by phone or mail, or other method, as needed.  
• 
Toxicity/adverse event assessment to evaluate if the study drug/study drugs are having 
harmful effects on you. Note: if a toxicity occurs, this will be assessed at each study visit 
and you may need to be seen more frequently until the issue is resolved. 
• 
Blood draw (about 5 tablespoons) for research purposes  
 
Typically, visits when you receive the study drug infusion will take about 4-5 hours.  Visits may 
take longer depending on how long it takes to prepare the study drug(s) for infusion.  It is 
possible that that visits could take 5-8 hours. 
 
If you miss an in-person visit, the study staff may contact you by phone or other method to 
obtain an update and assess your health to the extent possible.  If you have telemedicine visits 
for your regular care, this information can be obtained during those visits. 
 
End of Treatment Evaluation: 
When you discontinue study treatment for any reason you will have an end-of-treatment visit 
within 30 days and the following tests will be done, if possible, unless performed within the 
previous 2 weeks: 
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• 
Toxicity/adverse event assessment to evaluate if the study drugs are having harmful 
effects on you. Note: if a toxicity occurs, you may need to be seen about every 2 weeks 
until the issue is resolved.  
• 
Blood samples (about 5 tablespoons) for research purposes. 
• 
The Quality of Life assessment if you end the study treatment at Cycle 2 or Cycle 6.  
 
End of Treatment Evaluations if Ending Treatment Due to the Study Drug Expiration: 
The latest that ficlatuzumab will be available is March 31, 2021.  If you are continuing the study 
treatment into March 2021, your study doctor will discuss the transition with you ahead of time 
to determine continuation of treatment for your cancer. 
 
At that time, you will stop receiving the study drug, but your participation in the study will not 
end.  You will have an end-of-treatment visit as described above.  You may be asked to 
complete the quality of life assessment questionnaire if you are stopping the study treatment 
before the end of Cycle 6.  You will be followed for any new adverse events or pregnancy for 60 
days.  Then you will enter the follow-up portion of the study.  You will be followed every 3 
months to determine your survival status.  
 
Long-Term Follow up: 
• 
You will be followed for 60 days after the last dose of study drug for any new adverse 
events, and for pregnancy, if applicable. This may include a phone call to assess adverse 
events, or you may be assessed during a visit for your regular care. 
• 
Any toxicities/adverse events will be followed until they resolve or stabilize. 
• 
If you stopped the study treatment for due to disease progression, or due to the study drug 
expiration, you will be followed about every 3 months to determine your survival status. 
• 
If you stopped the study treatment for a reason other than disease progression, you will 
be followed about every 8 weeks to determine your survival and disease status. 
o If you experience disease progression during the follow-up period:  
 
A blood draw (about 5 tablespoons) for research purposes will be performed. 
 
You will then be followed every 3 months for 2 years to determine your survival 
status. 
 
The study procedures may overlap with your regular cancer care.  Information from your regular 
care will be collected for the study.  This includes physical exams, vital signs, and regular lab 
tests.  Only procedures done for the research are listed above.  There is a possibility that the 
tests or procedures may need to be done at times other than those listed above. These may be 
done if your doctor determines they are medically necessary to monitor your illness or any side 
effects you may be experiencing. It is important that you call your doctor if at any time you are 
experiencing side effects you cannot tolerate.  
  
How long will I be in this study? 
It is unknown how long you will be in the study. The screening evaluation will take place within 
the 4 weeks prior to the first study treatment.  You will continue the study treatment if it is 
working to shrink or stabilize your cancer or until March 31, 2021. The last ficlatuzumab 
infusions will be on or before March 31, 2021. Ficlatuzumab will not be available after that date 
because the study drug is expiring. 
 
Follow-up will begin when you stop the study treatment. If you experience disease progression, 
either during the study treatment or while in follow up, or if you stop the study treatment due to 
the study drug expiration you will then be followed for survival every 3 months for two years.  
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How many people will take part in this study? 
Up to 74 people will participate in this research study at all sites. Locally, we expect to enroll 
about 22 people in this research study.  
 
What benefits can I expect from being in this study? 
We cannot predict in advance whether you will receive any direct benefit from participating in 
this study or not. Taking part in this study may or may not make your health better. A possible 
benefit of your participation may be that researchers may learn more about your disease, which 
may, in turn, help others. 
 
What risks, side effects or discomforts can I expect from being in the study? 
Drugs for cancer are strong and have side effects. You may have side effects while on the 
study. As with any experimental procedure, there may be adverse events or side effects that are 
currently unknown. Side effects can go away shortly after drug administration is stopped, but 
some risks could be long-lasting, permanent, serious, life threatening, or even cause death. 
Everyone taking part in the study will be watched carefully for any side effects. Your doctor may 
also give you additional medications to ease any side effects you may experience during the 
study. You should talk to your study doctor about these medications and any side effects you 
may experience while taking part in the study. 
 
Ficlatuzumab Risks 
Because Ficlatuzumab is an investigational drug, there may be other risks that are unknown at 
this time. The following are the most commonly indicated as related to treatment in previous 
clinical studies: 
 
Side effects of Ficlatuzumab (occurring in 5% of participants or more) 
• 
Decreased appetite 
• 
Diarrhea 
• 
Swelling of the feet, ankles or other parts of the body 
• 
Nausea 
• 
Rash, or an appearance similar to acne 
• 
Bacterial skin infection, which may cause swelling, redness, and sensitivity 
• 
Vomiting 
 
Side effects of Ficlatuzumab (occurring in 5% of participants or less) 
• 
Dry skin 
• 
Feeling weak or tired 
• 
Headache 
• 
Electrolytes, such as potassium, magnesium, etc., may decrease (the most common 
symptoms of this are muscle tremor, weakness, confusion, irregular heartbeat) 
• 
Low albumin in the blood (symptoms can include swelling of the feet or ankles) 
• 
Low red blood cells (anemia) 
• 
Muscle pain or tenderness 
• 
Itchiness 
• 
Chills  
• 
Dizziness 
• 
Muscle Spasms 
• 
Infection in the blood  
• 
Pneumonitis (lung inflammation) which can cause difficulty breathing 
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One participant experienced a mild infusion-related reaction (e.g. chills, shaking, and fever) 
related to ficlatuzumab. The reaction was treated and resolved the same day. Approximately 4 
weeks later, the participant had a second mild infusion-related reaction to ficlatuzumab. The 
second reaction was treated and resolved the same day. No further infusion-related reactions 
were reported. 
 
This study uses the combination of ficlatuzumab and cetuximab. The risks for the combination 
of these drugs are currently unknown. Below please find details the risks of cetuximab alone. 
 
The following two risks have been found when ficlatuzumab is taken in combination with the 
same kind of medication as cetuximab. These are also risks of cetuximab alone. 
• 
Inflammation of the skin around your finger and toe nails 
• 
Bleeding gums 
 
Cetuximab (Erbitux®) Risks 
The information provided below was obtained from the manufacturer’s website: 
http://erbitux.com/understand-erbitux.html.  
 
For additional information, please request a copy of the current cetuximab package insert from 
your study doctor or visit: 
 http://uspl.lilly.com/erbitux/erbitux.html. 
 
Common: 
• 
Rash, which can look just like acne, but which can be severe 
• 
Fatigue 
• 
Fever 
• 
Skin changes, including dryness, itchiness, and cracking 
• 
Inflammation of the skin around your finger and toe nails 
• 
Mucositis / stomatitis (irritation or sores in the lining of the mouth and/or through the 
gastro-intestinal tract, which can become severe especially if cetuximab is given along 
with radiation) 
• 
Infection 
• 
Chills 
• 
Difficulty swallowing 
• 
Constipation 
• 
Upset stomach 
• 
Cough 
• 
Electrolyte imbalance (low levels of magnesium in the blood) 
• 
Increase in liver enzymes 
• 
Increase in the amount of hair growth 
• 
Sun sensitivity – you should avoid sun exposure while receiving cetuximab and for 2 
months after the last dose 
 
Infrequent: 
• 
Allergic reaction, which can cause hives, shortness of breath, wheezing, or back pain 
o There is an increased chance of allergic reaction if you have a red meat allergy or 
history of tick bites. 
• 
Nail changes 
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• 
Nausea and vomiting 
• 
Dry mouth 
• 
Diarrhea 
• 
Weight loss 
• 
Headache 
• 
Tiredness 
• 
Cardiopulmonary arrest – a temporary or permanent cessation of the heart 
• 
Eye dryness or infection 
 
Rare: 
• 
Allergic reactions that can cause severe difficulty breathing, irregular heartbeat, low blood 
pressure, and can even be life threatening; in rare circumstances, this can lead to death. 
• 
Sudden death 
• 
Aseptic meningitis (inflammation of the layers that surround the brain) 
• 
Interstitial Lung Disease which can cause inflammation in the lungs and breathing 
problems 
 
Blood Draw:  
Risks associated with the drawing of blood might include a small amount of pain from the 
puncture, bruising, bleeding, infection, or fainting. Every effort will be made to minimize 
discomfort. 
 
IV insertion 
Infrequent:  
• 
Mild pain, discomfort, and/or bruising at the injection or needle insertion site 
• 
Inflammation of the vein, as well as possible infection, bleeding, and soreness.  
 
Rare: 
• 
Severe pain, swelling, possibly an infection from the actual injection, fainting. 
 
Biopsy:  
The risks associated with a biopsy are soreness and discomfort. You may feel a stinging 
sensation each time the biopsy needle pierces the tumor. Serious bleeding and infection are 
very rare, but minor bleeding is relatively common. Alert your doctor immediately if the bleeding 
is heavy or prolonged. To prevent bleeding, your doctor may ask you to stop taking any 
medications that interfere with blood clotting, such as aspirin or Coumadin, before the biopsy. 
To prevent infection, you may be asked to take antibiotics before and after the procedure.  
 
Reproductive risks:  
You should not become pregnant or father a baby for the duration of your study participation 
and 60 days after the last dose of study drugs because the risks of receiving cetuximab and 
ficlatuzumab can affect an unborn baby. Women should not breastfeed a baby while on this 
study as harmful toxins can be passed to the baby through breastmilk. Women of childbearing 
age will have a pregnancy test within 14 days before beginning study treatment and again within 
3 days of the first study treatment. Also, if applicable, breastfeeding must be discontinued if you 
are receiving the study drugs.  
 
Avoiding sexual activity is the only certain method to prevent pregnancy. However, if you are a 
female of childbearing potential and you choose to be sexually active, you should use an 
appropriate “double barrier” method of birth control (if your blood counts are not low and after 
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consulting with your doctor you may use a diaphragm, intrauterine device [IUD], or 
contraceptive sponge, in addition to male use of a condom with a spermicide), or you should be 
using prescribed “birth control” pills, injections, or implants, if found to be acceptable by your 
doctor. 
 
If you are male and choose to participate in this study, your participation in this research may 
damage your sperm, which could cause harm to a child that you may father while on this study. 
If you are sexually active, you must agree to use a medically acceptable form of birth control in 
order to be in this study. Medically acceptable contraceptives include surgical sterilization, or a 
condom used with a spermicide. You should inform your partner of the potential for harm to an 
embryo, fetus (unborn child). She should know that if pregnancy occurs, you will need to report 
it to the study doctor, and she should promptly notify her doctor. Acceptable birth control 
methods must be used throughout the study and for 60 days after taking the last dose of study 
drugs. 
 
If you plan to change your birth control method while you are on the study, you must notify your 
doctor before doing so. If you choose to be sexually active during this study, you need to know 
that even with use of these birth control measures pregnancy could still result.  
 
The risks of receiving the study drugs while pregnant include potential loss of pregnancy or 
possible birth defects. If you become aware that you or your sexual partner is pregnant while 
you are taking part in this study, you must notify one of the doctors listed on this form 
immediately so that management of the pregnancy and the possibility of stopping the study 
drugs can be discussed 
 
Allergies and/or Anaphylaxis Risks  
While on the study you are at risk of experiencing an allergic reaction and/or anaphylaxis 
(severe reaction to a specific antigen) to the study treatments. Symptoms of an allergic 
reactions includes fever, chills, hives, rash, itching, joint pain, shortness of breath, low or high 
blood pressure, muscle stiffening, fainting, and sweating may occur during the injection/infusion 
and lasting about 24 hours. 
 
Your doctor may give you additional medications to ease allergic and/or anaphylaxis reactions 
you may experience during the study. You should talk to your study doctor about these 
medications and any side effects you may experience while taking part in the study. 
 
Radiation Exposure Risks: 
 
CT scan: A CT scan is non-invasive, but involves exposure to radiation. There is a potential risk 
of radiation exposure from CT scans; this risk is considered small. Sometimes, an intravenous 
(in the vein) contrast dye is given with a CT scan. This contrast dye is iodine based. A person 
who has allergies is more likely to have an allergic reaction to the dye. This reaction may be 
mild, such as skin rash or hives to severe, such as breathing difficulties or shock. You will be 
closely monitored and treated should this occur. A severe allergic reaction would require 
immediate medical treatment and could result in permanent disability or death. You should 
discuss any history of allergies or concerns with your doctor. You may also experience 
discomfort related to lying still in an enclosed space for a prolonged period of time. The study 
staff prior to performing the procedure will provide additional instructions to you. 
 
If you have questions or want additional information about risks and side effects, ask 
your study doctor. 
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What other choices do I have if I do not take part in this study? 
If you do not wish to take part in this research study, your doctor will discuss alternate treatment 
options with you, including their benefits and risks. These may include: 
• 
Treatment with other approved chemotherapy, or radiation therapies, if available and 
applicable to your disease 
• 
Treatment with immunotherapy, specifically nivolumab or pembrolizumab, if you have 
not previously received it 
• 
Taking part in another research study with drugs or radiation therapy, if available and 
applicable to your disease 
• 
Getting treatment for your symptoms only, with no further cancer therapy. This is called 
comfort care, or palliative care. This type of care helps reduce pain, tiredness, appetite 
problems, and other problems caused by the cancer. It does not treat the cancer directly, 
but instead tries to improve how you feel and tries to keep you as active and comfortable 
as possible.  
 
Talk to your doctor about each of these choices before you decide if you will take part in this 
study. If you decide not to participate, withdraw your participation after starting the study, or if 
you are discontinued from this study, your doctor will discuss all other treatment options with 
you. 
 
Can I stop being in this study? 
Yes. You can decide to withdraw at any time. It is important to tell the study doctor if you are 
thinking about withdrawing so any risks from the ficlatuzumab or cetuximab can be evaluated. 
Another reason to tell your study doctor that you are thinking about withdrawing is to discuss 
what follow-up care and testing could be most helpful for you to help minimize side effects. 
 
The study doctor may withdraw you from this study at any time if he/she believes it is in your 
best interest; if you do not follow the study rules; or if the study is stopped. 
 
When may participation in the study be stopped? 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent for any reason, including: 
• 
if it is in your best interest; 
• 
you do not consent to continue in the study after being told of changes in the research 
that may affect you. 
 
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures done so that you leave the study safely. 
 
What happens if I am injured because I took part in this study? 
If you believe that you are injured as a result of the research procedures being performed, 
please immediately contact Dr. Julie Bauman or the study coordinator at (520) 626-4101. 
 
If you suffer an injury from taking part in this study, you should seek treatment.  You or your 
insurance company will be billed for those services. If you do not have insurance, you will be 
financially responsible for those expenses. The University of Arizona has no funds set aside to 
pay for a research-related injury, added medical costs, loss of a job, or other costs to you or 
your family. 
 
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This, however, does not waive your rights in the event of negligence. If you suffer an injury from 
participating in this study, you should seek treatment.  The University of Arizona and Banner 
Health have no funds set aside for the payment of treatment expenses for this study.  
You will be provided with any new information that develops during the course of the research 
that may affect your decision whether or not to continue participation in the study 
What are the costs of taking part in this study? 
Some of the services you will receive and procedures you will undergo are being done only 
because you are participating in this research study. Examples of these “research-only” services 
and procedures include the study drug ficlatuzumab, research biopsy and the research blood 
work. The research-only procedures will be paid for by the study and will not be billed to you or 
your health insurance company.  
 
Some of the services and procedures you will receive during the research study are considered 
“routine clinical services” that you would have received even if you were not participating in the 
research study. Examples are the physical exams, performance status evaluations, standard 
blood tests, the cetuximab, and radiological imaging to evaluate your disease. These “routine 
clinical services” will be billed to your health insurance company, but you will be responsible for 
paying any deductibles, co-payments, or co-insurance that are a normal part of your health 
insurance plan. If you do not have health insurance, you will be responsible for those costs. To 
obtain more detailed information about what routine clinical services your health insurance is 
likely to pay for, contact your insurance company. 
 
Will I be paid for taking part in this study? 
Your involvement in this research study is voluntary and you will not be paid for your 
participation. 
 
Will my study-related information be shared, disclosed, and kept confidential? 
The University of Arizona has rules to protect information about you. Federal and state laws 
also protect your privacy. This part of the consent form tells you what information about you may 
be collected in this study and who might see or use it. 
 
Information related to this research study that identifies you and your protected health 
information (PHI) will be collected from your past, present, and future hospital and/or other 
health care provider medical records. The Sponsor-Investigator will retain the specified records 
and reports for up to 2 years after the marketing application is approved for the investigational 
drug. 
 
Any information about you obtained from this research will be kept as confidential (private) as 
possible. All records related to your involvement in this research study will be stored in a locked 
environment. You will not be identified by name in any publication of the research results unless 
you sign a separate consent form giving your permission (release). 
 
The people working on the study will collect information about you. This includes things learned 
from the procedures described in this consent form. They may collect other information 
including your name, address, date of birth, phone number, social security number and other 
details. Photocopies of actual treatment records may be required as part of this review. By 
signing the consent form, you allow access to your medical records, without removal of 
identifying information such as your name, initials, date of birth, sex, race, and location of the 
research study. 
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Existing health records may include information related to the diagnosis or treatment of sexually 
transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and study sponsor’s monitor may see 
this information while reviewing your regular health records for this study, but they WILL NOT 
create, collect, or disclose this type of information for the purposes of this research study. 
 
Generally, only people on the research team will know that you are in the research study and 
will see your information. However, there are some exceptions, and the Principal Investigator 
may give information about you to people outside of the University of Arizona if required. 
It is anticipated that there will be circumstances where your study related information and PHI 
will be released to persons and organizations described in this form. If you sign this form, you 
give permission to the research team to use and/or disclose your PHI for this study. Your 
information may be shared or disclosed with others to conduct the study, for regulatory 
purposes, and to help ensure that the study has been done correctly. These other groups 
include: 
 
• 
Office for Human Research Protections or other federal, state, or international regulatory 
agencies 
• 
Food and Drug Administration 
• 
Banner University Medical Group and Banner Health 
• 
The University of Arizona (UA) and the UA Institutional Review Board  
• 
The sponsor supporting the study (the University of Arizona Cancer Center), their agents 
or study monitors 
• 
In unusual cases, the investigators may be required to release your identifiable research 
information (which may include your identifiable medical record information) in response 
to an order from a court of law. 
• 
Authorized representatives of the source of support of this study and manufacturer of 
ficlatuzumab, Aveo Oncology and their agents (Parexel and Biodesix), will review and/or 
obtain your identifiable information (which may include identifiable medical record 
information) for the purpose of monitoring the accuracy and completeness of the 
research data and for performing required scientific analyses of the research data. While 
Aveo Oncology understands the importance of maintaining the confidentiality of your 
identifiable medical record information, we cannot guarantee the confidentiality of this 
information after it has been obtained by Aveo Oncology. The investigators involved in 
the conduct of this research study may receive funding from Aveo Oncology to perform 
the research procedures. 
• 
Your primary care physician or a specialist taking care of your health. 
Your PHI may no longer be protected under the HIPAA privacy rule once it is disclosed by the 
research team.   
We will use and disclose your information only as described in this form and in our Notice of 
Privacy Practices; however, people outside the University of Arizona who receive your 
information may not be covered by this promise. We try to make sure that everyone who needs 
to see your information keeps it confidential – but we cannot guarantee this. 
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The Banner Medical Group (BMG) uses an electronic health record (EHR). Medical services 
(such as blood draws, CT scans, and MRIs) and test results completed by BMG for this 
research project will be placed in your EHR. If you do not have a BMG medical record, one will 
be created for you. It is necessary to create a medical record for services completed by BMG so 
that BMG can appropriately bill for the service. Therefore, people involved with your future care 
and insurance may become aware of your participation and of any information added to your 
EHR as a result of your taking part in this study.   
 
Study information (like questionnaires, diaries, and surveys) gathered directly from you by the 
researchers will be part of your research records but will not be added to your EHR. Your 
research records are kept separate from the EHR and available to research staff working on this 
study. 
 
What study-related information and PHI will be obtained, used or disclosed from my 
medical record at Banner? 
Information related to this research study that identifies you and your PHI will be collected from 
your past, present, and future hospital and/or other health care provider medical records.  
 
The PHI you are authorizing to be used and/or disclosed in connection with this research study 
is: 
• 
Your medical history 
• 
Diagnostic information 
• 
Lab and scan results  
• 
Other information concerning treatment of your cancer 
Demographic information to be disclosed may include, but is not limited to, your name, address, 
phone number, or social security number. If you receive compensation for participating in this 
research study, information identifying you may be used or disclosed as necessary to provide 
that compensation. 
Your existing health records may include information related to the diagnosis or treatment of 
sexually transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and study sponsor’s monitor may see 
this information while reviewing your regular health records for this study, but they WILL NOT 
create, collect, or disclose this type of information for the purposes of this research study. 
When will my authorization expire? 
There is no expiration date or event for your authorization. Therefore, unless you cancel this 
authorization (as instructed below) this authorization will continue to be effective.  
Do I have to sign this authorization form? 
You do not have to sign this authorization. However, if you decide not to sign, you will not be 
able to participate in this research study; and it will not affect any non-study Banner Health 
medical treatment or health care, payment, enrollment in any health plans, or benefits. 
Also, by signing this form you are authorizing and permitting uses and/or disclosures of your 
PHI for future research purposes (e.g., future studies) as described in this document.  
What do I need to know if I decide to cancel my authorization? 
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After signing the authorization, you may decide to cancel your previous authorization for the 
research team to use your PHI. If you cancel the authorization, you will no longer be able to stay 
in the research study. Please note that any PHI collected before you cancel the authorization 
may still be used. You may revoke the authorization by contacting the Principal Investigator in 
writing. Contact information is under “Who can answer my questions about the study” at the end 
of this document.  
 
Will access be limited to your research study record during this study? 
You may not have access to the research information developed as part of this study until it is 
completed.   
 
Will my data or specimens be stored for future research?  
About Using Tissue and Blood for Research  
We would like to keep some of the tissue sample and blood for future research. If you agree, 
your tissue and blood will be kept and may be used in research to learn more about cancer and 
other diseases.  
 
Your tissue and blood may be helpful for research whether you do or do not have cancer. The 
research that may be done with your tissue and blood is not designed specifically to help you. It 
might help people who have cancer and other diseases in the future. 
 
You tissue and blood samples will be de-identified; that is, they will be assigned a code and the 
information linking the code with your identity will be stored in a separate secure location. Your 
samples may be shared with secondary researchers without identifiers. 
 
Reports about research done with your tissue and blood will not be given to you or your doctor. 
These reports will not be put in your health record. The research will not have an effect on your 
care. 
 
Your biological sample or genetic material may lead, in the future, to new inventions or 
products. If the research investigators are able to develop new products from the use of your 
biological sample or genetic material, there are currently no plans to share with you any money 
or other rewards that may result from the development of the new product. 
 
Things to Think About 
The choice to let us keep the left over tissue and your blood for future research is up to you. No 
matter what you decide to do, it will not affect your care or your participation in the main part of 
the study. 
 
If you decide now that your tissue and blood can be kept for research, you can change your 
mind at any time. Just contact the investigator and let us know that you do not want us to use 
your tissue. Then any tissue or blood that remains will no longer be used for research and will 
be returned to the institution that submitted it or destroyed. 
 
In the future, people who do research may need to know more about your health. While the 
institution/doctor may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who you are. 
Sometimes tissue and blood is used for genetic research (about diseases that are passed on in 
families). Even if your tissue and blood is used for this kind of research, the results will not be 
put in your health records. 
 
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Your genetic information is unique to you. You do share some genetic information with your 
family members. Although rare, there are examples where health insurers or employers have 
denied insurance or employment based on results from genetic testing. A Federal law, called 
the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against you 
based on your genetic information. Be aware that this Federal law does not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
  
Your tissue and blood will be used only for research and will not be sold. The research done 
with your tissue and blood may help to develop new treatments for cancer and other diseases in 
the future. 
 
Benefits 
The benefits of research using tissue and blood include learning more about what causes 
cancer and other diseases, how to prevent them, and how to treat them. 
 
Risks 
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private. The chance that this 
information will be given to someone else is very small. 
 
No matter what you decide to do, it will not affect your care. 
 
Future Use of PHI and Samples (specimens) 
Future research activity is part of this project. If you choose to participate in the future research 
activity your PHI will be included in this future research activity.  
 
By initialing the line below you agree to allow your information to be used and/or 
disclosed for the optional future research referenced above. 
 
_______ Initials 
Who can answer my questions about this study? 
If at any time you feel you have had a research-related injury, or for questions, concerns, or 
complaints about the study you may contact Dr. Julie Bauman or the study coordinator at (520) 
626-4101. 
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact the 
Human Subjects Protection Program at 520-626-6721 or online at 
http://rgw.arizona.edu/compliance/human-subjects-protection-program. 
 
If you are injured as a result of participating in this study or for questions about a study-related 
injury, you may contact Dr. Julie Bauman at (520) 626-4101. 
 
If you have any questions or concerns about the authorization for access to your PHI, you 
should contact Sue Colvin, Banner Research Regulatory Affairs Director, at (602) 839-4583 or 
sue.colvin@bannerhealth.com. You may also request and will be provided a copy of the Notice 
of Privacy Practices. 
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To cancel your authorization for access to PHI you must notify the Principal Investigator in 
writing at the following address: 
 
Julie E. Bauman, MD, MPH 
University of Arizona Cancer Center 
1515 N. Campbell Ave 
Tucson, AZ 85724 
 
An Institutional Review Board responsible for human subjects research at The University of 
Arizona reviewed this research project and found it to be acceptable, according to applicable 
state and federal regulations and University policies designed to protect the rights and welfare 
of participants in research.     
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Research Biopsy Details 
This section provides more detailed information about how the research biopsy is performed.   
 
You have been asked to have a cup forceps biopsy or core needle biopsy (removal of a small 
sample of tissue from a mass or lump) as a part of this study.  
 
Reason for the biopsy: 
The purpose of this biopsy is to determine the type of tumor cells present and how your tumor 
cells react to the study treatment.  
 
Biopsy Procedures: 
All patients will be evaluated for the safety and feasibility of obtaining tumor tissue at the time of 
enrollment. If the performing physician agrees the biopsy can be safely performed using local 
anesthesia, you will have the procedure performed in the area of your primary tumor. The 
biopsy is done for the research, but standard procedures for this type of biopsy are followed. 
The biopsy will be performed by trained personnel.  The biopsy may need to be done using 
ultrasound or CT guidance. The procedure will occur at the inpatient or outpatient office of the 
head and neck surgeon. The procedure may take 2-4 hours. 
 
The procedure is done using local anesthesia (numbing of the skin).  There are two methods for 
performing the biopsy:  Cup biopsy or core biopsy.  The cup biopsy involves a slender flexible 
forceps (scissor-like instrument) with movable cup-shaped jaws through a specially designed 
endoscope.  The core biopsy involves the use of a 1 centimeter, 18-gauge hollow needle. 
 
Both biopsy types involve:  
• 
Preparation of the biopsy site with a skin cleanser such as isopropyl (rubbing) alcohol or 
iodine 
• 
Injection of a local anesthetic (numbing medication), called lidocaine (a drug approved 
by the FDA), with the addition of a small amount of epinephrine (an FDA-approved drug) 
to constrict blood vessels, decrease bleeding, prolong anesthesia, and limit lidocaine 
toxicity  
 
Core biopsy involves: 
• 
Collection of three tissue specimens using the hollow needle. 
• 
Dressing the site with Neosporin Cream (an FDA-approved drug) antibiotic ointment and 
a Band-Aid that should be removed in 24 hours. 
 
Cup biopsy involves: 
• 
This may be internal or external. 
• 
A sharp tool is used to snip a part of your tumor. 
 
The biopsy samples will be maintained by the investigators of this research project. To protect 
your confidentiality, all personal identifiers (i.e., name, social security number, birth date) will be 
removed (de-identified) and replaced with a specific code number. The information linking these 
code numbers to your identity will be kept in a separate, secure location. The investigators on 
this study will keep the samples indefinitely. Your biologic samples may be given to 
investigators outside of University of Arizona or may be utilized in future studies. If this is the 
case, they will remain de-identified. 
 
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If you have an allergy to lidocaine, (numbing medicine required for biopsy) we may use an 
alternative anesthetic. If the biopsy site is infected, it will be treated with antibiotic ointment and 
the biopsy will be postponed by 24 hours. If, at that time, the biopsy is still not possible due to 
infection, the biopsy will not be performed.  
 
What are the possible risks, side effects, and discomforts of this biopsy? 
 
Both procedures may leave a very small, fine scar, which usually fades with time. 
 
Common: 
• 
Pain from the procedure 
• 
Bruising and soreness at the site of biopsy 
• 
Scarring at the site 
 
Rare: 
• 
Infection and bleeding 
 
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Signing the consent form 
I have read (or someone has read to me) this form, and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study and I authorize the 
use and/or disclosure of my PHI. I am not giving up any legal rights by signing this form.  I will 
be given a signed copy of this form. 
 
 
 
 
 
  
 
 
Printed name of subject 
 Signature of subject 
 
Date 
 
 
 
Investigator/Research Staff 
I have explained the research to the participant or the participant’s representative before 
requesting the signature(s) above.  There are no blanks in this document.  A signed copy of this 
form has been given to the participant or to the participant’s representative. 
 
 
 
 
 
  
 
 
Printed name of person 
obtaining consent 
 Signature of person obtaining 
consent 
 
Date 
 
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