Single-Arm Phase II Trial of Dual Inhibition of EGFR With Afatinib and Cetuximab With Correlative Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck
Phase: PHASE2
Conditions: Squamous Cell Cancers of the Head and Neck
Sponsor: Yale University

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CLINICAL STUDY PROTOCOL 
NCT No.: 
Protocol No.: 
NCT02979977 
1608018260 
Investigational 
Product: 
Afatinib 
Title: Single-Arm Phase II trial of Dual Inhibition of EGFR with Afatinib and Cetuximab with Correlative 
Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck. 
 
Clinical Phase: II 
 
Principal Investigator: Aarti Bhatia, MD, MPH 
 
Sponsor: Yale Cancer Center 
 
Funding Source: Funding provided by the National Comprehensive Cancer Network (NCCN) through a 
grant provided by Boehringer Ingelheim Pharmaceuticals, Inc. 
Version and Date of Protocol:  Version 7.0 dated 13 December 2022 
 
  
 
 
 
 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
Study Title: Single-Arm Phase II trial of Dual Inhibition of EGFR with Afatinib and Cetuximab with 
Correlative Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck  
 
 
 
 
 
 
Protocol No.: 1608018260 
 
 
 
 
 
I herewith certify that I agree to adhere to the study protocol  
and to all documents referenced in the study protocol. 
 
 
         _____________________________________________________ 
 
___________________ 
         Signature  
 
                             
 
Date 
 
 
 
 
 
 
 
 
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SPONSOR SIGNATURE PAGE 
 
Study Title: Single-Arm Phase II trial of Dual Inhibition of EGFR with Afatinib and Cetuximab with 
Correlative Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck  
 
 
 
 
 
Protocol Number: 1608018260 
 
 
 
 
 
I herewith certify that I agree to adhere to the study protocol 
and to all documents referenced in the study protocol. 
 
 
         _____________________________________________________ 
 
___________________ 
         Signature  
 
                             
 
Date 
 
 
 
 
 
 
 
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CLINICAL TRIAL PROTOCOL SYNOPSIS  
Protocol date: 
Protocol number: 
 13 December 2022 
1608018260 
Title of study: Single-Arm Phase II trial of Dual Inhibition of EGFR with Afatinib and Cetuximab with 
Correlative Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck 
Principal Investigator: Aarti Bhatia, MD, MPH 
Sponsor: Yale Cancer Center 
Clinical Phase: II 
Objectives:  
1. To determine the response of recurrent or metastatic squamous cell carcinoma of the head 
and neck region to treatment with a combination of afatinib and cetuximab. 
2. To determine impact on long-term outcome, safety and tolerability of the combination and 
laboratory correlates for more effective inhibition of Epidermal Growth Factor Receptor 
(EGFR) signaling with the combination of Cetuximab and Afatinib. 
Methodology: 
This study will be a single center, single-arm, open-label Phase II trial.  Patients with advanced 
squamous cell carcinoma of the head and neck, who are previously treated with a platinum based 
regimen or with immune checkpoint inhibitor therapy or both, will be eligible for participation on 
the study. After a baseline evaluation and biopsy (where feasible), they will be treated with 
weekly/bi-weekly IV cetuximab and daily oral afatinib. Biopsy will be repeated where feasible after 
4 weeks (window of +1 week) on therapy and again at disease progression or end of treatment. 
Treatment will continue until disease progression or development of grade 3 or higher drug related 
toxicities that fail to resolve to Grade 2 despite appropriate supportive care. 
No. of Patients: 
Total entered: 50 
 
Each Treatment: 50 
Indication: 
Advanced squamous cell carcinoma of the head and neck region, having previously been treated with 
a platinum-based regimen or with immune checkpoint inhibitor therapy or both. 
Main Criteria for Inclusion: 
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Protocol date: 
Protocol number: 
 13 December 2022 
1608018260 
1. Histologically confirmed squamous cell carcinoma of the head and neck that is metastatic, 
recurrent or locally advanced and not treatable with curative intent.  
2. Previous treatment with platinum-based regimen or immune checkpoint inhibitor therapy or 
both in the R/M (Recurrent/Metastatic) setting. 2-week washout period prior to treatment start 
will be required. 
3. Patients who have experienced progression of disease within 6 months following completion of 
a platinum-based chemoradiation in the definitive or adjuvant setting will be permitted. 
4. Prior cetuximab permitted if it was given as part of multi-modality therapy for initial treatment 
of locally advanced disease but not for recurrent/metastatic disease.    
5. Measurable disease based on RECIST v 1.1.  
6.    Age >18 years 
7.    ECOG performance status ≤2 
8.    Adequate organ function, defined as all of the following: 
- 
Hemoglobin ≥ 8 g/dl. 
- 
Absolute neutrophil count (ANC) ≥1000 / mm3.  
- 
Platelet count ≥75,000 / mm3. 
- 
Estimated creatinine clearance > 45ml / min. 
- 
Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal (Patients with 
Gilbert’s syndrome total bilirubin must be ≤4 times institutional upper limit of normal). 
- 
Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three times the 
upper limit of (institutional/central) normal (ULN) (if related to liver metastases ≤ five 
times ULN). 
9.    Ability to understand and the willingness to sign a written informed consent that is 
consistent with ICH-GCP guidelines. 
10.  Negative urine or serum pregnancy test for women of childbearing potential. 
11. A second eligibility review will always be provided by a Head and Neck Research Team 
associated for the New Haven Campus and a third review will be provided by the PI. 
Main Criteria for Exclusion: 
1. Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any investigational EGFR or 
panErbB reversible or irreversible inhibitor or any prior panitumumab or investigational EGFR-
directed monoclonal antibody. Cetuximab is permitted if used for locally advanced disease, as 
long as no disease progression within 6 months. Cetuximab use is not permitted for 
recurrent/metastatic disease. 
2. Radiotherapy within 2 weeks prior to enrolment. Palliative radiation to target organs may be 
allowed up to 2 weeks prior to enrolment, as long as there are other target lesions that can be 
monitored for response to study treatment. 
3. Known hypersensitivity to afatinib or its excipients. 
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Protocol date: 
Protocol number: 
 13 December 2022 
1608018260 
4. Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to 
be abstinent or use highly effective methods of birth control prior to study entry, for the 
duration of study participation and for at least 4 weeks after treatment has ended. 
5. Pregnant or nursing women. 
6. Any history of or concomitant condition that, in the opinion of the Investigator, would 
compromise the patient’s ability to comply with the study or interfere with the evaluation of the 
efficacy and safetyof the test drug. 
7. Concomitant malignancies at other sites that are being actively treated with systemic therapy.  
8. Requiring treatment with any of the prohibited concomitant medications listed in Section 4.2.2.1 
that cannot be stopped for the duration of trial participation. 
9. Clinically significant interstitial lung disease. 
10. Known history of untreated viral hepatitis or HIV. 
11. Patients with parenchymal brain metastases are not eligible, unless they have completed local 
therapy. 
12. Leptomeningeal carcinomatosis. 
Test Product(s): 
Dose: Afatinib dose 30 mg per day 
Mode of admin: oral 
Duration of Treatment: Until disease progression, development of ≥ grade 3 drug related toxicities 
that fail to resolve to Grade 2 despite appropriate supportive care, clinically significant deterioration 
of the patient’s condition, patient noncompliance, investigator determination that it is no longer in 
the patient’s best interest to continue, pregnancy, or withdrawal of consent. 
Criteria for Efficacy: Clinical efficacy of the combination treatment will be determined through 
assessment of response to treatment (tumor shrinkage) based on RECIST v 1.1., duration of 
response, progression-free survival and overall survival.  
Criteria for Safety: Safety of the combination will be assessed through collection of adverse event 
(AE) and serious adverse event (SAE) data and monitoring of laboratory tests. To ensure patient 
safety, we have pre-specified stopping rules based on grade of toxicities in the protocol. 
Statistical Methods: All statistical analyses will be performed using the SAS statistical software, 
version 9.4 (SAS Institute Inc., Cary, NC). 
We plan to enroll 50 patients which provide us 80% power to detect an alternative hypothetical ORR 
of 24% by rejecting a null hypothesis of 10%. This sample size will achieve 80% power to detect an 
absolute difference of 18% if the historical control of ORR is 15% (i.e. 33% vs. 15%).    
The primary analysis will use a 2-sided binomial test to compare the ORR with historical control of 
10%. 95% confidence interval of ORR will be reported as well. As an exploratory analysis, Logistic 
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Protocol date: 
Protocol number: 
 13 December 2022 
1608018260 
regression will be used to identify potential risk factors that are associated with ORR.  
The secondary endpoint is progression-free survival and overall survival with 1 year follow-up. We 
will use Kaplan-Meier survival analysis to estimate the median PFS and OS in the cohort. Additional 
Cox regression analyses will be carried out to examine the association between demographical or 
clinical variables and survival outcome.  
Study Duration: 2 years 
 
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FLOW CHART 
 
Screeninga  
Treatment Period 
Every 8 
weeks after 
cycle 2d 
Discontinuation  
Post-Treatment 
 
 
Cycle 1 
(Weekly/Bi-
weekly) 
Cycle 2 
(Weekly/Bi-
weekly) 
Cycle 3 and 
beyond 
(Weekly/Bi-
weekly) 
 
End of 
Treatment 
(EOT) 
End of 
Residual 
Effect 
Period 
(EOR)g 
Additional 
Follow-Uph 
End of 
Follow-
Upi 
Overall 
Survival 
Follow-
Upj 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical History  
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Physical Exam 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Height/Weight/Vitalsl 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
CBC with differential n 
X 
X 
X 
X 
 
X 
X 
 
 
 
CMP, Magnesium n 
X 
X 
X 
X 
 
X 
X 
 
 
 
AE assessment 
 
X 
X 
X 
 
X 
X 
X 
X 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
CT/MRI of involved disease sites 
X 
 
Xd 
 
X 
 
 
 
 
 

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P16 Status (IHC staining) 
X 
 
 
 
 
 
 
 
 
 
PT/PTT/INRc 
X 
X 
X 
X 
 
X 
X 
 
 
 
Pregnancy test (Urine or Serum β-
HCG)m 
X 
X 
X 
X 
 
X 
X 
 
 
 
Afatinib Administrationk 
 
X 
X 
X 
 
 
 
 
 
 
IV Cetuximab Administrationk 
 
X 
X 
X 
 
 
 
 
 
 
Tumor Measurements 
X 
 
X 
 
X 
 
 
 
 
 
Medically Feasible : Correlative Tumor 
Biopsies 
Xb 
Xb 
 
 
 
Xe 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
 
a: Screening history, concomitant medications, physical exam, height, weight, vitals, performance status and laboratory evaluations (including pregnancy test) should be 
obtained within 2 weeks prior to treatment initiation.  Screening EKG and CT scans or MRI should be obtained within 28 days prior to treatment initiation.  
b: Tumor sample for correlative analyses can be archival or fresh, should be since the last systemic treatment administered and should be obtained where feasible. 
Repeat tumor biopsy to be obtained at end of cycle 1 (4 weeks after treatment initiation, with a window of +1 week), where medically feasible 
c: Coagulation studies recommended every 4 weeks (+/- 3 days) only for patients on anticoagulation therapy (excluding a daily baby aspirin). 
d: Restaging scans for tumor assessment as appropriate for site of disease to be obtained at end of cycle 2 (8 weeks +/- 3 days), and then every 8 weeks thereafter (+/- 3 
days) through the EOR visit, or EoFU visit for patients who discontinued treatment for reasons other than disease progression 
e: Repeat tumor biopsy for correlative analyses to be obtained where medically feasible at disease progression or EOT. 
f: EOT visit within 7 days of discontinuation from study treatment period. 
g: EOR visit at 30 days (window of + 2 weeks) after discontinuation from study treatment period. 
h: Additional f/u visits for disease progression to continue every 4 weeks (with a window of +7 days) for a maximum of 24 weeks for patients who discontinued study 
treatment for reasons other than disease progression. 
i: Last visit for disease progression assessment. Follow-up period will continue until progression, start of new anti-cancer therapy, or a max of 24 weeks, whichever 
comes first. The EoFU visit will be performed within 2 weeks of known progression, start of new anti-cancer therapy, or completion of predefined follow-up progression 
period. 
j: Monthly (+/- 1 week) telephone f/u for survival (to continue until death). 

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k: Cetuximab will be administered beginning on cycle 1 day 1, and then subsequently weekly (+/- 1 day) or bi-weekly (+/- 2 days) at the discretion of the treating 
physician. Alternating Cetuximab dosing schedules from a weekly to bi-weekly dosing schedule, and vice versa, between and within cycles of treatment is permitted per 
protocol following Sponsor PI discussion and approval. Daily oral afatinib dosing will start the same day as the initial cetuximab administration. For patients who are on 
afatinib alone due to cetuximab being discontinued for a serious infusion reaction or for any other reason, they will be scheduled for follow-up on days 1 and 15 (+/- 3 
days) of the first two 28-day cycles. The following assessments will be performed during these visits: adverse event assessment, concomitant medications, physical 
exam, weight, vital signs and ECOG performance status, laboratory assessments (CBC with differential, CMP, Magnesium). Pregnancy test for reproductive age women 
and coagulation studies if on anticoagulant therapy will be performed every 4 weeks throughout the treatment period. After the first 2 cycles, visits can be scheduled on 
day 1 of every 28-day cycle (+/- 3 days) per physician discretion. 
l: Height to be collected at screening only 
m: Pregnancy test for women of child bearing potential to be conducted every 4 weeks (+/- 3 days) while on treatment. 
n: CBC with differential, CMP and magnesium performed weekly (+/- 1 day) or bi-weekly (+/- 2 days) while on treatment, prior to cetuximab dosing. Clinic visits weekly 
(+/- 1 day) or bi-weekly (+/- 2 days) depending on cetuximab dosing.

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Table of Contents 
CLINICAL STUDY PROTOCOL ....................................................................................................................... 1 
INVESTIGATOR SIGNATURE PAGE ............................................................................................................. 2 
SPONSOR SIGNATURE PAGE ........................................................................................................................ 3 
CLINICAL TRIAL PROTOCOL SYNOPSIS .................................................................................................... 4 
FLOW CHART ..................................................................................................................................................... 8 
ABBREVIATIONS ............................................................................................................................................ 15 
1. 
INTRODUCTION .................................................................................................................................... 16 
1.1 
MEDICAL BACKGROUND ................................................................................................. 16 
1.2 
DRUG PROFILE .................................................................................................................... 18 
1.2.1  Afatinib ............................................................................................................................................ 18 
1.2.2  Cetuximab ....................................................................................................................................... 19 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ............................................ 21 
2.1 
RATIONALE FOR PERFORMING THE TRIAL ............................................................. 21 
2.2 
TRIAL OBJECTIVES ............................................................................................................ 22 
PRIMARY OBJECTIVE ................................................................................................................................ 22 
SECONDARY OBJECTIVES ........................................................................................................................ 22 
2.3 
BENEFIT – RISK ASSESSMENT ....................................................................................... 22 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION .............................................................. 23 
3.1 
OVERALL TRIAL DESIGN AND PLAN ............................................................................ 23 
3.2 
DISCUSSION OF TRIAL DESIGN...................................................................................... 24 
3.3 
SELECTION OF TRIAL POPULATION ............................................................................ 24 
3.3.1 
Main diagnosis for study entry .............................................................................................. 24 
3.3.2 
Inclusion criteria.......................................................................................................................... 24 
3.3.3 
Exclusion criteria ......................................................................................................................... 25 
3.3.4 
Removal of patients from therapy or assessments ....................................................... 26 
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4. 
TREATMENTS ........................................................................................................................................ 28 
4.1 
TREATMENTS TO BE ADMINISTERED ........................................................................ 28 
4.1.1 
Identity of Investigational Product ...................................................................................... 28 
4.1.2 
Standard therapy: Cetuximab ................................................................................................ 28 
4.1.2 
Method of assigning patients to treatment groups ....................................................... 29 
4.1.3 
Selection of doses in the trial .................................................................................................. 29 
4.1.4 
Drug assignment and administration of doses for each patient .............................. 29 
4.1.5 
Blinding and procedures for unblinding ........................................................................... 33 
4.1.6 
Packaging, labelling, and re-supply ..................................................................................... 33 
4.1.7 
Storage conditions ...................................................................................................................... 34 
4.1.8 
Drug accountability .................................................................................................................... 35 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND rescue treatment ................ 35 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) ......... 35 
4.2.2 
Restrictions .................................................................................................................................... 36 
4.2.3 
Management of expected adverse events ......................................................................... 37 
4.3 
TREATMENT COMPLIANCE ............................................................................................ 43 
5. 
VARIABLES AND THEIR ASSESSMENT .......................................................................................... 45 
5.1 
TRIAL ENDPOINTS............................................................................................................. 45 
5.1.1 
Primary endpoint(s) .................................................................................................................. 45 
5.1.2 
Secondary endpoint(s) .............................................................................................................. 45 
5.2 
ASSESSMENT OF EFFICACY ............................................................................................. 45 
5.3 
ASSESSMENT OF SAFETY ................................................................................................. 45 
5.3.1 
Physical examination and ECOG performance status .................................................. 45 
5.3.2 
Vital signs ........................................................................................................................................ 45 
5.3.3 
Safety laboratory parameters ................................................................................................ 45 
5.3.4 
Electrocardiogram ...................................................................................................................... 46 
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5.3.5 
Other safety parameters ........................................................................................................... 46 
5.3.6 
Assessment of adverse events ............................................................................................... 46 
5.3.7 
Adverse event collection and reporting ............................................................................. 48 
5.4 
ASSESSMENT OF EXPLORATORY BIOMARKER(S) .................................................. 49 
5.4.1 
Biobanking ..................................................................................................................................... 50 
6. 
INVESTIGATIONAL PLAN .................................................................................................................. 50 
6.1 
VISIT SCHEDULE ................................................................................................................. 50 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...................................... 51 
6.2.1  Screening and run-in period(s) ............................................................................................. 51 
6.2.2 
Treatment period(s) .................................................................................................................. 51 
6.2.3 
Follow-up period and Trial Completion ............................................................................ 52 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .................................... 55 
7.1 
STATISTICAL DESIGN – MODEL .................................................................................... 55 
7.2 
DETERMINATION OF SAMPLE SIZE ............................................................................. 55 
7.3 
PLANNED ANALYSES ......................................................................................................... 56 
7.4 
HANDLING OF MISSING DATA ....................................................................................... 56 
8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS .............................................. 57 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT .... 57 
8.1.1 
Informed consent ........................................................................................................................ 57 
8.1.2 
Patient registration ..................................................................................................................... 57 
8.2 
DATA QUALITY ASSURANCE .......................................................................................... 58 
8.2.1 
Data monitoring ........................................................................................................................... 58 
8.2.2 
Safety monitoring ........................................................................................................................ 59 
8.2.3 
Project team meetings ............................................................................................................... 59 
8.2.4 
Audit plan ....................................................................................................................................... 60 
8.2.5 
Data management ....................................................................................................................... 60 
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8.3 
RECORDS ............................................................................................................................... 60 
8.3.1 
Source documents ....................................................................................................................... 60 
8.3.2 
Direct access to source data and documents ................................................................... 60 
8.3.3 
Storage of records ....................................................................................................................... 61 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS ................... 61 
8.4.1 
Listedness ....................................................................................................................................... 61 
8.4.2 
Expedited reporting to health authorities and IECs/IRBs ......................................... 61 
8.5 
STATEMENT OF CONFIDENTIALITY ............................................................................ 61 
8.6 
END OF TRIAL ..................................................................................................................... 62 
8.7 
PROTOCOL VIOLATIONS ................................................................................................. 62 
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL 
RELATED INJURY .............................................................................................................................. 62 
9. 
REFERENCES .......................................................................................................................................... 63 
10. 
APPENDICES ..................................................................................................................................... 65 
10.1 
APPENDIX 1 ......................................................................................................................... 65 
10.2 
APPENDIX 2  COCKCROFT-GAULT FORMULA .......................................................... 66 
10.3 
APPENDIX 3  ECOG PERFORMANCE STATUS ............................................................ 67 
10.4 
APPENDIX 4 RECIST 1.1 CRITERIA .............................................................................. 68 
 
 
 
 
 
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ABBREVIATIONS 
ADL 
Activities of Daily Living  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BI 
Boehringer Ingelheim 
CMP 
Comprehensive Metabolic Panel 
CRF 
Case Report Form 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
DP 
Disease Progression 
DSMC 
Data and Safety Monitoring Committee  
eCRF 
Electronic Case Report Form 
EGF  
Epidermal Growth Factor  
EGFR 
Epidermal Growth Factor Receptor  
EoFU 
End of Follow-Up 
EOR 
End of Residual Effect Period 
EOT 
End of Treatment 
GCP 
Good Clinical Practice  
HER 
Human Epidermal Growth Factor Receptor 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ILD 
Intersitital Lung Disease 
MRI 
Magnetic Resonance imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
OS 
Overall survival 
PC 
Patient Completion 
PCNA 
Proliferating Cell Nuclear Antigen 
pEGFR 
Phosphorylated Epidermal Growth Factor Receptor  
PFS 
Progression-Free Survival 
P-gp  
P-glycoprotein 
PI3K 
Phosphoinositide 3-Kinase 
PK 
Pharmacokinetics 
PTEN 
Phosphatase and Tensin homolog  
REP 
Residual Effect Period 
SAE 
Serious Adverse Event 
SCCHN 
Squamous Cell Cancers of the Head and Neck region  
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
TKI 
Tyrosine-Kinase Inhibitor 
WOCBP 
Women of child-bearing potential 
YCC 
Yale Cancer Center 
YCCI 
Yale Center for Clinical Investigation 
 
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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Approximately 62,000 patients will be newly diagnosed with squamous cell cancers of the head 
and neck region (SCCHN) in the United States in 2016 [1]. Majority of the patients present with 
advanced disease and despite recent advances, the cure rate is only about 50%. Due to the 
effects of field cancerization, development of recurrences and second primary tumors is a 
frequent occurrence [2]. Retreatment with locally directed therapies is fraught with difficulties 
and limitations. Many patients therefore, eventually need systemic therapy for symptom 
palliation and disease control to increase longevity [3].  
 
Until recently, chemotherapy regimens using platinum were a standard systemic therapy option 
for these patients. Now we know that the majority of SCCHN tumors overexpress the epidermal 
growth factor receptor (EGFR/ErbB1) and this correlates with poorer clinical outcomes [4]. The 
addition of the monoclonal antibody Cetuximab to standard chemotherapy has improved 
response rates, progression-free survival and overall survival in patients with advanced SCCHN 
[3]. The combination with chemotherapy however, has significant toxicities. Single agent 
Cetuximab is well tolerated but is only seen to have modest responses (10-15%), which aren’t 
durable [5]. Predictive biomarkers for efficacy are also not elicited. 
 
Recently, comprehensive genomic analysis of SCCHN tumor specimens has found the human 
epidermal growth factor receptor 2 (HER2/ErbB2) also to be amplified in a subset of patients 
[6]. Afatinib is an irreversible, oral pan-ErbB family tyrosine kinase inhibitor, seen to have 
potent preclinical activity against both wild-type and mutant EGFR and HER2 and clinical trials 
using Afatinib in the recurrent or metastatic setting have also shown encouraging results within 
the past year [7]. 
 
A multicenter randomized Phase III study assessed the efficacy of afatinib compared with 
methotrexate as second-line treatment in 483 patients with recurrent or metastatic SCCHN 
progressing on or after platinum-based therapy [8]. After a median follow-up of 6·7 months, 
progression-free survival was longer in the afatinib group than in the methotrexate group 
(median 2·6 months for the afatinib group vs 1·7 months for the methotrexate group; hazard 
ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030) and the drug had a manageable toxicity profile. 
 
A multicenter randomized Phase II trial compared Afatinib to Cetuximab in the recurrent or 
metastatic setting [9]. Crossover was permitted on disease progression to the other treatment 
arm. Afatinib showed antitumor activity comparable to cetuximab in this exploratory phase II 
trial. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical 
benefit in patients after crossover, suggesting a lack of cross-resistance. 
 
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Our own group presented data at the American Society of Clinical Oncology’s 2016 Annual 
Meeting from a single-arm Phase II study that combined Erlotinib, another EGFR tyrosine kinase 
inhibitor and Cetuximab with a chemotherapy backbone for patients with recurrent/metastatic 
head and neck cancer [10]. We saw very encouraging responses (50% had partial responses and 
an additional 29% had stable disease with a median progression-free survival of 5.8 months in 
the intent-to-treat population). Median overall survival was 8.1 months in the intent to treat 
population and 10.6 months in the per-protocol population. One patient had a pathological 
complete response (Image 1 attached) and two were consolidated with definitive radiation with 
no recurrence at 9 and 41 months follow-up. 
 
 
Image 1: Pathological complete response in a node in a patient with metastatic SCCHN treated 
with combination chemotherapy/cetuximab/erlotinib on trial. 
 
Based on its promising role in squamous cell cancers of the head and neck, several trials have 
been initiated and are evaluating the use of Afatinib as part of a chemotherapy combination 
induction regimen, in the adjuvant setting following chemoradiation and also as a radio 
sensitizing agent for locally advanced disease [11, 12].  
 
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1.2 
DRUG PROFILE 
1.2.1  
Afatinib  
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) and/or local product label information.  All references in this 
protocol concerning afatinib refer to the free base compound, which is used as the oral 
formulation. 
 
Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models 
it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumour growth 
inhibition and regression of established subcutaneous tumours derived from four human cell-
lines known to co-express ErbB receptors.  
 
Afatinib is moderately fast absorbed after oral administration. Maximum plasma concentrations 
of afatinib were achieved mainly at 2 to 5 hours after oral drug administration. Afatinib 
maximum plasma concentrations and area under the curve increased slightly over-proportional 
with increasing doses in the therapeutic range of 20-50mg. Moderate to high inter- and intra-
individual differences in plasma concentration were seen. Afatinib is highly distributed out of 
the blood and has a moderate to high clearance. The overall gMean terminal half-life at steady 
state was 37.2 hours in cancer patients. Steady state was reached no later than 8 days after the 
first administration. The major route of elimination of afatinib was via faeces. After food intake, 
a decreased systemic exposure was observed compared to administration under fasted 
conditions. The PK characteristics in Caucasian cancer patients were comparable to those 
observed in Japanese cancer patients.  
 
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts were 
the major circulating metabolites in the plasma. Afatinib did not show relevant inhibition or 
induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-drug interactions 
based on this mechanism will occur.  
 
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-gp 
inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken 
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single dose 
of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before afatinib, respectively. 
Pretreatment with the potent P-gp inducer rifampicin decreased the plasma exposure of 40 mg 
afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively. Caution should be exercised 
when combining afatinib with potent P-gp modulators. 
 
In pre-clinical studies afatinib is not irritant to intact skin but an ocular irritant. Afatinib is 
mutagenic in a single bacteria strain, but did not show genotoxic potential in vivo when tested 
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up to overt toxic/lethal doses. Studies on embryo-foetal development in rats and rabbits up to 
life-threatening doses have revealed no indication of teratogenicity. 
 
Two Phase I open-label dose-escalation studies determined the MTD with continuous dosing of 
afatinib in patients with advanced solid tumors at 40mg and 50mg daily, respectively [13, 14]. 
Both daily doses (40mg and 50mg) have been used in Phase II and Phase III trials depending on 
the patient population evaluated. Adverse events (AE) observed with afatinib are consistent 
with those reported for EGFR and dual EGFR/HER2 inhibitors. The most common AEs in 
Afatinib monotherapy trials were associated with gastrointestinal disorders (including diarrhea, 
and stomatitis), skin and subcutaneous tissue disorders (rash/acne, dry skin, pruritus), nail 
effects, fatigue and decreased appetite. Early and proactive management of diarrhea, 
mucositis/stomatitis and skin rash together with treatment interruptions and dose reductions is 
recommended in line with recent guidelines in the management of common toxicities of EGFR 
and EGFR/HER2 TKIs and monoclonal antibodies [15-19]. 
 
Afatinib was approved as monotherapy to treat patients with advanced or metastatic non-small 
cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) 
mutations. 
 
1.2.2  
Cetuximab  
Cetuximab (Erbitux®) is a recombinant, human/mouse chimeric monoclonal antibody that 
binds specifically to the extracellular domain of the human epidermal growth factor receptor 
(EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human 
IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 
152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.  
 
Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount 
of easily visible, white, amorphous cetuximab particulates. Cetuximab is supplied at a 
concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use vials. 
Cetuximab is formulated in a solution with no preservatives, which contains 8.48 mg/mL 
sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium 
phosphate monobasic monohydrate, and Water for Injection, USP.  
 
The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein 
that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, 
and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the 
skin and hair follicle. Expression of EGFR is also detected in many human cancers including 
those of the head and neck, colon, and rectum.  
 
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Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively 
inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming 
growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of 
cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, 
resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix 
metalloproteinase and vascular endothelial growth factor production. Signal transduction 
through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras 
somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR 
regulation.  
 
In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain 
human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab 
inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of 
cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of 
cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted 
in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.  
 
Cetuximab administered as monotherapy or in combination with concomitant chemotherapy or 
radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time 
curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab 
decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses 
>200 mg/m2, it appeared to plateau. The volume of the distribution for cetuximab appeared to 
be independent of dose and approximated the vascular space of 2–3 L/m2.  
 
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), 
concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean 
peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 μg/mL, 
respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 
hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with 
colorectal cancer.  
 
Cetuximab had an approximately 22%(90% confidence interval; 6%, 38%) higher systemic 
exposure relative to the EU-approved cetuximab used based on a population pharmacokinetic 
analysis.  
 
Cetuximab is approved in combination with radiation therapy for the initial treatment of locally 
or regionally advanced squamous cell carcinoma of the head and neck, in combination with 
platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent 
locoregional disease or metastatic squamous cell carcinoma of the head and neck or the 
treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and 
neck for whom prior platinum-based therapy has failed.  
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2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT  
2.1 
RATIONALE FOR PERFORMING THE TRIAL  
The addition of the monoclonal antibody Cetuximab, which targets the epidermal growth factor 
receptor (EGFR), to chemotherapy, has improved the response rate, progression-free survival 
and overall survival for patients with recurrent or metastatic squamous cell cancers of the head 
and neck (SCCHN) [3]. Cetuximab acts by binding to the extracellular portion of the EGFR 
molecule and competitively inhibiting the binding of its ligand. However, it does not interfere 
with ligand-independent EGFR signaling [20].  
 
Although clinically active in a subset of patients, most responders eventually acquire resistance 
to treatment [21]. Several researchers have published data on molecular mechanisms of 
acquired resistance to Cetuximab, including dysregulation of EGFR internalization/degradation, 
alternatively localized EGFR from the cell membrane into the cell's nucleus and strong activation 
of HER2, HER3 and cMET. Nuclear localized EGFR is highly associated with disease progression, 
worse overall survival, and enhanced resistance to radiation, chemotherapy, and to anti-EGFR 
therapies. EGFR up-regulation promotes increased dimerization with HER2 and HER3 leading to 
their transactivation. Blockade of EGFR and HER2 is shown to lead to loss of HER3 and 
PI(3)K/Akt dependent signaling. 
 
Afatinib is an oral, irreversible pan-ErbB family tyrosine kinase inhibitor with intracellular 
activity, which makes it an attractive combinatorial partner to Cetuximab to overcome some of 
the putative resistance mechanisms described above. A recently published randomized Phase II 
study has shown that it does not demonstrate cross-resistance with Cetuximab [9].  
 
We hypothesize that the combination of Cetuximab and Afatinib will demonstrate superior 
clinical efficacy than when used singly or sequentially in the management of advanced SCCHN 
and propose this single-arm Phase II trial. Tissue arrays will be constructed from where 
medically feasible tumor biopsies obtained pre-treatment, after 4 weeks on treatment with the 
combination and again at progression or end of treatment in an attempt to develop predictive 
biomarkers of response and study mechanisms of inherent or acquired resistance. Multiple high 
quality immunohistochemical assays will be performed and analyzed with automated image 
analysis (AQUA, Genoptix®) for EGFR, phospho-EGFR, HER-2, phospho-HER-2, HER-3, HER-4, 
phospho-Akt, PTEN, cyclin D1, p53 and nuclear proliferating cell nuclear antigen (PCNA).  
 
Results from this exploratory trial will inform future studies with this combination or with other 
novel targeted therapies in the metastatic setting. 
 
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2.2 
TRIAL OBJECTIVES  
PRIMARY OBJECTIVE 
To determine the response of advanced squamous cell carcinoma of the head and neck region to 
treatment with a combination of afatinib and cetuximab. Clinical efficacy of the combination 
treatment will be determined through assessment of response to treatment (tumor shrinkage) 
based on RECIST v 1.1., duration of response, progression-free survival and overall survival. 
 
SECONDARY OBJECTIVES 
To determine impact on long-term efficacy outcomes, safety and tolerability of the combination 
and laboratory correlates for more effective inhibition of Epidermal Growth Factor Receptor 
(EGFR) signaling with the combination of Cetuximab and Afatinib. Efficacy outcomes will be 
assessed by tumor response based on RECIST v 1.1., duration of response, progression-free 
survival and overall survival. Safety of the combination will be assessed through collection of 
adverse event (AE) and serious adverse event (SAE) data and monitoring of laboratory tests.  
 
2.3 
BENEFIT – RISK ASSESSMENT 
For patients with advanced head and neck cancer who have disease progression on a 
chemotherapy regimen using a platinum compound, there are few salvage therapies that are 
currently standard of care. We know that the majority of SCCHN tumors overexpress EGFR. 
Targeting the receptor helps gain disease control in a subset of these patients. Recently, it has 
been shown that resistance to the EGFR monoclonal antibody (Cetuximab) does not 
automatically confer cross-resistance to the small molecule inhibitor (Erlotinib) [9]. It therefore 
seems logical to test a combination of cetuximab and a potent EGFR small molecule inhibitor like 
afatinib to see if we can improve on response rates and durability of response seen with either 
agent alone. 
 
Cetuximab and Afatinib combination regimen at the proposed doses has been previously tested 
in patients with lung cancer who harbor the EGFR mutation and was shown to be safe and 
effective [22]. We have also built in adequate monitoring measures (periodic physical 
examinations and laboratory monitoring, AE and SAE reporting) into our trial design to ensure 
patient safety. 
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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
Baseline medical history and demographics, prior and concomitant medications, physical exam, 
weight, height, vital signs, ECOG performance status, laboratory assessments (CBC with 
differential, CMP, Magnesium levels, pregnancy test for women of reproductive age and 
coagulation studies (if on anticoagulant therapy), an EKG, CT or MRI of involved disease sites, 
human papillomavirus (HPV) status (immunohistochemical staining for p16) and a tumor 
biopsy (where feasible, after progression on previous line of treatment), will be obtained for all 
patients after they sign the consent form. 
 
Patients will initiate treatment on the afatinib and cetuximab combination regimen. Pre-
medication with decadron 10mg, H1 and H2 blockade (at the discretion of the treating facility 
and physician) may precede the first dose of Cetuximab in week 1 of cycle 1. Premedication with 
H1 blockade alone may be used beyond the initial dose for patients who do not experience an 
infusion reaction with the first dose. Oral Afatinib at 30mg daily will start the same day as the 
Cetuximab. Subsequently, Cetuximab will be dosed at 250mg/m2 body surface area, given 
intravenously weekly (+/- 1 day) or at 500 mg/m2 body surface area, given intravenously bi-
weekly (+/- 2 days), at the discretion of the treating physician. Each treatment cycle will be 28 
days (+/- 3 days) in length.  
 
Alternating Cetuximab dosing schedules from a weekly to bi-weekly dosing schedule, and vice 
versa, between and within cycles of treatment is permitted per protocol following Sponsor PI 
discussion and approval. 
  
While on study treatment, patients will be seen weekly (+/- 1 day) or bi-weekly (+/- 2 days) 
depending on the frequency of cetuximab dosing. During these visits, the following evaluations 
will be done: adverse event assessment, concomitant medications, physical exam, weight, vital 
signs and ECOG performance status. Laboratory assessments (CBC with differential, CMP, 
Magnesium) will be performed prior to cetuximab infusion throughout treatment. Pregnancy 
test for reproductive age women and coagulation studies if on anticoagulant therapy will be 
performed every 4 weeks  throughout treatment. CT or MRI (at physician discretion) will be 
performed at the end of cycle 2 (+/- 3 days) and every 2 cycles thereafter (+/- 3 days).  
 
Treatment will be discontinued in the event of ≥ grade 3 drug related toxicities that fail to 
resolve to Grade 2 despite appropriate supportive care or unequivocally progressive disease on 
clinical exam or surveillance scans. Treatment may also be discontinued for reasons noted in 
Section 3.3.4, including clinically significant deterioration of the patient’s condition, patient 
noncompliance, investigator determination that it is no longer in the patient’s best interest to 
continue, pregnancy, or withdrawal of consent. Tissue biopsies will be repeated, where 
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medically feasible, at the end of cycle 1, and at disease progression or end of treatment if 
discontinued for reasons other than disease progression. 
 
In the situation where patients withdraw consent for treatment on study, we will permit 
progression and survival data collection unless they specifically withdraw consent for data 
collection for the trial. 
 
3.2 
DISCUSSION OF TRIAL DESIGN 
This study will be a  single center, single-arm, open-label Phase II trial. The study is expected to 
enroll 50 patients with advanced squamous cell cancers of the head and neck, who have 
previously been treated with a platinum-based regimen or with immune checkpoint inhibitor 
therapy or both. After obtaining consent, patients will undergo a baseline evaluation including 
tumor assessment (scans performed within 4 weeks of treatment start will be accepted), biopsy 
(where feasible) and verification of HPV status and then initiate treatment with cetuximab 
weekly/bi-weekly and oral afatinib daily. Up to a 2-day interval between two 4-week cycles will 
be permitted. Following the first cycle of treatment, a tumor biopsy will be repeated where 
medically feasible (for correlative studies), and therapy will be continued. Tumor assessment 
will be repeated after cycle 2 and every 2 cycles thereafter. Tumor biopsy (for correlative 
studies) will be repeated again where medically feasible, at disease progression or end of 
treatment if discontinued for reasons other than disease progression. Results will be compared 
with historical controls. 
 
3.3 
SELECTION OF TRIAL POPULATION 
3.3.1 
Main diagnosis for study entry  
Advanced Squamous Cell Cancers of the Head and Neck Region. 
3.3.2 
Inclusion criteria 
1. Histologically or cytologically confirmed squamous cell carcinoma of the head and 
neck that is metastatic, recurrent or locally advanced and not treatable with curative 
intent. 
 
2. Previous treatment with a platinum-based regimen or immune checkpoint inhibitor 
therapy or both in the R/M (Recurrent/Metastatic) setting. 2-week washout period 
prior to treatment start will be required. 
 
3. Patients who have experienced progression of disease within 6 months following 
completion of a platinum-based chemoradiation in the definitive or adjuvant setting 
will be permitted. 
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4.  Prior cetuximab permitted if it was given as part of multi-modality therapy for initial 
treatment of locally advanced disease but not for recurrent/metastatic disease. 
 
5. Measurable disease based on RECIST v 1.1. Baseline measurements and evaluations 
must be obtained within 4 weeks of enrollment. Disease in previously irradiated sites 
is considered measurable if there has been unequivocal disease progression or 
biopsy-proven residual carcinoma following radiation therapy.  
 
6. Age >18 years 
 
7. ECOG performance status ≤2 
 
8. Adequate organ function, defined as all of the following: 
- 
Hemoglobin ≥ 8 g/dl. 
- 
Absolute neutrophil count (ANC) ≥1000 / mm3.  
- 
Platelet count ≥75,000 / mm3. 
- 
Estimated creatinine clearance > 45ml / min. 
- 
Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal 
(Patients with Gilbert’s syndrome total bilirubin must be ≤4 times 
institutional upper limit of normal). 
- 
Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 
three times the upper limit of (institutional/central) normal (ULN) (if 
related to liver metastases ≤ five times ULN). 
 
9. Ability to understand and the willingness to sign a written informed consent that is 
consistent with ICH-GCP guidelines. 
 
10. Negative urine or serum pregnancy test for women of childbearing potential 
 
11. A second eligibility review will always be provided by a Head and Neck Research 
Team associated for the New Haven Campus and a third review will be provided by 
the PI. 
 
3.3.3 
Exclusion criteria 
1. Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any 
investigational EGFR or panErbB reversible or irreversible inhibitor or any prior 
panitumumab or investigational EGFR-directed monoclonal antibody. Cetuximab is 
permitted if used for locally advanced disease, as long as no disease progression 
within 6 months. Cetuximab use is not permitted for recurrent/metastatic disease. 
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2. Radiotherapy within 2 weeks prior to enrollment. Palliative radiation to target 
organs may be allowed up to 2 weeks prior to enrolment, as long as there are other 
target lesions that can be monitored for response to study treatment. 
 
3. Known hypersensitivity to afatinib or its excipients  
 
 
4. Women of child-bearing potential (WOCBP) and men who are able to father a child, 
unwilling to be abstinent or use highly effective methods of birth control prior to 
study entry, for the duration of study participation and for at least 4 weeks after 
treatment has ended. 
 
5. Pregnant or nursing women. 
6. Any history of or concomitant condition that, in the opinion of the Investigator, 
would compromise the patient’s ability to comply with the study or interfere with the 
evaluation of the efficacy and safety of the test drug. 
7. Concomitant malignancies at other sites that are being actively treated with 
systemic therapy 
8. Requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2.1 that cannot be stopped for the duration of trial participation. 
9. Clinically significant interstitial lung disease. 
10. Known history of untreated viral hepatitis or HIV. 
11. Patients with parenchymal brain metastases are not eligible, unless they have 
completed local therapy. 
12. Leptomeningeal carcinomatosis. 
 
 
3.3.4 
Removal of patients from therapy or assessments 
Patients may discontinue study treatment at any time. Any patient who discontinues treatment 
will be encouraged to return to the study center to undergo treatment discontinuation 
assessments and to receive supportive care as indicated. We will permit progression and 
survival data collection unless the patient specifically withdraws consent for data collection for 
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the trial. The primary reason for discontinuation should be recorded. Reasons for 
discontinuation of a patient by the investigator include, but are not limited to, the following:  
• 
Documented disease progression  
• 
Intolerable side effects, defined as grade 3 or higher drug related toxicity that fails to 
resolve to Grade 2 despite appropriate supportive care 
• 
Clinically significant deterioration of the patient’s condition causing a change in 
performance status prior to treatment discontinuation   
• 
Patient noncompliance   
• 
Investigator determination that it is not in the patient’s best interest to continue 
participation   
• 
Pregnancy  
• 
Patient withdrawal of consent 
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4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
4.1.1 
Identity of Investigational Product 
Substance (INN) 
 
Afatinib  
(Brand name):  
 
GIOTRIF®/GILOTRIF®  
Pharmaceutical form: 
 
Film-coated tablet 
Source:  
 
 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength: 
20 and 30 mg film-coated tablets (the dose of  afatinib in the 
film-coated tablets is related to the free base equivalent to 
afatinib) 
Route of administration: 
Oral 
Posology 
Once daily 
4.1.2 
Standard therapy: Cetuximab 
Brand Name:                         
Erbitux 
Pharmaceutical form:             
Injection for intravenous infusion 
Source:                                        
to be covered by patient’s insurance carrier 
Unit strength:                           
400mg/m2 body surface area loading dose, followed by 250 
mg/m2 body surface area weekly thereafter 
                                                             OR  
                                                             500mg/m2 body surface area initial dose and bi-weekly 
thereafter 
Route of administration:       
Intravenous injection 
Posology:                                   
Weekly/Bi-weekly 
Premedications:  
May premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously and 
steroid (dexamethasone 10 mg oral/intravenous) 30–60 minutes prior to the first dose. It is also 
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recommended to give a dose of dexamethasone 8 mg PO approximately 12 hours before the first and 
second scheduled cetuximab infusions. Premedication should be administered for subsequent 
cetuximab doses based upon clinical judgment and presence/severity of prior infusion 
reactions.  
4.1.2 
Method of assigning patients to treatment groups 
Since this is an open-label, single-arm study, all enrolled patients will receive the combination of 
Cetuximab (standard therapy covered by patient’s insurance carrier) and Afatinib (provided by 
Boehringer Ingelheim). 
4.1.3 
Selection of doses in the trial 
Cetuximab at the proposed doses is FDA approved for the treatment of metastatic SCCHN. In the 
Phase I open-label dose-escalation study, the MTD of Afatinib was determined to be 40mg [14]. 
This dose has been tested in several Phase II and III trials as outlined in Section 1 above and 
found to be safe and effective. Afatinib 40 mg was also tested in combination with Cetuximab in 
patients with lung cancer who harbor the EGFR mutation and was shown to have a manageable 
side effect profile with not disproportionate treatment related mortality [22]. This was the dose 
initially used for patients accrued to the study, however, most patients needed a dose reduction 
to 30 mg daily. We will start all subsequent patients on this trial at a 30 mg daily dose. 
4.1.4 
Drug assignment and administration of doses for each patient 
4.1.4.1  
Administration of afatinib 
Patients will take a single oral dose of afatinib each day starting at a dose of 30 mg, continuously, 
until the development of progressive disease or unacceptable adverse events. Dose reductions 
of afatinib can occur.  See Sections 4.1.4.1.1 and 4.1.4.1.2. 
The medication should be taken at approximately the same time each day without food (at least 
one hour before or at least three hours after a meal).   
Missed doses of afatinib can be made up during the same day as soon as the patient remembers.  
However, if the next scheduled dose is due within 8 hours then the missed dose must be 
skipped. Patients with emesis must not take a replacement dose. 
If dosing of whole tablets is not possible, afatinib tablets can also be dispersed in approximately 
100 ml of non-carbonated drinking water. No other liquids should be used. The tablet should be 
dropped in the water, without crushing it, and occasionally stirred for up to 15 min until the 
tablet is broken up into very small particles. The dispersion should be drunk immediately. The 
glass should be rinsed with approximately 100 ml of water which should also be drunk. The 
dispersion can also be administered through a naso-gastric tube or enteral feeding tube. 
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Medication will be dispensed in bottles containing 30 tablets at the beginning of each treatment 
cycle.  For administrative purposes, a treatment cycle is defined as 28 (+/- 3) days.  Treatment 
will start after baseline evaluations and stop when the patient is diagnosed with disease 
progression or for any reason detailed in Section 3.3.4.  Study drug will be prescribed by the 
investigator and will be dispensed by the affiliated investigational pharmacy on day 1 of each 
cycle. 
4.1.4.1.1 Dose escalation for afatinib 
Afatinib dose will not be escalated beyond the 30 mg daily oral dose on this trial. 
4.1.4.1.2 Dose reduction for afatinib 
Treatment related AEs will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.1.2: 1. Given 
overlapping toxicities, afatinib dose reductions should precede cetuximab dose reductions. Dose 
reductions will apply to individual patients only. Once the dose has been reduced, it cannot be 
increased later. 
To prevent the development of more severe adverse events, treatment related diarrhea or rash 
should be managed early and proactively as described in Section 4.2.3. 
Table 4.1.4.1.2: 1 Dose reduction scheme for afatinib 
AE type and CTCAE Grade 
Action 
Dose reduction scheme 
Events related to study drug: 
 
• Diarrhea Grade 2 persisting for 2 or 
more consecutive days (48 hours) 
despite adequate anti-diarrheal 
medication/hydration                
• Reduced renal function to  ≥ Grade 2 
as measured by serum creatinine, 
proteinuria or decrease in 
glomerular filtration rate of more 
than 50% from baseline 
• Any other drug related AE Grade ≥3 
 
Pause treatment until 
patient has recovered to 
Grade ≤2 (Grade ≤1 for 
diarrhea or impaired renal 
function only) or baseline1. 
Resume treatment at 
reduced dose according to 
schedule opposite. 
If patient has not recovered 
to Grade ≤2 (Grade ≤1 for 
diarrhea or impaired renal 
function) or baseline1 within 
14 days, study treatment 
 
If patient was receiving Afatinib 30 mg 
daily, resume treatment at a dose of 
20 mg daily. 
If patient was receiving Afatinib 20 
mg daily, resume treatment at 20 mg 
intermittent dosing, 5 days on, 2 
days off. 
If patient was receiving Afatinib 20 
mg intermittent dosing, discontinue 
treatment. 
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AE type and CTCAE Grade 
Action 
Dose reduction scheme 
must be permanently 
discontinued2. 
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnoea, cough, fever) 
Pause afatinib while clinical 
assessment to exclude ILD is 
completed. 
If ILD is ruled out as a cause of 
symptoms, grade symptoms and 
relatedness and report as AEs.  If AEs 
are not related, resume afatinib at 
current dose.  If AEs are drug related, 
follow directions in row above. 
If ILD is confirmed, discontinue 
afatinib 
 
1 Baseline is defined as the CTCAE Grade at the start of treatment 
2 In the event that the patient is deriving obvious clinical benefit according to the investigator’s 
judgement, further treatment with afatinib will be decided in agreement between the sponsor 
and the investigator. 
 
In the event of any unrelated adverse events, the investigator may choose to interrupt the 
medication for up to 14 days, but no dose reduction should occur.  If the medication is 
interrupted for more than 14 days, the decision to continue with afatinib will be made by the 
sponsor in agreement with the investigator. 
4.1.4.2  
Administration of Cetuximab 
Pre-medication with dexamethasone 8 mg po or by feeding tube approximately 12 hours prior to 
cetuximab dosing for the first and second doses. This may be omitted if there is a relative 
contraindication (eg. poorly controlled diabetes or hypertension), and may be stopped after the second 
dose of cetuximab if no hypersensitivity is observed. Use of IV dexamethasone premedication on the 
treatment day is recommended.  
30-60 minutes after the recommended pre-medications per treating physician discretion, 
cetuximab will be administered intravenously at a dose of 400mg/m2 on cycle 1, day 1 of 
treatment (loading dose) and at a dose of 250mg/m2 every 7 days (+/- 1 day) thereafter. 
Alternatively, patients can be treated at a dose of 500mg/m2 every 14 days (+/- 2 days). 
Alternating Cetuximab dosing schedules from a weekly to bi-weekly dosing schedule, and vice 
versa, between and within cycles of treatment is permitted per protocol following Sponsor PI 
discussion and approval. 
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Do not administer cetuximab as an intravenous push or bolus.  
Administer via infusion pump or syringe pump. Do not exceed an infusion rate of 10 mg/min.  
Administer through a low protein binding 0.22-micrometer in-line filter.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.  
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.  
4.1.4.2.1 Dose escalation for cetuximab 
Cetuximab dose beyond the recommended and approved dosing will not be escalated on this 
trial. 
4.1.4.2.2 Dose reduction for cetuximab 
Infusion Reactions  
Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grade 3 
infusion reaction.  
Immediately and permanently discontinue Erbitux for serious infusion reactions. Afatinib may 
be continued by itself at the discretion of the treating physician, in patients who have 
experienced a serious infusion reaction with cetuximab. 
Dermatologic Toxicity  
Recommended dose modifications for severe (NCI CTC Grade 3 or 4) acneiform rash are 
specified in Table 4.1.4.2.2: 1 below. Afatininb should be dose reduced first per the guidelines in 
Table 4.1.4.1.2 above, before dose reducing cetuximab. 
Table 4.1.4.2.2: 1 Cetuximab Dose Modification Guidelines for Rash  
Grade 3/4 Acneiform 
Rash 
Erbitux 
Outcome 
Dose Modification 
1st occurrence 
Delay infusion 1 to 2 
weeks 
Improvement 
 
No Improvement 
Continue at 250 
mg/m2 (500mg/m2 
for bi-weekly dosing) 
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Discontinue Erbitux 
2nd occurrence 
Delay infusion 1 to 2 
weeks 
Improvement 
 
No Improvement 
Reduce dose to 
200mg/m2 
(400mg/m2 for bi-
weekly dosing) 
Discontinue Erbitux 
3rd occurrence 
Delay infusion 1 to 2 
weeks 
Improvement 
 
No Improvement 
Reduce dose to 
150mg/m2 
(300mg/m2 for bi-
weekly dosing) 
Discontinue Erbitux 
4th occurrence 
Discontinue Erbitux 
 
 
 
In the event of any adverse event, the treating physician may choose to interrupt cetuximab for 
up to 14 days.  Treatment can then be resumed at the same or lower dose level. If the medication 
is interrupted for more than 14 days, the decision to continue with cetuximab will be made by 
the sponsor in agreement with the investigator. 
4.1.5 
Blinding and procedures for unblinding 
4.1.5.1 
Blinding 
This is a single-arm, open-label study and will not employ randomization to assign treatment. All 
enrolled patients will receive the planned study treatment. 
4.1.5.2 
Procedures for emergency unblinding 
This is a single-arm, open-label study and will not employ randomization to assign treatment. All 
enrolled patients with receive the planned study treatment. 
4.1.6 
Packaging, labelling, and re-supply 
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20 and 30 mg. 
Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles. 
Bottles/boxes will be labelled according to local regulations and will include the following as a 
minimum; 
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• 
Study number  
• 
Product name (Afatinib) 
• 
Contents of the bottle (30 tablets) 
• 
Tablet strength (mg) 
• 
Batch number 
• 
Medication number 
• 
Use-by date 
• 
Storage information 
• 
Instructions for use 
• 
Sponsor name and address 
• 
A statement that the medication is for clinical study use only 
• 
A caution statement 
Erbitux (cetuximab) is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use 
vial or as a 200 mg/100 mL, single-use vial as a sterile, injectable liquid containing no 
preservatives.  
NDC 66733-948-23 100 mg/50 mL, single-use vial, individually packaged in a carton  
NDC 66733-958-23 200 mg/100 mL, single-use vial, individually packaged in a carton  
4.1.7 
Storage conditions 
Afatinib will be kept in their original packaging and a secure, limited access storage area 
according to the recommended storage conditions on the medication label.    
Cetuximab vials will be stored under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. 
Increased particulate formation may occur at temperatures at or below 0° C. This product 
contains no preservatives. Preparations of cetuximab in infusion containers are chemically and 
physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled 
room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the 
infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. 
Discard any unused portion of the vial.  
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4.1.8 
Drug accountability 
All study drug (Afatinib) will be provided by Boehringer Ingelheim (manufacturer). Cetuximab 
is commercially available.  
The recipient will acknowledge receipt of the drug (afatinib) by returning the drug receipt form 
indicating shipment content and condition.  Damaged supplies will be replaced. Study drug 
accountability records should be maintained by the site in accordance with the local SOPs and 
regulations. 
At the time of study closure, any unused or expired study drug will be destroyed at the site per 
Institutional SOPs. Any partially used study drug will be destroyed at the site, either during the 
course of the study or at the time of study closure, per Institutional SOPs. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
Rescue medication 
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. In cases of suspected overdose, afatinib should be 
withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may be 
achieved by emesis or gastric lavage. Potential adverse events should be treated 
symptomatically.  
Common adverse events of treatment with afatinib with specified management 
recommendations and/or requirements include diarrhea, stomatitis/mucositis, and rash/acne. 
To improve tolerability and the probability of clinical benefit, patients should receive prompt 
and appropriate supportive care at the first signs of symptoms. Suggested treatments for AEs 
are described below. 
Concomitant treatments 
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary.  
 
After study enrollment, palliative radiotherapy may be given for bone pain or for other reasons 
(e.g. bronchial obstruction, skin lesions), provided that the total dose delivered is in a palliative 
range according to institutional standards. The irradiated area cannot be used for tumor response 
assessment. During palliative radiotherapy, study treatment should be delayed and may be 
resumed once the patient has recovered from any radiation associated toxicity.  If medication is 
interrupted for more than 14 days, the decision to continue will be made by the sponsor in 
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agreement with the investigator.  Continuous interruption of >28 days due to palliative 
radiotherapy will not be allowed. 
 
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal remedies, 
nutritional supplements, must be recorded in the (e)CRF during the screening and treatment 
period, starting from the date of signature of informed consent, and ending at the EOT visit. After 
the EOT visit, only concomitant therapy indicated for treatment of an AE has to be reported.  
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will be 
made by the sponsor in agreement with the investigator. 
 
4.2.2 
Restrictions 
4.2.2.1 
Restrictions regarding concomitant treatment 
Concomitant medications, or therapy to provide adequate supportive care, may be given as 
clinically necessary. 
 
Palliative radiotherapy may be given as described in Section 4.2.1. 
 
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate and use of anti-androgens and/or 
gonadorelin analogues for treatment of prostate cancer), or radiotherapy (other than palliative 
radiotherapy for symptom control) is not allowed concomitantly with the administration of study 
treatment.  
 
Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib with P-gp modulators.  For a list of potent P-gp inhibitors and inducers see Appendix 10.1.  
 
4.2.2.2 
Restrictions on diet and life style 
Patients should be advised to avoid any foods known to aggravate diarrhea. 
To prevent skin related adverse events, it is recommended to avoid intense irradiation with UV 
light and harsh detergents, see also Section 4.2.3.2. 
4.2.2.3 
Restrictions regarding women of child-bearing potential  
Patients who are not of childbearing potential due to being postmenopausal (i.e. 12 months with 
no menses without alternative medical cause, predefined hormonal level according to local 
regulation or etc.) or being permanently sterilized (bilateral oophorectomy, bilateral 
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salphingectomy, hysterectomy and/or tubal ligation) do not need to use contraception to be 
eligible for the trial. 
All other patients are considered to have childbearing potential and must use adequate 
contraception throughout the trial (from screening until end of trial participation or 4 weeks 
after last dose of trial medication, whichever is later). 
Highly effective methods of birth control should be applied to women of childbearing potential 
as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year – 
placement of intrauterine device or intrauterine system, “double barrier” methods of 
contraception, male sterilisation or etc.) when used consistently and correctly, and must be in 
accordance with local regulations where applicable. The list of contraception methods meeting 
these criteria is provided in the patient information.  
Women who become pregnant while participating in the study must discontinue study 
medication immediately.  The pregnancy must be reported following procedures detailed in 
section 5.3.7.4 
4.2.3 
Management of expected adverse events 
Dermatologic adverse events and diarrhea are the most common side-effects associated with 
treatment with afatinib. Treatment of these side-effects should be proactive and should be 
started as early as possible after onset of symptoms. 
4.2.3.1 
Management of diarrhea and hydration status following treatment with afatinib 
Diarrhea occurs at a high frequency and generally begins within 2 weeks of exposure to afatinib. 
Although usually mild to moderate, diarrhea may lead to dehydration and compel treatment 
modification or discontinuation, so early management is essential (Table 4.2.3.1: 1). At the time 
of initiation of treatment with afatinib patients should be given a supply of loperamide to keep 
with them at all times or access to afatinib should be confirmed; and patients should be 
counselled on the appropriate use.  
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhea.  
 
 
Table 4.2.3.1: 1 Grade specific treatment recommendations for afatinib related diarrhea  
Severity  
(CTCAE Grading) 
Description  
Intervention 
concerning afatinib 
treatment 
Specific intervention 
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Mild (Grade 1) 
Increase of < 4 stools 
per day over baseline; 
mild increase in 
ostomy output 
compared with 
baseline 
Continue same dose 
Stop laxatives and advise 
patient to drink at least 8-
10 glasses of water of clear 
fluids per day; 
4 mg (2 tablets) of 
loperamide to be taken 
immediately, followed by 2 
mg (1 tablet) after each 
loose stool until bowel 
movements cease for 12 
hours 
Moderate (Grade 
2) 
Increase of 4-6 stools 
per day over baseline; 
i.v. fluids indicated < 
24 hours; moderate 
increase in ostomy 
output compared with 
baseline; not 
interfering with ADL 
Continue same dose 
unless Grade 2 
diarrhea continues 
for ≥ 2 days (48 
hours) in which case 
treatment must be 
interrupted until 
recovered to ≤ Grade 
1 followed by dose 
reduction 
Continue loperamide;  
assess for dehydration and 
electrolyte imbalance; 
consider IV fluids and 
electrolyte replacement  
Severe (Grade 3)  
Increase of ≥ 7 stools 
per day over baseline; 
incontinence; IV fluids 
> 24 hours; 
hospitalization; severe 
increase in ostomy 
output compared with 
baseline; interfering 
with ADL 
Dose interruption 
until recovered to 
≤Grade 1 followed by 
dose reduction* 
See Grade 2; plus: 
an infectious process 
should be ruled out with 
stool cultures; aggressive 
iv fluid replacement ≥ 24 
hours; hospitalization to 
monitor progress; 
consider prophylactic 
antibiotics if patient is also 
neutropenic;  
Life threatening 
(Grade 4) 
Life-threatening 
consequences (e.g. 
haemodynamic 
collapse)  
Dose interruption 
until recovered to 
≤Grade 1 followed by 
dose reduction* 
See Grade 3 
* If despite optimal supportive care and a treatment interruption, diarrhea does not resolve to 
CTC AE Grade ≤ 1 within 14 days, treatment with afatinib must be permanently discontinued. In 
the event that the patient is deriving obvious clinical benefit according to the investigator’s 
judgment, further treatment with afatinib will be decided in agreement between the sponsor 
and the investigator. 
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4.2.3.2 
Management recommendations for dermatological AEs following treatment with 
afatinib 
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.3.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.2.3.2: 2. For dose adjustment of afatinib 
refer to Table 4.1.4.1.2.   
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (4) 
Table 4.2.3.2: 1  General recommendations for prophylaxis while receiving afatinib 
Personal hygiene 
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath 
and shower formulations and tepid water. 
Use of very mild shampoos for hair wash. 
Only clean and smooth towels are recommended because of potential 
risk of infection. The skin should be patted dry after a shower, whereas 
rubbing the skin dry should be avoided. 
Fine cotton clothes should be worn instead of synthetic material. 
Shaving has to be done very carefully. 
Manicure, i.e. cutting of nails, should be done straight across until the 
nails no longer extend over the fingers or toes. Cuticles are not allowed 
to be trimmed because this procedure increases the risk of nail bed 
infections 
Sun protection 
Sunscreen should be applied daily to exposed skin areas regardless of 
season. Hypoallergenic sunscreen with a high SPF (at least SPF30, 
PABA free, UVA/UVB protection), preferably broad spectrum 
containing zinc oxide or titanium dioxide are recommended 
Patients should be encouraged to consequently stay out of the sun. 
Protective clothing for sun protection and wearing a hat should be 
recommended. 
Moisturizer treatment 
It is important to moisturize the skin as soon as anti-EGFR therapy is 
started. 
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Hypoallergenic moisturizing creams, ointments and emollients should 
be used once daily to smooth the skin and to prevent and alleviate skin 
dryness.  
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil 
based) and topical acne medications 
Prevention of 
paronychia  
Patients should keep their hands dry and out of water if ever possible. 
They should avoid friction and pressure on the nail fold as well as 
picking or manipulating the nail. 
Topical application of petrolatum is recommended around the nails due 
to its lubricant and smoothing effect on the skin. 
 
Table 4.2.3.2: 2 Grade specific treatment recommendations of skin reactions to afatinib 
Severity  
(CTCAE Grading) 
Description 
  
Specific intervention 
ACNEIFORM RASH 
Mild (Grade 1) 
Macular or papular eruptions or 
erythema without associated 
symptoms 
Consider topical antibiotics, e.g. 
clindamycin 2% or topical 
erythromycin 1% cream of 
metronidazole 0.75% or topical 
nadifloxacin 1%; 
Isolated scattered lesion: cream 
preferred 
Multiple scattered areas: lotion 
preferred 
Moderate (Grade 2) 
Macular or papular eruptions 
with pruritus or other associated 
symptoms; localized 
desquamation or other lesions 
covering <50% of BSA  
Topical treatment as for Grade 1  
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus 
an oral antibiotic (for at least 2 weeks) 
e.g. Doxycycline 100mg b.i.d. or 
Minocycline hydrochloride 100mg b.i.d 
Severe (Grade 3) 
Severe, generalized 
erythroderma or macular, 
popular or vesicular eruption; 
desquamation covering ≥ 50% of 
BSA; associated with pain, 
disfigurement, ulceration or 
desquamation 
Topical and systemic treatment as for   
Grade 2. 
Consider referral to dermatologist 
Consider systemic steroids 
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Life threatening 
(Grade 4) 
Generalized exfoliative, 
ulcerative, or bullous dermatitis 
See Grade 3 
Systemic steroids are recommended 
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS 
Mild (Grade 1) 
Mild or localized 
Topical polidocanol cream. 
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, 
cetirizine, levocetirizine, desloratidine, 
fexofenadine or clemastine) 
Moderate (Grade 2) 
Intense or widespread 
See Grade 1 plus oral antihistamines; 
Consider topical steroids, e.g. topical 
hydrocortisone 
Severe (Grade 3) 
Intense or widespread and 
interfering with activities of 
daily living (ADL) 
See Grade 2. 
XEROSIS (DRY SKIN) 
Mild (Grade 1) 
Asymptomatic 
Soap-free shower gel and/or bath oil. 
Avoid alcoholic solutions and soaps. 
Urea- or glycerin-based moisturizer. 
In inflammatory lesions consider 
topical steroids (e.g. hydrocortisone 
cream) 
Moderate (Grade 2) 
Symptomatic, not interfering 
with ADL 
See Grade 1. 
In inflammatory lesions consider 
topical steroids (e.g. hydrocortisone 
cream) 
Severe (Grade 3) 
Symptomatic, 
interfering with ADL 
See Grade 2. 
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate) 
Consider oral antibiotics 
FISSURES 
Mild (Grade 1) 
Asymptomatic 
Petroleum jelly, Vaseline® or 
Aquaphor for 30 minutes under plastic 
occlusion every night, followed by 
application of hydrocolloid dressing; 
antiseptic baths (e.g. potassium 
permanganate therapeutic baths, final 
concentration of 1:10,000, or 
povidone-iodine baths) 
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Topical application of  aqueous silver 
nitrate solutions to fissures 
Moderate (Grade 2) 
Symptomatic, not interfering 
with ADL 
See Grade 1.  
Consider oral antibiotics. 
Severe (Grade 3) 
Symptomatic, 
Interfering with ADL 
See Grade 2. 
1 If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the 
investigator may choose to pause treatment up to 14 days followed by a reduction in the dose of 
afatinib according to the dose reduction scheme in Table 4.1.4.1.2: 1 
 
4.2.3.3 
Management of mucositis/stomatitis  
General and grade specific recommendations are described in Table 4.2.3.3:1. For dose 
adjustment refer to Section 4.1.4.1.2 and for restrictions on concomitant therapies refer to 
Sections 4.2.2 and 10.1. 
 
Treatment is supportive and aimed at symptom control. These may include atraumatic cleansing 
and rinsing with non-alcoholic solutions such as normal saline, diluted salt and baking soda 
solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one quart of water 
every four hours); avoidance of agents containing iodine, thyme derivatives and prolonged use 
of hydrogen peroxide; dietary manoeuvres such as promotion of soft, non-irritating foods like 
ice-creams, mashed/cooked vegetables, potatoes and avoidance of spicy, acidic or irritating 
foods such as peppers, curries, chillies, nuts and alcohol. If the patient is unable to swallow foods 
or liquids, parenteral fluid and/or nutritional support may be needed. Examples of some of the 
agents suggested in Table 4.2.3.3:1 include: topical analgesics –viscous lidocaine 2%; mucosal 
coating agents - topical kaolin/pectin; oral antacids, maltodextrin, sucralfate; topical antifungals 
– nystatin suspension. (Adapted from 8) 
 
Table 4.2.3.3: 1 
Grade specific treatment recommendations of study-drug related 
mucositis/stomatitis  
Severity  
(CTCAE 
grading) 
Description  
Treatment recommendations 
Intervention 
concerning afatinib 
treatment/ dose 
modification 
Mild (Grade 1) 
Minimal 
symptoms; 
normal diet  
Oral rinses with agents such as 
non-alcoholic mouth wash,  
normal saline, diluted salt and 
baking soda solution. 
No change. 
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Moderate 
(Grade 2) 
Symptomatic, 
but can eat 
and swallow 
modified diet 
Addition of topical analgesic 
mouth treatments, topical 
corticosteroids, antiviral therapy 
if herpetic infection confirmed, 
antifungal therapy preferably 
topical on a case by case basis. 
Maintain dose if 
tolerable; Hold dose if 
intolerable until 
recovery to grade ≤1, 
then restart at the 
same dose. 
Severe (Grade 
3)  
Symptomatic 
and unable to 
adequately 
aliment or 
hydrate orally 
Same as for Grade 2; institute 
additional symptomatic therapy 
(topical or systemic) as clinically 
indicated. 
Hold dose until 
recovery to grade ≤2 
or baseline, then 
restart at the reduced 
dose according to 
Section 4.1.4. 
Life threatening 
(Grade 4) 
Symptoms 
associated 
with life-
threatening 
consequences  
Same as for Grade 2; institute 
additional symptomatic therapy 
(topical or systemic) as clinically 
indicated. 
Hold dose until 
recovery to grade ≤2 
or baseline, then 
restart at the reduced 
dose according to 
Section 4.1.4 
 
4.2.3.4 
Management of interstitial lung disease (ILD) and keratitis  
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to exclude interstitial lung 
disease (ILD). Study drugs should be interrupted pending investigation of these symptoms. If 
interstitial lung disease is diagnosed, study drug must be permanently discontinued and 
appropriate treatment instituted as necessary.  
Patients who present with symptoms of keratitis, such as acute or worsening eye inflammation, 
lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred 
promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is confirmed, 
treatment with afatinib should be interrupted or discontinued. If keratitis is diagnosed, the 
benefits and risks of continuing treatment with afatinib should be carefully considered. Afatinib 
should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe 
dry eye. Contact lens use is a risk factor for keratitis and ulceration.  
4.3 
TREATMENT COMPLIANCE 
Patients will be dispensed Afatinib on a monthly basis in pill bottles with 30 tablets each. At 
every follow-up visit, they will be asked to bring in their pill bottles and pill count will be 
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performed. Pill diary will also be provided to document every dose taken. Missed doses and 
compliance to treatment will be documented. 
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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
TRIAL ENDPOINTS 
5.1.1 
Primary endpoint(s) 
Objective Response Rate (Complete Response + Partial Response), defined by tumor shrinkage 
(mm), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.  
 
5.1.2 
Secondary endpoint(s) 
Duration of response (measured in weeks), Progression-free survival (PFS) in weeks, overall 
survival (OS) in months, toxicity assessments using CTCAE v4.0, analysis of tumor-tissue 
microarrays by high-quality immunohistochemical assays and automated image analysis (AQUA, 
Genoptix®) from biopsies obtained at baseline, after four weeks of treatment with the 
combination, and again at disease progression or end of treatment. 
 
5.2 
ASSESSMENT OF EFFICACY 
Response and progression will be evaluated in this study using Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) (9).  Tumor response will be assessed by 
investigator. 
 
See APPENDIX 10.4, RECIST 1.1 Criteria for details on lesion measurements and response 
assessment. 
 
5.3 
ASSESSMENT OF SAFETY 
The safety of afatinib will be assessed through collection and analyses of adverse events (AEs) 
and laboratory tests. AE’s and their management will be recorded at every treatment and 
follow-up visit while subjects are on study. SAE’s will be appropriately reported as per Section 
5.3.7. 
 
5.3.1 
Physical examination and ECOG performance status 
A physical examination will be performed as part of the screening visit prior to initiation of 
study treatment. Subsequently, patients will be seen for every cetuximab dose. A physical 
examination and ECOG performance status will be recorded at every evaluation.  
 
5.3.2 
Vital signs 
Vital signs will be recorded at every visit as outlined in Section 5.3.1 above. 
 
5.3.3 
Safety laboratory parameters 
Baseline Complete Blood Count (CBC) with differential, Comprehensive Metabolic Panel (CMP) 
and Magnesium levels will be obtained at the Screening visit to ensure eligibility criteria are 
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met. These laboratory evaluations will be repeated prior to every cetuximab dose throughout 
treatment. In addition, for women of childbearing potential, urine/serum Human Chorionic 
Gonadotropin (HCG) test will also be obtained at least every 4 weeks. Coagulation studies are 
recommended every 4 weeks for patients on anticoagulation therapy (excluding a daily baby 
aspirin). 
 
5.3.4 
Electrocardiogram 
Baseline EKG will be obtained at the screening visit to rule out active cardiac issues. Subsequent 
EKG’s will be obtained as clinically indicated. 
 
5.3.5 
Other safety parameters 
Studies such as Echocardiogram and Pulmonary Function Tests, etc. will be obtained as clinically 
indicated for individual patients. 
 
5.3.6 
Assessment of adverse events 
5.3.6.1 Definitions of adverse events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which: 
• 
results in death, 
• 
is life-threatening, 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability or incapacity, 
• 
is a congenital anomaly/birth defect, 
or 
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• 
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. 
Life-threatening in this context refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if 
more severe. 
If cancer is the indication for treatment, only cancers of new histology and cases where there is 
clear evidence of exacerbation of an existing cancer qualify as a serious event. 
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer. 
Severity of adverse event 
The severity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03. in the (e)CRF. 
 
For events not listed in the CTCAE, severity will be designated as mild, moderate, severe or life 
threatening, or fatal which respectively correspond to Grades 1, 2, 3, 4, and 5 on the NCI CTCAE, 
with the following definitions: 
 
• Mild:  An event not resulting in disability or incapacity and which resolves without 
intervention; 
• Moderate:  An event not resulting in disability or incapacity but which requires 
intervention; 
• Severe:  An event resulting in temporary disability or incapacity and which requires 
intervention; 
• Life-threatening:  An event in which the patient was at risk of death at the time of the 
event; 
• Fatal:  An event that results in the death of the patient. 
 
 
 
Causal relationship of adverse event 
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Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Assessment 
of causal relationship must be recorded for each adverse event.  
Causality will be reported as either “Yes” or “No”. 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE (i.e., the AE is possibly, probably, or definitely related to the 
investigational product).  
No: 
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
 
5.3.7 
Adverse event collection and reporting 
5.3.7.1 
AE collection 
The following must be collected and documented on the appropriate CRF(s) by the Investigator: 
• 
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual patient’s end of trial (through the EOR or end of follow-up visit):  
-all AEs (serious and non-serious) and all AESIs.  
• 
After the individual patient’s end of trial (after the EOR or end of follow-up visit, but 
including the overall survival follow-up period): the investigator does not need to 
actively monitor the patient for AEs but should only report relevant SAEs and relevant 
AESIs of which the investigator may become aware of. 
For Afatinib the residual effect period (REP) is defined as 30 days after last intake of it. 
5.3.7.2 
Exemptions to SAE reporting 
None 
 
5.3.7.3 
Information required 
For each adverse event, the investigator should provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator should determine the causal relationship and expectedness with the investigational 
drug to all AEs as defined in the listed adverse event section of Boehringer Ingelheim’s (BI’s) 
Investigator Brochure.  
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if applicable): 
• 
Worsening of the underlying disease or of other pre-existing conditions 
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• 
Changes in vital signs, EKG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.  
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions 
All (S)AEs, including those persisting after individual patient’s end of trial must be followed up 
until they have resolved, have been sufficiently characterized, or no further information can be 
obtained.  
5.3.7.4 
Pregnancy 
The sponsor-investigator shall be responsible to follow up on all information regarding a 
reported Drug Exposure during Pregnancy. The investigator shall ensure that any SAEs during 
and after pregnancy obtained by the Investigator will be reported to the Boehringer Ingelheim 
Unique Entry Point in the same format and timeline as any other SAE. 
5.3.7.5 
S(AE) reporting to Boehringer Ingelheim and NCCN  
The sponsor-investigator must report all SAEs and non-serious AEs which are relevant for the 
reported SAE to BI by fax using BI IIS SAE form to BI Unique Entry Point as detailed below in 
accordance with the timelines specified in the safety exchange agreement 
The SAE contact (fax number) is : 
Boehringer Ingleheim Pharmaceuticals, Inc 
               900 Ridgebury Road 
               Ridgefield, CT  06877 
               Fax: 1-203-837-4329 
In addition, SAEs must also be sent to NCCN via email to ORPReports@nccn.org or fax at 215-
358-7699. 
5.4 
ASSESSMENT OF EXPLORATORY BIOMARKER(S)  
Pre-treatment biopsies or archived tumor tissue (if no other systemic treatment was 
administered since that biopsy/excision) will be used to establish a baseline presence and 
quantification of EGFR, phosphorylated EGFR, and HER2 using immune-fluorescent staining and 
automated image analysis (AQUA, Genoptix®). These levels will then be compared with levels 
measured on tumor tissue obtained after 4 weeks of treatment with both Afatinib and 
Cetuximab to determine effects of treatment and again from tumor tissue obtained at the time of 
disease progression on treatment.   Through sequential measurement of these biomarkers we 
hope to determine the prevalence of over expression in our patient population, whether EGFR, 
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phosphor-EGFR and HER2 levels change with treatment with dual EGFR inhibitors and correlate 
with clinical response and whether they can be used in the future as predictive of response to 
treatment. 
 
Taking a core needle biopsy (CNB)is anticipated to be the most likely methodology employed in 
acquiring tissue for analysis in this patient group with advanced cancer of the head and neck 
region. This can usually be performed in a head and neck surgeon's office under local anesthesia. 
Tissue samples obtained from all participating sites will be transported to Yale Pathology to 
Veronique Neumeister’s lab for processing and analysis. Instructions for tissue acquisition and 
handling, and shipping of samples can be found in the study Laboratory Manual. 
 
5.4.1 
Biobanking 
A tissue repository will be created from the tumor samples derived from patients enrolled on 
this study. All samples will be submitted to Pete Doukas MD (cell 475-267-9188), Yale Head and 
Neck Biosample Repository (Dr. Benjamin Judson, Director) at Brady Memorial Laboratory 
BML212,, 310 Cedar St, New Haven Connecticut. Material may be archived for future use 
including but not limited to immunohistochemistry. Selected specimens will processed for 
immediate patient-derived xenograft development in the Burtness Lab. Collection of these 
samples will be coordinated with Sundong Kim (813-420-1746), Nathan Smith 286, 333 Cedar 
Street, New Haven, Connecticut. Development of patient-derived xenografts is conducted with 
funding from the Department of Defense [CA201045P1; PI: Barbara Burtness, MD]. 
5.4.2 
Sequencing 
Pre- and post-treatment tumor specimens from up to 50 enrolled patients will be submitted for 
whole exome sequencing to the Yale Center for Genome Analysis.  Outcome will be analyzed by 
the presence or absence of TP53 mutation, as well as TP53 mutation class (disruptive, gain of 
function, non-disruptive). This work is conducted with funding from the Department of Defense 
[CA201045P1; PI: Barbara Burtness, MD]. 
6. INVESTIGATIONAL PLAN  
 
6.1 
VISIT SCHEDULE 
The Trial Flow Chart summarizes the trial procedures to be performed at each visit.  Individual 
trial procedures are described in detail below.  It may be necessary to perform these procedures 
at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety.  
 
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6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS  
6.2.1  
Screening and run-in period(s) 
Baseline medical history and demographics, prior and concomitant medications, physical exam, 
weight, height, vital signs, ECOG performance status, laboratory assessments (CBC with 
differential, CMP, Magnesium levels, pregnancy test for women of reproductive age and 
coagulation studies if on anticoagulant therapy), EKG, CT or MRI of involved disease sites, HPV 
status (determined by p16 IHC staining) and a tumor biopsy (where feasible, obtained after 
progression on previous line of treatment), will be obtained for all patients at the initial 
screening visit after they sign the consent form. 
Medical history and demographics, prior and concomitant medications, physical exam, weight, 
height, vital signs, ECOG performance status, and laboratory assessments should be obtained 
within 48 hours of initiation of treatment, EKG and imaging should be obtained within 28 days 
of treatment initiation. 
6.2.2 
Treatment period(s)  
During the treatment period, patients will take afatinib once daily at a dose of 30mg. Subjects 
will visit clinic on day 1 (+/- 3 days) of each 28 day cycle and prior to every cetuximab dose 
thereafter. Pre-medication with decadron 10mg, H1 and H2 blockade may precede theinitial 
dose of Cetuximab in week 1 of cycle 1, per the discretion of the treating physician. 
Premedication with H1 blockade may be used beyond the initial dose for patients who do not 
experience an infusion reaction with the loading dose.  30-60 minutes after the recommended 
pre-medications, cetuximab will be administered intravenously at a dose of 400mg/m2 in the 
first week of treatment (loading dose) and at a dose of 250mg/m2 every week thereafter. 
Alternatively, cetuximab can also be administered at a dose of 500 mg/m2 every 2 weeks.  
While on study treatment, patients will be seen prior to every cetuximab dose. During these 
visits, the following evaluations will be done: adverse event assessment, concomitant 
medications, physical exam, weight, vital signs and ECOG performance status. Laboratory 
assessments (CBC with differential, CMP, Magnesium) will also be performed prior to the 
cetuximab dose, throughout the treatment period. Pregnancy test for reproductive age women 
and coagulation studies if on anticoagulant therapy will be performed every 4 weeks throughout 
the treatment period.  
 
For patients who are on afatinib alone due to cetuximab being discontinued for a serious 
infusion reaction or for any other reason, they will be scheduled for follow-up on days 1 and 15 
(+/- 3 days) of the first two 28-day cycles. The following assessments will be performed during 
these visits: adverse event assessment, concomitant medications, physical exam, weight, vital 
signs and ECOG performance status, laboratory assessments (CBC with differential, CMP, 
Magnesium). Pregnancy test for reproductive age women and coagulation studies if on 
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anticoagulant therapy will be performed every 4 weeks throughout the treatment period. After 
the first 2 cycles, visits can be scheduled on day 1 of every 28-day cycle (+/- 3 days) per 
physician discretion.  
 
Tissue biopsies will be repeated, where medically feasible, at the end of cycle 1, and at disease 
progression or end of treatment if discontinued for reasons other than disease progression.  
 
CT or MRI (at physician discretion) will be performed at the end of cycle 2 (+/- 3 days) and 
every 2 cycles thereafter (+/- 3 days). Treatment will be discontinued in the event of intolerable 
side effects or unequivocally progressive disease on clinical exam or surveillance scans. 
 
6.2.3 
Follow-up period and Trial Completion 
6.2.3.1 
End of treatment visit (EOT)  
The EOT visit will be performed at the time of permanent discontinuation of trial medication for 
any reason (within 7 days of treatment discontinuation as defined as the removal of the subject 
from the study treatment period). 
 
At this visit, patients will undergo the following evaluations:  adverse event assessment, 
concomitant medications, physical exam, weight, vital signs, ECOG performance status, 
laboratory assessments (CBC with differential, CMP, Magnesium). Tumor assessment and 
imaging will be performed if applicable. 
 
Tissue biopsies will be repeated at this visit, where medically feasible.  
 
6.2.3.2 
Residual effect period (REP) 
The REP is defined in Section 5.3.7. The End of REP (EoR) visit should be performed at 30 days (+ 
14 days) after permanent discontinuation of the trial medication.  
The information collected at this visit should include all new AEs that occurred after EOT and a 
follow-up of adverse events ongoing at EOT.  
Additionally, patients will undergo the following evaluations at this visit: concomitant 
medications, physical exam, weight, vitals, ECOG performance status, laboratory assessments 
(CBC with differential, CMP, Magnesium). Tumor assessment and imaging will be performed if 
applicable. 
 
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6.2.3.3 
Extended follow-up period 
6.2.3.3.1 Follow-up for progression 
Additional follow-up visits after the EoR visit will be performed for patients who did not progress 
on treatment. Visits should occur every 4 weeks (+7 days) for up to 24 weeks. 
The follow-up for progression period will end at the earliest if one of the following events is met: 
• 
Completion of the predefined follow-up for progression period 
• 
Lost to follow-up 
• 
Disease progression (either clinical or per RECIST) 
• 
Start of a new anti–cancer therapy   
• 
Death 
• 
End of whole trial as specified in Section 8.6 
At the end of the follow-up period, the EoFU (End of Follow-Up) visit will be performed.  The EoFU 
visit will be performed within 14 days of known progression, start of new anti-cancer therapy, or 
completion of predefined follow-up progression period. 
 
The following will be obtained and / or performed during the follow-up visits and the EoFU visit: 
adverse event assessment and follow-up of adverse events ongoing since EoR to EoFU, concomitant 
medications, physical exam, weight, vitals, and ECOG performance status,. Tumor assessment and 
imaging will be performed if applicable. 
 
Treatment with any other anti-cancer drug including the name and type of the anti-cancer drug and/or 
best supportive care and the date initiated should be recorded, if applicable. Additionally, the 
patient’s outcome should be recorded, including the date of and reason for death [if applicable], 
or the date of progressive disease. 
 
6.2.3.3.2 Follow-up for Overall Survival  
Patients who discontinued study treatment due to disease progression will have at least a monthly 
telephone call (+/- 1 week) to ascertain survival status. This will continue until patient death. 
 
6.2.3.4 
Trial completion for an individual patient 
A patient is considered to have completed the trial in case any of the following applies: 
• 
Completion of planned follow-up period (or follow-up for overall survival if applicable) 
• 
Lost to follow-up 
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• 
Withdrawal to be followed-up 
• 
Death 
At the earliest of the above criteria, the Patient Completion (PC) information should be entered in 
the (e)CRF. 
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7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE 
7.1 
STATISTICAL DESIGN – MODEL 
This is a single-arm prospective Phase II trial. 
7.2 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation was based on the primary endpoint, the objective response rate. 
Historical data with single agent Cetuximab have yielded response rates of 10-15%, as discussed 
in Section 1.1. We used Software PASS 2012 (Kayesville, UT) Inequality Tests for One 
Proportion module for sample size calculation.  The results were shown in the tables and 
figures below for different historical control rate. A sample size of 33 will allow us to detect an 
absolute difference of 20% (alternative hypothesis 30% - null hypothesis 10%) in ORR using a 
two-sided binomial test with 80% power and significance level of 0.05.  Should the historical 
ORR be 15% (null hypothesis), a sample size of 34 will achieve 80% power to detect an absolute 
difference of 20% in ORR too.   
Null hypothesis: ORR=10% 
 
Null hypothesis: ORR=15% 
 
Based on the calculation as above, we plan to enroll 50 patients which provide us 80% power to 
detect an alternative hypothetical ORR of 24% by rejecting a null hypothesis of 10%. This 
n
P1
30
50
70
90
110
0. 20
0. 25
0. 30
0. 35
0. 40
0. 45
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sample size will achieve 80% power to detect an absolute difference of 18% if the historical 
control of ORR is 15% (i.e. 33% vs. 15%).    
7.3 
PLANNED ANALYSES 
All statistical analyses will be performed using the SAS statistical software, version 9.4 (SAS 
Institute Inc., Cary, NC). Significance level will be set as p < 0.05, two-sided. Yale Center for 
Analytical Sciences will provide statistical support.  
Patient demographics and clinical characteristics will be summarized. The primary analysis will 
use a 2-sided binomial test to compare the ORR with historical control of 10%. 95% confidence 
interval of ORR will be reported as well. As an exploratory analysis, Logistic regression will be 
used to identify potential risk factors that are associated with ORR.  
The secondary endpoint is progression-free survival and overall survival with 1 year follow-up. 
We will use Kaplan-Meier survival analysis to estimate the median PFS and OS in the cohort. 
Additional Cox regression analyses will be carried out to examine the association between 
demographical or clinical variables and survival outcome.  
We expect 10 – 15 HPV + patients will be enrolled. We will compare the demographics and 
clinical characteristics between HPV + and HPV - subgroup, and then calculate the ORR by HPV 
status. An exploratory analysis will be conducted to compare the ORR using multivariate logistic 
regression, and a survival analysis for the secondary endpoint as well.   
7.4 
HANDLING OF MISSING DATA  
We will perform complete case analyses in which those with missing data will be excluded from the 
relevant analyses. We will not impute missing data. Missing data on one item will not preclude a 
patient’s observed data from being used in other analyses. For example, a patient might have missing 
response data but observed toxicity data. The toxicity data can be used in appropriate analyses.  
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8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) and relevant sponsor’s Standard Operating Procedures (SOPs). Standard 
medical care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility 
of the treating physician of the patient. 
The investigator must inform the sponsor immediately of any urgent safety measures taken to 
protect the study subjects against any immediate hazard, and also of any serious breaches of the 
protocol/ICH GCP. 
The rights of the investigator and of the sponsor with regard to publication of the results of this 
trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalization of the Clinical Trial Report. 
8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT  
8.1.1 
Informed consent 
Prior to patient participation in the study, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative. 
The patient must be informed that his/her personal study-related data will be used by the 
Principal Investigator in accordance with the local data protection law. The level of disclosure 
must also be explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorized 
monitors or Quality Assurance auditors appointed by the Sponsor or IRB, and by inspectors 
from regulatory authorities. 
8.1.2 
Patient registration  
The informed consent process must be completed before any study screening procedures may 
begin.  Following consent, patients will have all required screening procedures outlined in 
Section 6.2.1. The site principal investigator or other approved investigator must document that 
the patient has met all inclusion criteria and has none of the exclusion criteria.  
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8.2 
DATA QUALITY ASSURANCE 
The YCCI Project Manager will distribute all necessary study related materials and regulatory 
documents with instructions for their completion and submission to YCCI. Upon receipt of all 
required regulatory documents including the IRB approved protocol and informed consent form 
and participation in a study initiation meeting, the Project Manager will send a site activation 
notice to that participating site. Upon receipt of the activation notice patient screening and 
consent may proceed.  
 
8.2.1 
Data monitoring  
The study principal investigator and YCCI are responsible for monitoring the performance of all 
of the participating sites. This will be performed by conducting a study site initiation visit, as 
well as regularly scheduled monitoring visits and/or remote monitoring throughout the life of 
the protocol. At the end of the trial, the monitor will then perform a study site close-out visit at 
all participating sites.  
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. Following 
each site visit, a visit report will be generated containing information on site activities, and a 
summary of pertinent points and action items together with a copy of the follow-up letter will be 
sent to each investigative site.  
During these monitoring visits, some of the items that will be reviewed are the following:  
• 
Training of the sites  
• 
Site personnel qualifications to participate in the trial  
• 
That study related documents are current  
• 
That regulatory compliance is accomplished  
• 
That each subject has signed the informed consent  
• 
That the current and approved protocol is complied with (including reporting and 
logging of all protocol deviations)  
• 
That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, YCCI, NCCN and Boehringer Ingelheim, as appropriate  
• 
That source documentation matches CRFs  
• 
That required procedures for study drug accountability, distribution, and storage are 
followed.  
YCCI will document the required study monitoring activities in a Study Monitoring Plan. 
 
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8.2.2 
Safety monitoring 
The Study Principal Investigator, biostatistician and study team will monitor toxicity and 
outcome on a continual basis.  
The Yale Cancer Center Data and Safety Monitoring Committee (DSMC) will provide the primary 
oversight of data and safety monitoring. The Yale DSMC will review and monitor compliance, 
toxicity and deviations from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator. 
The DSMC will review this protocol at a minimum of once every six months. Information to be 
provided to the committee includes: a study narrative by the PI, a summary DSMC report 
produced by OnCore (which includes participant accrual, response, trial status history, SAEs, 
Adverse Events, Deviations and survival); audit results, and monitoring reports as applicable. 
Other information (e.g. scans, laboratory values) will be provided upon request. 
 
If the committee decides that changes should be made to this trial, recommendations will be 
made in writing to NCCN, Boehringer Ingelheim and Division Medical Director, which, in turn, 
have the authority to approve or disapprove these recommendations. These changes will be 
discussed with the Study Principal Investigator before they are implemented. These changes 
may include early termination of accrual. Other changes might include altering the accrual goals 
or changing the eligibility criteria for the trial.  
 
8.2.3 
Project team meetings 
Scheduled meetings will be held and will include the protocol investigators and research staff 
involved with the conduct of the protocol. 
 
During these meetings the investigators will discuss: 
• 
Safety of protocol participants (adverse events and reporting) 
• 
Validity and integrity of the data (data completeness on case report forms and complete 
source documentation) 
• 
Enrollment rate relative to expectation of target accrual, (eligible and 
ineligible\participants) 
• 
Retention of participants, adherence to the protocol and protocol violations 
• 
Protocol amendments 
 
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8.2.4 
Audit plan 
The YCCI Office of Quality Assurance and Training will audit the trial at least annually or as 
determined by the YCC DSMC. The overall principal investigator, study coordinator and/or data 
manager may request access to all source documents and other study documentation for on-site 
or remote monitoring, audit or inspection. 
 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the Principal 
Investigator or Yale. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, institutional 
policy, and any applicable regulatory requirements. 
 
8.2.5 
Data management  
The investigators are required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. OnCore will be the designated electronic data capture tool. All data should be entered 
onto OnCore within 2 weeks of each study visit.  AEs need to be entered within 72 hours and 
SAEs need to the entered within 24 hours of the site becoming aware of the event.  
 
8.3 
RECORDS 
8.3.1 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the (e)CRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available. 
For (e)CRFs all data must be derived from source documents. 
8.3.2 
Direct access to source data and documents 
The sponsor will allow access to all source data and documents for the purposes of monitoring, 
audits, IRB review, and regulatory inspections. Source documents provided to the coordinating 
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center for the purpose of auditing or monitoring will be de-identified and labeled with the study 
number, patient ID number, and patient initials. Upon inquiry, NCCN and Boehringer Ingelheim 
will be provided access to de-identified source data and documents pertaining to data resulting 
from patients on this study.  
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records maintained by the participating investigators, including but not limited 
to medical records and pharmacy records for the patients in this study. The clinical study site 
will permit access to such records. 
8.3.3 
Storage of records 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified.  
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 
8.4.1 
Listedness 
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For afatinib this is the current version of the Investigator’s Brochure. No AEs are classified as 
listed for matching placebo, study design, or invasive procedures. 
8.4.2 
Expedited reporting to health authorities and IECs/IRBs 
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs), to health authorities and IRB or Ethics Committees will be done according 
to local regulatory requirements. Further details regarding this reporting procedure are 
provided in the Investigator Site File. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
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Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the study need to 
be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB or Ethics Committees and the regulatory authorities. 
8.6 
END OF TRIAL 
The trial will end when the last patient has completed the last EOR visit or follow-up for 
progression visit, depending on whether that last patient progressed on treatment.  
8.7 
PROTOCOL VIOLATIONS 
YCCI will conduct ongoing monitoring of the study records of each participant accrued at each 
site throughout the course of the study in order to ensure proper conduct of this study and 
identify in a timely manner any protocol violations, as described in Section 8.2.1. Protocol 
violations will be reported to site’s IRBs in accordance with institutional policy. 
8.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL 
RELATED INJURY 
No monetary or financial compensation will be made available to study patients in the event of 
study related injury. However, reasonable medical care will be provided for treatment related 
injury. Subjects or their insurance providers will be responsible for costs related to treatment of 
study related injury. 
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9. 
REFERENCES 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 
66(1): p. 7-30. 
2. 
Slaughter, D.P., H.W. Southwick, and W. Smejkal, Field cancerization in oral stratified 
squamous epithelium; clinical implications of multicentric origin. Cancer, 1953. 6(5): p. 
963-8. 
3. 
Vermorken, J.B., et al., Platinum-based chemotherapy plus cetuximab in head and neck 
cancer. N Engl J Med, 2008. 359(11): p. 1116-27. 
4. 
Thomas, G.R., H. Nadiminti, and J. Regalado, Molecular predictors of clinical outcome in 
patients with head and neck squamous cell carcinoma. Int J Exp Pathol, 2005. 86(6): p. 
347-63. 
5. 
Vermorken, J.B., et al., Open-label, uncontrolled, multicenter phase II study to evaluate the 
efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or 
metastatic squamous cell carcinoma of the head and neck who failed to respond to 
platinum-based therapy. J Clin Oncol, 2007. 25(16): p. 2171-7. 
6. 
Cancer Genome Atlas, N., Comprehensive genomic characterization of head and neck 
squamous cell carcinomas. Nature, 2015. 517(7536): p. 576-82. 
7. 
Modjtahedi, H., et al., A comprehensive review of the preclinical efficacy profile of the ErbB 
family blocker afatinib in cancer. Naunyn Schmiedebergs Arch Pharmacol, 2014. 387(6): 
p. 505-21. 
8. 
Machiels, J.P., et al., Afatinib versus methotrexate as second-line treatment in patients with 
recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or 
after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 
trial. Lancet Oncol, 2015. 16(5): p. 583-94. 
9. 
Seiwert, T.Y., et al., A randomized, phase II study of afatinib versus cetuximab in 
metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol, 2014. 
25(9): p. 1813-20. 
10. 
Bhatia AK, M.R., Khan SA, Egleston BL, Alpaugh RK, Lango M, Ridge, JA, Burtness BA. 
Phase II trial of carboplatin/paclitaxel and cetuximab, followed by 
carboplatin/paclitaxel/cetuximab and erlotinib, in metastatic or recurrent squamous cell 
carcinoma of the head and neck. in ASCO. 2016. Chicago, IL. 
11. 
Burtness, B., et al., Afatinib versus placebo as adjuvant therapy after chemoradiation in a 
double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, 
clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized 
controlled trial. Trials, 2014. 15: p. 469. 
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12. 
Chung, C.H., et al., A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy 
followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally 
advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral Oncol, 2016. 
53: p. 54-9. 
13. 
Investigator’s brochure. Afatinib (BIBW 2992). Version 15, P.-P. Jul 2014. 
14. 
Gordon, M.S., et al., A Phase I, open-label, dose-escalation study of continuous once-daily 
oral treatment with afatinib in patients with advanced solid tumors. Invest New Drugs, 
2013. 31(2): p. 409-16. 
15. 
Lacouture, M.E., et al., Dermatologic adverse events associated with afatinib: an oral ErbB 
family blocker. Expert Rev Anticancer Ther, 2013. 13(6): p. 721-8. 
16. 
Lynch, T.J., Jr., et al., Epidermal growth factor receptor inhibitor-associated cutaneous 
toxicities: an evolving paradigm in clinical management. Oncologist, 2007. 12(5): p. 610-
21. 
17. 
Moy, B. and P.E. Goss, Lapatinib-associated toxicity and practical management 
recommendations. Oncologist, 2007. 12(7): p. 756-65. 
18. 
Yang, J.C., et al., Diarrhea associated with afatinib: an oral ErbB family blocker. Expert Rev 
Anticancer Ther, 2013. 13(6): p. 729-36. 
19. 
G. Giaccone, B.M., M. Reck. Epidermal Ggrowth Factor Receptor Inhibitor (EGFRI)-
associated rash: a suggested novel management paradigm. A consensus position from the 
EGFRI Dermatologic Toxicity Forum. in ECCO. 2007. Barcelona. 
20. 
Seshacharyulu, P., et al., Targeting the EGFR signaling pathway in cancer therapy. Expert 
Opin Ther Targets, 2012. 16(1): p. 15-31. 
21. 
Wheeler, D.L., et al., Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) 
family members. Oncogene, 2008. 27(28): p. 3944-56. 
22. 
Janjigian, Y.Y., et al., Dual inhibition of EGFR with afatinib and cetuximab in kinase 
inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer 
Discov, 2014. 4(9): p. 1036-45. 
 
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10. 
APPENDICES 
10.1 
APPENDIX 1 
List of potent inhibitors and inducers of P-glycoprotein (MDR1) 
Inhibitors 
Inducers 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin  
Conivaptan 
Cyclosporine  
Diltiazem 
Dronedarone 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lopinavir 
Nelfinavir 
Ritonavir 
Quinidine 
Ranolazine 
Saquinavir 
Tacrolimus 
Ticagrelor 
Verapamil 
Carbamazepine 
Phenytoin 
Rifampicin 
St John’s Wort 
Phenobarbital Salt 
Tipranavir 
Ritonavir 
 
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is 
important for the investigator to assess such status on concomitant therapies and in case of 
questions contact the sponsor. 
 
 
 
 
 
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10.2 
APPENDIX 2  COCKCROFT-GAULT FORMULA 
The following formula may be used for estimated creatinine clearance rate (eCCR) using Cockcroft-
Gault formula.  The use of on-line calculators or formulas which are institution standards for eCCR 
and differ slightly may also be used.  The calculations and results must be filed in the patient’s 
chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
When serum creatinine is measured in mg/dL; 
(
)
(
) [
]
(
)
mg/dL
in 
 
Creatinine
 
Serum
72
 
 
85
.0
kilograms
in 
 
Mass
Age
140
eCCR
⋅
⋅
⋅
−
=
Female
if
 
When serum creatinine is measured in µmol/L; 
(
)
(
)
(
)
µmol/L
in 
 
Creatinine
 
Serum
Constant
kilograms
in 
 
Mass
Age
140
eCCR
⋅
⋅
−
=
 
Where Constant is 1.23 for men and 1.04 for women. 
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10.3 
APPENDIX 3 
 
ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.4 
APPENDIX 4 RECIST 1.1 CRITERIA 
The criteria below are based on RECIST 1.1 (9). 
The preferred method of assessment is a spiral CT scan with IV and oral contrast, unless IV 
and/or oral contrast are medically contraindicated. CT scans of the chest, abdomen and other 
areas of known or newly suspected disease must be performed. Scans of the abdomen, pelvis 
and other areas of the body, but not chest, may be done with MRI instead of CT.  
 
Skin lesions followed as target lesions must be documented by color digital photography and 
must include in the image a ruler with millimeter subdivisions and a label that includes the 
patients ID and date.  
 
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at baseline 
if the patient has any signs and symptoms consistent with bone metastasis or a history of bone 
metastasis. Bone metastasis identified at baseline must be documented and assessed according 
to RECIST 1.1 at the times of the other tumor measurements indicated in the flow chart. During 
the study bone scans should be repeated as clinically indicated in patients without bone 
metastasis at Baseline.  
 
For the purposes of this study, patients should be re-evaluated for response at weeks 8, 16 and 
every 8 weeks thereafter.  In the event of a treatment delay, interruption or discontinuation of 
treatment, tumor assessment should continue to follow the original schedule.  
 
Follow-up tumor assessments must utilize the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of IV contrast) as were used for screening 
assessments to ensure comparability. A chest x-ray or skeletal x-ray which clearly demonstrates 
a new metastatic lesion may be used to document progression in lieu of CT/MRI/bone scan.    
 
Only those patients who have measurable disease present at baseline, have received at least 3 
weeks of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.   
 
Measurability of tumour at baseline 
Measurable lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter ≥10 
mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray).  Pathological lymph 
nodes, defined as lymph nodes with a short axis >15mm are also measurable. 
 
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Measurable disease 
Measurable disease requires the presence of at least one measurable lesion. Measurable lesion if 
limited to either small (<2cm) solitary visceral lesion or scant (<5cm) lymph nodes only 
metastasis should be evaluated for additional evidence of malignant nature and discussed with 
the sponsor before enrolling. 
Non-measurable disease 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or pathological lymph 
nodes with shortest axis ≥10 and <15 mm) as well as truly non-measurable lesions. Lesions 
considered truly unmeasurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/ abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
New lesions in irradiated fields 
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumor response. 
Methods of measurement 
All measurements must be recorded in metric notation, using a ruler or callipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. If a lesion is considered too small to measure, a 
default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied. 
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes). In the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is obligatory. 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 5 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to the chest, abdomen and pelvis. 
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Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement information 
from other techniques. 
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours where known residual 
benign tumours can remain). 
Baseline Documentation of Target and Non-target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be recorded, 
measured (longest diameter = LD) and numbered at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repetitive measurements (either by imaging techniques or clinically). Lymph nodes must be 
≥15mm in order to be considered as target lesions.  
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference to further characterise the 
objective tumour response of the measurable dimension of the disease (see Table 10.4:1). 
Table 10.4: 1 Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. 
Partial Response 
(PR) 
At least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD. 
Progression (PD) 
At least a 20% increase in the sum of LD of target lesions taking as 
reference the smallest sum LD recorded since the treatment started, 
together with an absolute increase in the sum of LD of at least 5mm. 
OR 
The appearance of one or more new lesions. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR, taking as reference the 
baseline SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD since the treatment started. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required and these lesions should be followed as 
“present” or “absent” (see Table 10.4:2). 
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Table 10.4: 2 
Evaluation of non-target lesions and new lesions 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size  
(<10 mm short axis) 
Non-CR/Non-PD  
Persistence of one or more non-target lesions or/and maintenance of 
tumour marker level above normal limits. 
Progression (PD)  
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Although a clear progression 
of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression 
status should be confirmed later by the review panel (or study chair). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
Confirmation 
In case of tumour response (CR or PR), confirmation will be performed with a repeat assessment 
no less than 4 weeks after the RECIST criteria for response have been met. In the case of SD, 
measurement must have met the SD criteria at least once after study entry at an interval of not 
less than 6 weeks. 
Evaluation of best response to study treatment 
The best response to study treatment (Table 10.4: 3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.4: 3). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
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Table 10.4: 3 
Algorithm for evaluation of overall response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
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