Randomized, Placebo-Controlled, Phase 2 Study Of Induction Chemotherapy With Cisplatin/Carboplatin, And Docetaxel With Or Without Erlotinib In Patients With Head And Neck Squamous Cell Carcinomas Amenable For Surgical Resection
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: M.D. Anderson Cancer Center

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CLINICAL STUDY PROTOCOL 
RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2 STUDY OF INDUCTION 
CHEMOTHERAPY WITH CISPLATIN/CARBOPLATIN, AND DOCETAXEL WITH OR 
WITHOUT ERLOTINIB IN PATIENTS WITH HEAD AND NECK SQUAMOUS CELL 
CARCINOMAS AMENABLE FOR SURGICAL RESECTION 
STUDY CHAIR:    Xiuning Le, MD 
STUDY CO-CHAIR 
JEFFREY MYERS, MD 
PROTOCOL VERSION: 5 
PROTOCOL DATE: November 11, 2022 

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TABLE OF CONTENTS 
1 
INTRODUCTION ...................................................................................................... 10 
1.1 Background Therapeutic Information ............................................................ 11 
1.2 Clinical Experiences with Erlotinib ................................................................. 11 
1.2.1 Phase 1 Studies in Cancer Patients ........................................................ 11 
1.2.2 Phase 1b/2 Experience in Patients with Head and Neck Cancer ....... 11 
1.3 Rationale for the Current Study ...................................................................... 13 
2 
STUDY OBJECTIVES ........................................................................................... 16 
3 
STUDY DESIGN AND PLAN ............................................................................... 18 
3.1 Treatment Plan and Regimen ......................................................................... 19 
3.1.1 Treatment Plan ........................................................................................... 19 
3.1.2 Dose Modifications for Chemotherapy .................................................... 22 
3.1.3 Dose Modifications for Erlotinib or Placebo ............................................ 29 
4 
PATIENT POPULATION ...................................................................................... 33 
4.1 Inclusion Criteria ............................................................................................... 33 
4.2 Exclusion Criteria .............................................................................................. 34 
5 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS .............................. 35 
5.1 Description, Handling and Administration of Docetaxel .............................. 35 
5.2 Description, Handling and Administration of Cisplatin / Carboplatin ........ 35 
5.3 Description, Handling and Administration of Erlotinib or Placebo ............. 35 
5.3.1 Formulation of Erlotinib .............................................................................. 35 
5.3.2 Packaging and Labeling of Erlotinib or Placebo .................................... 36 
5.3.3 Storage and Handling of Erlotinib or Placebo ........................................ 36 
5.3.4 Administration of Erlotinib or Placebo ..................................................... 36 
5.4 Drug Accountability .......................................................................................... 36 
5.5 Treatment Compliance ..................................................................................... 37 
5.6 Concomitant Medications ................................................................................ 37 
5.6.1 Permitted Concomitant Medications ........................................................ 37 
5.6.2 Prohibited Concomitant Medications ....................................................... 39 
5.6.3 Potential for Drug Interactions .................................................................. 39 

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5.6.4 Ophthalmologic Considerations ............................................................... 41 
6 
STUDY PROCEDURES ........................................................................................ 42 
6.1 Patient Enrollment and Treatment Assignment ........................................... 42 
6.2 Baseline Assessments ..................................................................................... 42 
6.3 Study Assessments .......................................................................................... 44 
6.3.1 Assessment During Chemotherapy ......................................................... 44 
6.3.2 Assessments at Surgery ........................................................................... 46 
6.3.3 End of Treatment Assessments ............................................................... 48 
6.4 Descriptions of Study Assessments .............................................................. 49 
6.4.1 Smoking History .......................................................................................... 49 
6.4.2 Performance Status ................................................................................... 50 
6.4.3 Clinical Laboratory Tests ........................................................................... 50 
6.4.4 Symptoms and Toxicity Assessment ...................................................... 50 
6.4.5 Radiology Assessments ............................................................................ 50 
6.4.6 Quality of Life .............................................................................................. 51 
6.4.7 Tumor Tissue Samples .............................................................................. 51 
6.4.8 Blood-based Biomarkers and Serum Pharmacokinetics ...................... 52 
6.4.9 Tissue and Blood Sample Repository ..................................................... 53 
6.4.10 Long-Term Follow-Up ................................................................................ 53 
6.5 Assessments for Premature Discontinuation from Study ........................... 54 
6.6 Criteria for Treatment Discontinuation ........................................................... 55 
7 
ADVERSE EVENTS .............................................................................................. 56 
7.1 Safety Assessment ........................................................................................... 56 
7.2 Definition of Adverse Event ............................................................................. 56 
7.3 Definition of Serious Adverse Event .............................................................. 57 
7.4 Definition of Adverse Drug Reaction ............................................................. 58 
7.5 Adverse Event Reporting Period .................................................................... 58 
7.6 Adverse Event Assessment and Documentation ........................................ 59 
7.7 Serious Adverse Event Reporting Requirements ........................................ 60 
7.8 Clinical Laboratory Abnormalities and Other Abnormal Assessments ..... 62 
7.9 Expected Adverse Events ............................................................................... 62 
7.10 Pregnancy and Breast Feeding ...................................................................... 63 

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8 
STATISTICAL METHODS .................................................................................... 64 
8.1 Objectives and Design ..................................................................................... 64 
8.2 Sample Size and Trial Conduct ...................................................................... 65 
8.2.1 Randomization ............................................................................................ 65 
8.2.2 Erlotinib-associated biomarkers (EAB) ................................................... 74 
8.3 Study Endpoints ................................................................................................ 75 
8.3.1 Safety ........................................................................................................... 75 
8.3.2 Efficacy ......................................................................................................... 75 
8.3.3 Quality of Life .............................................................................................. 76 
8.4 Planned Analysis .............................................................................................. 77 
8.4.1 Safety ........................................................................................................... 77 
8.4.2 Efficacy ......................................................................................................... 77 
8.4.3 Pharmacokinetics ....................................................................................... 78 
8.4.4 Quality of Life .............................................................................................. 78 
9 
RECORDING AND COLLECTING OF DATA ................................................... 79 
9.1 Case Report Forms .......................................................................................... 79 
9.2 Study Files and Patient Source Documents ................................................. 79 
9.3 Patient Data Confidentiality .............................................................................. 79 
10 LEGAL AND ETHICAL REQUIREMENTS ......................................................... 80 
10.1 Good Clinical Practice ........................................................................................ 80 
10.2 Institutional Review Board ............................................................................... 80 
10.3 Informed Consent ............................................................................................. 80 
10.4 Study Termination ............................................................................................ 81 
11 REFERENCE LIST ................................................................................................ 82 

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PROTOCOL SYNOPSIS 
 
 
Title of Study: 
Personalized, randomized, placebo-controlled, phase 2 study of induction 
chemotherapy with cisplatin/carboplatin, and docetaxel with or without 
erlotinib in patients with head and neck squamous cell carcinomas 
amenable for surgical resection 
 
Objectives: 
The primary objective of this study is to assess: 
 
• 
major pathologic response among patients with locally advanced oral 
cavity squamous cell carcinomas treated with induction 
cisplatin/carboplatin, docetaxel and erlotinib prior to surgery, and to 
compare it with the major pathologic response among patients 
treated with cisplatin/carboplatin, docetaxel, and placebo, in the trial 
population overall and in biomarker-defined subgroups. 
 
The secondary objectives of this study are to assess: 
 
• 
Safety and toxicity according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 
 
 
• 
Recurrence-free survival 
 
• 
Progression-free survival 
 
• 
Response rate and disease control rate, as determined by 
RECIST version 1.1 
 
• 
Percentage of viable tumor cells in the surgical specimen 
 
• 
To correlate tissue and blood-based biomarkers with outcome 
and toxicity 
 
• 
Quality of life, determined by the self-reported FACT-HN 
questionnaire 
 
Study Design: 
This is a randomized, double-blind, placebo controlled, phase 2 study of 
docetaxel and cisplatin/carboplatin with or without erlotinib in patients with 
HNSCC of the oral cavity amenable for surgical resection. Patients will be 
randomized to: 
Arm A — induction chemotherapy with concurrent erlotinib; 
Arm B — induction chemotherapy with concurrent placebo 
The clinical trial is divided in two stages: stage I (biomarker 
discovery/testing of previous findings) and stage II (biomarker-guided 
therapy). Fresh tissue and blood will be collected prior to initiation of 
induction chemotherapy for biomarker evaluation. In stage I, patients will 
be equally randomized to the control and experimental arms irrespective 
of their biomarker status. Upon completion of stage I, the biospecimens 
collected will be analyzed in search of predictive markers of benefit from 
erlotinib. These analyses will be informed by correlative studies of other 
erlotinib-based trials in HNSCC conducted at M. D. Anderson, pre-clinical 
data and other emerging data in the literature as regards to benefit from 
chemotherapy and/or EGFR inhibitors in this setting. When appropriate, 
techniques and cut-offs will be standardized to determine the most  
 

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Number of Patients 
Planned: 
practical, efficient, and robust biomarkers able to discriminate responders 
versus non-responders to chemotherapy+erlotinib. These biomarkers 
(herein referred to as erlotinib associated biomarkers [EAB]) will be CLIA 
certified (when appropriate) and incorporated into stage II. During stage 
II, patients will be adaptively randomized to the control or experimental 
arms according to their EAB status. 
 
100 patients 
Target Population: 
Patients with stage III, IVA or IVB resectable HNSCC of the oral cavity. 
 
Duration of Treatment: 
All patients will receive up to 3 cycles of chemotherapy with concurrent 
erlotinib (arm A) or placebo (arm B), followed by surgery. Post-operative 
(chemo)radiation will be delivered according to institutional guidelines and 
the best judgment of the treating physicians. 
 
Diagnosis and Main 
Eligibility Criteria: 
 
Inclusion criteria: 
 
1. Suspected or histologically/citologically confirmed HNSCC of the oral 
cavity, stage III, IVA or IVB (according to the AJCC 7th edition). 
Patients with a suspected lesion may be enrolled and a baseline 
biopsy will be obtained as part of the study. If squamous cell 
histology is not confirmed, patients will be discontinued from the 
study. 
 
2. Patients must have surgically resectable disease, in the opinion of 
the treating physician 
 
3. Age ≥ 18 years. 
 
4. ECOG PS ≤ 2 (Appendix C) 
 
5. Adequate bone marrow, hepatic and renal function defined by: 
6.   ANC ≥ 1.5 x 109/L; 
7. Platelet count ≥ 100 x 109/L; 
 
8. ALT (SGPT) ≤ 1.5 x upper limit of normal (ULN); 
 
9. Total bilirubin ≤ ULN (patient’s with Gilbert’s syndrome are eligible, 
even if total bilirubin is > ULN); 
 
10. Alkaline phosphatase ≤ 2.5 x ULN; 
 
11. Serum creatinine ≤ 1.5 x ULN. 
 
12. Patients with reproductive potential (e.g., females menopausal for less 
than 1 year and not surgically sterilized) must practice effective 
contraceptive measures for the duration of study drug therapy and for 
at least 30 days after completion of study drug therapy. Female 
patients of childbearing potential must provide a negative pregnancy 
test (serum or urine) ≤ 14 days prior to treatment initiation. 
 
13. Written informed consent to participate in the study according to the 
investigational review board (IRB). 
 
Exclusion criteria: 
 
1. Histology other than squamous cell carcinoma. 
 
2. Primary sites other than oral cavity. 

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3. Prior chemotherapy or biologic therapy for the same HNSCC. Prior 
chemotherapy or biologic therapy for a different previous HNSCC is 
allowed 
 
4. History of poorly controlled gastrointestinal disorders that could affect 
the absorption of the study drug (e.g., Crohn’s disease, ulcerative 
colitis). Patients requiring feeding tubes are permitted 
 
5. Other active solid malignancies within 2 years prior to randomization, 
except for basal cell or squamous cell skin cancer or in situ cervical 
or breast cancer or superficial melanoma. 
 
6. Serious underlying medical condition which would impair the ability of 
the patient to receive protocol treatment, in the opinion of the treating 
physician. 
 
7. History of allergic reactions to compounds of similar chemical 
composition to the study drugs (docetaxel, cisplatin, carboplatin, 
erlotinib or their excipients), or other drugs formulated with 
polysorbate 80. 
 
8. Any concurrent anticancer therapy, excluding hormonal therapy for 
prostate or breast cancer. 
 
9. Women who are pregnant or breast-feeding and women or men not 
practicing effective birth control. 
 
Study Procedures/ 
Frequency: 
Procedures: 
The study will include standard procedures at baseline, during 
chemotherapy, at surgery, and at the end of treatment (approximately 
within 8 weeks after surgery). 
At baseline, patients will be assessed for eligibility. A treatment history, 
medical history, smoking history, and current smoking status and tobacco 
use, and use of concomitant medications will be obtained. A physical 
exam will be performed, as well as a self-reported questionnaire for 
quality of life assessment (FACT-H&N), and an assessment of baseline 
symptoms and toxicities. Baseline blood-work for hematology, 
biochemistry, and blood-based biomarker studies will be obtained, as well 
as a pregnancy test (when appropriate), and baseline imaging studies. A 
new biopsy of the tumor will be obtained for histopathological examination 
and biomarker analysis. 
Eligible patients will be stratified according to their nodal stage (N0/N1 
versus N2/N3) and will be randomized to treatment arms A or B. 
For both arms, prior to each chemotherapy cycle, a physical exam will be 
performed, and patients will be reassessed for symptoms and toxicity, 
Blood-work for hematology, biochemistry, pregnancy test (when 
appropriate) will also be obtained prior to each cycle. Imaging studies, as 
well as a self-reported questionnaire for quality of life assessment (FACT- 
H&N) and blood-based biomarker studies, and erlotinib PK will be 
obtained after the last dose of chemotherapy. Patients will receive up to 3 
cycles of chemotherapy with concurrent daily erlotinib (arm A) or placebo 
(arm B). 
Following chemotherapy (preferably within 3 to 6 weeks after the last 
chemotherapy cycle), patients will undergo surgical resection and tumor 
tissue will be obtained for histopathological and biomarker evaluation. 

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Test Product, Dose, and 
Mode of Administration: 
 
Reference Therapy, 
Dose, and Mode of 
Administration: 
 
Criteria for Evaluation: 
An end of treatment evaluation is planned approximately within 8 weeks 
after surgery, and consists of a physical exam, symptoms and toxicities 
assessment (including retrospective evaluation of any unexpected 
surgical complications), blood-based biomarkers, and quality of life 
assessment. 
Treatment Arms: 
Arm A = Chemotherapy with Concurrent Erlotinib 
Docetaxel 75 mg/m2 IV followed by cisplatin 75 mg/m2 or carboplatin AUC 
6 mg.min/ml IV on Day 1 of each 21 day cycle for a maximum of 3 cycles, 
plus erlotinib 150 mg PO daily continuously until the day before surgery 
(including the day before surgery). 
Arm B = Chemotherapy with Concurrent Placebo 
Docetaxel 75 mg/m2 IV followed by cisplatin 75 mg/m2 or carboplatin AUC 
6 mg.min/ml IV on Day 1 of each 21 day cycle for a maximum of 3 cycles, 
plus placebo 150 mg PO daily continuously until the day before surgery 
(including the day before surgery). 
Supportive Care: 
Standard pre- and post-medications will be administered with docetaxel 
and cisplatin/carboplatin infusions. 
Growth factors (G-CSF support) are strongly recommended during 
chemotherapy. 
 
Erlotinib (arm A) or placebo (arm B) 150 mg PO daily. 
 
 
Arms A and B: Docetaxel 75 mg/m2 IV on day 1 every 21 days 
Cisplatin 75 mg/m2 or carboplatin AUC 6 mg.min/ml IV 
on day 1 every 21 days 
 
Safety: 
All patients who receive at least one study treatment will be included in 
the safety analysis. Frequency of AEs, SAEs, discontinuation of study 
drug due to AEs and changes from baseline laboratory parameter values 
will be evaluated. 
 
Efficacy: 
All randomized patients will be included in the efficacy analysis. 
Primary endpoint: Major pathologic response 
Secondary endpoints: recurrence-free survival, progression-free 
survival, response rates, percentage of viable tumor cells in the 
surgical specimen, quality of life, pharmacokinetics, and biomarkers. 
 
Statistical Methods: 
The clinical trial is divided in two stages: stage I (biomarker 
discovery/testing of previous findings) and stage II (biomarker-guided 
therapy), with 50 patients in each stage. The first 30 patients in stage I 
will be equally randomized between two arms, stratified by lymph node 
status (N0/1 vs. N2/3). Patients 31 to 50 will be adaptively randomized 
between the two arms based on major pathologic response and nodal 
status. In stage II, the next 50 patients will be adaptively randomized 
based on response, node status, and one predictive biomarker in order to 
maximize response probability based on patients’ molecular profile. 
Adaptive randomization assigns patients into the control arm and the 
experimental arm with the randomization probability proportional to the  
 

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treat success using the Bayesian adaptive method such that more 
patients will be treated with the better treatment (higher overall major 
pathologic response rate) compared with conventional equal 
randomization method. The design can also maintain the prespecified 
type I and type II error rates. The projected accrual rate is 3 patients per 
month. We expect that the study accrual will take approximately 3 years. 
We assume that we can identify one EAB as a predictive marker for the 
treatment group (cisplatin/carboplatin, and docetaxel with erlotinib) in 
Stage I. We also assume that the EAB positive rate is 50%. The major 
pathologic response rates under the null and alternative hypothesis in the 
overall population are 0.2 and 0.45. Detailed operating characteristics of 
the design based on simulation studies are described in the protocol. For 
the primary endpoint of major pathologic response, we will use the 
Bayesian probit model to assess the main effect of treatment, nodal 
status, and biomarker, and treatment by biomarker interaction. For other 
binary secondary endpoints, logistic regression model will be used to 
assess the effect of treatment and biomarker. Cox 
proportional hazards models will be used to assess the effect of treatment 
and biomarker on time to event outcomes (recurrence free survival and 
progression free survival). 
 
Protocol Date: 
11/11/2022 

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1 
INTRODUCTION 
 
 
 
There are over 500,000 worldwide and over 38,000 new cases in the US of cancer of 
the head and neck reported annually; most of these are epithelial in origin and therefore 
designated as squamous cell carcinomas (HNSCC).  Two-thirds of patients present with 
locally or regionally advanced disease and therapeutic efforts have focused on local 
control with surgery, radiation therapy, chemotherapy, or combined-modality 
approaches. Worldwide, HNSCC represent the third most prevalent cancer, and within 
HNSCC, the most frequent site of origin is the oral cavity. 
 
Most HNSCC overexpress the epidermal growth factor receptor (EGFR), and EGFR 
inhibitors have been evaluated in this setting, either as monotherapy1 or combined with 
cytotoxic chemotherapy.2 
 
Erlotinib (Tarceva®, OSI-774) is an orally active EGFR tyrosine kinase inhibitor 
developed for the treatment of non-small cell lung cancer (NSCLC), pancreatic cancer, 
and other solid tumors. 
 
In most regions, erlotinib is indicated for the treatment of patients with locally advanced 
or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen. This 
indication is based on data from NCIC CTG Study BR.21, a randomized, 
placebo-controlled study of single-agent erlotinib at a dose of 150 mg daily.  This trial 
demonstrated a statistically significant and clinically meaningful survival benefit, as well 
as delayed time to deterioration of lung cancer symptoms, in patients who received 
erlotinib.3 
Erlotinib in combination with gemcitabine is indicated for the first-line treatment of 
patients with locally advanced, unresectable, or metastatic pancreatic cancer. In some 
regions, the indication is restricted to patients with metastatic pancreatic cancer. This 
indication is based on data from NCIC CTG Study PA.3, a randomized, placebo- 
controlled study of erlotinib at a dose of 100 mg daily given in combination with 
gemcitabine IV versus gemcitabine alone. This trial demonstrated a statistically 
significant survival benefit in patients who received this combination.4 
 
Although an overview of information pertaining to erlotinib is presented below, more 
comprehensive information is presented in the erlotinib Investigator’s Brochure 
appended to this protocol. 

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1.1 
Background Therapeutic Information 
 
1.2 
Clinical Experiences with Erlotinib 
 
Rash (dermatosis), diarrhea, nausea, fatigue, stomatitis, vomiting, and headache are the 
most frequently reported toxicities with exposure to single-agent erlotinib. Patients 
receiving erlotinib in combination with chemotherapy agents have generally experienced 
the same types of adverse events as with single-agent alone. Laboratory abnormalities 
are observed infrequently with erlotinib as a single agent. These abnormalities primarily 
involve changes in liver function tests, including elevation of ALT, AST, and/or bilirubin. 
These same abnormalities have occasionally been observed in patients receiving 
erlotinib and concomitant gemcitabine, as well as in patients receiving erlotinib 
concurrently with carboplatin and paclitaxel. Further information regarding nonclinical 
and clinical experience with erlotinib is provided in the erlotinib Investigator’s Brochure. 
 
1.2.1 
Phase 1 Studies in Cancer Patients 
 
In phase 1 studies in cancer patients, the maximum tolerated dose (MTD) of single- 
agent erlotinib has been determined to be 150 mg daily, with diarrhea being the dose- 
limiting toxicity (DLT) despite supportive antidiarrheal treatment. Several phase 1b 
studies have been conducted to evaluate the MTD and pharmacokinetics of erlotinib 
when combined with standard doses of common chemotherapy regimens.  As 
expected, patients who received concomitant chemotherapy experienced more 
hematological toxicities including anemia, neutropenia, and thrombocytopenia than 
patients who received erlotinib as single-agent therapy.5  No evidence of 
pharmacokinetic drug-drug interaction was noted with any of the chemotherapy 
regimens evaluated, with the exception of capecitabine and paclitaxel/carboplatin. 
Capecitabine appears to increase the exposure of erlotinib and erlotinib appears to 
increase the exposure of platinum, although the magnitude of these increases was 
considered to be not clinically relevant. 
 
1.2.2 
Phase 1b/2 Experience in Patients with Head and Neck Cancer 
 
Erlotinib single agent was studied in a multicenter phase 2 trial involving 115 patients 
with recurrent / metastatic HNSCC. The overall objective response rate was 4.3%, 
whereas 38.3% of patients had stable disease (with a median duration of 16.1 weeks). 
The median progression-free survival was 9.6 weeks and the median overall survival 
was 6.0 months.6 

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Siu et al. evaluated the combination of cisplatin and erlotinib in a phase1 / 2 study of 51 
patients with recurrent / metastatic HNSCC. The recommended phase 2 dose was 
determined as cisplatin 75 mg/m2 every 21 days and erlotinib 100 mg/day. The intent- 
to-treat response rate was 21%, median progression-free survival was 3.3 months and 
median overall survival was 7.9 months. The combination was well tolerated, with 
minimal grade ≥ 3 toxicity.7 
 
Kim et al. presented the results of an M. D. Anderson single-arm, phase 2 study of the 
combination of cisplatin, docetaxel and erlotinib in patients with recurrent / metastatic 
HNSCC. The first six patients in that trial received cisplatin 75 mg/m2 every 21 days, 
docetaxel 60 mg/m2 every 21 days and erlotinib 100 mg daily for the first cycle, 
escalated to cisplatin 75 mg/m2 every 21 days, docetaxel 75 mg/m2 every 21 days and 
erlotinib 150 mg daily for cycles 2-6, if well tolerated. After no clinically significant grade 
≥ 2 toxicities were observed in the first six patients, all subsequent patients received 
cisplatin 75 mg/m2 every 21 days, docetaxel 75 mg/m2 every 21 days, and erlotinib 150 
mg daily beginning at cycle 1. Routine prophylactic granulocyte colony-stimulating factor 
(G-CSF) support was required during all cycles (including cycle 1) after patient #18 had 
an episode of grade 4 neutropenic fever. Thirty-two out of 48 evaluable patients 
achieved an objective response to treatment (8% CR, 58% PR), and 25% of patients 
had stable disease. Median progression-free and overall survival were 6 and 11  
months, respectively. The regimen was tolerable, and the most common treatment- 
related grade ≥ 3 toxicities were nausea (14%), diarrhea (14%), dehydration (14%), 
febrile neutropenia (10%), infection without neutropenia (8%) and skin rash (8%).8 
William et al. recently presented the results of an M. D. Anderson phase Ib study of 
standard dose (150 mg/day) versus high dose (200 or 300 mg/day) erlotinib prior to 
surgery in patients with resectable HNSCC, with the primary endpoint of biomarker 
modulation. The median time on treatment was 19 days. Molecular analysis on pre- and 
post-treatment tumor and blood specimens are ongoing. In 21 patients with oral cavity 
cancers treated on that study, response rates by standard Response Evaluation Criteria 
in Solid Tumors (RECIST) were 33%, indicating that a substantial proportion of locally 
advanced oral cavity squamous cell carcinomas exhibit fast and dramatic tumor 
shrinkage to erlotinib, thus justifying further studies of EGFR tyrosine kinase inhibitors in 
this patient population, as well as correlative molecular markers that can predict 
response to treatment.9 

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1.3 
Rationale for the Current Study 
 
The EGFR monoclonal antibody cetuximab is the only biologic agent approved for 
treating HNSCC, based on improvements in overall survival when combined with 
radiation therapy for locally advanced disease10 or when combined with platinum/5-FU 
for recurrent/metastatic disease (EXTREME trial)2. Erlotinib and other EGFR tyrosine 
kinase inhibitors have also demonstrated clinical activity in HNSCC, either as single 
agents6,9,11,12 or in combination with chemotherapy7,8,13. EGFR inhibitors are now being 
investigated for the management of earlier-stage HNSCC, including incorporation to 
platinum-based induction chemotherapy,14 and chemoprevention.15 
 
Despite the relatively late stage of clinical development of EGFR inhibitors for HNSCC, 
no molecular biomarkers have been identified that predict response to EGFR-targeted 
therapies in this disease. The discovery and development of novel and robust molecular 
markers of sensitivity/resistance of HNSCC to EGFR inhibitors would have enormous 
significance in personalizing treatments for this patient population; this development 
could assist in (1) avoiding treatment exposure of patients unlikely to respond to these 
agents, thus reducing toxicity and cost; (2) reducing the likelihood that overall “negative” 
results in EGFR-inhibitor trials conducted in an unselected population would cause 
dismissing a drug that could be active in a subgroup of patients. 
 
The addition of docetaxel to induction chemotherapy with cisplatin and 5-fluorouracil 
has been demonstrated to improve overall survival in patients with locally advanced 
HNSCC treated with radiation therapy or chemoradiation therapy as definitive 
treatment.16,17 As a result, the use of induction chemotherapy prior to non-surgical 
therapy has become more common. However, the role of taxane-based induction 
chemotherapy prior to surgical resection in locally advanced HNSCC is yet to be 
determined. 
 
Licitra et al. conducted a randomized study of surgery upfront versus induction cisplatin, 
5-fluorouracil (3 cycles) followed by surgery in 198 patients with oral cavity squamous 
cell carcinomas. The study was terminated early due to slow accrual. There was no 
improvement in overall survival in the experimental arm, but induction chemotherapy led 
to significant downstaging and less need for destructive surgery (i.e., mandibulectomy) 
and/or post-operative radiation therapy. A pathologic response to PF was seen in 27% 
of patients with stage III and 18% of patients with stage IVA/B. Patients with a 
pathologic response to induction chemotherapy had a statistically significant 
improvement in 
overall survival compared to patients with a suboptimal pathologic response.18 

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Moreover, the authors were able to identify a biomarker of response to induction 
chemotherapy: patients whose tumors lacked a non-functional p53 mutations had a 
statistically significant higher chance of achieving a pathologic response and prolonged 
survival, compared to patients whose tumors had a p53 mutation.19 Zhong et al. 
evaluated the role of cisplatin, docetaxel, 5-fluorouracil for 2 cycles as induction 
chemotherapy followed by surgery, compared to surgery upfront in 256 patients with 
oral cavity squamous cell carcinomas. There was no improvement in overall survival, 
but induction chemotherapy reduced the risk of distant metastases, particularly in 
patients with clinical N2 disease. Patients with a pathologic response also had improved 
overall survival compared to patients with an unfavorable pathologic response to 
induction chemotherapy.20 Taken together, these studies illustrate that: (1) induction 
chemotherapy can alter the natural course of oral cavity squamous cell carcinomas, as 
demonstrated by downstaging and a reduction in the risk of distant metastases; (2) 
pathologic response to induction chemotherapy can serve as a surrogate marker for 
long-term overall survival; (3) biomarkers, such as p53 mutations, may identify 
individuals more likely to benefit from induction chemotherapy. These findings led us to 
postulate that optimization of induction chemotherapy using novel agents and patient 
selection based on biomarkers could improve treatment outcomes of patients with oral 
cavity squamous cell carcinomas. 
 
The present trial is the first personalized, randomized, placebo-controlled, phase 2  
study of induction chemotherapy with cisplatin and docetaxel with or without erlotinib in 
patients with oral cavity HNSCC amenable for surgical resection. Our primary 
hypothesis is that the addition of erlotinib to induction chemotherapy will improve 
treatment efficacy (as assessed by pathologic response), particularly in a biomarker- 
defined subpopulation. If successful, this trial may assist in the development of a new 
standard-of- care, erlotinib-based, induction treatment in a biomarker-defined population 
of patients with HNSCC undergoing surgery. 
 
Erlotinib was chosen as the experimental agent because of ease of administration, 
demonstrated activity when combined to cisplatin and docetaxel for treatment of 
metastatic HNSCC,8 demonstrated activity as single agent when administered prior to 
surgical resection in patients with early/intermediate stage HNSCC (33% response rate 
in 21 patients with oral cavity cancers in our previous pre-operative single-agent 
erlotinib trial)9, and availability of biospecimens from several HNSCC clinical trials 
conducted at M. D. Anderson using erlotinib-based therapies that can inform biomarker 

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evaluation for this study. These include the erlotinib prevention of oral cancer (EPOC) 
study (N=150 patients, completed), the erlotinib pre-operative study (N=40 patients, 
completed), the single-arm, phase 2 trial of cisplatin, docetaxel and erlotinib in 
metastatic HNSCC (N=50 patients, completed), and the randomized phase 2 trial of 
cisplatin, docetaxel with or without erlotinib in recurrent/metastatic HNSCC (N=120 
patients, ongoing). Additionally, pre-clinical studies with erlotinib funded by the M. D. 
Anderson SPORE program (PI: Jeffrey Myers, MD, PhD) and the Conquer Cancer 
Foundation (William William, MD) are currently under way to determine the role of 
somatic mutations, protein expression profiles, non-coding RNAs and other molecular 
alterations in predicting activity of erlotinib in HNSCC. These experiments will also 
inform the development of predictive biomarkers for this clinical trial. 

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2 
STUDY OBJECTIVES 
 
The primary objective of this study is to assess: 
 
• major pathologic response among patients with locally advanced oral cavity 
squamous cell carcinomas treated with induction cisplatin/carboplatin, docetaxel and 
erlotinib prior to surgery, and to compare it with the major pathologic response 
among patients treated with cisplatin/carboplatin, docetaxel, and placebo, in the trial 
population overall and in biomarker-defined subgroups. 
 
The secondary objectives of this study are to assess: 
 
• Safety and toxicity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 
• Recurrence-free survival 
 
• Progression-free survival 
 
• Response rate and disease control rate, as determined by RECIST version 1.1 
 
• Percentage of viable tumor cells in the surgical specimen 
 
• To correlate tissue and blood-based biomarkers with outcome and toxicity 
 
• Quality of life, determined by the self-reported FACT-HN questionnaire 

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3 
STUDY DESIGN AND PLAN 
 
This is a randomized, double-blind, placebo controlled, phase 2 study of docetaxel and 
cisplatin/carboplatin with or without erlotinib in patients with HNSCC of the oral cavity 
amenable for surgical resection. Patients will be randomized to: 
 
Arm A — induction chemotherapy with concurrent erlotinib; 
 
Arm B — induction chemotherapy with concurrent placebo 
 
The clinical trial is divided in two stages: stage I (biomarker discovery/testing of previous 
findings) and stage II (biomarker-guided therapy). Fresh tissue and blood will be 
collected prior to initiation of induction chemotherapy for biomarker evaluation. In stage  
I, patients will be randomized to the control and experimental arms irrespective of their 
biomarker status. Upon completion of stage I, the biospecimens collected will be 
analyzed in search of predictive markers of benefit from erlotinib. These analyses will be 
informed by correlative studies of other erlotinib-based trials in HNSCC conducted at M. 
D. Anderson, pre-clinical data and other emerging data in the literature as regards to 
benefit from chemotherapy and/or EGFR inhibitors in this setting. When appropriate, 
techniques and cut-offs will be standardized to determine the most practical, efficient, 
and robust biomarkers able to discriminate responders versus non-responders to 
chemotherapy+erlotinib. These biomarkers (herein referred to as erlotinib associated 
biomarkers [EAB]) will be CLIA certified (when appropriate) and incorporated into stage 
II. During stage II, patients will be adaptively randomized to the control or experimental 
arms according to their EAB status. 
 
All patients randomized will be followed until the first post-operative, protocol-defined 
clinic visit. After that, clinical data up until the date of death will be obtained through 
chart review or by contacting the patients and/or their families. A schematic diagram of 
the study design is shown in Figure 3–1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
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Patients will be stratified by the following factors and randomized to Arm A or Arm B: 
 
• Nodal staging (N0/N1 versus N2/N3). The nod l staging will be defined by the best 
available information at the time of randomization. For example, patients will not be 
required to undergo pathologic staging with neck lymph node biopsies prior to 
treatment, but if pathologic staging is available, the information will be combined to 
imaging and clinical data to obtain the most accurate stage. 

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3.1 
 
Treatment Plan and Regimen 
3.1.1 Treatment Plan  
After assessment of eligibility and stratification factors, patients will be randomized to: 
Arm A: Chemotherapy (up to 3 cycles) with erlotinib followed by daily erlotinib; or 
Arm B: Chemotherapy (up to 3 cycles) with placebo followed by daily placebo 
 Use of cisplatin or carboplatin will be per the investigator’s choice.    
In both arms, three cycles of chemotherapy are planned. Patients may receive less 
than the planned number of chemotherapy cycles at the investigator’s discretion 
(e.g. due to intolerable toxicities or achievement of maximal treatment benefit) – in 
such cases, the reason for premature chemotherapy discontinuation should be 
documented in the chart. 
 
 
 
 
 
Erlotinib or placebo will be administered daily from day 1, cycle 1 until the day prior to 
surgery (including the day prior to surgery). Treatment should preferably start within 14 
days of randomization. 
 
Body surface area (BSA) for chemotherapy dose calculation will be determined 
according the following formula: 
BSA (m2) = [ height (cm) x weight (kg) ÷ 3600 ] ½ 
 
The actual body weight will be used for BSA calculation, but the investigators will 
consider using adjusted or ideal body weight if the BSA exceeds 2.0 m2. BSA should be 
recalculated prior to the start of every cycle of therapy. 
 
The dose of carboplatin to be administered will be calculated based on the patient’s 
actual body weight and the AUC dosing, using the Calvert formula. However, 
investigators will consider using adjusted or ideal body weight if the BSA exceeds 2.0 
m2. The creatinine clearance(CrCl) / glomerular filtration rate (GFR) used to calculate 
the carboplatin dose will be estimated, based on serum creatinine, using the Cockcroft- 
Gault formula: 
 
 
 

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For males: 
 
Cr Cl (mL/min) = [(140-age) x (weight in kg)] ÷ [72 x serum creatinine in mg/dL] 
 
 
 
For females: 
 
Cr Cl (mL/min) = [(140-age) x (weight in kg) x 0.85] ÷ [72 x serum creatinine in mg/dL] 
 
 
 
Carboplatin dosing, using the Calvert formula, is often based upon a calculated 
creatinine clearance using serum creatinine as a surrogate for renal function. Several 
assays are available to measure serum creatinine. In the United States and many parts 
of the world, most laboratories use methods that are standardized against reference 
material in which the creatinine value has been assigned by Isotope Dilution Mass 
Spectrometry (IDMS). Since 31 December 2010, all clinical laboratories in the United 
States have used creatinine methods standardized relative to the IDMS reference 
material. 

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The recalibration of serum creatinine measurements against the IDMS reference 
material may result in slight differences in reported serum creatinine levels in the low 
range of normal. If the total carboplatin dose is calculated based on an estimated GFR 
using an IDMS-standardized serum creatinine and the Calvert formula, carboplatin 
dosing could be higher than if the GFR had been directly measured, and could result in 
increased toxicity. 
 
If creatinine is determined by a method standardized to the IDMS reference material, 
the estimated GFR used in the Calvert formula to calculate area under the curve (AUC)- 
based dosing should not exceed 125 mL/min for patients who have not begun therapy. 
 
 
 
Calvert Formula 
 
Total carboplatin dose (mg) = (target AUC) x (GFR + 25) 
 
Maximum carboplatin dose (mg) = target AUC 6 (mg.min/mL) x (125 + 25) = 6 x 150 
mL/min = 900 mg 
 
 
 
Surgery will be performed preferably no earlier than 3 weeks and no later than 6 weeks 
after the last chemotherapy (cisplatin/carboplatin, docetaxel) administration. 
 
 
 
Post-operative (chemo)radiation therapy will be delivered according to institutional 
guidelines and the best judgment of the treating physicians, preferably within 6 weeks of 
surgical resection. While not formally required per protocol, it is strongly suggested that 
the following principles of (chemo)radiation therapy be followed: 
 
• Primary tumor and involved nodal stations to receive 60-66 Gy (2 Gy/fraction) 
 
• Uninvolved nodal stations to receive 44-64 Gy (1.6-2.0 Gy fraction) 
 
• Concurrent chemotherapy to be added to post-operative radiation therapy in 
patients with positive margins or extra-capsular nodal spread. Cisplatin 100 
mg/m2 on days every 3 weeks for 2-3 doses or cisplatin 40 mg/m2/week for 6-7 
doses are preferred regimens. Carboplatin AUC 2/week for 6-7 doses may be 
used, less preferably. 

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Table 3–1: 
Schedule of Study Drug Administration 
 
Treatmen 
t Arm 
Agent(s) 
Starting Dose 
Route 
Schedule 
A 
Docetaxel 
75 mg/m2 
IV 
Day 1 q 21 days ± 3 days a 
Cisplatin 
or carboplatin 
75 mg/m2 
AUC 6 mg.min/ml 
IV 
IV 
Day 1 q 21 days ± 3 days a 
Erlotinib 
150 mg/day 
PO 
Continuously b 
B 
Docetaxel 
75 mg/m2 
IV 
Day 1 q 21 days ± 3 days a 
Cisplatin 
or carboplatin 
75 mg/m2 
AUC 6 mg.min/ml 
IV 
IV 
Day 1q 21 days ± 3 days a 
Placebo 
150 mg/day 
PO 
Continuously b 
a For a maximum of 3 cycles. 
b Until the day prior to surgery (including the day prior to surgery). 
If the patient completes < 3 cycles of chemotherapy with a response (CR or PR) or stable 
disease but cannot continue chemotherapy (eg, due to toxicity), daily erlotinib (in Arm A) or daily 
placebo (in Arm B), at the most recent dose, will be continued until the day prior to surgery 
(including the day prior to surgery) 
 
 
 
3.1.2 
Dose Modifications for Chemotherapy 
 
Toxicities will be graded by using the NCI CTCAE version 4.0.  Refer to the following 
website for the CTCAE manual or the CTCAE document: 
 
http://ctep.cancer.gov 
 
The dose modifications outlined below are considered general guidelines. The 
investigator should use his or her best judgment when determining treatment 
interruptions and dose modifications.  For example, some grade 2 non-hematologic 
toxicities may require treatment delays and/or dose reductions, and some grade 3 or 4 
organ toxicities (e.g., hepatic, renal, cardiac, central nervous system) may require a 
permanent treatment discontinuation. If one chemotherapy agent (docetaxel or 
cisplatin/carboplatin) needs to be discontinued, the other chemotherapy agent 
(cisplatin/carboplatin or docetaxel) may be continued. Docetaxel or cisplatin/carboplatin 
dose will not be re-escalated once it has been reduced for toxicity. 
 
3.1.2.1 
Dose Modifications for Docetaxel 
 
The dose of docetaxel will be reduced according to the following guidelines. 

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Thrombocytopenia 
 
• If grade 4 thrombocytopenia occurs, the dose of docetaxel will be reduced by 25% 
for subsequent cycles. If grade 4 thrombocytopenia persists despite dose reduction, 
docetaxel treatment will be discontinued. 
 
Neutropenia 
 
The dose of docetaxel will be reduced for the following neutropenic conditions as 
outlined in Table 3–2: 
 
• Grade 4 neutropenia lasting ≥ 7 days 
 
• Grade 3 or 4 febrile neutropenia 

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Table 3–2: 
Docetaxel Dose Modifications for Neutropenia 
 
Dose Description 
Docetaxel Dose (mg/m2) 
starting dose 
75 mg/m2 
1st dose reduction due to neutropenia 
(patients not receiving prophylactic growth factor 
support) 
75 mg/m2 
add growth factor support 
1st dose reduction due to neutropenia 
(patients receiving prophylactic growth factor support) 
65 mg/m2 
continue growth factor support 
2nd dose reduction due to neutropenia 
50 mg/m2 
continue growth factor support 
 
If grade 4 neutropenia or grade 3-4 febrile neutropenia persists despite dose reduction 
to 50 mg/m2 with growth factor support, docetaxel treatment will be discontinued. 
 
Hepatic Dysfunction 
 
The dose of docetaxel will be reduced for abnormal liver function test as outlined in 
Table 3–3. 

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Table 3–3: 
Docetaxel Dose Modifications for Abnormal Liver Function 
 
Total 
Bilirubin 
Alkaline 
Phosphatase 
SGOT or SGPT 
Action 
> ULN 
OR 
> 5 x ULN 
OR 
> 5 x ULN 
Delay treatment ≤ 3 
weeks until recovery. 
If recovered*, reduce 
docetaxel dose by 
25%. If not 
recovered in ≤ 3 
weeks, discontinue 
docetaxel. 
≤ ULN 
AND 
≤ 5 x ULN 
AND 
1.6 – 5 x ULN 
Reduce docetaxel 
dose by 25% 
*Bilirubin ≤ ULN and alkaline phosphatase ≤ 5 x ULN and SGOT or SGPT ≤ 5 x ULN 
Note: a maximum of two dose reductions per patient are allowed. If liver toxicities persist 
despite two dose reductions, docetaxel treatment will be discontinued. Dose reductions 
triggered by elevated bilirubin levels will not be implemented in patients with Gilbert’s syndrome. 
 
Stomatitis 
 
• If grade 3 or 4 stomatitis occurs, the dose of docetaxel will be reduced 25% for 
subsequent cycles. If grade 3 or 4 stomatitis persists despite dose reduction, 
docetaxel treatment will be discontinued. 
 
Peripheral Neuropathy 
 
• If grade 3, or clinically significant grade 2 (as judged by the investigator) neuropathy 
occurs, the dose of docetaxel will be reduced by 25%. If grade 3, or clinically 
significant grade 2 (as judged by the investigator) neuropathy persists despite two 
dose reductions, docetaxel treatment will be discontinued. 
 
• If grade 4 neuropathy occurs, docetaxel treatment will be discontinued. 
 
Hypersensitivity Reactions 
 
• There are no dose reductions for hypersensitivity reactions. Management of acute 
hypersensitivity reaction should follow the Institutional guidelines. Re-treatment 
with docetaxel will be allowed at the investigator’s discretion. 
 
• If grade 4 hypersensitivity reactions occur, docetaxel treatment will be 
discontinued. 
 
Fluid Retention 
 
• There are no dose reductions for fluid retention. 

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Patients developing new onset edema, progression of existing edema, or another sign 
of fluid retention (e.g. 2 pound weight gain) are to be treated with oral 
diuretics. Regimens found to be effective in the management of fluid retention due to 
Taxotere are listed below. 
 
 
 
• Triamterene/hydrochlorothiazide one capsule (37.5 mg / 25 mg) po qd up to tid. 
 
• Furosemide 40 mg po daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy. Potassium supplementation should be 
given as needed. 
 
• If after a two-week trial, furosemide 40 mg po qd is ineffective, the patient may be 
treated with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with 
potassium supplementation as needed. 
 
 
 
Further therapy should be customized depending upon the clinical situation. The 
clinical tolerance of the patient, the overall tumor response and the medical judgment 
of the investigator will determine if it is in the patient’s best interest to continue or 
discontinue treatment." 
 
 
 
Other Non-Hematologic Toxicities 
 
• If grade 3 or 4 clinically significant (as judged by the treating physician) non- 
hematoligc toxicities occur (other than those listed above), docetaxel treatment 
will be withheld until the toxicity has resolved to ≤ grade 1 and then reinstituted (if 
medically appropriate) at a 25% dose reduction. If a grade 3 or 4 clinically 
significant toxicity recurs despite two dose reductions, docetaxel treatment will be 
discontinued. 
 
• If treatment is withheld for > 3 weeks due to a grade 3 or 4 toxicity, docetaxel 
treatment will be discontinued. 
 
3.1.2.2 
Dose Modifications for Cisplatin or Carboplatin 
 
If any grade 3 or 4 toxicity occurs that is consistent with the cisplatin or carboplatin side 
effect profile (e.g., renal toxicity manifested by BUN and serum creatinine elevation, 
tinnitus and audiologic impairment in the high frequency range [4000 to 8000 Hz], 

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nausea and vomiting, hyperuricemia, mild to moderate anemia, and irreversible 
peripheral neuropathy), the dose of cisplatin or carboplatin will be reduced as outlined in 
Table 3–4.  Additionally, the investigator may choose to switch from cisplatin to 
carboplatin (or vice versa) during cycles 2 to 6 as an attempt to minimize the incidence 
or severity of platinum-related toxicities. 

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Table 3–4: 
Cisplatin/Carboplatin Dose Modifications 
 
Dose Level 
Cisplatin Dose (mg/m2) 
Carboplatin Dose (AUC, 
mg.min/ml) 
0 
Starting Dose 
75 mg/m2 
6 
-1 
60 mg/m2 
5 
-2 
50 mg/m2 
4 
 
If toxicities persist despite two dose reductions, cisplatin or carboplatin treatment will be 
discontinued. 
 
3.1.2.3 
Re-treatment Criteria for Docetaxel and Cisplatin or Carboplatin 
 
Prior to receiving any dose of docetaxel and cisplatin / carboplatin, patients must have 
an ANC ≥ 1.5 x 109/L and a platelet count ≥ 100 x 109/L (see Table 3–5). If the ANC is 
< 1.5 x 109/L and platelet count is < 100 x 109/L, the treatment should be delayed for ≤ 3 
weeks.  If the patient is unable to be treated after a 3-week delay, the patient will be 
discontinued from chemotherapy.  Patients who have discontinued chemotherapy will 
be allowed to continue on daily, single-agent erlotinib or placebo as described in 
Section 3.1.1. 

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Table 3–5: 
Re-treatment Criteria for Subsequent Cycles of Docetaxel and Cisplatin / Carboplatin 
 
DAY 1 COUNTS AND MAJOR ORGAN TOXICITY GRADING 
Neutrophils (× 109/L) 
Platelets (× 109/L) 
Timing 
≥ 1.5 
AND 
≥ 100 
Treat on time 
< 1.5 
OR 
< 100 
Delay until recovery* 
* If patient does not recover in ≤ 3 weeks, chemotherapy will be discontinued. Patients will be 
allowed to continue on daily, single-agent erlotinib or placebo as described in Section 3.1.1 
 
3.1.3 
Dose Modifications for Erlotinib or Placebo 
 
3.1.3.1 
Erlotinib or Placebo Dose Reductions and Re-Escalation 
 
Erlotinib doses may be reduced and/or delayed for toxicities (see Table 3–7).  If a 
patient experiences several toxicities, dose adjustments are to be made based on the 
greatest degree of toxicity.  In the event of any toxicity requiring erlotinib dose reduction, 
the daily dose of erlotinib will be decreased according to the schedule below (Table 3– 
6). If significant toxicity is still apparent, the dose may be reduced a second time. 

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Table 3–6: 
Dose Modifications for Erlotinib 
 
Erlotinib Dose 
First Reduction 
Second 
Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
Patients who require a dose reduction must be evaluated until the toxicity stabilizes or 
improves. Doses that have been reduced one dose level for toxicity may be re- 
escalated to the previous dose level only if the toxicity abates or returns to baseline 
severity and the investigator believes it is in the best interest of the patient.  Doses that 
have been reduced two dose levels for toxicity may only be re-escalated to the previous 
dose level (i.e., dose level at first reduction) and only if the toxicity abates or returns to 
baseline severity and the investigator believes it is in the best interest of the patient. 
Doses that have been reduced two dose levels for toxicity may not be re-escalated to 
starting dose level. Any patient who fails to tolerate treatment at 50 mg/day will be 
discontinued from erlotinib or placebo. Patients will be allowed to continue receiving 
chemotherapy, until the planned numbered of chemotherapy cycles has been reached. 
 
Dose adjustments are to be made according to the organ system showing the greatest 
degree of toxicity (see Table 3–7). Patients experiencing toxicities that require a delay 
in erlotinib dosing for > 21 days will be discontinued from the study. 
 
 
Treatment with erlotinib should be used with extra caution in patients with total bilirubin 
> 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B 
and C) should be closely monitored during therapy with erlotinib. Erlotinib dosing 
should be interrupted or discontinued if changes in liver function are severe such as 
doubling of total bilirubin and/or tripling of transaminases in the setting of pre-treatment 
values outside normal range. 

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Table 3–7: 
Dose Reduction Criteria for Erlotinib-related Toxicities 
 
Toxicity 
(NCI CTCAE v4.0) 
Dose Modification a 
Diarrhea 
Grade 1 or 2 
None. Initiate therapy with loperamide (Section 5.6.1.2) 
Grade 3 b or 4 b 
Interrupt study drug until resolution to ≤ grade 2 and then restart 1 dose level 
lower. 
Rash 
Grade 1 
None 
Grade 2 c 
None. If rash persists and is intolerable over 10 – 14 days, then reduce by 1 
dose level and initiate treatment as outlined in Section 5.6.1.2. 
Grade 3 b, c 
Reduce by 1 dose level. If rash persists or worsens over 10 – 14 days, then 
interrupt study drug until resolution to ≤ grade 2 and then restart 1 dose level 
lower. 
Grade 4 
Permanently discontinue study drug. 
Interstitial Lung Disease 
Any Grade 
If ILD is suspected, study drug should be interrupted immediately pending 
diagnostic evaluation. If ILD is diagnosed, study drug should be discontinued 
permanently and appropriate treatment instituted as necessary. 
Other Toxicities 
Grade 1 or 2 
None 
Grade 3 b, d 
Interrupt study drug until resolution to ≤ grade 2 and then restart 1 dose level 
lower. 
Grade 4 
Permanently discontinue study drug. 
a Doses that have been reduced one dose level for toxicity may be re-escalated to the previous 
dose level only if the toxicity abates or returns to baseline severity and the investigator believes it 
is in the best interest of the patient. Doses that have been reduced two dose levels for toxicity 
may only be re-escalated to the previous dose level (ie, dose level at first reduction) and only if 
the toxicity abates or returns to baseline severity and the investigator believes it is in the best 
interest of the patient. Doses that have been reduced two or more dose levels for toxicity may not 
be re-escalated to starting dose level. Any patient who fails to tolerate treatment at 50 mg/day 
will be discontinued from the study. Patients will be allowed to continue receiving chemotherapy, 
until the planned numbered of chemotherapy cycles has been reached. 
b If the event does not resolve to ≤ grade 2 within 21 days, study drug will be discontinued. 
Appropriate measures should be taken to intensively treat dehydration. Since there have been 
rare reports of hypokalemia and acute renal failure (including fatalities) secondary to severe 
dehydration, renal function and serum electrolytes (including potassium) should be monitored in 
this setting. 
c Doxycycline and minocycline are often used to treat grade 2 or 3 rash even if there is no clear 
evidence for superinfection. Rash should not be classified as grade 3 solely on the basis of use of 
antibiotics, unless there is strong suspicion for superinfection in the opinion of the investigator. 
d Only if ≥ 2 grade level change from baseline. 

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3.1.3.2 
Erlotinib or Placebo Dose Interruptions 
 
Patients who have a continuous interruption of erlotinib or placebo dosing for ≤ 21 
consecutive days may re-start erlotinib or placebo at the appropriate dose, provided 
toxicities have improved as outlined above. 
 
Patients who have a continuous interruption of erlotinib or placebo dosing for > 21 
consecutive days are not allowed to re-start erlotinib or placebo. 

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4 
PATIENT POPULATION 
 
Patients with suspected or histologically confirmed HNSCC of the oral cavity, stage III, 
IVA or IVB (according to the AJCC 7th edition), who have an ECOG performance status 
of 0-2, will be enrolled. Patients with a suspected lesion may be enrolled and a baseline 
biopsy will be obtained as part of the study. If squamous cell histology is not confirmed, 
patients will be discontinued from the study. 
 
Questions about eligibility criteria should be addressed PRIOR to randomization.  The 
eligibility criteria for this study have been carefully considered.  Eligibility criteria are 
standards used to assure that patients who enter this study are medically appropriate 
candidates for this therapy. 
 
4.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for participation in 
this study. 
1. Suspected or histologically/citologically confirmed HNSCC of the oral cavity, stage 
III, IVA or IVB (according to the AJCC 7th edition). Patients with a suspected lesion 
may be enrolled and a baseline biopsy will be obtained as part of the study. If 
squamous cell histology is not confirmed, patients will be discontinued from the 
study. 
2. Patients must have surgically resectable disease, in the opinion of the treating 
physician 
3. Age ≥ 18 years. 
4. ECOG PS ≤ 2 (Appendix C) 
5. Adequate bone marrow, hepatic and renal function defined by: 
a.  ANC ≥ 1.5 x 109/L; 
b. Platelet count ≥ 100 x 109/L; 
c. ALT (SGPT) ≤ 1.5 x upper limit of normal (ULN); 
d. Total bilirubin ≤ ULN (patient’s with Gilbert’s syndrome are eligible, even if 
total bilirubin is > ULN); 
e. Alkaline phosphatase ≤ 2.5 x ULN; 
f. Serum creatinine ≤ 1.5 x ULN. 
6. Patients with reproductive potential (e.g., females menopausal for less than 1 year 
and not surgically sterilized) must practice effective contraceptive measures for the 
duration of study drug therapy and for at least 30 days after completion of study drug 
therapy. Female patients of childbearing potential must provide a negative 
pregnancy test (serum or urine) ≤ 14 days prior to treatment initiation. 

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7. Written informed consent to participate in the study according to the investigational 
review board (IRB). 
 
4.2 
Exclusion Criteria 
 
Patients who meet any of the following exclusion criteria are not to be enrolled in this 
study. 
1. Histology other than squamous cell carcinoma. 
2. Primary sites other than oral cavity. 
3. Prior chemotherapy or biologic therapy for the same HNSCC. Prior chemotherapy or 
biologic therapy for a different previous HNSCC is allowed 
4. History of poorly controlled gastrointestinal disorders that could affect the absorption 
of the study drug (e.g., Crohn’s disease, ulcerative colitis). Patients requiring feeding 
tubes are permitted 
5. Other active solid malignancies within 2 years prior to randomization, except for 
basal cell or squamous cell skin cancer or in situ cervical or breast cancer or 
superficial melanoma. 
6. Serious underlying medical condition which would impair the ability of the patient to 
receive protocol treatment, in the opinion of the treating physician. 
7. History of allergic reactions to compounds of similar chemical composition to the 
study drugs (docetaxel, cisplatin, carboplatin, erlotinib or their excipients), or other 
drugs formulated with polysorbate 80. 
8. Any concurrent anticancer therapy, excluding hormonal therapy for prostate or 
breast cancer. 
9. Women who are pregnant or breast-feeding and women or men not practicing 
effective birth control. 

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5 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS 
 
The term “study drug” refers to the chemotherapy (docetaxel and cisplatin / carboplatin) 
and to erlotinib. The patient is considered “on treatment” until all study drug is 
discontinued. 
 
5.1 
Description, Handling and Administration of Docetaxel 
 
MDACC will use its own commercial supply of docetaxel in this study. Docetaxel will 
be prepared and administered according to local practice and in accordance with the 
most recent Package Inserts/Data Sheets. 
 
Pre-medications: To reduce the severity of fluid retention and hypersensitivity 
reactions, all patients will be pre-medicated with corticosteroids, such as oral 
dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to 
docetaxel administration. Considerations for modification of the corticosteroid regimen 
(including schedule and dose reductions) should be made in patients receiving the 
prophylactic anti-emetics fosaprepitant or aprepitant. 
 
5.2 
Description, Handling and Administration of Cisplatin / 
Carboplatin 
 
MDACC will use its own commercial supply of cisplatin or carboplatin in this study. 
Cisplatin or carboplatin will be prepared and administered according to local practice 
and in accordance with the most recent Package Inserts/Data Sheets. 
 
Pre-medications:  All patients will receive anti-emetics and/or appropriate hydration 
prior to and after cisplatin or carboplatin administration according to current institutional 
guidelines. 
 
5.3 
Description, Handling and Administration of Erlotinib or 
Placebo 
 
5.3.1 
Formulation of Erlotinib 
 
Astellas Pharma/OSI Pharmaceuticals will supply tablets containing erlotinib 
hydrochloride equivalent to 150 mg, 100 mg, and 25 mg of erlotinib (Arm A) or matching 
placebo (Arm B). All tablets are round, white, film-coated, and bi-convex with no  
imprint. Additional information can be found in the Erlotinib Investigator’s Brochure. 

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5.3.2 
Packaging and Labeling of Erlotinib or Placebo 
 
Erlotinib or placebo will be supplied in blue-white, high-density, polyethylene bottles of 
30 tablets each. If the dose has been modified to 50mg, then two bottles with 30 tablets 
of 25mg each of erlotinib (Arm A) or matching placebo (Arm B) will be supplied. The 
bottles will have a tamper-evident seal and a child-resistant cap. 
 
5.3.3 
Storage and Handling of Erlotinib or Placebo 
 
Erlotinib or placebo drug tablets should be stored between 15°C and 30°C (59°F and 
86°F). 
 
5.3.4 
Administration of Erlotinib or Placebo 
 
Erlotinib (Arm A) or placebo (Arm B) tablets should be taken at approximately the same 
time each day, preferably in the morning. Each dose is to be taken with up to 200 mL 
(~ 1 cup or 8 oz) of water, and should be taken on an empty stomach either 1 hour 
before or 2 hours after a meal or medications, including vitamins and other 
supplements. Any consumption of grapefruit and grapefruit juice should be avoided 
while on erlotinib treatment (see Section 5.6.3). 
 
The entire dose must be taken at one time. If the patient vomits after taking the 
tablet(s), the dose should be replaced only if the tablet(s) can actually be seen and 
counted. 
 
If necessary, patients may receive erlotinib or placebo via a feeding tube. The 
suggested method of preparation and administration is as follows: the tablet is placed in 
approximately 6 ounces of water, and allowed to dissolve (usually for 15-20 minutes); 
once dissolved the solution is then administered via the feeding tube, followed by a free 
water flush. 
 
5.4 
Drug Accountability 
 
A drug accountability log for erlotinib (Arm A) or placebo (Arm B) will be maintained.  
The information contained on the log should be sufficient to comply with applicable GCP 
regulations.  Drug accountability log information may include, but is not limited to, the 
following:  number of bottles and date the study drug was received, number of bottles 
dispensed to each patient (including bottle number, date dispensed/returned, patient 
identifier information, protocol number, dose, and lot/batch number), quantity of tablets 
returned by the patient, current balance, and the initials of the person who recorded the 
accountability log information. At the time of study closure, both the unused, used, and 

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expired study drug will be destroyed by MD Anderson’s Investigational Pharmacy 
Services per MD Anderson’s institutional SOPs. Astellas Pharma/OSI Pharmaceuticals 
will be provided with the documentation of the drug destruction upon request. 
 
5.5 
Treatment Compliance 
 
Compliance of erlotinib (Arm A) or placebo (Arm B) will be assessed by counting tablets 
at the scheduled patient visits. In addition, pill diaries will be used by the patient and 
reviewed by the research nurse to assess compliance during the patient’s scheduled 
visits.  Data regarding missed or modified doses will be recorded in the patient’s chart. 
 
5.6 
Concomitant Medications 
 
All concomitant medications will be recorded on the patient’s medical record. 
 
5.6.1 
Permitted Concomitant Medications 
 
5.6.1.1 
Pre-medications for Chemotherapy 
 
Standard pre- and post-medications will be administered with docetaxel and cisplatin / 
carboplatin infusions (see Section 5.1 and Section 5.2). 
 
5.6.1.2 
Anti-diarrhea and Anti-rash Therapies 
 
Skin rash or dermatosis has been observed during the first several days of treatment 
with erlotinib in many patients and has been noted to diminish in severity despite 
continued treatment. Patients should be told that skin toxicity is to be expected during 
treatment with erlotinib. Skin toxicity may take the form of dry skin, rash, acneiform 
eruption, or hair or nail changes. Prophylactic treatment of the skin may prevent or 
reduce skin toxicity.  The patient should be encouraged to use an alcohol-free, emollient 
cream applied twice a day to the entire body as soon as the patient starts therapy with 
erlotinib.  Creams and ointments are recommended because they have a greater ability 
to retain moisture than lotions. Examples of suitable emollient creams include: 
Neutrogena® Norwegian formula, SARNA® Ultra, Vanicream™, Aveeno® (fragrance-free 
formulation), and Eucerin® cream. Other over-the-counter aqueous creams or 
emulsifying ointments may also provide symptomatic benefit. Lotions should be 
avoided because they often contain alcohol, which will dry the skin. Patients should 
also be encouraged to use a titanium dioxide or zinc oxide-based sunscreen product 
applied to sun-exposed areas twice per day. 

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Patients who develop skin toxicity and are symptomatic should be treated with topical 
therapy such as hydrocortisone cream or clindamycin gel.  If needed, oral minocycline 
or oral doxycycline may be combined with the topical therapy.  For more severe rash, 
oral corticosteroids may be beneficial.21  Patients who fail to respond to these measures 
may have the dose of erlotinib interrupted or reduced. A suggested algorithm for 
treatment of erlotinib-related skin toxicities is presented in Table 5-1. 
 
 
 
Table 5-1: 
Treatment of Erlotinib-Related Skin Toxicities 
Toxicity 
Grade 
Macular Rash 
Pustular Rash 
Dry Skin 
Pruritus 
Ulcerative 
lesions 
1 
Hydrocortisone 
topical cream/ 
lotion 
Clindamycin gel 
(for isolated 
lesions)/ lotion 
(for scattered 
lesions) 
- 
- 
- 
2 
Oral 
methylprednisolone 
(if > 2 body 
regions) 
Topical 
hydrocortisone if 
<2 body regions 
Minocycline or 
doxycycline 100 
mg po BID for 
10-14 days 
Emollient 
applied BID 
Topical 
antihistamine or 
diphenhydramine 
25-50 mg po q6h 
prn 
- 
3 
Oral 
methylprednisolone 
Minocycline or 
doxycycline 100 
mg po BID for 
10-14 days 
Emollient 
applied BID 
Diphenhydramine 
25-50 mg po q6h 
or hydroxyzine 
25-50 mg po q6h 
prn 
Silver 
sulfadiazine 
ointment 
Dermatology consult 
4 
Discontinue therapy 
 
 
 
Minocycline is known to interfere with anticoagulants and oral contraceptives.  Patients 
treated with minocycline who are taking anticoagulants and/or oral contraceptives 
should be monitored accordingly. 
 
Anti-diarrheal medications may be introduced if symptoms occur. Previous trials have 
shown that the frequency and severity of diarrhea rarely hindered administration of 
erlotinib and could be managed with loperamide (see Table 3–7). The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until 
diarrhea-free for 12 hours. 

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5.6.1.3 
Anticoagulant Therapies 
 
Concomitant treatment with warfarin or other coumarin-derived anticoagulants are 
permitted provided increased vigilance occurs with respect to monitoring their 
anticoagulation status. INR elevations and/or bleeding events have been reported in 
some cancer patients taking warfarin while on erlotinib. For this study, patients taking 
warfarin or other coumarin-derived anticoagulants while on study drug should be 
monitored as clinically indicated for changes in prothrombin time or INR. 
 
5.6.1.4 
Hematopoietic Growth Factors 
 
Prophylactic G-CSF support is strongly recommended and should be administered at 
least 24 hours after infusion of chemotherapy, beginning at cycle 1 and continued for 
the duration of treatment with chemotherapy. Treating physicians may discontinue G- 
CSF administration at cycles ≥ 2 provided that the patient did not have febrile 
neutropenia or grade 4 neutropenia lasting ≥ 7 days on previous cycles, and provided 
that the patient is experiencing adverse events associated with G-CSF administration. 
 
5.6.1.5 
Anti-emetic Therapy 
 
Prophylactic anti-emetics may be administered at the discretion of the investigator. 
 
5.6.2 
Prohibited Concomitant Medications 
 
5.6.2.1 
Cytotoxic or Biological or Immune Response Modifiers 
 
No other cytotoxic therapy, biological or immune response modifiers or other 
molecularly targeted therapies for the treatment of cancer may be administered to 
patients while they are on study drug, excluding hormonal treatment for breast and 
prostate cancer. 
 
5.6.2.2 
Other Investigational Drug Therapies 
 
Patients should not receive any other investigational drugs with potential anti-neoplastic 
activity until disease progression has been documented. 
 
5.6.3 
Potential for Drug Interactions 
 
Erlotinib is protein bound (92% to 95% in humans) and metabolized by hepatic 
cytochromes CYP3A4 and CYP1A2 and pulmonary cytochrome CYP1A1. Therefore, a 
potential for drug-drug interaction exists when erlotinib is co-administered with drugs 
that are highly protein bound or that are CYP3A4 or CYP1A2 inhibitors/inducers (see 
Appendix D). 

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Substances that are potent inhibitors of CYP3A4 activity (e.g., ketoconazole) decrease 
erlotinib metabolism and increase erlotinib plasma concentrations. This increase may 
be clinically relevant as adverse experiences are related to dose and exposure. 
Therefore, for this study, such agents should be avoided and, if that is not possible, 
caution should be used when administering CYP3A4 inhibitors to patients who are on 
study drug. 
 
Substances that are potent inducers of CYP3A4 activity (e.g., rifampin, phenytoin) 
increase erlotinib metabolism and significantly decrease erlotinib plasma  
concentrations. This decrease in exposure may be clinically relevant, as preclinical 
studies suggest that higher concentrations are more efficacious in in vivo animal tumor 
models.  However, the relationship between exposure and efficacy in cancer patients 
has not been adequately studied. Therefore, for this study, such agents should be 
avoided, and if that is not possible, caution should be used when administering CYP3A4 
inducers to patients who are on study drug.  For more information, refer to the erlotinib 
Investigator’s Brochure. 
 
In vitro studies have shown that the metabolism of docetaxel may also be modified by 
the concomitant administration of compounds that induce, inhibit, or are metabolized by 
CYP3A4, such as cyclosporine, terfenadine, ketoconazole, erythromycin, and 
troleandomycin.  Caution should be exercised with these drugs when treating patients 
receiving docetaxel as there is a potential for a significant interaction. 
 
As mentioned in Section 5.6.1.3, INR elevations and/or bleeding events have been 
reported in some cancer patients taking warfarin while on erlotinib. During this study, 
patients taking warfarin or other coumarin-derived anticoagulants should be monitored 
as clinically indicated for changes in prothrombin time or INR. 
 
Erlotinib clearance can be induced by smoking via CYP1A2 induction.  Smokers should 
be advised to stop smoking while taking erlotinib, as plasma concentrations of erlotinib 
are reduced due to the effect of cigarette smoking. 
 
Aqueous solubility of erlotinib is dependent on pH with increased solubility at a pH less 
than 5; maximal solubility occurs at a pH of approximately 2.  Co-administration of 
erlotinib with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure 
(AUC) and maximum concentration (Cmax) by 46% and 61%, respectively. There was 
no change in Tmax or half-life. Therefore, drugs that alter the pH of the upper GI tract 
may alter the solubility of erlotinib and hence its bioavailability.  Increasing the dose of 

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erlotinib when co-administered with such agents is not likely to compensate for the loss 
of exposure. While the concomitant use of erlotinib and proton pump inhibitors is not 
forbidden during this study, patients will be advised to avoid medications that decrease 
stomach acid while participating on this study [e.g. Zantac® (ranitidine), Pepcid® 
(famotidine), Tagamet® (cimetidine), Protonix® (pantoprazole), Nexium® 
(esomeprazole), Prilosec® (omeprazole), Prevacid® (pantoprazole), or Aciphex® 
(rabeprazole)]. Short-acting antacids (e.g., Tums®, Maalox®, Mylanta®, Rolaids®) may 
be taken while on study, preferably more than 2 hours before or after the dose of 
erlotinib or placebo. 
 
Grapefruit juice is a CYP3A4 inhibitor that interferes with the metabolism of erlotinib. 
Therefore, consumption of grapefruit or grapefruit juice should be avoided during 
erlotinib treatment. 
 
5.6.4 
Ophthalmologic Considerations 
 
Patients with dry eyes should be advised to use an ocular lubricant. Patients who 
continue to wear contact lenses may have an increased risk of ocular adverse events 
(e.g., keratitis). The decision to continue to wear contact lenses should be discussed 
with the patient’s treating oncologist and ophthalmologist prior to the patient going on 
study. 
 
5.6.5 
Unblinding Procedures 
 
Un-blinding of single cases by the sponsor and/or investigator will only be performed if 
relevant for the safety of the participant. In emergency situations, the investigator would 
contact the sponsor, who would contact the study statistician and the investigational 
pharmacy to obtain immediate blinding information for the participant. The sponsor 
would then pass this information on to the investigator to enable the participant to be 
treated. In non-emergency situations, the same procedures would apply, however the 
study statistician and the study sponsor will discuss and evaluate the request, then, 
would be responsible for making the decision of whether or not to un-blind. Additionally, 
Dr. Agueda Cohen, Medical Monitor and the Clinical Research Monitor at the IND Office 
will also be notified in writing when un-blinding occurs. 

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Un-blinding of all participants will occur at the end of study, whereby the sponsor and 
investigators will be provided with a list containing data on which arms each of his/her 
patients were randomized to. 
 
 
6 
STUDY PROCEDURES 
 
Patients may be accrued to and treated on this study at M. D. Anderson Cancer Center, 
including M. D. Anderson’s Regional Care Centers. The study procedures to be 
conducted for each patient enrolled in the study are detailed in the text that follows. 
 
6.1 
Patient Enrollment and Treatment Assignment 
 
Before recruitment of patients into the study, written IRB approval of the protocol, 
informed consent forms, and any additional patient information must be obtained. The 
investigator will maintain a patient log for all screened (including patients that failed 
screening) and randomized patients. Study-related procedures must not commence 
before obtaining consent.  However, results from assessments performed before 
obtaining informed consent that are considered “routine standard of care” (e.g., 
laboratory results, CT scans, etc.) may be used to determine eligibility. 
 
The physician in charge of the patient is responsible for verifying that the patient is 
eligible before requesting randomization. If any of the inclusion criteria are not met or 
any of the exclusion criteria are met, the patient should not be enrolled. 
 
Randomization will be performed via a centralized, web-based randomization system. 
Patients who are randomized will be assigned to a treatment arm and given a unique 
patient number by the centralized, web-based system. Once enrolled in the study, the 
patient will only be identified by initials and the assigned patient number. 
 
Patients will start treatment preferably within 14 days of randomization. 
 
 
 
 
6.2 
Baseline Assessments 
 
Patients will be screened for the study according to the Baseline Assessments as 
outlined in Table 6–1. 

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Table 6–1: 
Baseline Assessments 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• Treatment history 
•  Vital signs 
• Medical history 
•  ECOG PS 
• Smoking history 
•  TNM stage 
• Height and weight 
Within 14 days prior to 
treatment initiation 
Current Smoking 
Status and Tobacco 
Use 
• Assessment of patient’s current smoking status 
and tobacco use 
Within 14 days prior to 
randomization 
Symptoms & 
Toxicities 
• Evaluation and documentation of symptoms and 
toxicities using the NCI CTCAE v4.0 
Within 14 days prior to 
treatment initiation 
Concomitant 
Medications 
• Documentation of concomitant medications 
Within 14 days prior to 
treatment initiation 
Quality of Life 
• FACT-H&N 
Within 14 days prior to 
treatment initiation 
Hematology 
• 
CBC with hemoglobin, platelets, and WBC with 
differential 
Within 14 days prior to 
treatment initiation 
Biochemistry 
• Albumin 
• Glucose 
• 
Alkaline 
•  LDH 
phosphatase 
• Potassium 
• Total bilirubin 
• SGOT (AST) 
• BUN 
• SGPT (ALT) 
• Creatinine 
• Sodium 
• Magnesium 
Within 14 days prior to 
treatment initiation 
Pregnancy Test 
• 
Urine or serum (for women of childbearing 
potential only) 
Within 14 days prior to 
treatment initiation 
Radiology 
• 
CT or MRI scans of the head and neck 
• 
Additional imaging studies as clinically indicated 
• 
Optional imaging studies 
Within 30 days prior to 
treatment initiation 
Tumor Tissue 
Collection for 
Biomarkers 
• 
A biopsy of primary lesion for biomarker 
analysis 
Within 30 days prior to 
randomization 
Blood-based 
biomarkers 
• 
Blood sample 
Within 30 days prior to 
treatment initiation 

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6.3 
Study Assessments 
 
6.3.1 
Assessment During Chemotherapy 
 
Patients in each arm will be evaluated prior to chemotherapy cycles according to the 
assessments outlined in Table 6–2. 

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Table 6–2: 
Assessments During Chemotherapy (All Arms) 
 
Investigations 
Timing 
Physical Exam 
Including: 
• BSA 
• Vital signs 
Within 7 days prior to cycles 2-3, and 
at least 14 days after the last dose of 
chemotherapy 
Current 
Smoking 
Status and 
Tobacco Use1 
• 
Assessment of patient’s current smoking 
status and tobacco use 
Within 7 days prior to cycles 2-3, and 
at least 14 days after the last dose of 
chemotherapy 
Hematology 
• 
CBC with hemoglobin, platelets, and WBC 
with differential 
Within 7 days prior to cycles 2-3, and 
at least 14 days after the last dose of 
chemotherapy 
Biochemistry1 
• Albumin 
• 
Alkaline 
phosphatase 
• Total bilirubin 
• BUN 
• Creatinine 
• Glucose 
• LDH 
• Potassium 
• SGOT (AST) 
• SGPT (ALT) 
• Sodium 
• Magnesium 
Within 7 days prior to cycles 2-3, and 
at least 14 days after the last dose of 
chemotherapy 
Pregnancy 
Test 
• 
Urine or serum (for women of childbearing 
potential only) 
If/when clinically indicated 
Radiology 1 
• 
CT or MRI scans of the head and neck 
• 
Additional imaging studies as clinically 
indicated 
• 
Optional imaging studies 
At least 14 days after the last dose of 
chemotherapy 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of symptoms 
and toxicities using the NCI CTCAE v4.0 
On an ongoing basis throughout the 
study until the final study visit 
Concomitant 
Medications 
• 
Documentation of concomitant medications 
On an ongoing basis throughout the 
study until the final study visit 
Quality of Life1 • 
FACT-H&N 
At least 14 days after the last dose of 
chemotherapy 
Blood-based 
biomarkers1 
• Blood sample 
At least 14 days after the last dose of 
chemotherapy 
Erlotinib PK1 
• 
Blood sample 
At least 14 days after the last dose of 
chemotherapy 
Erlotinib or 
Placebo 
Treatment 
Compliance 
• 
Count tablets and record findings 
At each clinic visit 
1 If information / studies have already been obtained but chemotherapy is delayed for any reason, repeated 
studies are not necessary prior to next cycle of chemotherapy. 

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6.3.2 
Assessments at Surgery 
 
After completing chemotherapy, patients will undergo surgical resection. Evaluations will 
be performed according to Table 6-3. 

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Table 6–3: 
Assessments at Surgery 
 
Investigations 
Timing 
Surgical 
procedure 
• 
Title of operation 
Through chart review 
Tumor Tissue 
Collection 
• 
pTNM 
• 
Pathologic response 
• 
Percentage of viable tumor cells 
• 
Status of resection margins 
• 
Number of lymph nodes removed at 
each level 
• 
Number of lymph nodes positive for 
cancer at each level 
• 
Evaluation of extra-capsular nodal 
spread 
• 
Evaluation of peri-neural invasion 
• 
Evaluation of vascular invasion 
• 
Biomarker evaluation 
As information becomes available 

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6.3.3 
End of Treatment Assessments 
 
For all patients, the End of Treatment Visit will occur approximately within 8 weeks after 
surgery, and preferably before initiating post-operative radiation therapy. Patients will be 
evaluated according to the assessments outlined in Table 6–4. For patients that do not 
undergo surgery, an end of treatment assessment will not be performed. 

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Table 6–4: 
End of Treatment Assessments 
 
Investigations 
Timing 
Physical 
Exam 
Including: 
• Vital Signs 
Approximately within 8 weeks after 
surgery 
Blood-based 
biomarkers 
• Blood sample 
Approximately within 8 weeks after 
surgery 
Erlotinib PK 
• Blood sample 
Approximately within 8 weeks after 
surgery 
Pregnancy 
Test 
• Urine or serum (for women of 
childbearing potential only) 
If/when clinically indicated 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of 
symptoms and toxicities using the 
NCI CTCAE v4.0 
• 
Retrospective evaluation of any 
unexpected surgical 
complications 
Approximately within 8 weeks after 
surgery 
Quality of 
Life 
• 
FACT-H&N 
Approximately within 8 weeks after 
surgery 
 
 
 
 
6.4 
Descriptions of Study Assessments 
 
6.4.1 
Smoking History 
 
The following definitions of cigarette smoking status will be used to categorize and 
stratify patients in the study: 
 
• Current cigarette smoker: has smoked > 100 cigarettes in entire lifetime and is 
either currently smoking or quit smoking < 1 week ago 
 
• Former cigarette smoker:  has smoked > 100 cigarettes in entire lifetime and quit 
smoking ≥ 1 week before randomization 
 
• Never smoker:  has smoked ≤ 100 cigarettes in entire lifetime and stopped or never 
smoked cigarettes 
 
Tobacco use other than cigarette smoking will also be assessed according to Tables 6- 
1 to 6-4. 

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6.4.2 
Performance Status 
 
The performance status of all patients will be graded at scheduled intervals according to 
the ECOG PS scale. 
 
6.4.3 
Clinical Laboratory Tests 
 
Clinical laboratory tests will be performed to assess eligibility for enrolment and will be 
repeated according to Tables 6-1 to 6-4. 
 
Laboratory tests can be repeated more frequently, if clinically indicated. 
 
6.4.4 
Symptoms and Toxicity Assessment 
 
The symptoms and adverse events of all patients will be graded at scheduled intervals 
according to the NCI CTCAE, v4.0. Patients will be monitored continuously throughout 
the study for the occurrence of adverse events. Planned medical interventions (e.g., 
planned surgical resection) will not be considered an adverse event. For the purpose of 
this study, adverse events that in the opinion of the treating investigator are related to 
planned surgical procedure (e.g., usual pain, usual bleeding, intra- or post-operative 
electrolyte imbalances and other clinically insignificant laboratory abnormalities) will not 
be captured and/or reported. Unexpected surgical complications will be retrospectively 
reviewed at the end of treatment assessments, as described in Table 6-4. 
 
6.4.5 
Radiology Assessments 
 
CT or MRI scans of the head and neck will be obtained according to Tables 6-1 to 6-4. 
Additional methods may be performed at physician discretion. 
 
Response and progression will be evaluated in the study using the international criteria 
proposed by the RECIST committee22 (see Appendix E), and preferably by the same 
investigator or collaborator. 
 
To ensure comparability, the baseline radiology/scans and subsequent radiology/scans 
to assess response should, preferably, be performed using identical techniques. 
 
Patients enrolled to this study may also be offered optional participation in a separate 
IRB-approved protocol evaluating additional imaging modalities for HNSCC. An 
independent informed consent process will be followed for accrual to such protocol. 

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6.4.6 
Quality of Life 
 
Quality of life will be measured by the FACT-H&N quality of life questionnaire (see 
Appendix F). The patient should complete the questionnaire at scheduled intervals 
according to Tables 6-1 to 6-4. 
 
6.4.7 
Tumor Tissue Samples 
 
Baseline tumor tissue samples from the primary tumor will be collected for 
histopathological examination and biomarkers.  Samples will be obtained by an 
outpatient punch-biopsy or large-cup forceps biopsy performed under local anesthesia, 
preferably with a minimum of 4-5 mm diameter (which allows for the preparation of at 
least 30 slides). These specimens should be fixed in 10% formalin, preferably 
immediately and not more than 1 (one) hour after excision. Fixed biopsy samples will be 
processed for paraffin-embedding according to the Institutional Standard Operating 
Procedures. The paraffin blocks and slides should be labeled with the protocol number 
and the patient’s unique study identification number and stored at room temperature. A 
portion of the specimen obtained (or a second biopsy) will also be embedded in optimal 
cutting temperature compound immediately after received and not more than 1 (one) 
hour after excision, frozen, and stored at -80 oC for future biomarker analysis. All 
samples stored at -80 oC should be placed in appropriate containers, labeled with the 
protocol number and the patient’s unique study identification number. 
 
Tumor tissue will also be obtained at surgical resection. The recommended procedure 
for obtaining the tissue specimens is as follows: the primary tumor should be identified 
on exam under anesthesia and at least 2 (two) large-cup forceps biopsies obtained prior 
to ligation of the tumor vessels, to avoid ischemia-induced activation of phosphatases. A 
portion of the tissue will be fixed in 10% formalin immediately after received and not 
more than 1 (one) hour after excision. Fixed biopsy samples will be processed for 
paraffin-embedding according to the Institutional Standard Operating Procedures. The 
paraffin blocks and slides should be labeled with the protocol number and the patient’s 
unique study identification number and stored at room temperature. Another portion of 
the tumor specimen (preferably one sample ≥ 2 mm3 or 100 mg) will be embedded in 
optimal cutting temperature compound immediately after received and not more than 1 
(one) hour after excision, frozen and stored at -80 oC for biomarker analysis. The 
remaining specimens resected during surgery will be used for routine histopathological 
diagnosis and will also be stored for future biomarker studies. 

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The surgical specimens will be evaluated for pathologic staging (pTNM) according to the 
AJCC 7th edition, pathologic response, quantification of percentage of viable tumor cells, 
status of resection margins, number of lymph nodes removed at each level, number of 
lymph nodes positive for cancer at each level, presence of extra- capsular nodal spread, 
peri-neural invasion and vascular invasion. To determine the pathologic response, 
specimens will be grossed and processed by the head and neck pathologist. The entire 
specimen measurement and the size of visible residual tumor will 
be documented. At least 1 block/1 cm of tumor will be submitted (average of 5-10 
blocks/patient). All slides prepared from blocks taken from each specimen will be 
reviewed by the head and neck pathologist, as well as slides from each dissected lymph 
node. 
 
Biomarkers to be evaluated in tumor tissue samples will include (but are not restricted 
to): EGFR, phospho-EGFR, IGF-1R, phospho-IGF-1R, IGF-2R, IGF-1, IGF-2, IGFBP-3, 
survivin, Ki-67, caspase-3, HIF-1 alpha, CD31, MMP-2, MMP-9, e-cadherin, gamma 
catenin, vimentin, fibronectin, p16, p53, markers of human papillomavirus infection, 
phosphorylation status of multiple kinases (using antibody arrays when appropriate), 
non-coding-RNA and messenger-RNA expression levels (using high-throughput 
microarray chips or sequencing), high-throughput genomic analysis (including genome 
sequencing and SNP analysis), high-throughput proteomic analysis, and other 
biomarkers that may emerge to be important related to the use of cisplatin/carboplatin, 
docetaxel and/or EGFR-targeted therapy. 
 
6.4.8 
Blood-based Biomarkers and Serum Pharmacokinetics 
 
Blood will be collected, at scheduled intervals according to Tables 6-1 to 6-4, using 
three (3) EDTA (10 mL) Vaccutainer tubes for plasma and blood cells separation and 
storage. Samples for pharmacokinetics should preferably be obtained within 2 hours 
before the next erlotinib or placebo dose. Samples from the main campus will be 
forwarded to the core laboratory to be processed within one hour of collection. Samples 
from the Regional Care Centers (Katy, Sugarland, Bay Area, and Woodlands) will be 
collected and placed in ice-bags for delivery to the core laboratory by 3 PM on the day it 
is collected. 
 
Sample processing: blood will be centrifuged in a standard clinical centrifuge at 2500 
RPM at 4 oC for 10 minutes. 

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Plasma: Aliquots of plasma 1.5 – 2.0 mL should then be transferred into each cryovial, 
labeled with the protocol number and the patient’s unique study identification number. 
Care must be taken not to collect the “cell layer – buffy coat” and to leaving a small 
portion of plasma behind for buffy coat collection. Plasma cryovials will be stored at -80 
oC until analysis. 
 
Buffy coat: From each Vaccutainer, carefully collect the buffy coat – cell layer and place 
into a cryovial x 3 vials - prelabeled with the protocol number and the patient’s unique 
study identification number. These cryovials will be stored at -80 oC until analysis. 
 
Blood-based biomarkers will include (but are not restricted to): a panel of 59 cytokine 
and angiogenic factors measured by available Luminex multiplex beads kits (EMD- 
Millipore 39-Plex for cytokines/chemokines, 17-Plex for angiogenic/growth factors, and 
Human CVD Biomarker Panel 1 and ELISA assays for osteopontin, free and total IGF-1 
and IGF-2, IGFBP-3, insulin, peptide C, free fatty acids, triglycerides, fructosamine, high-
throughput proteomic analysis, plasma circulating free-DNA, plasma miRNA, and 
high-throughput genomic analysis (including genome sequencing) and other biomarkers 
that may emerge to be important for to the use of cisplatin/carboplatin, docetaxel and/or 
EGFR-targeted therapy. 
 
6.4.9 
Tissue and Blood Sample Repository 
 
As part of the study, a tissue and blood sample repository will be created. The objective 
of this tissue sample repository will be to provide material for future evaluations of other 
relevant biomarkers that may be associated with clinical outcomes. A written informed 
consent will be obtained from patients enrolled in this study so that these remaining 
samples may be analyzed in the future for biomarkers not described in this protocol. 
Banking of these remaining samples will be optional. 
 
6.4.10 
Long-Term Follow-Up 
 
After the End of Treatment evaluation, information on additional oncologic treatment 
(including post-operative (chemo)radiation), time to disease progression/recurrence, 
sites of recurrence, development of second primary tumors, additional therapy for 
recurrence, long-term survival, and other relevant clinical data will be obtained.  
 
Two years of long-term follow up is required. The trial is deemed completed after last 
subject completed trial planned treatment and two years of follow up, and primary trial 
report is finalized in publication format.  
 

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6.5 
Assessments for Premature Discontinuation from Study 
 
If a patient discontinues treatment early (see Section 6.6), every attempt should be 
made to keep the patient in the study and perform the required End of Treatment 
assessments (see Section 6.3.3) and Long-Term Follow-up Information (see Section 
6.4.10). 

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6.6 
Criteria for Treatment Discontinuation 
 
Study medication should be discontinued in the following instances: 
 
• Disease progression (patients with evidence of clinical or symptomatic benefit 
despite radiological progression may continue treatment with erlotinib until the day 
before surgery); 
• Adverse event (see Section 7.2) either: 
− Resulting in death; 
− Requiring withdrawal from study; and/or 
− Fail to recover from hematological and/or nonhematological toxicity despite a 
dosing interruption of more than 21 days (see Section 3.1). 
• Medical or ethical reasons, including noncompliance, following discussion between 
the investigator and the Principal Investigator; 
• Patient’s request (excluding adverse events). 
 
 
Patients discontinued from treatment will remain on study and all attempts will be made 
to complete all assessments described in Section 0. 

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7 
ADVERSE EVENTS 
 
7.1 
Safety Assessment 
 
Assessments will consist of monitoring and recording of adverse events and serious 
adverse events, physical examination, measurement of protocol-specific laboratory 
variables and vital signs, as well as other tests deemed important for this protocol. The 
specific procedures and intervals for assessment are described in Section 0. 
Circumstances in which these assessments should be reported as adverse events are 
described in Section 7.5 and 7.6. All patients who have received at least one exposure 
to study drug will be evaluated for safety of the study drug. 
 
7.2 
Definition of Adverse Event 
 
An adverse event or adverse experience is any untoward medical occurrence in a study 
patient who is administered a study drug that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of the 
study drug, whether or not considered related to the study drug. 
 
Pre-existing conditions that increase in frequency or severity or change in nature during 
or as a consequence of use of a drug in human clinical trials will also be considered 
adverse events. Adverse events may also include pre- or post-treatment complications 
that occur as a result of protocol-mandated procedures (eg, invasive procedures such 
as biopsies). For the purpose of this study, adverse events that in the opinion of the 
treating investigator are related to planned surgical procedure (e.g., usual pain, usual 
bleeding, intra- or post-operative electrolyte imbalances and other clinically insignificant 
laboratory abnormalities) will not be captured and/or reported. 
 
Any continuing medical condition or clinically significant laboratory abnormality with an 
onset date before the first date of study drug administration should be considered 
pre-existing and should be documented in the chart. 
An adverse event does not include: 
• Relapse or progression of the underlying malignant disease; however, the 
associated signs, symptoms, or diagnoses should be recorded as adverse events 
(e.g., “jaundice” due to new or increasing liver metastases, or “tumor pain” or “bone 
pain” due to progressive disease); 

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• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is the adverse event; 
• Situations where an untoward medical occurrence has not occurred 
(e.g., hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the patient is hospitalized for observation; 
• Pregnancy (see Section 7.10). 
 
7.3 
Definition of Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
• Death; 
• Life-threatening situation (patient is at immediate risk of death); 
• Inpatient hospitalization or prolongation of an existing hospitalization (excluding 
those for study drug administration, protocol-related procedures, palliative or hospice 
care, or placement of an indwelling catheter, unless associated with other serious 
events); 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect in the offspring of a patient who received study 
drug; 
• Other: Important medical events that may not result in death, be immediately life- 
threatening, or require hospitalization, may be considered a serious adverse event 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events are: 
− 
Intensive treatment in an emergency room or at home for allergic bronchospasm; 
− 
Blood dyscrasias or convulsions that do not result in hospitalization; 
− 
Development of drug dependency or drug abuse. 
 
Clarification of Serious Adverse Events 
 
• Death is an outcome of a serious adverse event and not a serious adverse event in 
itself. When death is an outcome, the event(s) resulting in death should be reported 
(e.g., “pulmonary embolism” with a fatal outcome). The appropriate diagnosis or 
term should be recorded and assigned severity grade 5; 
• In instances of death due to “Disease Progression” the cause of death should be 
indicated as the event or condition resulting in death to the extent possible (e.g., 
“respiratory failure” due to progressive lung cancer). If no appropriate term with a 
grade 5 severity in the CTCAE can be identified, then a term should be selected 
from the CTCAE category “Death”; 

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• The term “Disease Progression” should be avoided in situations in which a patient is 
admitted for management of conditions that are secondary to disease progression. 
Instead, the medical condition should be recorded (e.g., “seizure” secondary to brain 
metastases); 
• “Occurring at any dose” does not imply that the patient is receiving study drug at the 
time of the event. Dosing may have been administered as treatment cycles or 
interrupted temporarily prior to the onset of the serious adverse event, but may still 
have contributed to the event; 
• “Life-threatening” means that the patient was at immediate risk of death from the 
event as it occurred. This does not include an event that might have led to death if it 
had occurred with greater severity. Grade 4 events (e.g., thrombocytopenia) are not 
always serious unless they have life-threatening consequences or result in 
hospitalization; 
• Complications that occur during hospitalization are adverse events. If a complication 
prolongs the hospitalization, it is a serious adverse event; 
• “Inpatient hospitalization” means the patient has been formally admitted to a hospital 
for medical reasons, for any length of time. Presentation and care within an 
emergency department does not necessarily constitute a serious adverse event; 
• The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  If a diagnosis is unavailable at the time 
of initial reporting, a follow-up report should be submitted once a diagnosis is made 
or when the discharge summary is available. 
 
7.4 
Definition of Adverse Drug Reaction 
 
An adverse drug reaction (ADR) is any response to a medicinal product that is noxious 
and/or unintended and related to any dose.  The phrase “response to a medicinal 
product” means that a causal relationship between the medicinal product and the 
adverse event is at least a reasonable possibility (i.e., the relationship cannot be ruled 
out). 
 
7.5 
Adverse Event Reporting Period 
 
Adverse events (as defined in section 7.2) that occur after the patient is 
registered/randomized and up to 30 days after the last study drug administration must 
be recorded as outlined in Table 7-1.  Should a patient discontinue from or complete the 
study and commence subsequent anticancer therapy within 30 days of the last study 
drug administration, adverse events attributable to this subsequent therapy should not 
be recorded. 

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Table 7-1. Recommended Adverse Event Recording Guidelines for Phase II 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
NR 
NR 
Yes 
Yes 
Yes 
Unlikely 
NR 
NR 
Yes 
Yes 
Yes 
Possible 
Yes 
Yes 
Yes 
Yes 
Yes 
Probable 
Yes 
Yes 
Yes 
Yes 
Yes 
Definitive 
Yes 
Yes 
Yes 
Yes 
Yes 
NR= Adverse Event will not be recorded 
 
Any new serious adverse event that occurs more than 30 days after last study drug 
administration should be reported if considered related to study drug (e.g., secondary 
cancer). The evaluation of an adverse event should continue until the adverse event 
resolves, until the start of subsequent anticancer therapy, or until the investigator or 
sponsor determines the patient’s condition is stable. 
 
 
 
7.6 
Adverse Event Assessment and Documentation 
 
A consistent methodology for eliciting adverse events should be adopted. Examples of 
non-directive questions include:  “How have you felt since your last clinical visit?” or 
“Have you had any new or changed health problems since you were last here?”  New 
findings on physical examination or clinically significant changes in ECGs may qualify 
as an adverse event. See Section 7.8 for guidelines on reporting Clinical Laboratory 
Abnormalities. 
 
Adverse events will be assessed by the investigator and recorded on the patient’s chart, 
including the dates of onset and resolution, severity, relationship to study drug, 
seriousness, and the action taken with the study drug. 
 
Correct medical terminology/concepts should be used when recording adverse event 
terms. Abbreviations should be avoided. A diagnosis is preferred rather than individual 
signs and symptoms (e.g., record pneumonia rather than fever, cough, pulmonary 
infiltrate). 
 
The adjectives “severe” and “serious” are not synonymous. Serious is a regulatory 
definition (see Section 7.3), while severity describes the intensity of the adverse event. 
Severity should be recorded and graded according to the NCI CTCAE, v4.0 (refer to the 
following website for the CTC manual or the CTC document): 

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http://ctep.cancer.gov 
 
The relationship to study drug therapy should be assessed using the following 
definitions: 
• Not Related: Evidence exists that the adverse event has an etiology other than the 
study drug (e.g., pre-existing condition, underlying disease, intercurrent illness, or 
concomitant medication). This includes events that are considered remotely or 
unlikely related to study drug. 
• Related: A temporal relationship exists between the event onset and administration 
of the study drug. It cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies. In case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  It should 
be emphasized that ineffective study drug treatment should not be considered as 
causally related in the context of adverse event reporting. This includes events that 
are considered possibly, probably, or definitely related to study drug. 
 
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment. 
 
7.7 
Serious Adverse Event Reporting Requirements 
 
Serious Adverse Event Reporting for MD Anderson – IND Sponsored Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might 
have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 

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intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
• 
Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should 
be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the 
event). 
• 
All life-threatening or fatal events, that are unexpected, and related to 
the study drug, must have a written report submitted within 24 hours 
(next working day) of knowledge of the event to the Safety Project 
Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB. 
• 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, 
unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day 
time period that are related to the study treatment must be reported to 
the IND Office. This may include the development of a secondary 
malignancy. 
 
 
 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 

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It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
Serious Adverse Event Reporting for Astellas Pharma/OSI Pharmaceuticals 
 
All serious adverse events related to erlotinib must be reported, by FAX (303-546-  
7706), to Astellas Pharma/OSI Pharmaceuticals Pharmaceuticals Drug  Safety 
Department. This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 
days following completion of active protocol therapy must also be reported. 
Serious 
adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Astellas Pharma/OSI Pharmaceuticals study drug (or 
therapy) is suspected. 
 
7.8 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments 
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs 
and/or symptoms that are associated with laboratory findings requiring study  
withdrawal, dose modification, or medical intervention (e.g., anemia requiring 
transfusions or hyperglycemia requiring treatment) or other abnormal assessments  
(e.g., ECG, radiographs, vital signs) must be recorded as adverse events (or serious 
adverse events) if they meet the definition of an adverse event (or serious adverse 
event) as described in Section 7.2 and 7.3.  In addition, laboratory abnormalities 
equating to DLT or any laboratory abnormalities marked as clinically significant should 
also be recorded as adverse events. The investigator will report the most severe grade 
of the clinically significant laboratory abnormality and will evaluate its relationship to the 
study drug and clinical condition.  All clinically significant abnormal laboratory results will 
be followed until they return to normal or stabilize. 
 
7.9 
Expected Adverse Events 
 
The erlotinib Investigator’s Brochure contains a complete description of the safety 
information for erlotinib. 
 
An unexpected adverse event or ADR is any event for which the nature or severity is 
not consistent with the information contained in the Investigator’s Brochure. 

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Based on clinical results, dermatosis or rash, diarrhea, fatigue, nausea, vomiting, 
stomatitis, headache, cough, dyspnea, and infection were the most frequently observed 
undesirable effects in cancer patients following exposure to oral erlotinib.  
Hematological toxicity has not been observed in patients receiving single-agent erlotinib 
treatment. 
 
Diarrhea (sometimes severe) has occurred in patients receiving oral erlotinib and was 
mostly managed by loperamide; however, reduction in the dose of erlotinib was 
occasionally necessary with continuous daily dosing. There have been rare reports of 
renal failure and hypokalemia and some were secondary to severe dehydration due to 
diarrhea, nausea, vomiting, and/or anorexia. In more severe or persistent cases of 
diarrhea that may lead to dehydration or in patients with aggravating risk factors of renal 
impairment, study drug therapy should be interrupted and appropriate measures should 
be taken including rehydration. 
 
There have been infrequent reports of serious ILD, including fatal events, in patients 
receiving erlotinib for treatment of NSCLC and other advanced solid tumors. In Study 
BR.21 in NSCLC patients, the incidence of ILD (0.8%) was the same in the placebo and 
erlotinib groups.  However, one cannot completely rule out a potential causal 
relationship between erlotinib exposure and the rare occurrence of ILD. 
 
In the event of acute onset of new or progressive, unexplained pulmonary symptoms 
such as dyspnea, cough, and fever, study drug should be interrupted pending 
diagnostic evaluation (see Table 3–7). If ILD is diagnosed, study drug should be 
discontinued and appropriate treatment instituted as necessary. 
 
For further details regarding AEs considered to be possibly associated with study drug, 
refer to the ‘Summary of Data and Guidance for the Investigator’ section of the erlotinib 
Investigator’s Brochure. 
 
7.10 
Pregnancy and Breast Feeding 
 
Erlotinib should not be used during pregnancy or while breast feeding. 

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8 
STATISTICAL METHODS 
 
8.1 
Objectives and Design 
 
The primary objective of this study is to assess: 
 
• major pathologic response among patients with locally advanced oral cavity 
squamous cell carcinomas treated with induction cisplatin/carboplatin, docetaxel and 
erlotinib prior to surgery, and to compare it with the major pathologic response 
among patients treated with cisplatin/carboplatin, docetaxel, and placebo, in the trial 
population overall and in biomarker-defined subgroups. 
 
The secondary objectives of this study are to assess: 
 
• Safety and toxicity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 
• Recurrence-free survival 
 
• Progression-free survival 
 
• Response rate and disease control rate, as determined by RECIST version 1.1 
 
• Percentage of viable tumor cells in the surgical specimen 
 
• To correlate tissue and blood-based biomarkers with outcome and toxicity 
 
• Quality of life, determined by the self-reported FACT-HN questionnaire 
 
The clinical trial is divided in two stages: stage I (biomarker discovery/testing of previous 
findings) and stage II (biomarker-guided therapy). Fresh tissue and blood will be 
collected prior to initiation of induction chemotherapy for biomarker evaluation. In stage  
I, patients will be randomized to the control and experimental arms irrespective of their 
biomarker status. Upon completion of stage I, the biospecimens collected will be 
analyzed in search of predictive markers of benefit from erlotinib. These analyses will be 
informed by correlative studies of other erlotinib-based trials in HNSCC conducted at M. 
D. Anderson, pre-clinical data and other emerging data in the literature as regards to 
benefit from chemotherapy and/or EGFR inhibitors in this setting. When appropriate, 
techniques and cut-offs will be standardized to determine the most practical, efficient, 
and robust biomarkers able to discriminate responders versus non-responders to 
chemotherapy+erlotinib. These biomarkers (herein referred to as erlotinib associated 

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biomarkers [EAB]) will be CLIA certified (when appropriate) and incorporated into stage 
II. During stage II, patients will be adaptively randomized to the control or experimental 
arms according to their EAB status. 
 
8.2 
Sample Size and Trial Conduct 
 
This study is a randomized phase 2 trial. Randomization is used to achieve patient 
comparability across treatments. A total of 100 evaluable patients will be randomized. 
Patients that are enrolled but are not randomized for any reason will be considered 
screen failures, and will be replaced so that the sample size achieves 100 randomized 
patients. 
 
8.2.1 
Randomization 
 
Patients will be randomized to either Chemotherapy/Placebo or Chemotherapy/Erlotinib 
using a website housed on a secure server at MDACC and maintained by the MDACC 
Department of Biostatistics. Access to the website will be gained through usernames 
and passwords provided by the MDACC Department of Biostatistics to the research 
personnel at MDACC. Training on the use of the trial website to randomize patients on 
the study will be provided by J. Jack Lee or the designated IT personnel from the 
Department of Biostatistics. 
 
This is a double-blinded randomized trial. When a patient is enrolled on the study, the 
patient's information as regards to stratification factors and biomarker status (when 
appropriate) will be entered to the database by the study personnel. After the 
randomization button is clicked, the patient will be assigned to a treatment arm. 
Information on the treatment arm will not be available to the research personnel that 
have direct contact with the patient (e.g., research nurses and investigators). Through 
the web interface, the MDACC pharmacy can enter the patient medical record number 
and the information on the treatment arm will be available on the screen for proper 
medication dispensing. All data on randomization will be stored in a secure SQL server 
database. 
 
The clinical trial is divided in two stages: stage I (biomarker discovery/testing of previous 
findings) and stage II (biomarker-guided therapy), with 50 patients in each stage. The 
first 30 patients in stage I will be equally randomized between two arms, stratified by 
lymph node status (N0/1 vs. N2/3). Patients 31 to 50 will be adaptively randomized 
between the two arms based on major pathologic response and nodal status. In 

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stage II, upon the identification of a predictor biomarker of Chemotherapy/Erlotinib, the 
next 50 patients will be adaptively randomized based on response, nodal status, and 
the predictive biomarker (as described in Section 8.2.2) in order to maximize response 
probability based on patients’ molecular profile.  Adaptive randomization assigns 
patients into the control arm and the experimental arm with the randomization 
probability proportional to the treatment success using the Bayesian probit model such 
that more patients will be treated with the better treatment (higher overall major 
pathologic response rate) compared with conventional equal randomization method. 
The design can also maintain the pre-specified type I and type II error rates. The 
projected accrual rate is 3 patients per month. We expect that the study accrual will 
take approximately 3 years. 
 
The primary endpoint is major pathologic response as defined in the study endpoints 
section which will be evaluated at the time of surgery (about 2 months from the start of 
the treatment). All randomized patients will be included in the primary analysis.  Early 
drop outs prior to the time of major pathologic response evaluation will be counted as 
failures. We expect 33% of patients will be N0/N1, and 67% of patients will have N2/N3 
status. We assume that we can identify one EAB as a predictive marker for the 
treatment group (cisplatin/carboplatin, and docetaxel with erlotinib) in Stage I. We also 
assume that the EAB positive rate is 50%. The major pathologic response rates under 
the null and alternative hypothesis are assumed as in Tables 8-1a, 8-1b, and 8-1c. 

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Table 8-1a: The hypothesized major pathologic response for treatment and biomarker combinations for simulation 
assuming 50% 
biomarker positive rate. 
Null 
Alternative 
Biomarker status 
Control 
Treatment 
Control 
Treatment 
Negative 
0.20 
0.20 
0.20 
0.20 
Positive 
0.20 
0.20 
0.20 
0.69 
Overall 
0.20 
0.20 
0.20 
0.445 
 
Table 8-1b: The hypothesized major pathologic response for treatment and biomarker combinations for 
simulation for N0/N1 (33% of patients) 
Null 
Alternative 
Biomarker status 
Control 
Treatment 
Control 
Treatment 
Negative 
0.267 
0.267 
0.267 
0.267 
Positive 
0.267 
0.267 
0.267 
0.767 
Overall 
0.267 
0.267 
0.267 
0.517 
 
Table 8-1c: The hypothesized major pathologic response for treatment and biomarker combinations for 
simulation for N2/N3 (67% of patients) 
Null 
Alternative 
Biomarker status 
Control 
Treatment 
Control 
Treatment 
Negative 
0.167 
0.167 
0.167 
0.16 
Positive 
0.167 
0.167 
0.167 
0.65 
Overall 
0.167 
0.167 
0.167 
0.40 

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i
i 
i
o
The Bayesian Probit Model: 
 
A Bayesian probit model is used to predict response based on response and nodal status 
in the first stage, and based on response, nodal, and biomarkers in the second stage. The 
model is specified below: 
 
Pr(yi = 1|xi ) = Φ(xtp), 
 
 
where yi is the binary outcome of the ith patient, Φ is the standard normal CDF, xi is the 
vector of covariates of the ith patient, and p is the vector of regression coefficients to be 
estimated. The vector of xi includes intercept, indicator of treatment, indicator of nodal 
status, also may include biomarkers and their interaction terms with treatment. If treatment 
arm is better than the control arm, the coefficient associated with treatment will be positive; 
if treatment is worse than the control arm, its coefficient will be negative; if no difference 
then the coefficient will be zero. Effects of biomarkers and their interaction with treatment 
can be interpreted similarly. 
 
A latent variable z is introduced in this Bayesian probit model, where Zi follows a truncated 
normal distribution and Ei is the error term which follows an i.i.d. standard normal 
distribution specified below : 
 
 
Zi = xtp + E , where E  ~ i. i. d. N(0,1) 
 
 
 
Gibbs sampling of the probit model 
 
Assuming a normal prior on the p, p ~ N(bO, BO), 
 
 
We have the full conditional distributions of p and z defined as: 
 
 
-1 
′ 
-1 
B = (Bo + X X) 
 
p|z ~ N(B(B-1 bo + X′Z), B) 
 
 
Zi |p, xi,yi = O ~ N( X′p, 1)[zi < 0] 

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Zi |p, xi,yi = 1 ~ N( X′p, 1)[zi ଛ O] 
 
 
where X is the design matrix consist of vector of covariates xi,. 
 
 
A normal prior on p with mean 0 and standard error of 10 (a non-informative prior) will be 
used at the beginning of the trial. As trial goes on and data accumulates, the posterior 
distribution of p will be updated and inference will be made on p at the interim and at the 
end of the trial to make decisions. 
 
 
8.2.1.1 
Trial Conduct and Simulations 
 
Within the first stage, we will equally randomize the first 30 patients into control and 
treatment arms stratified by nodal status to train the model before the adaptive 
randomization takes place. Starting from the 31st patient and up to the 50th patients, we will 
calculate the probability of the treatment being better than the control based on observed 
data irrespective to their marker status. More specifically, we will calculate the probability 
of treatment being better (PTB): 
t 
t 
PTB = Pr(Ptrt > Pcontrol | Data) = Pr(x1p - xop > 0 | Data), 
where x1 and xo are covariates (treatment, nodal status) representing patients in the 
treatment and the control arm, respectively. We will apply a tuning parameter A (set as 0.5 
by default) on PTB to calculate the adaptive randomization probability (ARP) using the 
following formula: 
 
 
 
 
ARP = 
PTB;t 
PTB;t + (1 - PTB);t 
 
 
and patient will be randomized to the treatment arm with probability ARP.  The 
randomization will be implemented in a web-based database system developed in the 
Department of Biostatistics to capture the patients’ medical demographic variables, 
biomarkers, and treatment outcomes. Treatment outcome will be evaluated and entered 
timely to facilitate the proper implementation of the adaptive randomization. 

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The trial will be placed on hold for new patient accrual after the 50th patient has been 
randomized in stage I. At that time, we will complete biomarker analysis in tumor 
specimens and blood, and we will define EAB that will be used for adaptive 
randomization in stage II, as described in Section 8.2.2. 
 
An interim analysis will be carried out after all 50 patients enrolled in the first stage have 
been evaluated. We will fit the probit model with only the main effect of treatment and 
nodal status. Three possibilities could emerge from the interim analysis: 
• Interim result A (erlotinib-based therapy not beneficial): defined as Pr(Ptrt  >   
Pcontrol | Data) < 0.7  for all these three sets of patients: 1) all patients, 2) marker 
positive patients, and 3) marker negative patients. Based on 5000 simulation trials, 
the probabilities of stopping for futility are 46.6% under the null and 1.4% under the 
alternative hypothesis (Table 8-2). 
• Interim result B (erlotinib-based therapy beneficial, but EAB could not be defined  
during stage I): defined as Pr(Ptrt  > Pcontrol | Data) ଛ 0.7 in all patients, or marker 
positive, or marker negative, and the probability for a positive test for treatment by 
marker  interaction is not sufficiently high, i.e. Prob(βinter > 0 !Data) < 0.91. 
 
• Interim result C (erlotinib-based therapy beneficial with corresponding EAB defined  
during stage I): defined as the absence of interim results A and B. Based on 5000 
simulation trials, the probability of declaring erlotinib-based therapy is better than 
the control with the corresponding EAB identified is 60% under the alternative 
hypothesis and 10% under the null hypothesis. 

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Table 8-2: Probability of early stopping at interim analysis. 
 
Hypothesis 
Interim result A: 
Prob( p_trt > p_ctrl 
Data) < 0.7 for all 
three sets of 
patients*. 
Interim result B: 
Prob(p_trt > p_ctrl Data) ≥ 0.7 
for at least one of 3 sets of 
patients 
and 
Prob(βinter > 0 !Data) < 0.91 
Interim result C: 
Prob(p_trt > p_ctrl Data) >= 
0.7 for at least one of 3 sets 
of patients, 
and 
Prob(βinter > 0 !Data) 
ଛ 0.91 
Null 
0.466 
0.434 
0.100 
Alternative 
0.014 
0.382 
0.604 
*the 3 sets of patients are 1) all patients, 2) EAB negative patients, and 3) EAB positive patients. 
 
After the interim analysis has been completed, the trial will re-open for accrual to stage 
II, and treatment assignment will be performed as described below. 
 
In interim result A, erlotinib-based induction chemotherapy has been declared not 
beneficial in the population overall and in the EAB negative and positive population. 
Therefore, all subsequent patients will be treated in an open-label fashion in Arm B with 
cisplatin/carboplatin and docetaxel. Patients will not receive erlotinib or placebo.  
Hence, the term “early stopping” refers to the stopping of the randomization in stage II. 
EAB may not be analyzed real time prior to treatment. A total of 50 patients will be 
treated in stage II. The primary analysis will be focused on describing the major 
pathologic response rate to induction cisplatin/carboplatin and docetaxel. Secondary 
analysis will focus on retrospectively identifying biomarkers predictive of major 
pathologic response to induction cisplatin/carboplatin and docetaxel in patients 
accrued to stages I and II (CAB or chemo-associated biomarker). If a CAB is identified, 
it could inform future clinical studies that could prospectively assess the role of this 
chemotherapy regimen prior to surgical resection in the CAB positive and/or CAB 
negative groups. 
 
Assuming that the prevalence of the CAB for predicting chemo response is 50%, 
a sample size of 75 patients treated with chemo under interim result A achieves at least 
74% power to detect a difference of 20% or higher in major pathologic response between 
the CAB positive group and the CAB negative group using Fisher’s exact test with one sided 

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significance level of 10% (Table 8-3). 
 
 
 
Table 8-3. Power for marginally treatment effect and interaction effect at the end of stage II for 
interim results B and C. 
1 
2 
3 
One-sided significance level, α 
0.100 
0.100 
0.100 
major pathologic response in 
0.100 
0.090 
0.050 
major pathologic response in 
0.300 
0.310 
0.350 
Power ( % ) 
74 
81 
97 
n per group 
37 
37 
37 
 
 
 
In interim result B, an EAB could not be defined, but erlotinib-based induction 
chemotherapy could be beneficial in the population overall. Therefore, randomization to 
arms A and B will continue, using the same algorithm applied to patients 31 to 50 in 
stage I (i.e., adaptive randomization based on major pathologic response). A total of 
50 eligible patients will be accrued to stage II. EAB may not be analyzed prior to 
randomization, and EAB will not be used to influence randomization. 
 
In interim result C, EAB has been defined and could potentially identify patients with a 
higher chance of major pathologic response to cisplatin/carboplatin, and docetaxel 
plus erlotinib. A total of 50 eligible patients will therefore be accrued to stage II. All 
patients will have EAB status determined prior to randomization in a CLIA certified 
environment. Within stage II (starting from the 51st patient), we will calculate the 
probability of the treatment being better than the control based on observed data and 
their marker status by adding two terms added to the p coefficients, the EAB status 
and the interaction term between treatment and EAB. 
 
 
In interim results B and C, to test the overall treatment effect at end of the trial,  we will 
fit the reduced probit model with only the intercept and the main effect of treatment and 
nodal status to examine whether the coefficient associated with the treatment main 
effect if significantly greater than 0. For each trial, we declare treatment being success 

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if the posterior probability of the coefficient being greater than 0 is bigger than a 
threshold of 0.93, i.e. 
PSTrt = Prob({Jtrt > 0 |Data) ଛ 0.93 
 
This threshold was calibrated such that our Bayesian adaptive randomization design 
yields a type I error rate <=10%. The overall power for the marginal effect of treatment 
under the alternative hypothesis is 93.2% with 10% type I error rate (Table 8-4). 
 
In addition, to test the treatment by EAB interaction, a full model with main effect of 
treatment, nodal status, and marker, and the trt by marker interaction will be carried out  
to examine if the p coefficient associated with the interaction term is significantly different 
from zero. Formally, we declare that the EAB is a predictive marker if the posterior 
probability of the coefficient being greater than 0 is bigger than a threshold of delta=0.91, 
i.e. 
PSI = Prob({Jinter > 0 |Data) ଛ 0.91 
 
The threshold was calibrated such that under the null (no EAB effect) the type I error rate 
was <= 10%. The overall power for the interaction term under the alternative hypothesis 
is 71.2% with 8.7% type I error rate (Table 8-4). 

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Table 8-4: Power for marginally treatment effect and interaction effect at the end of stage II for interim results B and C. 
 
 
 
 
Hypotheses 
Power for testing 
marginal treatment effect 
Success= 
Prob({Jtrt > 0 |Data) ଛ 0.93 
Power for testing 
trt by EAB interaction 
Success= 
Prob({Jinter > 0 |Data) ଛ 0.91 
Interim result B 
Interim result C 
Overall Interim result B 
Interim result C 
Overall 
Null 
0.0916 
0.012 
0.0996 
0.0256 
0.061 
0.0866 
Alternative 
0.345 
0.587 
0.932 
0.140 
0.572 
0.712 
 
 
 
Details of other operating characteristics of the design based on the simulation studies 
were summarized in the Appendix G (Tables A.8-5, A.8-6, and A.8-7). 
 
8.2.2 
Erlotinib-associated biomarkers (EAB) 
 
 
 
After completion of stage I, accrual to the study will be placed on hold. 
 
The biospecimens (blood and tumor tissue) collected during stage I will be analyzed in 
search of predictive markers of benefit from erlotinib. These analyses will be informed 
by correlative studies of other erlotinib-based trials in HNSCC conducted at M. D. 
Anderson, pre-clinical data, and other emerging data in the literature as regards to 
benefit from chemotherapy and/or EGFR inhibitors in this setting. Potential biomarkers 
to be evaluated are described in Section 6. Additional markers may be added as 
knowledge becomes available of their potential role as predictors of benefit from 
chemotherapy and/or erlotinib. When appropriate, techniques and cut-offs will be 
standardized to determine the most practical, efficient, and robust biomarkers able to 
discriminate responders versus non-responders to chemotherapy+erlotinib. These 
biomarkers are herein referred to as erlotinib associated biomarkers [EAB]. 
 
Before proceeding to stage II, a test for interaction will be applied to evaluate the 
performance of each EAB in the stage I population. EABs will be ranked according to 
the absolute value of the interaction term and the posterior probability of the coefficient 
being greater or smaller than 0. The highest ranking EABs that occur in at least 20% of 

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the patients accrued to stage I will be considered for selection to be incorporated into 
the randomization algorithm in stage II. The principal investigators, in consultation with 
the biostatisticians, will use their best judgment to select the final EABs to be used 
prospectively for randomization in stage II. In addition to the statistical properties of the 
model, the investigators may take into account feasibility of analyzing EABs in real time 
in a CLIA-certified environment, cost-effectiveness, reproducibility of the lab test and 
other practical aspects related to biomarker development, prior to the final EAB 
selection. When appropriate, two or more EABs may be combined if this improves the 
discriminatory abilities of pathologic responders versus non-responders to erlotinib- 
based therapies. 
 
Before re-opening accrual to the trial (stage II), the selected EABs will be CLIA-certified. 
An amendment will be submitted to the IRB that includes, in this section of the protocol, 
a description of the selected EABs, and the definitions of marker positive and marker 
negative patients. Once the amendment is approved, the randomization algorithms will 
be updated and accrual to stage II will commence. 
8.3 
Study Endpoints 
 
8.3.1 
Safety 
 
All patients who receive at least one treatment with any of the study drugs will be 
included in the safety analysis.  Frequency of AEs, SAEs, discontinuation of study drug 
due to AEs and changes from baseline laboratory parameter values will be evaluated. 
 
8.3.2 
Efficacy 
 
All patients randomized will be included in the efficacy analysis. 
 
The primary efficacy endpoint is major pathologic response. The secondary efficacy 
endpoints are recurrence-free survival, progression-free survival, response rate and 
disease control rate, and percentage of viable tumor cells in the surgical specimen. 
 
The primary analysis of efficacy is to compare major pathologic response in patients 
who receive erlotinib plus chemotherapy to patients who receive placebo plus 
chemotherapy. 
 
8.3.2.1 
Definition of major pathologic response 
 
The following criteria will be used to guide documentation and reporting of response: 

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a. Complete pathological response: no residual carcinoma in the primary tumor site 
or lymph nodes. 
 
b. Partial response to therapy, either i) minimal residual disease/near total effect 
(eg, ≤10% of tumor remaining) or ii) evidence of response to therapy but with 
11%–50% of tumor remaining, or iii) >50% of tumor cellularity remains evident 
when compared with the previous sample, although some features of response 
to therapy present. 
 
c. Minimal evidence of response to therapy. 
 
Major pathologic response is defined as complete pathologic response or a partial 
pathologic response to therapy with minimal residual disease/near total effect (eg, ≤10% of 
tumor remaining) and no residual carcinoma in the lymph nodes. 
 
8.3.2.2 
Definition of Response by Imaging Studies 
 
Response will be defined according to RECIST criteria as described in Appendix E. 
 
8.3.2.3 
Stable Disease Duration 
 
The duration of stable disease will be measured from the start of treatment until the first 
date that progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
8.3.2.4 
Progression-free and Recurrence-free Survival 
 
Progression-free survival will be measured from the start of treatment until the first date 
that progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started) or death. 
Patients will be censored at the time of their last follow-up or at the time of surgery, or at 
the time of radiation therapy (if surgery has not been performed), whichever occurs first. 
 
Recurrence-free survival will be measured from the date of surgery until the first date 
that recurrence is objectively documented or death. For patients that do not undergo 
surgery but receive definitive radiation therapy, recurrence-free survival will be 
measured from the date of completion of radiation therapy until the first date that 
recurrence is objectively documented or death. Patients that do not receive surgery or 
definitive radiation therapy will not be evaluated for recurrence-free survival. 
 
 
8.3.3 
Quality of Life 
 
Quality of life data will be obtained at scheduled intervals according to Tables 6-1 to 6- 
4. Quality of life will be analyzed. 

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8.4 
Planned Analysis 
 
Descriptive statistics will be used to summarize the outcomes. For the primary endpoint 
of major pathologic response, we will use the Bayesian probit model to assess the main 
effect of treatment, nodal status, and biomarker, and treatment by biomarker interaction. 
For other binary secondary endpoints, logistic regression model will be used to assess 
the effect of treatment and biomarker.  Cox proportional hazards models will be used to 
assess the effect of treatment and biomarker on time to event outcomes (recurrence 
free survival and progression free survival). 
 
8.4.1 
Safety 
 
All patients who receive at least one dose of any of the study drugs will be considered 
evaluable for all safety analyses. 
 
Descriptive statistics will be used to summarize safety data. Adverse events will be 
coded to preferred term and mapped to system organ class using a MedDRA™ 
dictionary, and summary tables for all adverse events will be generated. Incidence 
rates will be summarized for each preferred term and system organ class.  Additional 
summary tables will be generated for the following population subsets: patients with 
serious adverse events, patients with related adverse events, patient deaths, and 
patients who discontinue due to adverse events.  Depending on the doses achieved in 
this study, adverse events may also be summarized by dose level.  Severity, 
investigator-attributed relationship to study drug, duration, and outcome of events will 
also be recorded. 
 
8.4.1.1 
Adverse Events 
 
All adverse events will be evaluated by incidence, serious adverse events, deaths, and 
discontinuation due to adverse events. Severity, investigator-attributed relationship to 
study drug, duration, and outcome of the events will also be recorded. These adverse 
events will be coded to preferred term and mapped to system organ class using the 
MedDRA™ dictionary.  The number and percent of each event will be computed and 
summarized by system organ class. 
 
8.4.2 
Efficacy 
 
All randomized patients will be considered evaluable for all efficacy analyses. Efficacy 
will be analyzed according to the intent-to-treat principle. 

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8.4.3 
Pharmacokinetics 
 
Patients in Arm A and Arm B who complete 1 cycle of dosing and have erlotinib or 
placebo administered the day before blood collection for PK will be included in the 
pharmacokinetic analyses. The interactions between PKs, smoking status and efficacy 
will be evaluated in an exploratory fashion. 
 
8.4.4 
Quality of Life 
 
All patients who receive at least 1 dose of study therapy will be included in the Quality of 
Life analyses. 

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9 
RECORDING AND COLLECTING OF DATA 
 
9.1 
Case Report Forms 
 
Electronic case report forms (CRFs) will be used for this study, stored under M. D. 
Anderson’s database. In addition, DMI and CORe will be used as the electronic case 
report form (eCRF) for this protocol. Adverse events and protocol specific data will be 
entered into DMI and CORe. Concomitant medications will not be captured in case 
report forms in DMI. Con meds will be captured in the source document (Clinic Station). 
 
9.2 
Study Files and Patient Source Documents 
 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents include investigators’ Study Files and original patient clinical source 
documents generated at the study site. The term “original” means the first recording of 
the data. 
 
The investigator will ensure the Study Files are maintained, including the CRFs and 
query forms, protocol/amendments, IRB and regulatory approvals with associated 
correspondence, informed consents, study drug records, staff curriculum vitae, all 
correspondence, and other appropriate documents. 
 
Patient clinical source documents may include, but are not limited to, patient 
hospital/clinic records, physicians’ and nurses’ notes, appointment books, laboratory 
reports, ECGs, radiographs, pathology and special assessment reports, and consultant 
letters. The investigator must assure that all original source documents are available to 
support monitoring activities. 
 
9.3 
Patient Data Confidentiality 
 
All laboratory and clinical data gathered in this protocol will be stored in a password 
protected database. All patient information will be handled using synonymous 
identifiers. Linkage to patient identity is only possible after accessing a password- 
protected database. Access to the database is only available to individuals directly 
involved in the study.  Information gathered for this study will not be reused or disclosed 
to any other person or entity, or for other research. Once the research has been 
completed, identifiers will be retained for as long as is required by law and by 
institutional regulations, and at that point will be destroyed. 

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10 
LEGAL AND ETHICAL REQUIREMENTS 
 
10.1 
Good Clinical Practice 
 
The investigator will ensure that this study is conducted in full compliance with GCP, 
which includes ICH GCP guidelines, applicable GCP regulations, and with any other 
applicable laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the study patient. 
 
10.2 
Institutional Review Board 
 
The investigator must submit this protocol, the informed consent form(s) to the IRB. 
Approval from the board/committee must be obtained before starting the study and 
documented in writing to the investigator specifying the protocol number, protocol 
version, documents reviewed, and date on which the committee met and granted the 
approval. Written evidence of the approval must be made available to the sponsor. 
Any modifications made to the protocol after receipt of IRB approval must also be 
submitted to the board/committee for approval prior to implementation. 
 
Appropriate reports on the progress of the study will be made to the IRB in accordance 
with applicable regulations, institutional policy, and in agreement with policies 
established by the sponsor. 
 
10.3 
Informed Consent 
 
The investigator will submit the informed consent to the sponsor for approval prior to 
submitting to the IRB/IEC. The investigator is responsible for obtaining written,  
informed consent(s) from each patient interested in participating in this study prior to 
conducting any study-related procedures. Written informed consent should be obtained 
after adequate, thorough, and clear explanation of the aims, methods, objectives, 
potential risks and benefits of the study, as well as any use of the patient’s genetic 
information from the study.  The investigator must use the most current IRB-approved 
consent form for documenting written informed consent. Each informed consent will be 
appropriately signed and dated by the patient and the person obtaining consent. The 
investigational site must retain the original signed consent and provide a copy to the 
patient.  Documentation of the consent process should be documented in the subject’s 
medical record. 

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Significant new safety information received by the investigator should be provided to 
current and future study subjects at the first available opportunity. 
 
10.4 
Study Termination 
 
The sponsor, the investigator, and/or the regulatory authorities reserve the right to 
terminate the study at any time. Should termination be necessary, all parties will 
formulate and coordinate termination procedures. In terminating the study, the sponsor 
and the investigator will assure that patients’ safety and rights are carefully protected. 

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