Clinical trial NCT01064479
Conditions: Metastatic Squamous Cell Carcinoma of the Hypopharynx Metastatic Squamous Cell Carcinoma of the Larynx Metastatic Squamous Cell Carcinoma of the Oral Cavity Metastatic Squamous Cell Carcinoma of the Oropharynx Recurrent Hypopharyngeal Squamous Cell Carcinoma Recurrent Laryngeal Squamous Cell Carcinoma Recurrent Oral Cavity Squamous Cell Carcinoma Recurrent Oropharyngeal Squamous Cell Carcinoma Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IV Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IV Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-02-05; Completion date: 2020-11-03
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well combination chemotherapy with or without erlotinib hydrochloride works in treating patients with squamous cell carcinoma of the head and neck that has spread to other parts of the body or has come back. Drugs used in chemotherapy, such as docetaxel, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy with or without erlotinib hydrochloride may be an effective treatment for squamous cell carcinoma of the head and neck.

Detailed description:
PRIMARY OBJECTIVES:

I. Assess the efficacy of adding erlotinib hydrochloride (erlotinib) to chemotherapy to improve progression free survival in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.

SECONDARY OBJECTIVES:

I. Evaluate overall survival, response rate, disease control rate, and duration of response by treatment with or without erlotinib.

II. Evaluate quality of life (patient reported outcomes) by treatment with or without erlotinib.

III. Evaluate the safety profile of erlotinib in combination with chemotherapy. IV. Correlate the occurrence of erlotinib-induced rash with outcomes. V. To evaluate the steady-state pharmacokinetics of erlotinib. VI. To explore the prognostic and predictive value of epidermal growth factor receptor related biomarkers and other biomarkers, including blood and tissue proteomic and blood and tissue genomic markers, that may be associated with clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive docetaxel intravenously (IV) over 1 hour and cisplatin IV over 2 hours or carboplatin IV over 2 hours on day 1, and erlotinib hydrochloride orally (PO) daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression and unacceptable toxicity. Patients achieving complete response, partial response, or stable disease may continue erlotinib hydrochloride treatment.

ARM B: Patients receive docetaxel and cisplatin or carboplatin as in Arm I and placebo PO daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression and unacceptable toxicity. Patients achieving complete response, partial response, or stable disease may continue placebo treatment.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: Patients receive docetaxel IV over 1 hour and cisplatin IV over 2 hours or carboplatin IV over 2 hours on day 1 and erlotinib hydrochloride PO daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression and unacceptable toxicity. Patients achieving complete response, partial response, or stable disease may continue erlotinib hydrochloride treatment. arm 2: Patients receive docetaxel and cisplatin or carboplatin as in Arm I and placebo PO daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression and unacceptable toxicity. Patients achieving complete response, partial response, or stable disease may continue placebo treatment.
Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Docetaxel intervention 4: Erlotinib Hydrochloride intervention 5: Laboratory Biomarker Analysis intervention 6: Pharmacological Study intervention 7: Placebo intervention 8: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given PO intervention 5: Optional correlative studies intervention 6: Optional correlative studies intervention 7: Given PO intervention 8: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2 STUDY OF DOCETAXEL 
AND CISPLATIN / CARBOPLATIN WITH OR WITHOUT ERLOTINIB IN PATIENTS 
WITH METASTATIC OR RECURRENT SQUAMOUS CELL CARCINOMA OF THE 
HEAD AND NECK 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATORS: 
 Xiuning Le, MD 
 
 
 
 
PROTOCOL VERSION: FINAL VERSION 
 
PROTOCOL DATE APRIL 29, 2014 


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TABLE OF CONTENTS 
1 
INTRODUCTION  ................................................................................................... 11 
1.1 Background Therapeutic Information  ........................................................... 12 
1.2 Clinical Experiences with Erlotinib  ................................................................ 12 
1.2.1 Phase 1 Studies in Cancer Patients  ....................................................... 12 
1.2.2 Phase 2 Experience in Patients with Head and Neck Cancer  ........... 12 
1.2.3 Phase 3 Experience with Erlotinib  .......................................................... 13 
1.3 Rationale for the Current Study  ..................................................................... 14 
2 
STUDY OBJECTIVES  .......................................................................................... 18 
3 
STUDY DESIGN AND PLAN  .............................................................................. 19 
3.1 Treatment Plan and Regimen  ........................................................................ 20 
3.1.1 Treatment Plan  .......................................................................................... 20 
3.1.2 Dose Modifications for Chemotherapy  ................................................... 23 
3.1.3 Dose Modifications for Erlotinib or Placebo  ........................................... 30 
4 
PATIENT POPULATION  ..................................................................................... 34 
4.1 Inclusion Criteria  .............................................................................................. 34 
4.2 Exclusion Criteria  ............................................................................................. 35 
5 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS  ............................ 36 
5.1 Description, Handling and Administration of Docetaxel  ............................ 36 
5.2 Description, Handling and Administration of Cisplatin / Carboplatin  ....... 36 
5.3 Description, Handling and Administration of Erlotinib or Placebo  ............ 36 
5.3.1 Formulation of Erlotinib  ............................................................................. 36 
5.3.2 Packaging and Labeling of Erlotinib or Placebo  ................................... 37 
5.3.3 Storage and Handling of Erlotinib or Placebo  ....................................... 37 
5.3.4 Administration of Erlotinib or Placebo  .................................................... 37 
5.4 Drug Accountability  ......................................................................................... 37 
5.5 Treatment Compliance  ................................................................................... 38 
5.6 Concomitant Medications  ............................................................................... 38 
5.6.1 Permitted Concomitant Medications  ....................................................... 38 
5.6.2 Prohibited Concomitant Medications  ...................................................... 40 
5.6.3 Potential for Drug Interactions  ................................................................. 41 
5.6.4 Ophthalmologic Considerations  .............................................................. 42 


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6 
STUDY PROCEDURES  ....................................................................................... 44 
6.1 Patient Enrollment and Treatment Assignment  .......................................... 44 
6.2 Baseline Assessments  ................................................................................... 44 
6.3 Study Assessments  ......................................................................................... 46 
6.3.1 Assessment During Chemotherapy  ........................................................ 46 
6.3.2 Assessments Following Chemotherapy  ................................................. 48 
6.3.3 End of Treatment Assessments  .............................................................. 50 
6.4 Descriptions of Study Assessments  ............................................................. 51 
6.4.1 Smoking History  ......................................................................................... 51 
6.4.2 Performance Status  .................................................................................. 52 
6.4.3 Clinical Laboratory Tests  .......................................................................... 52 
6.4.4 Symptoms and Toxicity Assessment  ...................................................... 52 
6.4.5 Radiology Assessments  ........................................................................... 52 
6.4.6 Quality of Life  ............................................................................................. 53 
6.4.7 Tumor Tissue Samples  ............................................................................. 53 
6.4.8 Blood-based Biomarkers and Serum Pharmacokinetics  ..................... 53 
6.4.9 Tissue and Blood Sample Repository  .................................................... 54 
6.4.10 End of Treatment Assessments  .............................................................. 54 
6.4.11 Long-Term Follow-Up  ............................................................................... 54 
6.5 Assessments for Premature Discontinuation from Study  .......................... 55 
6.6 Criteria for Study Discontinuation  ................................................................. 56 
7 
ADVERSE EVENTS  ............................................................................................. 57 
7.1 Safety Assessment  ......................................................................................... 57 
7.2 Definition of Adverse Event  ............................................................................ 57 
7.3 Serious Adverse Event Reporting Requirements  ....................................... 58 
7.4 Definition of Adverse Drug Reaction  ............................................................ 60 
7.5 Adverse Event Reporting Period  ................................................................... 60 
7.6 Adverse Event Assessment and Documentation  ....................................... 61 
7.7 Serious Adverse Event Reporting Requirements  ....................................... 62 
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  ................................................................................... 65 
8.1 Objectives and Design  .................................................................................... 65 
8.2 Sample Size  ..................................................................................................... 65 
8.2.1 Randomization  ........................................................................................... 65 
8.3 Study Endpoints  ............................................................................................... 66 
8.3.1 Safety  .......................................................................................................... 66 
8.3.2 Efficacy  ........................................................................................................ 66 
8.3.3 Quality of Life  ............................................................................................. 67 
8.4 Interim Analysis  ................................................................................................ 67 
8.5 Planned Analysis  ............................................................................................. 67 
8.5.1 Safety  .......................................................................................................... 68 
8.5.2 Efficacy  ........................................................................................................ 68 
8.5.3 Pharmacokinetics  ...................................................................................... 68 
8.5.4 Quality of Life  ............................................................................................. 68 
9 
STUDY CONDUCT  ............................................................................................... 69 
9.1 Adherence to the Protocol .............................................................................. 69 
9.2 Recording and Collecting of Data  ................................................................. 69 
9.2.1 Case Report Forms  ................................................................................... 69 
9.2.2 Study Files and Patient Source Documents  .......................................... 69 
9.3 Legal and Ethical Requirements  ................................................................... 70 
9.3.1 Good Clinical Practice  .............................................................................. 70 
9.3.2 Institutional Review Board/Independent Ethics Committee Approval 70 
9.3.3 Informed Consent  ...................................................................................... 70 
9.3.4 Study Termination  ..................................................................................... 71 
9.3.5 Regulatory Approval .................................................................................. 71 
10 REFERENCE LIST  ............................................................................................... 72 


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PROTOCOL SYNOPSIS 
 
 
Title of Study: 
A Randomized, Placebo-Controlled, Phase 2 Study of Docetaxel and 
Cisplatin / Carboplatin with or without Erlotinib in Patients with Metastatic 
or Recurrent Squamous Cell Carcinoma of the Head and Neck 
Objectives: 
The primary objective of this study is to: 
• 
Assess the efficacy of adding erlotinib to chemotherapy to improve 
PFS in patients with metastatic or recurrent SCCHN. 
The secondary objectives of this study are to: 
• 
Evaluate overall survival, response rate, disease control rate, and 
duration of response by treatment with or without erlotinib; 
• 
Evaluate quality of life (patient reported outcomes) by treatment with 
or without erlotinib; 
• 
Evaluate the safety profile of erlotinib in combination with 
chemotherapy; 
• 
Correlate the occurrence of erlotinib-induced rash with outcomes; 
• 
To evaluate the steady-state pharmacokinetics of erlotinib; and 
• 
To explore the prognostic and predictive value of EGFR-related 
biomarkers and other biomarkers, including blood and tissue 
proteomic and blood and tissue genomic markers, that may be 
associated with clinical outcomes 
Study Design: 
This is a randomized, placebo-controlled, phase 2 study of docetaxel and 
cisplatin/carboplatin with or without erlotinib in patients with metastatic or 
recurrent SCCHN. Patients will be randomized (1:1) to: 
Arm A: chemotherapy with concurrent erlotinib followed by maintenance 
erlotinib 
Arm B: chemotherapy with concurrent placebo followed by maintenance 
placebo 
All patients randomized will be followed until disease progression or  
death or until sufficient efficacy data have been collected to evaluate PFS 
and OS. 
Number of Patients 
Planned: 
120 patients (1:1 randomization) 
Target Population: 
Patients with metastatic or recurrent SCCHN of the oral cavity, 
oropharynx, hypopharynx, or larynx, whose definitive treatment was 
completed ≥ 6 months prior to randomization, and for whom no 
chemotherapy has been administered for recurrent / metastatic disease. 
Duration of Treatment: 
All patients will receive up to 6 cycles of chemotherapy with concurrent 
erlotinib (arm A) or placebo (arm B). Patients who complete up to 6  
cycles of chemotherapy with a response (CR or PR) or stable disease will 
continue on erlotinib (arm A) or placebo (arm B) in a maintenance phase 
until disease progression. 
Diagnosis and Main 
Inclusion criteria: 


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Eligibility Criteria: 
1.   Histologically confirmed metastatic or recurrent SCCHN of the oral 
cavity, oropharynx, hypopharynx or larynx. Metastatic or recurrent 
lesions of the nasopharynx and sinus are excluded. 
2. Radiologically measurable disease, defined as at least one lesion  
that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 20 mm with conventional techniques or 
as ≥ 10 mm with spiral CT scan. Measurable lymph nodes are 
required to be ≥ 15 mm in size (short axis diameter). 
3. Age ≥ 18 years. 
4. ECOG PS ≤ 2. 
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. Total bilirubin ≤ ULN (excluding Gilbert’s disease); 
d. ALT (SGPT) ≤ 1.5 x 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. 
7. Written informed consent to participate in the study according to the 
investigational review board (IRB) or independent ethics committee 
(IEC). 
 
Exclusion criteria: 
 
1. Histology other than squamous cell carcinoma. 
2. Primary sites other than oral cavity, oropharynx, hypopharynx, and 
larynx. 
3. Prior palliative chemotherapy for metastatic or recurrent disease. 
4. Prior biological therapy for metastatic or recurrent disease within 3 
weeks prior to randomization. 
5. Patients with known, untreated brain metastases. Patients with 
treated (irradiated or resected) brain metastases are eligible if 
treatment was completed more than 28 days prior to study entry and 
if clinical neurologic function is stable. 
6. Pre-existing peripheral neuropathy ≥ grade 2. 
7. 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. 
8. Other active malignancies requiring chemotherapy treatment within 2 
years prior to randomization, except for adequately treated basal cell 
or squamous cell skin cancer or in situ cervical or breast cancer or 
superficial, resected melanoma. 
9. Serious underlying medical condition which would impair the ability of 
  
the patient to receive protocol treatment, in the opinion of the treating   


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physician. 
10. 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. 
11. Any concurrent anticancer therapy, excluding hormonal therapy for 
prostate or breast cancer. 
12. Dementia or significantly altered mental status that would prohibit the 
understanding and giving of informed consent. 
13. 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, following chemotherapy (maintenance phase), and at the 
end of treatment (approximately 30 days after the last dose of the study 
drug). 
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 (optional) studies will be 
obtained, as well as a pregnancy test (when appropriate), and baseline 
imaging studies. Historical tissue or a new biopsy of the tumor will be 
obtained for biomarker analysis (optional). 
Eligible patients will be stratified according to recurrence-free interval (de 
novo metastatic disease / recurrence ≥ 6 months after definitive therapy 
vs. recurrence < 6 months after definitive therapy), current smoking 
status and prior EGFR inhibitor therapy, and will be randomized (1:1) 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, 
current smoking status and tobacco use, and concomitant medications 
use. Blood-work for hematology, biochemistry, pregnancy test (when 
appropriate), and blood-based biomarker studies (optional), and erlotinib PK 
(optional) 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) will be obtained prior to cycles 3 and 5. Patients will receive up to 6 
cycles of chemotherapy with concurrent daily erlotinib (arm A) or placebo 
(arm B). 
Following chemotherapy, for patients who exhibit a complete or partial 
response or stable disease, maintenance erlotinib (arm A) or placebo 
(arm B) will be continued until disease progression. During this phase, 
physical exam, hematology, biochemistry studies, and pregnancy test 
(when appropriate) will be performed every 21 days (± 14 days). 
Assessment of symptoms and toxicities, and concomitant medications 
use will be done on an ongoing basis. Imaging studies, as well as a self- 
reported questionnaire for quality of life assessment (FACT-H&N), and 
blood-work for blood-based biomarkers (optional) and erlotinib PK 
(optional) will be obtained every 6 weeks (± 14 days). 


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An end of treatment evaluation is planned approximately 30 days after 
the last dose of the study drug, and consists of a physical exam, 
symptoms and toxicities assessment, use of concomitant medications, 
and blood-work for hematology, biochemistry, pregnancy test (when 
appropriate) , blood-based biomarkers (optional) and erlotinib PK (optional). 
Treatment Arms: 
Arm A = Chemotherapy with Concurrent Erlotinib followed by 
Single-Agent 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 6 cycles, 
plus erlotinib 150 mg PO daily continuously. A total of six cycles are 
planned, and a minimum of 4 cycles of chemotherapy are strongly 
encouraged. For patients with a complete or partial response or stable 
disease, erlotinib 150 mg PO daily will be continued beyond 
chemotherapy until disease progression. 
Arm B = Chemotherapy with Concurrent Placebo followed by Single- 
Agent 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 6 cycles, 
plus placebo 150 mg PO daily continuously. A total of six cycles are 
planned, and a minimum of 4 cycles of chemotherapy are strongly 
encouraged. For patients with a complete or partial response or stable 
disease, placebo 150 mg PO daily will be continued beyond 
chemotherapy until disease progression. 
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. 
Test Product, Dose, and 
Mode of Administration: 
Erlotinib (arm A) or placebo (arm B) 150 mg PO daily. 
Reference Therapy, 
Dose, and Mode of 
Administration: 
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 
Criteria for Evaluation: 
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: Progression free survival 
Secondary endpoints: OS, RR, duration of response, quality of life, 
occurrence of erlotinib-induced rash, pharmacokinetics, and biomarkers. 
Pharmacokinetics: 
All patients who complete the pharmacokinetic sampling (optional) will be 
included in the pharmacokinetic analysis. 
Statistical Methods: 
Assuming two-sided type I error rate of 0.10, accrual rate of 4 patients per 
month, and additional 4 months of follow-up after the last patient is 
randomized, this trial will have 80% of power to detect an improvement in 
the median PFS from 3.0 months in Arm B to 4.9 months in arm A  


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(hazard ratio=0.612), assuming 108 events (progression or death) at the 
time of analysis. With a total of 120 patients the accrual period will be 30 
months. 
Kaplan-Meier methods will be used to summarize OS and PFS. In the 
primary analysis, differences in PFS in Arm A versus Arm B will be tested 
using a stratified log-rank test with a two-sided alpha of 0.10. Analyses 
will be stratified by recurrence-free interval (de novo metastatic disease / 
recurrence ≥ 6 months after definitive therapy vs. recurrence < 6 months 
after definitive therapy), prior EGRF inhibitor treatment, cigarette smoking 
status (current vs former vs never). The purpose of the statistical testing 
is not to draw definitive conclusions regarding the superiority of adding 
erlotinib to chemotherapy. A statistically significant difference (p-value ≤ 
0.10) in favor of erlotinib will provide justification that a strategy of adding 
erlotinib to chemotherapy warrants further investigation. Hazard ratios for 
OS and PFS will be presented using point estimates and 95% confidence 
intervals. 
One interim analysis will be performed to allow for the early termination of 
the trial in light of evidence that one treatment arm is superior to the other 
treatment arm or there is no difference between the two treatment arms. 
The interim analysis will be performed when 54 out of the expected 108 
events have been observed. Using O’Brien-Fleming outer test 
boundaries, the two-sided Z-score test cut-offs for comparing to the 
absolute value of the test statistics at the interim and final analyses for 
rejecting the null hypothesis will be 2.538 and 1.662, respectively. The 
inner (futility) Z-score boundaries for stopping and accepting the null 
hypothesis are 0.246 and 1.662. 
Tumor response (CR+PR), disease control (CR+PR+SD), and rash rates 
will be estimated by treatment arm with 95% confidence intervals. A 
logistic regression model will be used to test for treatment differences 
with terms in the model for treatment, recurrence-free interval, and 
smoking status. 
 
Exploratory analyses will be conducted to correlate occurrence of rash 
and biomarker status with outcomes to treatment. 
 
Protocol Date: 
October 2, 2012 


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GLOSSARY OF ABBREVIATIONS 
 
 
ADR 
ALT 
AST 
adverse drug reaction 
alanine aminotransferase 
(SGPT) 
aspartate aminotransferase 
MTD 
Na 
NCI 
NOS 
maximum tolerated dose 
sodium 
National Cancer Institute 
not otherwise specified 
(SGOT) 
ORR 
objective response rate 
AUC 
area under the curve 
PD 
progressive disease 
BP 
blood pressure 
PE 
physical examination 
BSA 
body surface area 
PFS 
progression-free survival 
BUN 
blood urea nitrogen 
PR 
partial response 
°C 
degrees Celsius 
PS 
performance status 
CA 
Compentent Authority 
QA 
quality assurance 
CAVG 
CI 
average plasma concentration 
confidence interval 
QoL 
RECIST 
quality of life 
Response Evaluation Criteria in 
Cmax 
CRA 
maximum plasma concentration 
Clinical Research Associate 
SD 
Solid Tumors 
stable disease 
CR 
complete response 
SOC 
system organ class 
CRF 
case report form 
Tmax 
time to maximum concentration 
CTCAE 
Common Terminology Criteria 
TNM 
tumor, node, metastases 
for Adverse Events 
TTP 
time to progression 
CT scan 
computerized tomography scan 
ULN 
upper limit of normal 
DLT 
dose-limiting toxicity 
US 
United States 
DVT 
deep venous thrombosis 
WHO 
World Health Organization 
ECG 
electrocardiogram 
EGFR 
epidermal growth factor receptor 
ECOG 
Eastern Cooperative Oncology 
Group 
EORTC 
European Organization for the 
Research and Treatment of 
Cancer 
EOT 
end-of-treatment 
°F 
degrees Fahrenheit 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HQoL 
health-related quality of life 
HPLC 
high performance liquid 
chromatography 
HR 
hazard ratio 
IC50 
50% inhibitory concentration 
ICH 
International Conference on 
Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
application 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IV 
intravenous 
K 
potassium 
kg 
kilogram 
LD 
lethal dose 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
mL 
milliliter 
MRI 
magnetic resonance imaging 


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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 carcinoma (SCCHN). Worldwide, this represents the third 
most prevalent cancer. Two-thirds of patients present with locally or regionally 
advanced disease and therapeutic efforts have focused on local control with radiation 
therapy (RT), chemotherapy, or combined-modality approaches and organ preservation. 
Sixty-five percent of these patients will relapse.  Distant metastases are found in 10% of 
patients at diagnosis and develop in another 25% after initial treatment of the primary 
site. When these patients relapse, many have aggressive, platinum-resistant disease, 
illustrating the need for developing novel agents in this setting. 
 
Most SCCHN 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. OSI Pharmaceuticals, Inc., Genentech, Inc., and F. Hoffmann- 
La Roche Ltd are co-developing erlotinib globally. 
 
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 


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Although an overview of information pertaining to erlotinib is presented below, more 
comprehensive information is presented in the erlotinib Investigator’s Brochure. This 
document should be reviewed before study initiation. 
 
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 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 SCCHN. The overall objective response rate was 4.3%, 
whereas 38.3% of patients had stable disease (with a median duration of 16.1 weeks). 


. 
Page 13 
 
 
 
The median progression-free survival was 9.6 weeks and the median overall survival 
was 6.0 months.6 
 
Siu et al. evaluated the combination of cisplatin and erlotinib in a phase1 / 2 study of 51 
patients with recurrent / metastatic SCCHN. 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 a single-arm, phase 2 study of the combination of 
cisplatin, docetaxel and erlotinib in patients with recurrent / metastatic SCCHN. 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.8 
 
 
 
1.2.3 
Phase 3 Experience with Erlotinib 
 
Four randomized, placebo-controlled, phase 3 studies have been conducted with 
erlotinib. Three of these studies were conducted in patients with NSCLC and 1 in 
patients with pancreatic cancer. 
 
Phase 3 Studies with Chemotherapy in Patients with NSCLC 
 
Two phase 3 trials that combined daily erlotinib given concurrently with standard 
chemotherapy in previously untreated NSCLC patients (TALENT9 and TRIBUTE10) did 
not meet their respective study objectives of improving survival, time to disease 
progression, response rate or duration of response. 
 
Phase 3 Single-agent Study in Patients with NSCLC 


. 
Page 14 
 
 
 
A randomized, placebo-controlled study of single-agent erlotinib at 150 mg/day in 
second- and third-line NSCLC (BR.21) was conducted under the sponsorship of OSI in 
collaboration with the NCIC CTG3.  In this 731 patient trial, statistically significant and 
clinically relevant prolongation in overall survival was observed for erlotinib compared to 
placebo (6.7 vs 4.7 months; HR = 0.73; 95% CI:  0.60 – 0.87, P < 0.001), indicating that 
erlotinib reduced the risk of death by 27% compared with placebo. The actuarial 
12-month survival rates were 31.2% and 21.5% for the erlotinib and placebo arms, 
respectively.  Secondary endpoints of PFS and response rate were also significantly 
better for erlotinib. 
 
The planned primary QoL analysis and time to deterioration of patient reported 
symptoms showed statistically and clinically meaningful benefit for patients randomized 
to erlotinib.11 
 
As expected, the most common side effects were rash (75% vs 17% for placebo) and 
diarrhea (54% vs 18% for placebo), which were generally mild to moderate in severity 
and led to treatment discontinuations in only a small percentage of patients (5% for 
erlotinib vs 2% for placebo).3 
 
Phase 3 Study in Combination with Chemotherapy in Patients with Pancreatic Cancer 
 
A study in first-line pancreatic cancer (PA.3) was conducted under the sponsorship of 
OSI in collaboration with the NCIC CTG.4  A total of 569 patients were treated with 
either erlotinib or placebo in combination with the approved dose-schedule of 
gemcitabine in pancreatic cancer (weekly × 7, 1 week off, and then weekly × 3 q 4 
weeks).  A statistically significant 27% improvement in overall survival (HR = 0.79) was 
seen in patients receiving erlotinib in combination with gemcitabine as compared to 
patients receiving gemcitabine plus placebo. Median and 1-year survival in the erlotinib 
plus gemcitabine arm were 6.4 months and 24%, respectively, as compared with 5.9 
months and 17% in the gemcitabine plus placebo arm. A statistically significant 
improvement in PFS (HR = 0.77) was also demonstrated for the erlotinib arm. 
 
1.3 
Rationale for the Current Study 
 
For patients with recurrent or metastatic SCCHN treated with conventional 
chemotherapy, response rates are in the range of 30%, median progression-free 
survival (PFS) is only 2 months and median overall survival (OS) is only 6 months. For 
example, the Liverpool Head and Neck Oncology Group randomized 200 patients to 
receive cisplatin alone or methotrexate alone or cisplatin plus methotrexate or cisplatin 


. 
Page 15 
 
 
 
plus 5-fluorouracil. There was no significant difference in the response rates. A survival 
benefit was evident for the cisplatin alone arm compared with metotrexate alone.12 
Forastiere et al. randomized 277 patients to cisplatin plus 5-fluorouracil, carboplatin plus 
5-fluorouracil or standard dosed methotrexate. The response rates were 32% for 
cisplatin/5-fluorouracil, 21% for carboplatin/5-fluorouracil, and 10% for methotrexate, 
respectively. Median survival times were similar for all three treatment groups (5.0 – 6.6 
months). The duration of response was 4.2 months for cisplatin/5-fluorouracil, 5.1 
months for carboplatin/5-fluorouracil and 4.1 months for methotrexate. This study 
supports the use of cisplatin or carboplatin-based regimens for management of HNSCC, 
with no clear differences in outcomes.13 Jacobs et al. compared the cisplatin/5- 
fluorouracil regimen with either cisplatin alone or 5-fluorouracil alone in a randomized 
phase 3 trial which included 249 patients. The overall response rate to cisplatin/5- 
fluorouracil (32%) was superior to that of cisplatin (17%) or 5-fluorouracil (13%). 
However, there was neither a difference in median time to progression (1.7-2.4 months) 
nor survival (5.0-6.1 months) among the three groups.14 
 
Combinations of a platinum salt with a taxane (docetaxel or paclitaxel), have shown the 
most promising results in this setting, although improved survival has not been 
demonstrated with any of these regimes. The paclitaxel plus cisplatin combination was 
directly compared to the cisplatin/5-fluorouracil regimen in the Intergroup trial E1395 
conducted by the Eastern Cooperative Oncology Group. The objective response rate 
was 27% with the taxane-based regimen and 26% with 5-fluorouracil-based regimen. 
Median overall survival was 8.7 months in the cisplatin/5-fluorouracil group and 
8.1 month in the cisplatin/paclitaxel group.15 Sixty-eight patients were treated with 
docetaxel 65 mg/m2 and carboplatin AUC 6 every 21 days in a SWOG phase 2 study.16 
The overall response rate was 25%. The median PFS was 3.8 months and the median 
overall survival 7.4 months. A phase 2 study of cisplatin and docetaxel demonstrated a 
response rate (RR) of 40%, median time to progression of 4 months and median OS of 
9.6 months.17 
 
In recent years, EGFR inhibitors have been developed for treatment of SCCHN, both in 
the setting of locally advanced disease (either as part of an induction chemotherapy 
program18,19 or delivered concomitant with radiation therapy20), as well as in the setting 
of recurrent / metastatic disease (as single agent1 or combined with cytotoxic 
chemotherapy2). 
 
Cetuximab, a monoclonal antibody directed against the EGFR, has recently been 
approved by the FDA as first line therapy in combination with concomitant RT for the 


. 
Page 16 
 
 
treatment of locally or regionally advanced SCCHN and as a single agent for second 
line therapy for the treatment of recurrent or metastatic SCCHN after failure of platinum- 
based therapy. This represented the first new drug approved in this disease in nearly 
50 years. The concomitant RT study was a randomized, controlled study in 424 
patients and showed improved locoregional control (24.4 vs. 14.9 mo., p=0.005) and 
improved survival (49.0 vs. 29.3 mo., p=0.03) for the cetuximab arm.20 
 
The cetuximab monotherapy study was a single arm Phase 2 study in 103 patients who 
demonstrated documented progression within 30 days after 2-6 cycles of a platinum- 
based chemotherapy regimen. The RR was 13% with a median duration of response of 
5.8 months.1  Another single arm Phase 2 study of cetuximab and platinum 
chemotherapy in 96 patients with platinum-refractory recurrent or metastatic SCCHN 
showed a RR of 10%; median PFS was 85 days and OS was 183 days.21  A Phase 3 
ECOG study of cisplatin plus cetuximab or placebo in 117 patients with metastatic or 
recurrent SCCHN failed to meet the primary endpoint of improvement of PFS (4.2 vs. 
2.7 mo, respectively, hazard ratio 0.78); however, patients treated with cetuximab who 
developed skin rash showed superior survival (p=0.013). Objective RR was significantly 
better for the cetuximab arm (26% vs. 10%, p=0.03).22 A phase 3 study of platinum/5- 
fluorouracil +/- cetuximab involving 442 patients demonstrated a statistically significant 
improvement in response rate (16% versus 20%), time to treatment failure (4.8 versus 
3.0 months) and OS (10.1 versus 7.4 months) for the cetuximab-containing arm.2 
Nonetheless, it is still unknown whether an EGFR inhibitor combined to a 
platinum/taxane based regimen will be more effective than platinum/taxane alone. 
 
Gefitinib, a small molecule EGFR tyrosine kinase inhibitor, has also been studied in the 
setting of recurrent / metastatic disease. Response rates with single agent therapy 
have been 7.6% with 500 mg/day (n = 47) and 2.7% with 250 mg/day in a phase 3 
study, with median OS of 5.6-6.0 months.23 Nonetheless, when gefitinib was combined 
with cisplatin and docetaxel in a pilot phase 2 study, impressive response rates (50%) 
and median PFS (5.1 months) were observed.24 
 
Taken together, these results demonstrate that EGFR is a valid target in the treatment 
of SCCHN, and that combining chemotherapy with an EGFR inhibitor in the setting of 
recurrent / metastatic disease might lead to improved outcomes. Indeed, the single-arm, 
phase 2 study of cisplatin, docetaxel and erlotinib previously reported by Kim et al.8  met 
its primary endpoint: the median progression-free survival of 6 months compared 
favorably with historical controls from a previous phase 2 study performed at the same 
institution using the cisplatin and docetaxel regimen in a similar patient population 


Page 17 
. 
 
 
 
 
(median PFS of 4 months).17 Moreover the cisplatin, docetaxel and erlotinib regimen 
was tolerable. 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 
 
Hence, the present study is designed to confirm, in the setting of randomized phase 2 
clinical trial, the data previously obtained by Kim et al.8 The results of the present study 
might justify, in the future, further investigation of the cisplatin, carboplatin, docetaxel, 
erlotinib regimen in the scenario of a phase 3 study. 


Page 18 
. 
 
 
 
 
 
2 
STUDY OBJECTIVES 
 
The primary objective of this study is to: 
 
• Assess the efficacy of adding erlotinib to chemotherapy to improve PFS in patients 
with metastatic or recurrent SCCHN. 
 
The secondary objectives of this study are to: 
 
• Evaluate overall survival, response rate, disease control rate, and duration of 
response by treatment with or without erlotinib; 
• Evaluate quality of life (patient reported outcomes) by treatment with or without 
erlotinib; 
• Evaluate the safety profile of erlotinib in combination with chemotherapy; 
• Correlate the occurrence of erlotinib-induced rash with outcomes; 
• To evaluate the steady-state pharmacokinetics of erlotinib; and 
• To explore the prognostic and predictive value of EGFR-related biomarkers and 
other biomarkers, including blood and tissue proteomic and blood and tissue 
genomic markers, that may be associated with clinical outcomes 


Page 19 
. 
 
 
 
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 metastatic or recurrent 
SCCHN. Patients will be randomized (1:1) to: 
 
Arm A — chemotherapy with concurrent erlotinib followed by maintenance erlotinib; 
Arm B — chemotherapy with concurrent placebo followed by maintenance placebo. 
All patients randomized will be followed until death or until sufficient efficacy data have 
been collected to evaluate PFS and OS. A schematic diagram of the study design is 
shown in Figure 3–1. 


Page 20 
. 
 
 
Stratify by: 
R 
A 
Recurrence-free interval 
N 
(de novo metastatic 
D 
disease / recurrence ≥ 6 
O 
months after definitive 
M 
therapy vs. recurrence < 6 
I 
months after definitive 
Z 
therapy) 
E 
Smoking Status 
1:1 
(current vs former vs never) 
Prior EGFR Inhibitor (yes 
vs no) 
 
 
Figure 3–1: 
Study Schematic 
 
ARM A 
Docetaxel + Cisplatin 
(or carboplatin) + 
erlotinib 
Daily 
erlotinib 
 
 
 
 
 
 
 
 
ARM B 
Docetaxel + Cisplatin 
(or carboplatin) + 
placebo 
Daily 
placebo 
 
 
 
 
 
Patients will be stratified by the following factors and randomized to Arm A or Arm B 
using a minimization technique: 
 
• Recurrence-free interval (de novo metastatic disease / recurrence ≥ 6 months after 
definitive therapy vs. recurrence < 6 months after definitive therapy); 
 
• Cigarette smoking status (current vs former vs never). 
 
Definitions of cigarette smoking status: 
 
– Current cigarette smoker:  has smoked > 100 cigarettes in entire lifetime 
and is either currently smoking or quit smoking < 1 week prior to 
randomization 
 
– Former cigarette smoker:  has smoked > 100 cigarettes in entire lifetime 
and quit smoking ≥ 1 week prior to randomization 
 
– Never smoker: has smoked ≤ 100 cigarettes in entire lifetime and stopped 
or never smoked cigarettes 
 
• Prior EGFR Inhibitor Therapy (yes vs no) 
 
3.1 
Treatment Plan and Regimen 
 
3.1.1 
Treatment Plan 
 
After assessment of eligibility and stratification factors, patients will be randomized to: 
 


Page 21 
. 
 
 
Arm A:  Chemotherapy (up to 6 cycles) with erlotinib followed by daily erlotinib; or 


Page 22 
. 
 
 
 
 
Arm B:  Chemotherapy (up to 6 cycles) with placebo followed by daily placebo 
Use of cisplatin or carboplatin will be per the investigator’s choice. 
In both arms, six cycles of chemotherapy are planned, and at least 4 cycles of 
chemotherapy are strongly recommended. 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. 
 
In Arm A, erlotinib will be administered daily throughout the study.  In Arm B, placebo 
will be administered daily throughout the study.  After discontinuation of chemotherapy, 
patients with a response (CR or PR) or stable disease will continue to receive daily 
erlotinib (in Arm A) or daily placebo (in Arm B), at the most recent dose, until objective 
disease progression or death or intolerable toxicity.  A schedule of study drug 
administration is shown in Table 3–1. Treatment must 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: 
 
 
 
For males: 
 
Cr Cl (mL/min) = [(140-age) x (weight in kg)] ÷ [72 x serum creatinine in mg/dL] 
 
 
 
For females: 


Page 23 
. 
 
 
 
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. 
 
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) = 


Page 24 
. 
 
 
 
 
6 x 150 mL/min = 900 mgTable 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 
Continuously b 
Erlotinib 
150 mg/day 
PO 
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 
Continuously b 
Placebo 
150 mg/day 
PO 
a For a maximum of 6 cycles. 
. 
b If the patient completes 6 cycles of chemotherapy with a response (CR or PR) or stable disease 
daily erlotinib (in Arm A) or daily placebo (in Arm B), at the most recent dose, will be continued 
until objective disease progression or death or intolerable toxicity. 
If the patient completes < 6 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 objective disease progression 
or death or intolerable toxicity. 
 
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. Delaying or discontinuing one chemotherapy 
agent (docetaxel or cisplatin/carboplatin) will result in delaying or discontinuing of the 
other chemotherapy agent (cisplatin/carboplatin or docetaxel). Docetaxel or 
cisplatin/carboplatin 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. 


Page 25 
. 
 
 
 
 
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 


Page 26 
. 
 
 
 
 
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. 


Page 27 
. 
 
 
 
 
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. 
 
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. 


Page 28 
. 
 
 
 
 
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], 


Page 29 
. 
 
 
 
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. 


Page 30 
. 
 
 
 
 
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 require docetaxel discontinuation (for 
any reason) will also discontinue cisplatin / carbopatin treatment. Patients who require 
cisplatin / carboplatin discontinuation (for any reason) will also discontinue docetaxel 
treatment. Patients who have discontinued chemotherapy will be allowed to continue on 
daily, single-agent erlotinib or placebo as described in Section 3.1.1. 


Page 31 
. 
 
 
 
 
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. 


Page 32 
. 
 
 
 
 
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. 


Page 33 
. 
 
 
 
 
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 histologically confirmed metastatic or recurrent SCCHN of the oral cavity, 
oropharynx, hypopharynx or larynx who have an ECOG performance status of 0-2, 
measurable disease and no prior chemotherapy for their metastatic or recurrent disease 
will be enrolled. 
 
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. Histologically confirmed metastatic or recurrent SCCHN of the oral cavity, 
oropharynx, hypopharynx or larynx. Metastatic or recurrent lesions of the 
nasopharynx and sinus are excluded. 
2. Radiologically measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan. 
Measurable lymph nodes are required to be ≥ 15 mm in size (short axis diameter). 
3. Age ≥ 18 years. 
4. ECOG PS ≤ 2 (Appendix B) 
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. Total bilirubin ≤ ULN (excluding Gilbert’s disease); 
d. ALT (SGPT) ≤ 1.5 x 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. 
7. Written informed consent to participate in the study according to the investigational 
review board (IRB) or independent ethics committee (IEC). 


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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, oropharynx, hypopharynx, and larynx. 
3. Prior palliative chemotherapy for metastatic or recurrent disease. 
4. Prior biological therapy for metastatic or recurrent disease within 3 weeks prior to 
randomization. 
5. Patients with known, untreated brain metastases. Patients with treated (irradiated or 
resected) brain metastases are eligible if treatment was completed more than 28 
days prior to study entry and if clinical neurologic function is stable. 
6. Pre-existing peripheral neuropathy ≥ grade 2. 
7. 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. 
8. Other active malignancies requiring chemotherapy treatment within 2 years prior to 
randomization, except for adequately treated basal cell or squamous cell skin cancer 
or in situ cervical or breast cancer or superficial, resected melanoma. 
9. Serious underlying medical condition which would impair the ability of the patient to 
receive protocol treatment, in the opinion of the treating physician. 
10. 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. 
11. Any concurrent anticancer therapy, excluding hormonal therapy for prostate or 
breast cancer. 
12. Dementia or significantly altered mental status that would prohibit the understanding 
and giving of informed consent. 
13. 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 
 
OSI 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 
 
 
OSI requires that a drug accountability log for erlotinib (Arm A) or placebo (Arm B) 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, 
the unused, used and expired study drug will be destroyed at MDACC per Institutional SOPs 
and OSI will be provided with documentation when this has occurred. 


Page 39 
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5.5 
Treatment Compliance 
 
Compliance of erlotinib (Arm A) or placebo (Arm B) will be assessed by counting tablets 
at the scheduled patient 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 chart. 
 
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. 
 
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.25  Patients who fail to respond to these measures 


Page 40 
. 
 
 
 
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 
methylprednisolon
e (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. 
 
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 


Page 41 
. 
 
 
 
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 
Radiotherapy and Surgery 
 
No radiotherapy is allowed during treatment. For the rare patient who experiences 
response to the investigational treatment and is able to undergo salvage and/or 
consolidation surgery and/or radiotherapy, treatment with erlotinib (Arm A) or placebo 
(Arm B) single agent may be resumed after surgery and/or radiotherapy (even if 
treatment interruption has been longer than 21 days) and continued until disease 
progression, after approval by the principal investigator of the trial. 
 
5.6.2.3 
Palliative Concomitant Medication 
 
Patients may receive palliative concomitant medication while on study. 
 
5.6.2.4 
Other Investigational Drug Therapies 
 
Patients should not receive any other investigational drugs with potential anti-neoplastic 
activity until disease progression has been documented. 


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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 C). 
 
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. 


Page 43 
. 
 
 
 
 
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 
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 
 
Unblinding of single cases by the investigator will only be performed if relevant for the 
safety of the participant. In emergency situations, the investigator would contact the 
study statistician and pharmacy to obtain immediate blinding information for the 
participant. The information will be forwarded to the investigator to enable the 
participant to be treated. In non-emergency situations, the same procedures would 


Page 44 
. 
 
 
 
apply, however the study statistician will discuss and evaluate the request, then, would 
be responsible for making the decision of whether or not to unblind. 


Page 45 
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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 presented in Appendix A and 
detailed in the text that follows. 
 
6.1 
Patient Enrollment and Treatment Assignment 
 
Before recruitment of patients into the study, written IRB/IEC 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 must start treatment within 14 days of randomization. 
 
Investigators will be notified when the target enrollment in each treatment arm has been 
reached. 
 
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 
• 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 
• 
Chest X-ray and 
• 
CT or MRI scans of all disease sites (excluding 
bones) 
• 
Additional imaging studies as clinically indicated 
Within 30 days prior to 
treatment initiation 
Tumor Tissue 
Collection for 
Biomarkers 
(optional) 
• 
Either historical or new biopsy of primary lesion 
and/or lymph node and/or metastatic site for 
biomarker analysis 
Prior to treatment 
initiation 
Blood-based 
biomarkers 
(optional) 
• 
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. 


Page 48 
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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 2-6 
Current 
Smoking 
Status and 
Tobacco Use1 
• 
Assessment of patient’s current smoking 
status and tobacco use 
Within 7 days prior to cycles 2-6 
Hematology 
• 
CBC with hemoglobin, platelets, and WBC 
with differential 
Within 7 days prior to cycles 2-6 
Biochemistry1 
• Albumin 
• 
Alkaline 
phosphatase 
• Total bilirubin 
• BUN 
• Creatinine 
• Glucose 
• LDH 
• Potassium 
• SGOT (AST) 
• SGPT (ALT) 
• Sodium 
• Magnesium 
Within 7 days prior to cycles 2-6 
Pregnancy 
Test 
• 
Urine or serum (for women of childbearing 
potential only) 
If/when clinically indicated 
Radiology 1 
• 
Chest X-ray and 
• 
CT or MRI scans of all disease sites 
(excluding bones). 
• 
Additional imaging studies as clinically 
indicated 
Within 7 days prior to cycles 3 and 5 
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 
Within 7 days prior to cycles 3 and 5 
Blood-based 
biomarkers1 
(optional) 
• Blood sample 
Within 7 days prior to cycles 2-6 
Erlotinib PK1 
(optional) 
• 
Blood sample 
Within 7 days prior to cycles 2-6 
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 Following Chemotherapy 
 
After completing chemotherapy, patients will be evaluated every 21 days (± 14 days) 
according to the assessments outlined in Table 6-3 until objective disease progression 
or death. 


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Table 6–3: 
Assessments Following Chemotherapy 
 
Investigations 
Timing 
Physical Exam 
Including: 
• 
Vital Signs 
Every 21 days (± 14 days) 
Current 
Smoking 
Status and 
Tobacco use 
• 
Assessment of patient’s current 
smoking status and tobacco use 
Every 21 days (± 14 days) 
Hematology 
• 
CBC with hemoglobin, platelets, and 
WBC with differential 
Every 21 days (± 14 days) 
Biochemistry 
• Total bilirubin, creatinine and SGPT 
(ALT), sodium, magnesium 
Every 21 days (± 14 days) 
Blood-based 
biomarkers 
(optional) 
• Blood sample 
Every 6 weeks (± 14 days) until disease 
progression or death 
Erlotinib PK 
(optional) 
• 
Blood sample 
Every 6 weeks (± 14 days) until disease 
progression or death 
Pregnancy 
Test 
• 
Urine or serum (for women of 
childbearing potential only) 
If/when clinically indicated 
Radiology 
• 
Chest X-ray and 
• 
CT or MRI scans of all disease sites 
(excluding bones). 
• 
Additional imaging studies as 
clinically indicated 
Every 6 weeks (± 14 days) until disease 
progression or death 
Symptoms & 
Toxicities 
• 
Evaluation and documentation of 
symptoms and toxicities using the 
NCI CTCAE v4.0 
On an ongoing basis until the final study 
visit 
Concomitant 
Medications 
• 
Documentation of concomitant 
medications 
On an ongoing basis until the final study 
visit 
Quality of Life • 
FACT-H&N 
Every 6 weeks (± 14 days) until disease 
progression or death 
Erlotinib 
Treatment 
Compliance 
• 
Count tablets and record findings 
At each clinic visit 


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6.3.3 
End of Treatment Assessments 
 
For all patients, the End of Treatment Visit will occur approximately 30 days after the 
last dose of study drug (i.e., 30 days after the last dose of erlotinib maintenance 
treatment). At this visit, patients will be evaluated according to the assessments outlined 
in Table 6–4. 


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Table 6–4: 
End of Treatment Assessments 
 
Investigations 
Timing 
Physical 
Exam 
Including: 
• 
Vital Signs 
Approximately 30 days after the last 
dose of study drug 
Hematology 
• 
CBC with hemoglobin, platelets, 
and WBC with differential 
Approximately 30 days after the last 
dose of study drug 
Biochemistry • Total bilirubin, creatinine and SGPT 
(ALT) 
Approximately 30 days after the last 
dose of study drug 
Blood-based 
biomarkers 
(optional) 
• 
Blood sample 
Approximately 30 days after the last 
dose of study drug 
• 
Erlotinib PK 
(optional) 
• 
Blood sample 
Approximately 30 days after the 
last dose of study drug 
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 
Approximately 30 days after the last 
dose of study drug 
Concomitant 
Medications 
• 
Documentation of concomitant 
medications 
Approximately 30 days after the last 
dose of study drug 
 
 
 
 
6.4 
Descriptions of Study Assessments 
 
6.4.1 
Smoking History 
 
The smoking history of all patients will be collected within 14 days prior to 
randomization. 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 


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• Never smoker: has smoked ≤ 100 cigarettes in entire lifetime and stopped or never 
smoked cigarettes 
 
For all patients, smoking status will be re-evaluated at each clinic visit. 
 
Tobacco use other than cigarette smoking will also be assessed at baseline and 
according to Tables 6-1 to 6-3. 
 
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 6-3. 
 
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.  All adverse events that occur from the 
time of study drug administration until the completion of the study will be recorded on 
the patient’s chart as an adverse event, regardless of the potential relationship to the 
study drug. The date of onset, severity, and investigator’s opinion of potential 
relationship of the event to protocol therapy will be recorded. 
 
6.4.5 
Radiology Assessments 
 
Chest X-rays and CT or MRI scans of all disease sites (excluding bone) will be obtained 
according to Tables 6-1 to 6-3. 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 committee26 (see Appendix D), 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 (i.e., 
scans performed immediately following bolus contrast administration should be made 
with a standard volume of contrast, the identical contrast agent). 


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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 6-3. 
 
6.4.7 
Tumor Tissue Samples 
 
Optional baseline tumor tissue samples from either the primary lesion and/or lymph 
node and/or metastatic site (either historical or new biopsy) will be collected for 
exploratory analyses of biomarkers.  For newly collected tissues, samples will be 
obtained by an outpatient core biopsy, or a punch-biopsy performed under local 
anesthesia with a minimum of 4-5 mm diameter (which allows for the preparation of at 
least 30 slides). These specimens should be fixed in 10% formalin, preferably 
immediately and not more than 1 (one) hour after excision. Fixed biopsy samples will be 
processed for paraffin-embedding according to the Institutional Standard Operating 
Procedures. The paraffin blocks and slides should be labeled with the protocol number 
and the patient’s unique study identification number and stored at room temperature. A 
portion of the specimen obtained may also be embedded in optimal cutting temperature 
compound immediately after received and not more than 1 (one) hour after excision, 
frozen, and stored at -80 oC for future biomarker analysis. All samples stored at -80 oC 
should be placed in appropriate containers, labeled with the protocol number and the 
patient’s unique study identification number. 
 
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), micro-RNA and 
messenger-RNA expression levels (using high-throughput microarray chips), high- 
throughput genomic 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 
 
Optional blood will be collected, at scheduled intervals according to Tables 6-1 to 6-3, 
using three (3) EDTA (10 mL) 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 


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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. For serum samples, blood will be centrifuged in a standard clinical centrifuge 
at 2500 RPM at 4 oC for 10 minutes. Aliquots of 2.0-2.5 mL should then be transferred 
into cryovials, labeled with the protocol number and the patient’s unique study 
identification number. Cryovials will be stored at -80 oC. 
 
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 (Bio-Plex 
27-Plex & 23-Plex Kits [Bio-Rad, Hercules, CA] and Human CVD Biomarker Panel 1 
[Linco Research, Inc., St, Charles, MO]), VEGF, solubleVEGFR-1, soluble VEGFR-2, 
osteopontin, free and total IGF-1 and IGF-2, IGFBP-3, insulin, peptide C, free fatty 
acids, triglycerides, fructosamine, high-throughput proteomic analysis, high-throughput 
genomic analysis 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 samples may 
be analyzed in the future for biomarkers not described in this protocol. 
 
6.4.10 
End of Treatment Assessments 
 
If a patient has not progressed or died by the End of Treatment visit (30 days after the 
last dose of study drug), quality of life and radiology assessments may continue to be 
collected. All new serious adverse events occurring more than 30 days after last study 
drug administration (i.e., after the End of Treatment visit) and considered at least 
possibly drug-related must be reported to OSI.  See Section 7.7 for serious adverse 
event reporting requirements. 
 
6.4.11 
Long-Term Follow-Up 
 
After the End of Treatment visit, information may be collected on post-study additional 
therapies, disease response / progression, and long-term survival, as well as any new 
or ongoing drug-related adverse events. Patients (or their family members or 
designees) may be contacted by telephone or in writing or by electronic mail or during 


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clinic visits after treatment discontinuation for collection of long-term follow-up data. 
Long-term follow-up clinical information may also be obtained through chart reviews. 
 
 
 
 
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 
6.4.11). 


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6.6 
Criteria for Study Discontinuation 
 
Study medication should be discontinued in the following instances: 
 
• Relapse or disease progression (patients with evidence of clinical or symptomatic 
benefit despite radiological progression may continue treatment with erlotinib upon 
agreement between OSI and the investigator); 
• 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 up to 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). 


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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 6. 
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). 
 
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 on the appropriate CRF page. 
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); 
• 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); 


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• 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 
Serious Adverse Event Reporting Requirements 
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 
 
 
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 subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood  dycrasias or convulsions that do not 
result in hospitalization, or 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). 


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• 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. 
 
 
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. 
 
 
 
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”; 
• 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 


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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 
 
Any adverse event (i.e., a new event or an exacerbation of a pre-existing condition) that 
occurs after the patient is registered/randomized and up to 30 days after the last study 
drug administration must be recorded as an adverse event on the appropriate page(s) 
of the CRF.  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. 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. 


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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. 
 
All 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): 
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. 


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7.7 
Serious Adverse Event Reporting Requirements 
 
Serious Adverse Event Reporting to OSI Pharmaceuticals 
 
All serious adverse events related to erlotinib must be reported, by FAX (303-546- 
7706), to OSI 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 OSI 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. 
 
Based on clinical results, dermatosis or rash, diarrhea, fatigue, nausea, vomiting, 
stomatitis, headache, cough, dyspnea, and infection were the most frequently observed 


Page 64 
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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.  Men and 
premenopausal women of child-bearing potential must use one of the following forms of 
birth control Birth Control Specifications: You should use birth control, such as barrier 
methods, condom or diaphragm with spermicide, or abstinence, while participating in 
the study and for 30 days following the last dose of the study drug. 
Females:  If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant will result in your removal from this study. 
 
 
Males: Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy.Pregnancy and breast feeding are exclusion criteria.  If a female patient or 


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partner of a male patient becomes pregnant while receiving study drug or within 120 
days after the last dose of study drug, a Pregnancy Form must be completed and 
submitted to the sponsor in a timely manner. The pregnancy must be followed during 
the entire course, with perinatal and neonatal outcomes recorded even if completely 
normal and without an adverse event. 


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8 
STATISTICAL METHODS 
 
8.1 
Objectives and Design 
 
8.2 
Sample Size 
A sample size of 120 patients (randomized 1:1 to Arm A and Arm B) will be needed to 
detect a 1.9 month improvement in the median PFS (from 3.0 to 4.9 months) in the 
erlotinib-containing arm over the placebo arm. The corresponding hazard ratio between 
arm A and arm B is 0.612 based on the assumption that the time to event follows an 
exponential distribution.  Assuming two-sided type I error rate of 0.10, accrual rate of 4 
patients per month, and additional 4 months of follow-up after the last patient is 
randomized, a trial with 60 patients each arm will have 80% of power to detect a 1.9 
month improvement in the median PFS, assuming 108 events (progression or death) at 
the time of analysis. With a total of 120 patients the accrual period will be 30 months. 
 
 
 
 
8.2.1 
Randomization 
 
An adaptive randomization method by Pocock and Simon27 will be used with a 
minimization probability parameter of 0.90. The randomization process will be 
controlled to ensure a balanced stratification by treatment arm for the following factors: 
• Cigarette smoking status (current vs former vs never); 
• Recurrence-free interval (de novo metastatic disease / recurrence ≥ 6 months after 
definitive therapy vs. recurrence < 6 months after definitive therapy); and 
• Prior EGFR inhibitors (yes vs no) 
Patients will be randomized to either Chemotherapy/Placebo or Chemotherapy/Erlotinib 
using the Clinical Trial Conduct website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct) which is 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 pharmacy personnel at MDACC. 
 
Training on the use of the Clinical Trial Conduct website to randomize patients on the 
study will be provided by Lei Feng from the Department of Biostatistics for the pharmacy 
personnel at MDACC. This is a double-blinded trial with stratified randomization. When 
a patient is enrolled on the study, the research nurse of the study will email the MDACC 
pharmacy with patient's information on medical record number and stratification factors. 
Through the web interface, the MDACC pharmacy can enter the patient medical record 
number and the information on stratification factors. After the randomization button is 
clicked, the result of the randomization will be displayed on the screen for the pharmacy 
to view. For all other clinical personnel on the study, the information on treatment will be 
blinded.  All data on randomization will be stored in a secure SQL server database. 


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8.3 
Study Endpoints 
 
8.3.1 
Safety 
 
All patients who receive at least 1 treatment study 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 PFS. The secondary efficacy endpoints are OS, RR, 
duration of response, quality of life, occurrence of erlotinib-induced rash, PK, and 
biomarkers. 
 
The primary analysis of efficacy is to compare PFS in patients who receive erlotinib plus 
chemotherapy to PFS in patients who receive placebo plus chemotherapy. 
 
8.3.2.1 
Definition of Response 
 
Response will be defined according to RECIST criteria as described in Appendix D. 
 
8.3.2.2 
Response Duration 
 
The duration of overall response will be measured from the time that the measurement 
criteria are met for complete or partial response (whichever status is recorded first) until 
the first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
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 Overall 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. 
 
Overall survival will be measured from the start of treatment until death. 


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8.3.3 
Quality of Life 
 
Quality of life data will be obtained at scheduled intervals according to Tables 7-1 to 7- 
3. Quality of life will be analyzed. 
 
8.4 
Interim Analysis 
 
One interim analysis will be performed to allow for the early termination of the trial in 
light of evidence that one treatment arm is superior to the other treatment arm or there  
is no difference between the two treatment arms.  In order to provide an overall 
significance level of 0.10 for the study, the interim analysis will use a Lan-DeMets 
monitoring boundary with an O’Brien-Fleming stopping rule.28  The interim analysis will 
be performed when 54 out of the expected 108 events have been observed.  Using 
O’Brien-Fleming outer test boundaries, the two-sided Z-score test cut-offs for comparing 
to the absolute value of the test statistics at the interim and final analyses for rejecting 
the null hypothesis will be 2.538 and 1.662, respectively.  The inner (futility) Z-score 
boundaries for stopping and accepting the null hypothesis are 0.246 and 1.662.. 
 
8.5 
Planned Analysis 
 
Data will be summarized for arms A and B. Kaplan-Meier methods will be used to 
summarize OS and PFS. 
Analyses will be stratified by recurrence-free interval (de 
novo metastatic disease / recurrence ≥ 6 months after definitive therapy vs. recurrence 
< 6 months after definitive therapy), prior EGFR inhibitor treatment, and cigarette 
smoking status (current vs former vs never).  Hazard ratios for OS and PFS will be 
presented using point estimates and 95% confidence intervals. 
 
Tumor response (CR+PR) and disease control (CR+PR+SD) will be estimated by 
treatment arm with 95% confidence intervals.  A logistic regression model will be used 
to test for treatment differences with terms in the model for treatment, recurrence-free 
interval, and smoking status. 
 
A two-sided alpha (i.e., significance level) of 0.10 will be used to compare treatment 
arms, following the approach proposed by Korn et al.29 and Simon et al.30  The purpose 
of the statistical testing is not to draw definitive conclusions regarding the superiority of 
adding erlotinib to chemotherapy.  A statistically significant difference (p-value ≤ 0.10) in 
favor of erlotinib will provide justification that a strategy of adding erlotinib to 
chemotherapy warrants further investigation 
 
Exploratory analyses will be conducted to correlate occurrence of rash and biomarker 
status with outcomes to treatment. 


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8.5.1 
Safety 
 
All patients who receive at least 1 dose of erlotinib 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. 
 
8.5.1.1 
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. 
 
8.5.2 
Efficacy 
 
All randomized patients will be considered evaluable for all efficacy analyses. Efficacy 
will be analyzed according to the intent-to-treat principle. 
 
8.5.3 
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. 
 
8.5.4 
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 
STUDY CONDUCT 
 
9.1 
Adherence to the Protocol 
 
The investigator is responsible for ensuring the study is conducted in accordance with 
the procedures and evaluations described in this protocol. 
 
Changes to the protocol may be made only when a written protocol amendment 
provided by the sponsor has been signed by the investigator and approved by the IRB 
and applicable regulatory agencies in accordance with local requirements. 
 
9.2 
Recording and Collecting of Data 
 
9.2.1 
Case Report Forms 
 
Electronic case report forms (CRFs) will be used for this study, stored under M. D. 
Anderson’s Protocol Data Management Systems (PDMS) database. 
 
9.2.2 
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. 
 
 
 
9.2.3 
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 


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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. 
 
 
 
9.3 
Legal and Ethical Requirements 
 
9.3.1 
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. 
 
9.3.2 
Institutional Review Board/Independent Ethics Committee Approval 
 
The investigator must submit this protocol, the informed consent form(s) to the IRB/IEC. 
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/IEC 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/IEC in 
accordance with applicable regulations, institutional policy, and in agreement with 
policies established by the sponsor. 
 
9.3.3 
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/IEC- 


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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. 
 
Significant new safety information received by the investigator should be provided to 
current and future study subjects at the first available opportunity. 
 
9.3.4 
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. 
 
9.3.5 
Regulatory Approval 
 
The sponsor will determine the appropriate local, national, and/or regional regulatory 
approval(s) that need to be obtained in order to conduct this study. 


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10 
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