Conditions: Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase II trial studies how well erlotinib hydrochloride works before surgery in treating patients with stage III non-small cell lung cancer. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving erlotinib hydrochloride before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the rate of mediastinal nodal clearance and complete pathological response after neoadjuvant erlotinib (erlotinib hydrochloride) in patients with epidermal growth factor receptor (EGFR) mutated stage III non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To determine the progression free survival in patient population of EGFR mutated stage III NSCLC patients who are treated with neoadjuvant erlotinib therapy.

II. To determine the overall survival. III. To estimate the overall response rate from neoadjuvant erlotinib. IV. To estimate the surgical resection rate. V. To evaluate the safety of neoadjuvant erlotinib.

TERTIARY OBJECTIVES:

I. To determine several molecular and cellular biomarkers in the tumors, the skin and the serum that are predictive of the efficacy of neoadjuvant erlotinib.

OUTLINE:

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) for 2 months and then undergo thoracotomy.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then every 6 months for 5 years.

Arms:
arm 1: Patients receive erlotinib hydrochloride PO QD for 2 months and then undergo thoracotomy.

Interventions: intervention 1: Erlotinib Hydrochloride intervention 2: Therapeutic Conventional Surgery intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo thoracotomy intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
 
Version 1.7 Nov 5, 2014 
Page 1 
 
EValuation of Erlotinib as a Neoadjuvant 
Therapy in stage III NSCLC patients with 
EGFR mutations (EVENT trial) 
 
 
Principal Investigator 
Haiying Cheng M.D. 
Montefiore Medical Center/Albert Einstein College of Medicine 
Chanin Bldg Rm 626 
1300 Morris Park Avenue  
Bronx, NY 10461 
Phone : 718-405-8404/Fax: 718-405-8501 
Email : hcheng@montefiore.org  
 
Coordinating Center 
Montefiore Medical Center 
Department of Oncology, 2nd floor  
1695 Eastchester Road 
Bronx, NY 10461  
Phone: 718-405-8404/Fax: 718-405-8501 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 2 
 
 
Co-Investigators: 
 
Steven Keller, M.D.  
 
 
 
Bilal Piperdi, MD 
Chief, Cardiothoracic Surgery  
 
Montefiore Medical Center 
Montefiore Medical Center 
 
 
Department of Oncology, 2nd floor  
111 East 210th Street 
 
 
 
Email: bpiperdi@montefiore.org  
Bronx, NY 10467-2490  
 
 
 
Phone: 718-405-8238/Fax: 718-405-8292       
Email: skeller@montefiore.org                             
 
 
 
 
 
 
 
 
Roman Perez-Soler, M.D.  
 
 
Stuart Packer, M.D. 
Montefiore Medical Center 
 
 
Montefiore Medical Center –Weiler Division 
Department of Oncology, Hofheimer 100 
Department of Oncology 
111 East 210th Street 
 
 
 
1695 Eastchester Road, Second Floor 
Bronx, NY 10467-2490  
 
 
Bronx, NY 10461 
Phone: 718-920-4826/Fax: 718-798-7474 
Phone : 718-405-8404/Fax: 718-405-8501 
Email: rperezso@montefiore.org                     
 Email: spacker@montefiore.org 
 
 
 
 
 
 
 
 
Rasim Gucalp, M.D.  
 
 
 
Missak Haigentz, M.D.  
Montefiore Medical Center-Moses Division 
Montefiore Medical Center 
Department of Oncology, Hofheimer 100 
Department of Oncology, Hofheimer 100 
111 East 210th Street 
 
 
 
111 East 210th Street 
Bronx, NY 10467-2490  
 
 
Bronx, NY 10467-2490  
 
 
Phone: 718-920-4826/Fax: 718-798-7474 
Phone: 718-920-4826/Fax: 718-798-7474 
Email: rgucalp@montefiore.org  
            Email: mhaigent@montefiore.org 
 
Chengchang Zhu, MD     
 
 
Ronald Scheff, MD  
Montefiore Medical Center 
 
 
Weill Cornell Medical College  
  
Department of Anatomical Pathology 
 
520 East 70th St, Starr 3 
E 233rd  Street,   
 
 
 
New York, NY 10065 
Bronx, NY 10461 
 
 
 
Telephone : (646) 962-2006 
Phone: (718) 920-7866  
                           Fax: (646) 962 -1603 
Fax:  (718) 920-7611 
 
 
 
 
Email:  
 
 
 
 
 
 
Benjamin P. Levy, MD   
 
             Balazs Halmos, M.D.   
Depart of Medicine, Hematology/Oncology        New York Presbyterian Medical Center 
Beth Israel Hospital 
 
 
 
Columbia University Medical Center 
325 West 15th Street 
 
 
 
161 Ft. Washington Avenue 9th Floor 
New York, N.Y. 10011   
 
 
New York, NY  
Telephone:(212) 604-6017 
 
 
Phone: 212- 305- 8291 
Fax:(212) 604-6038                        
 
Fax: 212- 305- 6762 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 3 
 
Statistician: 
 
 
Mimi Kim, PhD 
 
 
 
 
Albert Einstein College of Medicine 
 
 
 
1300 Morris Park Avenue, Belfer 1312C 
 
 
 
Bronx, New York 10461 
 
 
 
Phone: 718-430-3575/Fax: 718-430-8780 
 
 
 
Email: mimi.kim@einstein.yu.edu 
 
Research Coordinators: 
 
 
Jessica Sides (Primary)  
 
 
   Srikanth Gajavelli 
Montefiore Medical Center-Weiler Division 
   Montefiore Medical Center 
Department of Oncology, Second Floor                Department of Oncology 
1695 Eastchester Road  
 
 
   1521 Jarrett Place 
Bronx, New York 10461 
 
               Bronx, NY 10461 
Phone: 718-405-8539 
 
                              Phone : 718-379-6865/ 
Fax: 718-405-8526                                             Fax : 718-405-8526 
Email: jsides@montefiore.org                            Email : sgajavel@montefiore.org  
 
Shakira Forde  
 
 
                  
Regulatory/IRB Consultant 
 
 
     
Montefiore Medical Center-Weiler Division 
 
Department of Oncology 
 
 
 
 
     
2 South Room 59                                                       
Bronx, NY 10461                                                      
Phone: 718-904-2534/Fax: 718-822-0335 
Email: sforde@montefiore.org  
 
Research Nurses:  
 
 
 
Cheryl Baker, CFNP 
 
 
 
 
Yoko Eng, NP 
Montefiore Medical Center 
Montefiore Medical Center- 
Weiler Division  
Moses Division 
Department of Oncology, Second Floor  
 
Department of Oncology, Gold Zone 
1695 Eastchester Road  
   
 
 
111 E. 210th Street 
Bronx, New York 10461 
 
 
 
Bronx, New York 10467 
Phone: 718-405-8508/Fax: 718-405-8526 
 
Phone:718-920-2090/Fax:718-405-7412 
Email: cbaker@montefiore.org  
 
 
Email: yeng@montefiore.org 
 
Karen Fehn, RN 
Montefiore Medical Center-Weiler Division 
Department of Oncology, Second Floor 
1695 Eastchester Road 
Bronx, NY 10461 
Phone: 718-405-8446/Fax: 718-405-8526 
Email: kfehn@montefiore.org 
 
 
Study Agents and Their Suppliers:  
 


 
Version 1.7 Nov 5, 2014 
Page 4 
 
1. Erlotinib Hydrochloride (OSI-774; Tarceva),  IND# 53728, Astellas /Genentech 
BioOncology.FDA approval date: 18-Nov-04. Erlotinib, clinical trial material that is “commercial 
in nature” will be provided by the sponsor. Study is IND exempt approved by the FDA  


 
Version 1.7 Nov 5, 2014 
Page 5 
 
TABLE OF CONTENTS 
 
Section  
Page 
 
1.0 
OBJECTIVES 
7 
 
2.0 
BACKGROUND 
7   
 
3.0 
PATIENT ELIGIBILITY 
16 
 
  
 
4.0 
TREATMENT 
18    
 
5.0 
TOXICITIES, ASSESSMENT, AND DOSE MODIFICATIONS 
                
 
19                
 
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
 
 
 
22                
 
7.0       RESPONSE ASSESSMENT 
 
 
 
 
                                    
 
23 
 
8.0       CORRELATIVE STUDIES 
 
 
 
 
 
 
 
 
26 
 
9.0 
PATIENT REGISTRATION                                                                                                          29 
 
10.0   
PHARMACEUTICAL INFORMATION                                                                                     30 
 
11.0 
AGENT ACCOUNTABILITY     
 
 
 
 
 
 
           39 
 
12.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
 
                   
39 
 
13.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
 
 
 
45 
 
14.0 
FOLLOW UP     
46    
 
15.0 
REGULATORY CONSIDERATIONS   
 
                                                               46 
 
 
16.0 
DATA MONITORING / QUALITY ASSURANCE /RECORD RETENTION   
 
47 
 
17.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
 
 
 
47 
 
18.0 
STATISTICAL CONSIDERATIONS  
 
 
    
    
 
 
48 
     19.0 
REFERENCES                                                                                                
    
 
51 
 
APPENDIX A 
MODEL INFORMED CONSENT 
 
APPENDIX B 
ELIGIBILITY CHECKLIST FOR PATIENT REGISTRATION 
 
APPENDIX C 
NCI COMMON TOXICITY CRITERIA 
 
APPENDIX D 
ECOG PATIENT PERFORMANCE STATUS 
 
APPENDIX E 
 
CASE REPORT FORMS  
 
APPENDIX F 
 
AJCC TNM STAGING SYSTEM FOR LUNG CANCER (7TH 
edition) 
 
 


 
Version 1.7 Nov 5, 2014 
Page 6 
 
SCHEMA 
 
 
 
 
* Patients with non-progressive disease who are not going for surgery should 
have mediastinal restaging done by either EUS/EBUS or mediastinoscopy  
Stage III NSCLC 
(N2 node confirmed by 
mediastinoscopy or EUS) 
PET/CT and MRI brain negative 
 
  EGFR mutation testing 
 
EGFR mutation positive 
Erlotinib 150mg  PO daily for 2 
months 
Re-staging by PET/CT +/- 
mediastinal restaging (*) and 
evaluation for surgery 
 
Surgically resectable 
 
Surgery 
Chemotherapy +/- radiation (at 
investigator’s discretion) 
 
Unresectable 
Chemotherapy +/- radiation or 
erlotinib  
(at investigator’s discretion) 
 
Progressive disease 
Chemotherapy +/- radiation 
(at investigator’s discretion) 
 
EGFR mutation negative 


 
Version 1.7 Nov 5, 2014 
Page 7 
 
1.0  OBJECTIVES: 
 
1.1 Primary Objective 
 
• 
To estimate the rate of mediastinal nodal clearance and complete pathological 
response after neoadjuvant erlotinib in patients with EGFR mutated stage III 
NSCLC. 
 
1.2 Secondary Objectives   
 
• 
To determine the progression free survival in patient population of EGFR mutated 
stage III NSCLC patients who are treated with neoadjuvant erlotinib therapy  
 
• 
To determine the overall survival (exploratory objective) 
 
• 
To estimate the overall response rate from neoadjuvant erlotinib 
 
• 
To estimate the surgical resection rate 
 
• 
To evaluate the safety of neoadjuvant erlotinib 
 
1.3 Objectives of correlative studies 
 
• 
The objectives of the correlative studies are: to determine several molecular and cellular 
biomarkers in the tumors, the skin and the serum that are predictive of the efficacy of 
neoadjuvant erlotinib. Formalin-fixed, paraffin-embedded tumor (FFPE) blocks or 
slides from the original diagnosis and at the time of surgery, fresh frozen tumor 
samples, skin samples (optional), and peripheral blood will be collected from study 
patients who consent to these studies at the time of pre- and post-treatment.  ( We 
acknowledge here that a significant portion of the patients will not have both pre 
and post-specimen due to expected high response rate to erlotinib therapy) 
 
2.0   BACKGROUND: 
 
Stage III NSCLC:  
 
Lung cancer is the most common cause of cancer mortality in the United States and 
throughout the world. Approximately 213,000 new cases are estimated to be diagnosed in 
2007.1 At initial presentation, fewer than one-half of patients will have surgically 
resectable lung cancer. Approximately one-quarter of patients will present with locally 
advanced stage III disease. Historically, stage III lung cancer was defined as 
locoregionally advanced disease due to primary tumor extension into extrapulmonary 
structures (T3 or T4) or mediastinal lymph node involvement (N2 or N3) without 
evidence of distant metastases (M0).2 With the 2009 revisions to the TNM staging 


 
Version 1.7 Nov 5, 2014 
Page 8 
 
system, stage III lung cancers now include T3 tumors greater than 7 cm in size and T3 
tumors with multiple nodules in the same lobe, when associated with N1 involvement.3 
 
Most patients are not considered candidates for immediate surgical resection and 
typically treated with combined modality therapy utilizing chemotherapy concurrently 
with radiation.4   Depending on the extent of loco-regional disease; some patients are 
locally unresectable and receive definitive chemoradiation while other patients receive a 
lower dose of neoadjuvant chemoradiation followed by attempted surgical resection.  
 
Outcome from clinical trials in Stage III NSCLC:  
 
Depending on clinical circumstances, the principal forms of treatment that are considered 
for patients with locally advanced stage III NSCLC includes surgery, radiation therapy 
(RT), chemotherapy, or combinations of these modalities. The management of stage III 
NSCLC usually requires a multidisciplinary combined modality approach.  
 
Prior to the recognition of the benefits of systemic chemotherapy for patients with 
metastatic NSCLC, the standard of care for patients with locally advanced unresectable 
or inoperable disease was radiotherapy. A meta-analysis based on individual data from 
3033 patients from 22 trials demonstrated a statistically significant benefit of combining 
chemotherapy with radiation for these patients (Non-Small Cell Lung Cancer 
Collaborative Group 1995). The greatest difference was seen in the 12 cisplatin-based 
trials involving 1780 patients. The hazard ratio (HR) in favor of cisplatin 0.87 (p=0.005) 
corresponded to an absolute reduction in the risk of death of 4% at 2 years, and 2% at 5 
years.5 
 
A recent individual patient-based meta-analysis examined the role of chemotherapy given 
either sequentially or concomitantly with radiation compared to radiation alone.6   A 
separate meta-analysis examined and compared the results of randomized trials of 
concomitant chemotherapy and radiation therapy (ChRT) with sequential chemotherapy 
and radiation.7 There were 4917 patients in the 31 trials examining sequential 
chemotherapy and radiation to radiation alone. Data were available from 22 trials 
comprising a total of 3839 patients. Sixteen trials used platinum-based regimens and 15 
of the trials used a radiation dose below 60 Gy. Combined modality therapy improved 
survival (HR=0.88; p<0.001), corresponding to an absolute benefit in survival of 
2.7% at 3 years. There was no detectable interaction between the timing of the 
administration of chemotherapy or the nature of the drugs used with survival.6  
 
There were 3332 patients in 21 trials that examined concomitant ChRT to radiation alone 
with data available for analysis from 2910 patients in 16 trials. Chemotherapy was 
administered daily or weekly in the majority of trials and only 308 patients did not 
receive a platinum agent. Concomitant therapy produced a survival advantage (HR=0.87; 
p<0.001), corresponding to an absolute increase in survival of 3.2% at 3 years and 1.2% 
at 5 years. There was no evidence of benefit to subgroups based on timing of 
chemotherapy (daily, weekly, or other) or the addition of induction chemotherapy. The 
most favorable hazard ratios were seen with platinum and etoposide combinations or with 


 
Version 1.7 Nov 5, 2014 
Page 9 
 
taxanes alone, but the numbers of patients were small and the results were not 
conclusive.6 
 
A separate analysis focused on examining trials comparing sequential chemotherapy and 
radiation with concomitant ChRT.7  Data from 6 trials encompassing a total of 1205 
patients were assessed; 97% of patients had Stage IIIA or IIIB disease, with 97% having 
performance status of 0 or 1. While there was no difference seen in pulmonary toxicity 
between the sequential and concomitant groups, the relative risk of Grade 3 or 4 
esophagitis was higher in the group treated with concomitant therapy (relative risk 
[RR]=4.9; p<0.0001). There was improved survival in the concomitant group (HR=0.84; 
p=0.004), translating to an absolute improvement in survival of 5.7% at 3 years. 
Compared to the sequential group survival of 10.6% at 5 years, the survival of 15.1% at 5 
years in the concomitant group represented an absolute increase of 4.5%. These benefits 
seem primarily attributable to a decrease in locoregional progression in the concomitant 
group, albeit at the expense of increased esophageal toxicity.7 
 
Current standards of chemotherapy given to patients with metastatic disease cannot be 
given at full doses safely with radical doses of thoracic radiation.8  It is possible to 
hypothesize that the lack of improvement in systemic control seen in the meta-analysis 
reported by Auperin and colleagues (2007) may be either a reflection of the 
undertreatment of occult systemic disease by outdated regimens given at full dose or the 
use of standard chemotherapy regimens at suboptimal doses.4 
 
The conclusion arising from these efforts is that concurrent ChRT produces the highest 
cure rates. However, the median survival in most of these trials remains 20-24 
months and the progression free survival of 12-13 months. 
 
Chemotherapy Prior to or Post Chemo/RT Has Not Improved Survival as 
Compared to Chemo/RT Alone:  
 
Chemoradiation is a loco-regional modality. After chemoradiation the majority of 
patients develop systemic metastases which ultimately cause death. Additional 
chemotherapy either before or after chemoradiation has not improved survival. The 
recent Hoosier Oncology Group phase III trial demonstrated no improvement in outcome 
with the addition of three cycles of docetaxel 75mg/m2 after definitive 
chemoradiotherapy as compared to chemoradiation alone.9 The control group had a 
progression free survival of 12.9 months compared to 12 months for the docetaxel arm. 
Median overall survival was 24.1 months for the observation arm and 21.5 months for the 
docetaxel arm.  
 
CALGB 39801 demonstrated no improvement with induction chemotherapy prior to 
chemoradiation as compared to chemoradiation alone.10 Two year overall survivals were 
29 % and 31%.  
 


 
Version 1.7 Nov 5, 2014 
Page 10 
 
In unselected group of patients, the addition of the EGFR small molecule tyrosine kinase 
inhibitor gefitinib after chemoradiotherapy and consolidation chemotherapy failed to 
improve progression free survival or overall survival in a phase III SWOG trial.11 
 
Role of surgery in patients with Stage III NSCLC 
 
The role of surgery in patients with clinically stage IIIA NSCLC remains uncertain.4 Two 
large randomized studies examined the role of surgery in potentially resectable stage III 
NSCLC. A phase III Intergroup 0139 trial compared definitive chemoradiotherapy versus 
concurrent chemotherapy and 45Gy of radiation followed by surgery.12 the most recently 
updated data has shown a statistically significant improvement in 5 year progression free 
survival for the surgical arm of 22% vs 11% without a statistically significant overall 
survival benefit due to early surgical mortality.   
 
In the EORTC trial, patients with potentially resectable stage III disease were treated with 
three cycles of chemotherapy and then randomized to either surgery or radiation. The 
primary endpoint was overall survival. The reported 5year overall survival in the 
radiation arm and surgery arm were 14% and 15.7% respectively. However, the surgical 
resectability rate in the surgical arm was only 50%.13 
 
Based on these trials, it is a general consensus that the surgical resection after a standard 
chemoradiation adds little value over continuation of chemoradiation. However, both of 
the trials had significant flaws and in practice the surgical evaluation is done for patients 
with stage III disease who are appropriate candidate for surgery after initial induction 
therapy. There is an unmet need to develop more effective, targeted therapies as an 
initial induction or neoadjuvant therapy for patients with stage III NSCLC. 
 
Prognostic value of mediastinal node clearing after neoadjuvant:  
 
In the trials evaluating the role of surgery in stage III NSCLC patients, patients who had 
nodal clearance (N0 in final pathology) or mediastinal down staging (N0, N1 disease in 
final pathology) after preoperative or neoadjuvant therapy has the best long term survival. 
In the Intergroup 0139 trial, nodal clearance (pN0) in the surgical group was 37%. In the 
surgical group, the best outcome was seen in patients who have N0 disease after 
neoadjuvant therapy. The 5yr survival rates are any TN0: 41%; any TN1-3: 24% and no 
surgery: 8%.12 
 
In the EORTC trial, the rate of mediastinal down-staging in the surgery group was 25% 
ypN0 and 16% ypN1. The best outcome was seen in patients who had mediastinal down-
staging (ypN0, N1 group) with the 5year survival rate of 29%.13 
 
There are also several large prospective and retrospective studies confirming that 
sterilization of mediastinum as an important predictor of good outcome after neoadjuvant 
therapy and surgical resection. In a large prospectively collected database of 136 patients 
with stage IIIA disease who had surgical resection after neoadjuvant therapy, the 5 year 


 
Version 1.7 Nov 5, 2014 
Page 11 
 
overall survival rate was 33%. Patients with pathological down staging (N0, N1) had 
improved 5year survival of 45% vs. 20% in the group without mediastinal downstaging.14 
 
In another series of 92 patients with pathologically proven N2 disease who underwent 
surgical resection after induction chemotherapy, the 5 year overall survival was 33% and 
again the patients who had mediastinal down staging  had better 5 year overall survival of 
49 vs. 27%.15 
 
Based on the results of the above mentioned studies, the mediastinal nodal clearance 
after neoadjuvant therapy is a very good surrogate marker for long term survival. 
The mediastinal nodal clearance can serve as a surrogate primary endpoint for long term 
survival in evaluating newer preoperative or neo-adjuvant therapy for patients with stage 
III NSCLC. 
 
EGFR Signaling Transduction Pathway and Erlotinib HCL (Tarceva®) in NSCLC 
 
Epidermal growth factor receptor (EGFR, also known as HER1 or erb B) is a member of 
the ErbB tyrosine kinase receptor family, which also includes HER2, HER3, and HER4.16 
The ErbB receptors are present in the plasma membrane and share a common structure 
composed of an extracellular ligand-binding domain, transmembrane segment, and an 
intracellular tyrosine kinase domain. ErbB receptors are activated by a variety of 
receptor-specific ligands including epidermal growth factor (EGF), transforming growth 
factor-alfa (TGF-α), amphiregulin, heparin-binding EGF (HB-EGF), epiregulin, 
neuregulin, and betacellulin. As a result of ligand binding, receptor dimerization, trans-
autophosphorylation, and initiation of signaling occur. Several major signaling pathways 
mediate the downstream effects of EGFR activation: the cell proliferation pathway 
(Ras/Raf/MAP kinase), and survival pathway [phosphatidylinositol 3-kinase (PI3K)/Akt 
and Jak/Stat or protein kinase C (PKC)]. Many carcinogenic processes are mediated by 
EGFR signaling including cell survival, proliferation, angiogenesis, and invasiveness.16-21  
 
Erlotinib (Tarceva® formerly OSI-774), a quinazoline derivative, is a potent and highly 
selective, small tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase 
autophosphorylation, and subsequently prevents the receptor-mediated signaling 
pathways.17 It reversibly competes with the adenosine triphosphate (ATP) at the ATP-
binding site within the intracellular tyrosine kinase (TK) domain of the EGFR protein. Its 
mechanisms of action and clinical development have been extensively reviewed.17-21 
Erlotinib inhibits the growth of tumor cells, interferes with cell cycle progression, causing 
accumulation in G1 phase, and induction of apoptosis of a variety of tumor cell lines in 
vitro and in vivo.22 In phase I studies, the recommended phase II dose and schedule was 
150 mg daily by mouth. The minimum plasma steady-state concentrations was above the 
targeted concentration at 1.20  0.62 g/mL, and the mean half-life was about 24 hours. 
The most common side effects and dose-limiting toxicities were skin rash and diarrhea.39 
Perez-Soler et al reported that erlotinib has a single agent activity of 12.3% in 57 EGFR+ 
patients with advanced NSCLC who failed first-line cisplatin-containing chemotherapy. 
Treatment was well tolerated, the most common adverse effect being a maculopapular 
acneiform rash in 44 pts (78%). In 731 EGFR unselected patients, a double-blind, 
international, randomized trial (BR.21) comparing erlotinib 150 mg by mouth daily to 


 
Version 1.7 Nov 5, 2014 
Page 12 
 
placebo, erlotinib had a response rate of 8.9%, as compared to the placebo had a response 
rate of less than 1 percent (p <0.001). The median duration of the response was 7.9 
months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 
months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). 
Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; 
P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of 
toxic effects.24,39  On November 18, 2004, the FDA approved erlotinib for treatment of 
patients with locally advanced or metastatic NSCLC after failure of at least one prior 
chemotherapy regimen.  
 
Erlotinib in EGFR mutated NSCLC:   
One of the major advances in the treatment of NSCLC over last several years has been 
identification of subgroup of patients who will benefit from targeted therapies. The 
mutations in EGFR tyrosine kinase domain was first described in 2004.26,27 Multiple 
prospective studies have proven that mutations in the EGFR tyrosine kinase domain are 
the best predictors of response and progression-free survival benefit with EGFR TKI. 
Over 80% of the mutations in EGFR are in frame deletions in exon 19 (del E766-A750) or 
point mutations in exon 21 (L858R). These mutations destabilize the kinase auto-inhibitory 
loop leading to constitutive activation of the receptor.  The initial data defining the EGFR 
mutation as a predictor were derived from phase II studies in which all patients received 
treatment with erlotinib or gefitinib, and these have subsequently been confirmed in 
larger, phase III trials.28-30  
Although mutations are clearly more common in adenocarcinomas, from women and 
never smokers, recent studies have identified EGFR mutations in smoker as well as 
males. In a multi-institutional study conducted in Spain, EGFR mutations were 
found 350 (17%) of 2,105 patients. The incidence of EGFR mutations was 8%, 10%, 
and 6% in men, former, and current smokers, respectively.31 In a large study reported by 
the group from Memorial Sloan Kettering Cancer Center, EGFR mutations occur with 
an incidence of 23% in 2,142 patients with stage I through IV lung adenocarcinoma. 
Tumors from 19% of men and 13% of current/former smokers harbor EGFR sensitizing 
mutations. Although there is a decrease in the incidence of mutations with increased 
number of pack-years smoked, a substantial number of EGFR mutations were found in 
patients with a significant history of smoking. EGFR mutations in men and 
former/current smokers represent 31% and 40%of all mutations, respectively. In 
addition, the incidence of EGFR mutation is very similar between early stage (stage 
I-IIIA) and advanced stage patients. Among 1,085 patients with stage I to IIIA, 218 
patients (20%) had EGFR mutations.32 
In patients with advanced stage IV disease, initial treatment with an EGFR TK inhibitor 
has been compared with cytotoxic chemotherapy in multiple phase III trials. The most 
extensive data come from the IPASS trial, in which 1217 patients were randomly 
assigned to either gefitinib or chemotherapy with carboplatin plus paclitaxel. Patients 
were included based upon clinical criteria consistent with responsiveness to gefitinib; all 
had adenocarcinoma and were either never smokers or former light smokers (≤10 pack-
years and none for at least 15 years). For the entire cohort, progression-free survival was 
significantly better with gefitinib compared to chemotherapy (12-month progression-free 
rate 25 versus 7 percent, HR 0.74). However, the difference in overall survival was not 


 
Version 1.7 Nov 5, 2014 
Page 13 
 
statistically significant (median 18.8 versus 17.4 months, HR 0.90, 95% CI 0.79-1.02).33  
 
Results were dependent upon the EGFR mutation status. EGFR mutations were present in 
60 percent of the 437 evaluable patients, and among these, 96 percent had either an exon 
19 deletion or the exon 21 L858R mutation. For patients whose tumors contained an 
EGFR mutation, progression-free survival was significantly prolonged with gefitinib in 
contrast to carboplatin plus paclitaxel (median 9.5 versus 6.3 months, HR 0.48).33 
However, overall survival was not increased with gefitinib (median 22 months in both 
groups, HR 1.00). Among mutation positive patients who initially received carboplatin 
plus paclitaxel, 64 percent subsequently were treated with an EGFR tyrosine kinase 
inhibitor. For those without an EGFR mutation, progression-free survival was 
significantly shorter with gefitinib (median 1.5 versus 6.5 months, HR 2.85, 95% CI 
2.05-3.95).33  However, the difference in overall survival was not statistically significant 
(median 11.2 versus 12.7 months, HR 1.18). Among those initially assigned to gefitinib, 
76 percent subsequently received chemotherapy, most of which was platinum-based.  
 
In the OPTIMAL trial from China, 154 patients with known EGFR mutations and 
measurable disease were randomly assigned to erlotinib or gemcitabine plus 
carboplatin.34 Treatment with erlotinib significantly improved progression-free 
survival (13.1 versus 4.6 months, HR 0.16, 95% CI 0.10-0.26). Similarly, the 
objective response rate was significantly improved with erlotinib (83 versus 36 
percent). 34 
In the EURTAC trial, 174 patients with EGFR mutations were randomly assigned to 
erlotinib or platinum-based chemotherapy. Results of a planned interim analysis were 
presented at the 2011 American Society of Clinical Oncology (ASCO) meeting and 
subsequently published in the Lancet Oncology. The objective response rate in 
erlotinib arm was 58%. Progression-free survival, the primary endpoint of the trial, 
was significantly increased with erlotinib compared with chemotherapy (median 
10.4 versus 5.2 months, HR 0.37). The difference in overall survival was not statistically 
significant, but more than 80 percent of patients initially treated with chemotherapy 
subsequently received an EGFR tyrosine kinase inhibitor. 35 
In the CALGB 30406 trials, erlotinib 150mg daily was compared to erlotinib 150mg 
daily with carboplatin AUC6 and paclitaxel 200mg/m2 as the first line therapy in 
never/light former smokers with advanced NSCLC. Overall 182 patients were 
randomized: 82 patients to erlotinib alone and 100 patients to erlotinib and 
chemotherapy. Over 80% of patients in the study were Caucasians and about 60% of 
them were women. In the subgroup of patients with EGFR mutation, erlotinib alone 
resulted in objective response rate of 67% with median PFS and OS of 15.7 and 37.3 
months respectively. Addition of chemotherapy to erlotinib did not result in increase 
response rate, PFS or OS in EGFR mutated patients. 36 
Based on these and other trials, erlotinib or gefitinib monotherapy has become a standard first 
line therapy for stage IV patients with EGFR mutation. Erlotinib monotherapy is associated 
with 58-83% objective response rate in stage IV patients with EGFR mutations. This far 
exceeds the expected response rate from standard chemoradiation in stage III unselected 
NSCLC patients. The median progression free survival from erlotinib monotherapy in stage 


 
Version 1.7 Nov 5, 2014 
Page 14 
 
IV disease with EGFR mutation is 10-13 months; similar to what we will normally achieved 
with standard chemoradiation in unselected patients with stage III NSCLC. 
 
Rationale of Current Study:  
 
The best management of patients with stage III NSCLC requires multidisciplinary 
approach. The current chemoradiation regimens have reached a plateau. A recent attempt 
to improve the outcome by increasing the dose of radiation has not been successful. 
Although the surgery and radiation offers a good local control, the big challenge in 
patients with stage III disease is systemic relapse. A molecular agent that inhibits the 
development of systemic metastases for patients with stage III disease should be 
started as an initial therapy for the best outcome. Based on the experience in 
advanced disease, the addition of a targeted therapy to a standard regimen is not always 
successful. 
 
The EGFR mutated tumors form a subset of lung cancer that has significant responses 
from erlotinib and gefitinib. The response rate from erlotinib in stage IV patients with 
EGFR mutations were 67, 83 and 58% in CALGB 30406, OPTIMAL and EURTAC 
trials respectively.33-36 These response rates far exceed the response rate seen with 
preoperative chemotherapy or chemoradiotherapy in stage III patients. The complete 
pathological responses have been described in patients with EGFR mutated stage IV 
disease who underwent resection of the primary tumors.37 
 
The primary objective of this study is to estimate the rate of mediastinal nodal clearance 
after two months of neoadjuvant erlotinib in patients with stage III NSCLC with EGFR 
mutation. The mediastinal clearance is a robust measure of long term survival in patients 
with stage III NSCLC and will allow us to objectively evaluate effectiveness of the 
proposed regimen in short period of time. Rationale for correlative studies 
 
Molecular and Cellular Determinants of erlotinib    
 
Significant advances have been made over last several years in understanding both innate 
and acquired resistance to erlotinib in EGFR mutated tumors. Although several molecular 
or cellular basis for these resistance have been studied in pre-clinical models, these have 
not been validated in actual human specimens. Our study offers a great opportunity to 
examine some of these molecular markers in pre- and post-erlotinib specimen.  
 
Recently it has been demonstrated that the polymorphisms in BIM protein are related to 
resistance to tyrosine kinase inhibitors including erlotinib. We plan also to examine BIM 
polymorphism from pre-erlotinib peripheral blood specimen our study. We will also plan 
to examine the BIM expression by immunohistochemistry in pre- and post erlotinib 
treated specimens. These data will be correlated with clinical and pathological response 
to validate BIM polymorphism and BIM-expression with complete pathological response 
and mediastinal down staging.  
 


 
Version 1.7 Nov 5, 2014 
Page 15 
 
Recent studies have shown that more than half of the patients with acquired resistance to 
erlotinib have another mutation in exon 20 (T790M) conferring resistance to drug. 
Several studies have also shown that T790M mutation could present in pre-treatment 
specimen in about 30-35% of patients with erlotinib sensitive EGFR mutated tumors in 
low frequency. The theory of possible clonal selection by erlotinib in those patients is not 
very well validated. We plan to examine T790M mutation in both pre and post erlotinib 
specimens and correlate with complete pathological response and mediastinal 
downstaging. 
 
EGFR mutated tumors also used alternative pathway particularly c-met/HGF pathway to 
circumvent EGFR inhibition. C-met and HGF overexpression has been associated with 
both innate and acquired resistance to erlotinib. We plan to examine baseline and post 
treatment c-met and HGF expression by IHC and correlate with response. 
 
Autophagy as a mechanism of resistance to EGFR inhibition 
 
Our recent work showed that erlotinib exposure induced autophagy in NSCLC cell lines. 
Autophagy is a self-protective mechanism that provides energy through the degradation 
and recycling of cytoplasmic contents and promotes cell survival. Autophagy has been 
shown to be a resistance mechanism to several chemotherapy and the proteosome 
inhibitors. Erlotinib exposure induced autophagy in both erlotinib resistance and sensitive 
cell lines. Inhibition of autophagy can be a potential mechanism to overcome the 
resistance to erlotinib. We plan to validate this finding examining autophagic markers 
(LC3-2 staining and electron microscopy (in limited number of patients) ) in pre and 
post-erlotinb treated specimens. 
 
 
Expression of Epithelial to Mesenchymal Transition (EMT) Markers and Sensitivity to 
Erlotinib    
 
The expression of epithelial cell markers (such as E-cadherin, β-catenin) correlates with 
the sensitivity of NSCLC cells to erlotinib, whereas the loss of these epithelial cell 
markers expression and the expression of EMT markers (such as vimentin and/or 
fibronectin) correlate with resistance to erlotinib in in vitro and in vivo models [69, 70]. 
Furthermore, a small retrospective analysis of E-cadherin immunohistochemistry (IHC) 
expression on primary tumor samples from NSCLC patients suggests that the strong E-
cadherin expression was associated with a significantly longer time to progression (n=28 
and 37, respectively; hazard ratio, 0.37; log rank P=0.0028) and a nonsignificant trend 
toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy 
alone. We thus propose to determine the E-cadherin, vimentin and fibronectin expression 
by IHC in tumor specimens obtained from NSCLC patients enrolled in this study, and to 
correlate the level of expression with clinical efficacy.  
 
Rash as a surrogate marker of clinical response and survival   EGFR is expressed at high 
level in the skin and play a vital role in normal physiological function and the skin. 
Dysregulation of EGFR is implicated in psoriasis, although the mechanism is poorly 


 
Version 1.7 Nov 5, 2014 
Page 16 
 
delineated and the good animal model for this disease is lacking. Treatments of all anti-
EGFR therapeutic agents are associated with high incidence of skin changes (60-90%). 
Although most patients tolerate the rash well, severe skin rash is one of the dose-limiting 
toxicities and may lead to treatment interruption or discontinuation. Analysis of previous 
clinical studies suggested that the severity of rash correlates with survival in patients 
receiving erlotinib. Although the mechanisms for rashes are largely unknown, several 
ongoing studies are evaluating the relationship between skin and tumor EGFR 
expression, the relationship between the severity of skin rashes and clinical efficacy. Our 
unpublished data suggest that acute inflammatory reaction is present in the skin of mice 
that have received oral erlotinib treatment. However, the role of this acute inflammatory 
reaction in humans is not known.  
 
3.0   PATIENT ELIGIBILITY: 
3.1 Inclusion criteria 
 
o Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIA or 
IIIB non-small cell lung cancer; [according to AJCC Staging, 7th edition; see 
Appendix G] within 6  weeks of registration. The patient should have 
histologically or cytologically confirmed N2 disease. 
o Activating mutation in EGFR  
o No prior chemotherapy or radiation for lung cancer.   
o Patients may be potentially resectable or unresectable. 
o Stage III A or B disease, including no distant metastases- based on following 
diagnostic workup: 
 History/physical examination prior to registration. 
 CT Scan of the chest or PET Scan within 28 days of study entry 
 CT Scan of abdomen or MRI of abdomen or Pet Scan  within 28 days of 
study entry 
 An MRI of the brain  or Head CT Scan with contrast within 28 days of 
study entry 
 PET scan within 28 days of study entry  
 Mediastinoscopies are highly recommended. 
o Patients must have measurable or evaluable disease. 
o ECOG Performance Status 0-2.  
o Age > 18. 
o CBC/differential obtained within 2 weeks prior to registration on study, with   
adequate bone marrow function defined as follows: 
 Absolute neutrophil count (ANC) >1,500 cells/ul 
 Platelets > 100,000 cells/ul 
  Hemoglobin > 9.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb > g/dl is acceptable.) 
 Serum creatinine < 1.5 x ULN 
 Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN) 
 AST and ALT < 2.5 x the ULN 
 Women of childbearing potential must have: 


 
Version 1.7 Nov 5, 2014 
Page 17 
 
o A negative serum or urine pregnancy test (sensitivity  25IU HCG/L) 
within 72 hours prior to the start of study drug administration 
o Persons of reproductive potential must agree to use and utilize an 
adequate method of contraception throughout treatment and for at 
least 4 weeks after study drug is stopped prior to study enrollment, 
women of childbearing potential must be advised of the importance 
of avoiding pregnancy during trial participation and the potential risk 
factors for an unintentional pregnancy. 
o Ability to take oral medication  
o Patient must sign study specific informed consent prior to study entry. 
 
3.2 Exclusion Criteria 
o Pleural or pericardial effusion  
o Pleural effusions allowed if one of the following conditions are met: 1) 
Negative cytology after adequate sampling by thoracentisis 2) Effusion 
seen on CT scan but not on chest x-ray and deemed too small to tap under 
CT or ultrasound guidance  
o Severe, active co-morbidity, defined as follows: 
o Cardiac Symptoms; any of the following should be considered for 
exclusion:   
 Uncontrolled angina, congestive heart failure or MI within (6 
months) 
 Diagnosed congenital long QT syndrome 
 Any history of clinically significant ventricular arrhythmias (such 
as ventricular tachycardia, ventricular fibrillation, or Torsades de 
pointes) 
 Prolonged QTc interval on pre-entry electrocardiogram (> 450 
msec)  
 
o History of significant bleeding disorder unrelated to cancer, including: 
 Diagnosed congenital bleeding disorders (e.g., von Willebrand’s 
disease) 
 Diagnosed acquired bleeding disorder within one year (e.g., 
acquired anti-factor VIII antibodies) 
 Ongoing or recent ( 3 months) significant gastrointestinal 
bleeding 
    
o Prisoners or subjects who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) 
illness 
o Men and Women who: 
 are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for at least 4 weeks after 
cessation of study drug, or Women who: 


 
Version 1.7 Nov 5, 2014 
Page 18 
 
 have a positive pregnancy test at baseline, or 
 are pregnant or breastfeeding 
  
4.0   TREATMENT: 
4.1 Neoadjuvant erlotinib 
 
Patients will be evaluated by a thoracic surgeon and medical and/or radiation oncologist 
and be determined to have either locally unresectable disease or potentially resectable 
disease.  
 
Patients, who are eligible for the study, will be treated with preoperative/ neoadjuvant 
erlotinib 150 mg PO daily for two months. 
 
Patients will be evaluated with repeat imaging studies (PET/CT or CT C,A,P) and will be 
evaluated for surgical resection. Patients who had progressive disease or are NOT a 
surgical candidate will come off the study and will be treated according to standard 
therapies. Patients may continue on erlotinib (off the study) if this is felt appropriate by 
the treating physicians. All patients will be followed up for progression free and overall 
survival.   
4.2 Surgery 
 
Patients who had significant clinical down staging and deemed medically fit to tolerate 
surgery will have surgical resection within 4-6 weeks after last staging imaging studies. 
Patients will continue on erlotinib until one day prior to surgical resection.  
 
Patients with non-progressive disease who are not going for surgery should have 
mediastinal restaging done by either EUS/EBUS or mediastinoscopy. 
 
The patient could receive either adjuvant chemotherapy, radiotherapy or both after 
surgical resection at the discretion of the treating physician. For the patients with 
unresectable, non-progressive disease, repeat mediastinal staging is required prior to 
proceeding with either chemotherapy, radiotherapy or both. Patients are also required to 
have repeat mediastinal evaluation even if the treating physician decides to continue on 
erlotinib beyond study duration.   
  
4.2.1 Mediastinoscopy 
 
A mediastinoscopy is highly recommended for all patients prior to neoadjuvant 
therapy for confirmation of mediastinal disease and also for tissue acquisition for 
EGFR mutation testing.  
 
4.2.2 Pulmonary resection 
 


 
Version 1.7 Nov 5, 2014 
Page 19 
 
Thoracotomy may be performed 4 weeks after neoadjuvant therapy. Surgery is 
performed if post neoadjuvant induction CT scan shows no significant 
progression of disease. Patients must be medically fit to tolerate surgery as 
deemed by the operative surgeon (post operative predicted FEV1> 40% predicted, 
no severe active comorbidity-see section 3). Complete surgical resection is the 
goal. This may entail pneumonectomy, bilobectomy, or lobectomy. Any 
procedure less than lobectomy is not recommended. Intraoperative frozen sections 
are performed at the discretion of the surgeon (bronchial resection margin is 
recommended). Reasons for incomplete resection will be documented. Bronchial 
stump coverage with local vascularized tissue is recommended.  
 
4.2.3 Handling of mediastinal lymph nodes at thoracotomy 
 
At the time of thoracotomy, mediastinal lymph node dissection is performed at 
the nodal station biopsied positive on prior mediastinoscopy. Either a full 
mediastinal lymph node dissection or mediastinal lymph node sampling is 
performed at all other lymph node stations at the discretion of the surgeon. For 
right sided lesions, this will include lymph node station 2, 4, 7, 8, 9, 10, and 11. 
Station 12 and 13 will be submitted along with the lung specimen. For left sided 
lesions, this will include lymph node station 5, 6, 7, 8, 9, 10, and 11. Station 12 
and 13 will be submitted along with the lung specimen. On the left side, 
dissection or sampling of station 2 and 4 are at the discretion of the surgeon. 
 
Proper documentation of mediastinal lymph node sampling in operative report is 
mandatory for the study. If the specific stations are not sampled, the reason should 
be documented in operative report. Failure to document mediastinal node 
sampling will be considered major protocol violation. 
 
4.2.4 Operative complications 
 
In hospital and 30 day morbidity and mortality will be prospectively monitored. 
 
 
5.0  TOXICITIES, DOSE MODIFICATIONS, AND MANAGEMENT: 
 
Adverse events should be coded according to CTCAE version 4 (Appendix C).38   
5.1 Erlotinib Dose Modification/Toxicity Management 
 
5.1.1  Dose Modifications 
 
Discontinue Erlotinib (TARCEVA ) for: 
 
 Interstitial Lung Disease (ILD). 


 
Version 1.7 Nov 5, 2014 
Page 20 
 
 Severe hepatic toxicity that does not improve significantly or resolve within 
three weeks  
 Gastrointestinal perforation  
 Severe bullous, blistering or exfoliating skin conditions. 
 Corneal perforation or severe ulceration. 
 
Withhold Erlotinib (TARCEVA): 
 
 During diagnostic evaluation for possible ILD. 
 For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation 
of TARCEVA. 
 In patients without pre-existing hepatic impairment for total bilirubin levels 
greater than 3 times the upper limit of normal or transaminases greater than 5 
times the upper limit of normal, and consider discontinuation of erlotinib 
(TARCEVA.). 
 In patients with pre-existing hepatic impairment or biliary obstruction for 
doubling of bilirubin or tripling of transaminases values over baseline and 
consider discontinuation of erlotinib (TARCEVA ) 
 For persistent severe diarrhea not responsive to medical management (e.g., 
loperamide). 
 For severe rash not responsive to medical management. 
 For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more 
than 2 weeks.  
 For acute/worsening ocular disorders such as eye pain, and consider 
discontinuation of erlotinib (TARCEVA ). 
 
Reduce Erlotinib (TARCEVA ) by 50 mg decrements: 
 
 If severe reactions occur with concomitant use of strong CYP3A4 inhibitors 
[such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin 
(TAO), voriconazole, or grapefruit or grapefruit juice] or when using 
concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., 
ciprofloxacin). Avoid concomitant use if possible. 
 When restarting therapy following withholding treatment for a dose-limiting 
toxicity that has resolved to baseline or grade ≤ 1.  
 
Drugs Affecting Gastric pH 
 


 
Version 1.7 Nov 5, 2014 
Page 21 
 
 Avoid concomitant use of erlotinib (TARCEVA)  with proton pump inhibitors 
if possible. Separation of doses may not eliminate the interaction since proton 
pump inhibitors affect the pH of the upper GI tract for an extended period. 
 If treatment with an H2-receptor antagonist such as ranitidine is required, 
erlotinib (TARCEVA) must be taken 10 hours after the H2-receptor antagonist 
dosing and at least 2 hours before the next dose of the H2-receptor antagonist. 
 Although the effect of antacids on erlotinib pharmacokinetics has not been 
evaluated, the antacid dose and the erlotinib (TARCEVA ) dose should be 
separated by several hours, if an antacid is necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 22 
 
6.0   SCHEDULE OF EVALUATIONS / STUDY CALENDAR: 
6.1 Schedule of Evaluations  
Parameter 
Pre-
study 
Neoadju
vant 
Erlotini
b 
Q 
2wks*** 
(D1,15,2
9,43) 
Neoadj
uvant 
Erlotini
b 
(D57) 
Surgery 
( within 4-6 
weeks from 
PET/CT 
scan) 
Post-
Surgical  
Follow 
uph 
End of 
Treatmen
t Visit 
FU** 
History 
X 
X 
X 
 
X 
 
X 
Physical examination 
X 
X 
X 
 
X 
X 
X 
Weight 
X 
X 
X 
 
X 
X 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
Performance status 
(ECOG) 
X 
X 
X 
 
X 
X 
X 
CBC, differential, 
platelet count 
X 
X 
X 
 
X 
X 
X 
7, LFTs, Cal,  Mg, A 
X 
X 
X 
 
X 
X 
X 
Serum HCG A 
X 
 
 
 
 
 
 
PFTsB 
X 
 
 
 
 
 
 
AE Evaulation 
 
X 
X 
 
X 
X 
 
CT scan chest or total 
body PET/CT Scan  and   
CT Scan or MRI of 
Abdomen or total body 
PET/CT Scanc 
X 
 
X 
 
 
 
 
 
Every six 
month for 
first year 
then 
yearly till 
5 years 
PET/CT Scand 
X 
 
X 
 
 
 
 
MRI of Brain  or CT of 
Head with contrast * 
X 
 
If 
clinical
ly 
indicat
ed 
 
 
 
If 
clinically 
indicated 
Mediastinoscopy/ 
EUS/EBUS g 
X 
 
If 
clinical
ly 
indicat
ed## 
 
 
 
 
Surgical Evaluation 
X 
 
X 
 
 
 
 
Operative & Surgical 
pathology report 
 
 
 
 
X 
 
 
Perioperative morbidity 
form 
 
 
 
 
X 
 
 
 EKG f  
X 
 
 
 
 
 
 
Pill diary 
 
X 
X 
 
 
 
 
A -Pre-enrollment laboratory tests should be performed within 14 days of study entry. HCG is required only for 
patients who are women with childbearing potential and must be done within 72 hours prior to start of study drug 
administration. 
B- PFTs within 8 weeks of study entry 
C- CT Scan of the chest or Pet Scan within 28 days of study entry and a  CT Scan or MRI of abdomen through the Liver 
within 28 days of study entry 
*An MRI of the brain with contrast or Head CT Scan within 28 days of study entry 


 
Version 1.7 Nov 5, 2014 
Page 23 
 
d-PET/CT scan within 6 weeks of study entry is highly recommended and required for operable patients. If a PET scan 
is performed then a bone scan is not required.  
f- EKG within 6 weeks of study entry. 
g- Mediastinoscopies are highly recommended for documentation of N2 disease. EUS or EBUS may substitute 
mediastinoscopy in appropriate clinical setting.  
h- Subjects who do not receive surgery will have an end of treatment visit 30 days (±3 days) after Post-Treatment Visit.  
 
**Follow for survival and recurrence every 3 months for first year, every 6 months afterward and document on follow 
up form. 
*** specified dates +/- 2 working days 
## required for patients with non-progressive disease NOT undergoing surgery. 
 
7.0  
RESPONSE ASSESSMENT: 
7.1 Eligibility 
 
RECIST 1.1 will be used for tumor measurements after neoadjuvant erlotinib.41 
 
Only patients with measurable or evaluable disease at baseline will be included:  
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter  20 mm using conventional techniques or 10 
mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT scan), 
i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also 
abdominal masses that are not confirmed and followed by imaging techniques; 
and. 
 All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
 The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
 Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  


 
Version 1.7 Nov 5, 2014 
Page 24 
 
7.2 Methods of Measurement  
 
 CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 5 mm contiguous reconstruction algorithm.  This applies 
to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
 
 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
 When the primary endpoint of the study is objective response evaluation, ultrasound 
(US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation has not 
yet been fully and widely validated. Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in 
some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, 
such techniques can be useful in confirming complete pathological response when 
biopsies are obtained. 
 
 Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response when all lesions have disappeared. 
 
 Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g., after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumor types such as germ cell tumors). 
7.3 Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs should be identified as target lesions and  
recorded and measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  


 
Version 1.7 Nov 5, 2014 
Page 25 
 
 A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference by 
which to characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.  
 
7.4 Response Criteria 
Evaluation of target lesions 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference the 
baseline sum LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level 
* Incomplete Response/         
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker 
level above the normal limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or study 
chair). 
7.5 Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria  
 


 
Version 1.7 Nov 5, 2014 
Page 26 
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
8.0    CORRELATIVE STUDIES: 
 
Informed consent must be signed prior to obtaining and/or submission of any materials 
for the laboratory correlative studies.  
8.1 Statement of Hypotheses and Objectives: 
 
The objective of the correlative studies is to identify molecular and cellular makers in the 
tumor and the skin that will predict either a response or resistance to erlotinib in EGFR 
mutated tumors. We plan to identify the molecular markers that will predict the rate of 
mediastinal nodal clearance in stage III NSCLC patients with EGFR mutation.  
 
 
Based on the literature and our preliminary data, we hypothesize that: 
 
1) The polymorphism and baseline BIM expression will predict a response to erlotinib 
 
2) Baseline c-met expression and the presence of T790M mutation in pre-treatment tumor 
specimens will predict resistance to erlotinib 
 
3) We expect to see autophagy induction in post-treatment specimens compare to pre-
treatment specimens. We plan to correlate the baseline autophagy with either sensitivity 
or resistance to erlotinib 
  


 
Version 1.7 Nov 5, 2014 
Page 27 
 
4) The expression of Epithelial to Mesenchymal Transition (EMT) Markers and 
sensitivity to erlotinib. 
 
5) The presence of ≥ grade 2 skin changes is associated with erlotinib-associated 
inhibition of pEGFR and immune and inflammatory changes in the skin, which correlate 
with clinical response and patient survival to erlotinib.  
 
6) Patients who develop significant skin rashes have more competent T-cell mediated 
immunity that correlate with better clinical outcome.  
8.2  Background and Rationale (see section 2.0).  
8.3 Tissue Requirements and Assays 
 
Although high throughput techniques like microarray and proteomics will allow 
simultaneous determination of up to thousands of genes and proteins in patients before 
and after the treatment, it is limited by the need for large amounts of tumor tissues and 
labored collection. Thus, we will focus on several biomarkers suggested by our and 
others preclinical studies for erlotinib to predict their clinical response and benefit, and 
only performed array-based genomic analysis and proteomics in selected patients.  
 
8.3.1 Tissue requirements: 
 
Tumor samples: We will put all efforts to obtain at least the diagnostic tissue 
blocks for the correlative studies. Tumor tissues will be available from the 
diagnostic biopsy. Pre- and post-treatment tumor biopsies will be obtained in 
available patients. The tumors will be embedded in OCT solution or snap frozen 
in a liquid nitrogen bath. Aliquots of tumors will be fixed in formalin and 
embedded in paraffin.  
 
Skin samples: Serial 3mm-punch skin biopsies under local anesthesia on the back 
of upper torso are minimal invasive and can be done within 20 minutes during an 
outpatient visit. This is required only for all patients enrolled in the study who 
consent to the biopsy, with or without the presence of grade 2 or above skin rash 
after initiation of erlotinib. A separate or immediate after clinic visit with the 
treating physician might be arranged to perform the skin biopsy as needed.  These 
samples (~400 mg) will be snapped frozen immediately in liquid nitrogen, and 
embedded in paraffin.   
 
Timing of tumor or skin biopsy: Pre-treatment biopsy could be obtained within 2 
weeks before initiation of the drug treatment. The onset of skin rashes is usually 
two weeks in patients and last for at least 24 hours after last dose of erlotinib, 
Thus we will perform post-treatment skin biopsy during the planned surgical 
resection for lung cancer OR at the peak of skin rash as per patient and treating 
physician’s discretion. 
 


 
Version 1.7 Nov 5, 2014 
Page 28 
 
8.3.2 Tissue resources: 
 
The following tissue resources are allowed to collect tissue samples at the time of 
initial diagnosis, pre- and post-treatment.  
8.3.2.1 Formalin-fixed, paraffin-embedded (FFPE) tumor blocks 
8.3.2.2 Endobronchial brush and wash 
8.3.2.3CT-guided core biopsy of tumor 
8.3.2.4 Punch biopsy of skin 
8.3.2.5 Peripheral blood 
 
8.3.3 The following assays will be performed: 
 
1. Histological Evaluation  
2. DNA isolation and mutational analysis 
3. FISH 
4. Tissue microarray (TMA) and Immunohistochemistry (IHC) 
5. ELISPOT assay 
 
Histological Evaluation: Specimens will be evaluated by routine hematoxylin and eosin 
(H&E) stain for the following assessments: 1) percentage of variable tumor; and 2) non-
neoplastic adjacent normal tissue. 
 
DNA Isolation and Mutational Analyses: Tumor cells will be isolated on sections from 
FFPE tissue blocks by macrodissection if the slides consist of more than 75% of tumor. If 
the slides consist of less than 75% of tumor, we will first isolate tumor cells from normal 
cells on the slide onto a thin polymer film (CapSure LCM Caps, Arcturus, Mountain 
View, CA) by a PixCell IIe Laser Capture Microdissection (LCM) System (Arcturus, 
Mountain View, CA). The tumor cells will be dissociated from the film in proteinase K-
containing lysis buffer.  The 75% is chosen arbitrarily. Our previous experience reveals 
that we can detect a heterozygous point mutation by direct sequencing if it is present at 
least at 15% (data not shown). An estimate of 3,000 to 10,000 laser shots using a laser 
beam of 7.5-µm diameter will be needed to obtain enough analyzable DNA for at least 10 
PCR reactions. As normal controls, DNA isolated from adjacent normal lung tissues 
either by LCM or by macrodissection (if normal tissues is >75%) will be used.  
 
 
Genomic DNA will be isolated from tumor samples by the DNeasy tissue kit (Qiagen). 
Targeted gene segments will be amplified by PCR and the mutation status will be 
determined by the standard procedures. 
 
Tissue Microarray: The development of tissue arrays allows the evaluation of each of 
many proteins in many sets of normal and tumor tissues using a single slide for each 
probe. It provides a powerful way to follow up the candidate protein changes proposed in 
this study with control of technical variation. We will determine the changes in protein 
expression on tissue microarray (TMA) by IHC and correlate these altered protein 
changes with the clinical response to erlotinib. Five-m sections of normal and tumor 
tissues embedded in paraffin will be stained with H&E to identify morphologically 


 
Version 1.7 Nov 5, 2014 
Page 29 
 
representative area of normal and tumor tissues, from which core biopsies will be taken. 
The tissue microarray will be done with the Tissue Arrayer (Beecher Instruments, Silver 
Spring, MD). From each specimen (donor), tissue cores with a diameter of 0.6 or 1.0 mm 
are punched and arrayed on a blank paraffin block (recipient). The spacing between the 
centers of two adjacent specimens on the array ranged from 3 mm to 8 mm. Two to three 
hundred cores could be created within the array block. Then the recipient block is 
incubated at 370C oven for 1 hour to soften the paraffin and melt the surface of the block.  
 
Immunohistochemistry (IHC): Tissue arrays containing diagnostic, pre- and post-
treatment tumor and normal human NSCLC tissues (as described above) will be cut in 5-
µm sections, deparaffinized, rehydrated, and quenched with 1.5% H2O2. For EGFR 
studies, the slides will be treated with DakoCytomation Target Retrieval Solution 
(DAKO, Carpinteria, CA) in a steam bath at 95°C for 45 minutes. After equilibration in 
PBS for 15 minutes, the slides were placed in an autostainer (DAKO, Carpinteria, CA) 
and stained with antibodies to EGFR (DAKO; 1:100 dilution). Immunoreactivity will be 
detected using DAKO EnVision methods (DAKO) according to the manufacturer 
recommended procedures. The activated EGFR is detected using antibodies against the 
phosphorylated forms of EGFR (p-EGFR). Similar IHC staining will be performed using 
with antibodies specific for other proteins as described previously.[88] For negative 
controls, slides will be treated with the same procedure, including antigen retrieval, 
except for omission of the primary antibodies. The level of expression will be assessed as 
percentage of positive staining cells, and scored as 0 (0%), +1 (1-25%), +2 (26-50%) and 
+3 (51-100%) as described before [89]. Cell pellets from human NSCLC cell lines known 
to be positive or negative for EGFR will be used as positive or negative controls for 
EGFR expression. Negative controls will also be performed by omission of the primary 
antibody. A sample of recording IHC results is illustrated in Appendix I. 
 
Human IFN-γ ELISA:  We will collect 5 ml of peripheral blood using citrate, EDTA, or 
heparin as anticoagulant from the patients before and 2 weeks after treatment. Plasma 
will be collected by centrifuging the blood for 10 minutes at 1000 x g within 20 minutes 
of collection. The plasma will be stored at ≤ 20°C or shipped on dry ice. We will analyze 
the patient plasma samples for in vitro T-cell function by ELISPOT assay using tumor 
specific antigens. A positive interferon gamma (IFN-γ) response to a common antigen 
(such as whole influenza virus or EBV) will be used as a control. The results will be 
correlated to the skin changes and clinical outcome of the patients.  
 
9.0    PATIENT REGISTRATION:  
 
 
All patients will be registered through the Clinical Trials Office at Montefiore Medical 
Center (Telephone: 718-379-6861) Monday through Friday 9:00am – 5:00pm Eastern 
Standard Time. Eligibility Checklist and Registration Form with supporting 
documentation, and the signed Patient Consent Form must be emailed to the clinical 
trials office at Montefiore Medical Center, cpdmu-registration@montefiore.org , at 
the time of registration and prior to patient treatment. Please copy the Montefiore 
Study and Regulatory Coordinator on this email, as well as the Principal 
Investigator at Montefiore. E-mail addresses are available at the cover sheet of this 
protocol document.  


 
Version 1.7 Nov 5, 2014 
Page 30 
 
At the time of registration, all eligibility criteria must be checked. Patients must meet all of the 
eligibility requirements listed in Appendix B (Eligibility Checklist) (Section 3.0). Patients must 
not start protocol treatment prior to registration. 
It is the treating physician’s responsibility to review all data submitted to the 
Clinical Trials Office for accuracy and completeness and he/she must sign the off 
study form.  
 
10.0   PHARMACEUTICAL INFORMATION 
       10.1 Erlotinib (Tarceva®) 
 
Chemical Name: Erlotinib is a quinazolinamine with the chemical name N-(3-
ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. 
TARCEVA 
contains erlotinib as the hydrochloride salt, which has the following structural 
formula: 
 
 
Other Names: CP-358, 774, USAN: OSI-774 (Erlotinib) hydrochloride, Tarceva®  
 
Classification:  Signal Transduction Inhibitor, Tyrosine kinase Inhibitor (EGFR) 
 
Molecular Formula: 
C22H23N3O4.HCl  
Molecular Weight: 429.90 
 
Mode of Action:  
The mechanism of clinical anti-tumor action of erlotinib is not fully characterized. 
Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated 
with the epidermal growth factor receptor (EGFR). Specificity of inhibition with 
regard to other tyrosine kinase receptors has not been fully characterized. EGFR 
is expressed on the cell surface of normal cells and cancer cells. 
 
How Supplied:  
Erlotinib tablets are available in 25 mg, 100 mg and 150 mg erlotinib and contain 
the following inactive ingredients: lactose monohydrate, hypromellose, 
hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium 
starch glycolate, sodium lauryl sulfate and titanium dioxide.    All tablets are 
round, white, film-coated bi-convex tablets without markings.  Erlotinib 
hydrochloride, clinical trial material will be provided by Astellas, the study 
sponsoe. 
 


 
Version 1.7 Nov 5, 2014 
Page 31 
 
Storage:  
The intact bottles should be stored at controlled room temperature15°C-30°C- 
(59°F and 86°F).  Tarceva® tablets are supplied in blue-white high-density 
polyethylene (HDPE) bottles of 30 each with some overage.  
 
Route of Administration:  Oral. 
 
Method of Administration 
Tarceva® tablets should be taken at approximately the same time each day.  Each 
Tarceva® dose is to be taken with up to 200 mL (~ 1 cup or 8 oz) of water one 
hour before or two hours after meals or medications, including vitamins and iron 
supplements.  Tarceva® should not be taken with grapefruit juice.  The entire 
dose must be taken at one time.  If the patient vomits after taking the tablet(s), the 
dose is replaced only if the tablet(s) can actually be seen and counted. 
 
Warnings and Precautions 
 
Interstitial Lung Disease (ILD):  
 
Cases of serious ILD, including fatal cases, can occur with TARCEVA treatment. 
The overall incidence of ILD in approximately 32,000 TARCEVA-treated 
patients in uncontrolled studies and studies with concurrent chemotherapy was 
approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 
days to more than 9 months (median 39 days) after initiating TARCEVA therapy. 
Withhold TARCEVA for acute onset of new or progressive unexplained 
pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic 
evaluation. If ILD is confirmed, permanently discontinue TARCEVA  
 
Renal Failure 
 
Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal 
insufficiency can occur with TARCEVA treatment. Renal failure may arise from 
exacerbation of underlying baseline hepatic impairment or severe dehydration. 
The pooled incidence of severe renal impairment in the 3 monotherapy lung 
cancer studies was 0.5% in the TARCEVA arms and 0.8% in the control arms. 
The incidence of renal impairment in the pancreatic cancer study was 1.4% in the 
TARCEVA plus gemcitabine arm and 0.4% in the control arm. Withhold 
TARCEVA in patients developing severe renal impairment until renal toxicity is 
resolved. Perform periodic monitoring of renal function and serum electrolytes 
during TARCEVA treatment. 
 
Hepatotoxicity with or without Hepatic Impairment 
 
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with 
TARCEVA treatment in patients with normal hepatic function; the risk of hepatic 
toxicity is increased in patients with baseline hepatic impairment. In clinical 
studies where patients with moderate to severe hepatic impairment were excluded, 


 
Version 1.7 Nov 5, 2014 
Page 32 
 
the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies 
was 0.4% in the TARCEVA arms and 0% in the control arms. The incidence of 
hepatic failure in the pancreatic cancer study was 0.4% in the TARCEVA plus 
gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 
patients with moderate hepatic impairment (Child-Pugh B) associated with 
significant liver tumor burden, 10 of these 15 patients died within 30 days of the 
last TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died 
from rapidly progressing liver failure and the remaining 8 patients died from 
progressive disease. Six out of the 10 patients who died had baseline total 
bilirubin > 3 x ULN. 
 
Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) 
during treatment with TARCEVA. Increased frequency of monitoring of liver 
function is required for patients with pre-existing hepatic impairment or biliary 
obstruction. Withhold TARCEVA in patients without pre-existing hepatic 
impairment for total bilirubin levels greater than 3 times the upper limit of normal 
or transaminases greater than 5 times the upper limit of normal. Withhold 
TARCEVA in patients with pre-existing hepatic impairment or biliary obstruction 
for doubling of bilirubin or tripling of transaminases values over baseline. 
Discontinue TARCEVA in patients whose abnormal liver tests meeting the above 
criteria do not improve significantly or resolve within three weeks. 
 
Gastrointestinal Perforation 
 
Gastrointestinal perforation, including fatal cases, can occur with TARCEVA 
treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, 
NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic 
ulceration or diverticular disease may be at increased risk of perforation. The 
pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer 
studies was 0.2% in the TARCEVA arms and 0.1% in the control arms. The 
incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% 
in the TARCEVA plus gemcitabine arm and 0% in the control arm. Permanently 
discontinue TARCEVA in patients who develop gastrointestinal perforation. 
 
Bullous and Exfoliative Skin Disorders 
 
Bullous, blistering and exfoliative skin conditions, including cases suggestive of 
Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were 
fatal, can occur with TARCEVA treatment. The pooled incidence of bullous and 
exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in 
the TARCEVA arms and 0% in the control arms. The incidence of bullous and  
exfoliative skin disorders in the pancreatic cancer study was 0.4% in the 
TARCEVA plus Gemcitabine arm and 0% in the control arm. Discontinue 
TARCEVA  treatment if the patient develops severe bullous, blistering or 
exfoliating conditions. 
 


 
Version 1.7 Nov 5, 2014 
Page 33 
 
Myocardial Infarction/Ischemia 
 
In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the 
TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of 
these patients died due to myocardial infarction. In comparison, 3 patients in the 
placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), 
and one died due to myocardial infarction. The pooled incidence of myocardial 
infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the 
TARCEVA arms and 0.4% in the control arms. 
 
Cerebrovascular Accident 
 
In the pancreatic carcinoma trial, seven patients in the TARCEVA/gemcitabine 
group developed cerebrovascular accidents (incidence: 2.5%). One of these was 
hemorrhagic and was the only fatal event. In comparison, in the 
placebo/gemcitabine group there were no cerebrovascular accidents. The pooled 
incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies 
was 0.6% in the TARCEVA arms and 0.9% in the control arms. 
 
Microangiopathic Hemolytic Anemia with Thrombocytopenia 
 
The pooled incidence of microangiopathic hemolytic anemia with 
thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the 
TARCEVA arms and 0.1% in the control arms. The incidence of 
microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic 
cancer study was 1.4% in the TARCEVA plus gemcitabine arm and 0% in the 
control arm. 
 
Ocular Disorders 
 
Corneal perforation or ulceration can occur with TARCEVA treatment. Other 
ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or 
keratitis have been observed with TARCEVA treatment and are known risk 
factors for corneal ulceration/perforation. The pooled incidence of ocular 
disorders in the 3 monotherapy lung cancer studies was 17.8% in the TARCEVA 
arms and 4% in the control arms. The incidence of ocular disorders in the 
pancreatic cancer study was 
12.8% in the TARCEVA plus gemcitabine arm and 11.4% in the control arm. 
Interrupt or discontinue TARCEVA therapy if patients present with 
acute/worsening ocular disorders such as eye pain  
 
Hemorrhage in Patients Taking Warfarin 
 
Severe and fatal hemorrhage associated with International Normalized Ratio 
(INR) elevations can occur when TARCEVA and warfarin are administered 


 
Version 1.7 Nov 5, 2014 
Page 34 
 
concurrently. Regularly monitor prothrombin time and INR during TARCEVA 
treatment in patients taking warfarin or other coumarin-derivative anticoagulants  
 
Embryo-Fetal Toxicity 
 
Based on its mechanism of action, TARCEVA can cause fetal harm when 
administered to a pregnant woman. When given during organogenesis, erlotinib 
administration resulted in embryo-fetal lethality and abortion in rabbits at doses 
approximately 3 times the recommended human daily dose of 150 mg. If 
TARCEVA is used during pregnancy, or if the patient becomes pregnant while 
taking this drug, the patient should be apprised of the potential hazard to a fetus. 
 
Advise females of reproductive potential to use highly effective contraception 
during therapy, and for at least 2 weeks after the last dose of TARCEVA. Advise 
patients to contact their healthcare provider if they become pregnant, or if 
pregnancy is suspected, while taking TARCEVA. 
 
ADVERSE REACTIONS 
 
The following serious adverse reactions, which may include fatalities, are 
discussed in greater detail above: 
 
 Interstitial Lung Disease (ILD) Renal Failure  
 Hepatotoxicity with or without Hepatic Impairment  
 Gastrointestinal Perforation  
 Bullous and Exfoliative Skin Disorders  
 Myocardial Infarction/Ischemia  
 Cerebrovascular Accident  
 Microangiopathic Hemolytic Anemia with Thrombocytopenia  
 Ocular Disorders  
 Hemorrhage in Patients Taking Warfarin  
 
Clinical Trial Experience 
 
Because clinical trials are conducted under widely varying conditions, adverse 
reaction rates observed in the clinical trials of a drug cannot be directly compared 
to rates in the clinical trials of another drug and may not reflect the rates observed 
in practice. 
 
Safety evaluation of TARCEVA is based on more than 1200 cancer patients who 
received TARCEVA as monotherapy, more than 300 patients who received 
TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received 
TARCEVA concurrently with other chemotherapies.  
 
The most common adverse reactions with TARCEVA are rash and diarrhea 
usually with onset during the first month of treatment. The incidences of rash and 


 
Version 1.7 Nov 5, 2014 
Page 35 
 
diarrhea from clinical studies of TARCEVA for the treatment of NSCLC and 
pancreatic cancer were 70% for rash and 42% for diarrhea. 
 
Non-Small Cell Lung Cancer 
 
First-Line Treatment of Patients with EGFR Mutations 
 
The most frequent (≥ 30%) adverse reactions in TARCEVA-treated patients were 
diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In TARCEVA-
treated patients the median time to onset of rash was 15 days and the median time 
to onset of diarrhea was 32 days. 
 
The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients 
were rash and diarrhea. Dose interruptions or reductions due to adverse reactions 
occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA 
treated patients discontinued therapy due to adverse reactions. In TARCEVA-
treated patients, the most frequently reported adverse reactions leading to dose 
modification were rash (13%), diarrhea (10%), and asthenia (3.6%). 
 
Selected, common adverse reactions in the study, occurring in at least 10% of 
patients who received TARCEVA or chemotherapy and an increase in ≥ 5% in 
the TARCEVA treated group, are summarized by NCI-CTC (version 3.0) Grade 
in Table 1. The median duration of TARCEVA treatment was 9.6 months in the 
study 4. 
 
Table 1: Selected Adverse Reactions with an Incidence Rate ≥ 10% and an 
Increase of ≥ 5% in the TARCEVA-treated Group 
 
 
TARCEVA  N = 84  
Chemotherapy † N = 83  
MedDRA Preferred Term  
All Grades %  
Grades 3-4 %  
All Grades %  
Grades 3-4 %  
Rash ‡ 
 85  
14  
2  
0  
Diarrhea  
62  
5  
21  
1  
Cough  
48  
1  
40  
0  
 Dyspnea  
45  
8  
30  
4  
 Dry skin  
21  
1  
2  
0  
 Back pain  
19  
2  
5  
0  
 Chest pain  
18  
1  
12  
0  
 Conjunctivitis  
18  
0  
0  
0  
 Mucosal inflammation  
18  
1  
6  
0  
Pruritus  
16  
0  
1  
0  
 Paronychia  
14  
0  
0  
0  
Arthralgia  
13  
1  
6  
1  
Musculoskeletal pain  
11  
1  
1  
0  
 
DRUG INTERACTIONS 
 
CYP3A4 Inhibitors 
Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent 
CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 67%. When TARCEVA was 


 
Version 1.7 Nov 5, 2014 
Page 36 
 
co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the 
erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 
17%, respectively. Dose modifications are recommended. 
 
CYP3A4 Inducers 
 
Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to TARCEVA 
decreased erlotinib AUC by 58% to 80%. Dose modifications are recommended  
 
Drugs Affecting Gastric pH 
 
Co-administration of TARCEVA with omeprazole decreased erlotinib AUC by 46% and 
co-administration of TARCEVA with ranitidine 300 mg decreased erlotinib AUC by 
33%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 
10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning 
dose), erlotinib AUC decreased by 15%. Increasing the dose of TARCEVA when co-
administered with such agents is not likely to compensate for the loss of exposure. 
Scheduling modifications are recommended  
 
Cigarette Smoking 
 
Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are 
recommended  
 
Anticoagulants 
 
Interaction with coumarin-derived anticoagulants, including warfarin, leading to 
increased International Normalized Ratio (INR) and bleeding adverse reactions, which in 
some cases were fatal, have been reported in patients receiving TARCEVA. Regularly 
monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. 
Dose modifications of TARCEVA are not recommended 
 
USE IN SPECIFIC POPULATIONS 
 
Pregnancy 
 
Pregnancy Category D 
 
Risk Summary 
 
Based on its mechanism of action, TARCEVA can cause fetal harm when administered to 
a pregnant woman. When given during organogenesis, erlotinib administration resulted in 
embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the 
recommended human daily dose of 150 mg. If TARCEVA is used during pregnancy, or if 
the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to a fetus. 


 
Version 1.7 Nov 5, 2014 
Page 37 
 
 
Animal Data 
 
Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality 
and abortion in rabbits when given during the period of organogenesis at doses that result 
in plasma drug concentrations approximately 3 times those achieved at the recommended 
dose in humans (AUCs at 150 mg daily dose). During the same period, there was no 
increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses 
resulting in exposures approximately equal to those in humans at the recommended daily 
dose. In an independent fertility study female rats treated with 30 mg/m2/day or 60 
mg/m2/day (0.3 or 0.7 times the recommended daily dose, on a mg/m2 basis) of erlotinib 
had an increase in early resorptions that resulted in a decrease in the number of live 
fetuses. 
 
No teratogenic effects were observed in rabbits or rats dosed with erlotinib during 
organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug 
concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 
times the recommended dose of 150 mg/day on a mg/m2 basis). 
 
Nursing Mothers 
 
It is not known whether erlotinib is present in human milk. Because many drugs are 
present in human milk and because of the potential for serious adverse reactions in 
nursing infants from TARCEVA, a decision should be made whether to discontinue 
nursing or discontinue the drug, taking into account the importance of the drug to the 
mother. 
 
Pediatric Use 
The safety and effectiveness of TARCEVA in pediatric patients have not been 
established. 
 
Geriatric Use 
 
Of the 1297 subjects in clinical studies of TARCEVA for the treatment of NSCLC and 
pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall 
differences in safety or efficacy were observed between subjects 65 years and older and 
those younger than 65. 
 
Females and Males of Reproductive Potential 
 
Contraception 
 
Females 
Counsel patients on pregnancy planning and prevention. Advise female patients of 
reproductive potential to use highly effective contraception during treatment with 
TARCEVA, and for at least 2 weeks after the last dose of TARCEVA. Advise patients to 


 
Version 1.7 Nov 5, 2014 
Page 38 
 
contact their healthcare provider if they become pregnant, or if pregnancy is suspected, 
while taking TARCEVA. 
 
Patients with Hepatic Impairment 
 
Patients with hepatic impairment (total bilirubin > upper limit of normal (ULN) or Child-
Pugh A, B and C) should be closely monitored during therapy with TARCEVA. 
Treatment with TARCEVA should be used with extra caution in patients with total 
bilirubin > 3 x ULN  
 
In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. 
However, erlotinib exposure was similar in patients with moderately impaired hepatic 
function (Child-Pugh B) compared with patients with adequate hepatic function including 
patients with primary liver cancer or hepatic metastases. 
 
Patients with Renal Impairment 
 
Less than 9% of a single dose is excreted in the urine. No clinical studies have been 
conducted in patients with compromised renal function. 
 
OVERDOSAGE 
 
Single oral doses of TARCEVA up to 1,000 mg in healthy subjects and weekly doses up 
to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg 
single-agent TARCEVA in healthy subjects were poorly tolerated after only a few days 
of dosing. Based on the data from these studies, an unacceptable incidence of severe 
adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur 
above the recommended dose In case of suspected overdose, TARCEVA should be 
withheld and symptomatic treatment instituted. 
 
Availability: 
 
Tarceva (Erlotinib) is commercially available and is not currently approved for 
neoadjuvant treatment but it has indication for the first line of patients with metastatic 
non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor 
receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as 
detected by an FDA-approved test;  as the maintenance treatment of patients with locally 
advanced or metastatic non-small cell lung cancer whose disease has not progressed after 
four cycles of platinum-based first-line chemotherapy and for the treatment of patients 
with locally advanced or metastatic non-small cell lung cancer after failure of at least one 
prior chemotherapy regimen. In the U.S., Tarceva (Erlotinib) is marketed by both 
Genentech BioOncology and Astellas. Clinical trial material that is “commercial in 
nature” will be provided by Astellas 
 
References 
 
Investigator’s Brochure: OSI 774 (Erlotinib, Tarceva®) Edition 17, dated 21 Mar 2013. 


 
Version 1.7 Nov 5, 2014 
Page 39 
 
 
11.0 
 AGENT ACCOUNTABILITY: 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from manufacturer using a Drug Accountability Record Form.   
 
12.0   REGULATORY AND  REPORTING REQUIREMENTS: 
12.1 Definitions 
An adverse event can occur on any clinical trial; it is the responsibility of the Principal 
Investigator and his/her research team to identify, review and report all necessary adverse 
events to the institutional IRB, the sponsor and governmental agencies (i.e., NCI and/or 
FDA) as appropriate. Adverse events should be identified through standard, routine 
protocol review and clinical assessment of each subject participating in the clinical trial. 
This review should be timely in order to meet the requirements for adverse event 
reporting defined below.  
 
An adverse event An Adverse Event (AE) is defined as any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
erlotinib whether or not considered related to erlotinib. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific occurrence of one 
or more adverse events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication. All 
AEs considered related to trial medication will be followed until resolution even if this 
occurs post-trial. 
 
Adverse events (AEs) will use the descriptions and grading scales found in the revised 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix C). 
A list of adverse events that have occurred or might occur (Reported Adverse Events and 
Potential Risks) can be found in Section 6 (Pharmaceutical Information).  The reported 
procedures to be followed are presented in the investigators’ brochures.    
 
In the context of multicenter clinical trials, Adverse Events can be characterized as either 
internal adverse events or external adverse events. From the perspective of one particular 
institution engaged in a multicenter clinical trial, internal adverse events are those 
adverse events experienced by subjects enrolled by the investigator(s) at that institution, 


 
Version 1.7 Nov 5, 2014 
Page 40 
 
whereas external adverse events are those adverse events experienced by subjects 
enrolled by investigators at other institutions engaged in the clinical trial. In the context 
of a single-center clinical trial, all Adverse Events would be considered internal adverse 
events. 
 
Unanticipated Problem 
 
Any event, deviation, or problem that meets ALL of the following criteria: 
 
unexpected; AND 
 
possibly, probably or definitely related to study participation; AND fatal, life-
threatening, or serious OR suggests greater risk of harm to study 
 
participant(s)or others than was previously known or recognized. 
 
Unexpected 
 
An event can be categorized as unexpected if it occurs in one or more subjects 
participating in a research protocol; and the nature, severity, or frequency of which is not 
consistent with either: 
i. 
The known or foreseeable risk of adverse events associated with the procedures involved 
in the research that are described in protocol-related documents such as: the IRB-
approved research protocol; any applicable investigator brochure: the current IRB-
approved informed consent document; or other relevant sources of information, such as 
product labeling and package inserts; or 
ii. 
The expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
 
Serious Adverse Event (SAE)  
  
An adverse event or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
i. 
death, 
ii. 
a life-threatening adverse reaction, 
iii. 
inpatient hospitalization or prolongation of existing hospitalization, 
iv. 
persistent or significant incapacity or substantial disruption of the ability to 
v. 
conduct normal life functions, or 
vi. 
a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
12.2 Determination of reporting requirements 
Reportable Events 
 


 
Version 1.7 Nov 5, 2014 
Page 41 
 
Any event that meets the definition of an Unanticipated Problem must be reported to the 
IRB within 5 business days. For multicenter studies, this would include such events that 
occur at external sites.  
 
Other events that must be reported to the IRB include: 
 
The death of a participant in a “greater-than-minimal-risk” protocol being conducted 
at a site under the jurisdiction of the Einstein IRB, even if “anticipated”, if it occurs 
within 30 days of a study-related procedure or the administration of a study drug. 
 
A Protocol Deviation that may place the participant or others at greater medical, 
physiological, social risk or economic risk than was previously known or recognized. 
 
Any deviation from IRB or Institutional Policy or Procedure which has the potential 
to adversely impact one or more subject or the overall integrity of data collected. 
 
Any reporting the PI is required to report directly to the FDA (e.g. the PI is the 
sponsor- Investigator, a protocol involving the use of an HUD). 
 
Any incident, experience, or outcome that indicates that the participant or others were 
placed at greater medical, physiological, social risk or economic risk than was 
previously known or recognized. 
 
Any reporting that the IRB cites as a condition of approval of the protocol. 
 
Complaint from a participant or other individual when the complaint indicates 
unexpected risks or the complaint cannot be resolved by the research team. 
 
Deviation from the IRB Informed Consent Policy. 
 
Systematic data collection errors. 
 
Breach of confidentiality. 
 
Any action taken to eliminate an apparent immediate hazard to a research subject. 
 
Incarceration of a research subject. 
 
Sponsor or regulatory audit that requires corrective action. 
 
Suspension or restriction of an Investigator’s clinical professional license. 
 
Disqualification or suspension of the Investigator by the FDA, NIH or other agency. 
 
A record of non-reportable events and deviations must be maintained by the PI in a log 
and for greater than minimal risk studies must be submitted to the IRB as part of the 
annual review of the protocol.  Adverse events (AEs) will be recorded in the case report 
form for the duration of the trial, regardless of whether or not the event(s) are considered 
related to trial medication. All AEs considered related to trial medication will be followed 
until resolution even if this occurs post-trial. 
Reporting requirements may include the following considerations:  
 
1) whether the patient has received an investigational or commercial agent;  
2) the characteristics of the adverse event including the grade (severity), the relationship 
to the study therapy (attribution), and the prior experience (expectedness) of the adverse 
event 
3) the phase (1, 2, or 3) of the trial 
4) whether or not hospitalization or prolongation of hospitalization was associated with 
the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND) (5-AZA). In some instances, the investigational agent may be 


 
Version 1.7 Nov 5, 2014 
Page 42 
 
available commercially, but is actually being tested for indications not included in the 
approved package label.  
 
 
Steps to determine if an adverse event is to be reported in an expedited manner: 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. The CTCAE provides descriptive terminology 
and a grading scale for each adverse event listed.   
 
Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, 
Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is  considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is NOT listed in section 6.5. the 
current NCI Agent-Specific Adverse Event List for the investigational agent. 
 
Step 5: Review the ”Additional instructions, requirements, and exceptions for this 
protocolspecific requirements for expedited reporting of specific adverse events that 
require specialmonitoring. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE: If the patient received at least one dose of investigational agent, follow the 
guidelines for investigation agents. If no investigational agent was administered, follow 
the guidelines for non-investigational agents. 
 
12.3 Reporting methods 
 
Any event that meets the definition of an Unanticipated Problem must be reported to the 
Montefiore-Einsetin IRB within 5 business days. The Unanticipated Problem Report 
Form 
can 
be 
found 
on 
the 
Einstein 
IRB 
website: 
http://einstein.yu.edu/administration/institutional-review-board/forms.aspx. 
All 
Reportable Events must be submitted to the IRB within 5 business days of the 
identification of the event by the research staff. Only the Principal Investigator may sign 
off on reportable event submissions, although any member of the research team may 
initiate the report. A record of non-reportable events and deviations must be maintained 


 
Version 1.7 Nov 5, 2014 
Page 43 
 
by the PI in a log and for greater than minimal risk studies must be submitted to the IRB 
as part of the annual review of the protocol. 
 
For events that are deemed reportable at participating sites, a copy of the reportable event 
must be submitted to Montefiore Medical Center within 2 business days.  You may send 
to the Principal Investigator and the Study Coordinator.  All contact information is 
located at the cover page of this document.   If not reportable, Adverse Events should be 
logged in the CRF page, and any non-reportable serious and/or unanticipated adverse 
events should be logged on the Adverse Event Log provided by Montefiore for review at 
the Montefiore Data Safety Monitoring Committee meetings and during IRB annual 
review.   
 
Montefiore will submit all reportable events to Astellas Drug Safety within 5 business 
days by submitting to: Astellas Drug Safety: safety-US@astellas.com OR Fax number: 
847-317-1421.   
12.4 Trial Monitoring 
 
This trial will be monitored by the Albert Einstein Cancer Center Data Safety Monitoring 
Committee (AECC DSMC). A copy of the monitoring plan is maintained at the CPDMU.  
The DSMC as part of its function performs quarterly reviews of Clinical Trials 
Compliance Audits, monthly reviews Adverse Events Reports, and monthly reviews of 
internally monitored Phase I/Phase II trials for accrual and response. Other monitoring 
activities are established as necessary in a protocol specific manner.   
 
This trial will be part of the monthly Quality Assurance Audits.  Each patient will be 
evaluated within 8 weeks of registration.  This permits evaluation of consent, eligibility, 
and treatment/dose modification/Adverse Event (AE) reporting, and data quality for the 
first cycle (or month) of treatment.  Patients at participating sites are evaluated for 
eligibility and consent at the time of registration by clinical and administrative staff.   
 
This trial may also be eligible for quarterly Quality Enhancement Audit. Each audit 
consists of a review of regulatory documents, pharmacy drug accountability (if 
applicable) and patient case review, confirming eligibility, protocol compliance and 
source documentation  
 
The results of the audit will be presented at the following month’s DSMC meeting. The 
DSMC has the authority to close trial to patient accrual should the risk to patients be 
excessive or results require a corrective plan from the Principal Investigator.  All study 
suspensions and closures will be forwarded to the IRB and study sponsor.  All audit 
reports are forwarded to the DSMC and presented to the DSMC by the Audit Committee 
Coordinator.  
 
12.5 Expedited reporting for investigational agents 
 


 
Version 1.7 Nov 5, 2014 
Page 44 
 
Follow guidelines in section 12.2 regarding criteria that required expedited reporting. 
 
For any adverse events that occur more than 30 days after the last dose of treatment, only 
those that have an attribution of possibly, probably, or definitely AND meet the reporting 
requirements in Sections 12.2 must be reported on an expedited adverse event report form 
as per guidelines in section 12.2 
 
Adverse events that require expedited reporting are outlined below: for the 
investigational agent erlotinib.  
 
The following be reported as a SAE: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
Unexpected AND  Possibly, Probably or Definitely Related/Associated with the 
Intervention. 
 
 ALL Grade 4 (life threatening or disabling) Events – Unless expected AND 
specifically listed in protocol as not requiring reporting. 
 
 ALL Grade 5 (fatal) Events – When participant is enrolled and actively 
participating in the trial OR when event occurs within 30 days of the last study 
intervention. 
 
 
Additional instructions, requirements and exceptions for this protocol:: 
 
With respect to determining the specific day by which the event must be reported, the day 
the reporter learns of the adverse event constitutes “Day 0”. 
12.6  Responsibilities of participating sites 
 
Serious adverse events will be reported to each participating institution according to 
protocol guidelines and local policies and procedures governing the local Institutional 
Review Board. 
 
A copy of all SAE’s should be faxed to the Coordinating Center, Montefiore Medical 
Center (see cover page) within two (2) business days by the participating site. Other 
events that should be reported include: (1) any pregnancy occurring in association with 
use of erlotinib, and (2) any new information regarding any SAE. 
 
12.7  Responsibilities of the Coordinating Center (Montefiore Medical Center) and 
Astellas. 
 
The Coordinating Center (Montefiore Medical Center) will maintain records and 


 
Version 1.7 Nov 5, 2014 
Page 45 
 
provide reports to Astellas  for the following Adverse Experiences: (1) all serious, 
unexpected, adverse events, (2) any significant increase in the frequency of serious 
expected adverse events, and (3) an annual progress report including number of patients 
accrued, date on study, date off study, vital status (alive/dead and date alive/dead). 
 
 
 
13.0    REMOVAL OF PATIENTS FROM PROTOCOL THERAPY: 
 
 
Extraordinary medical circumstances or withdrawal of consent by the patient:  
 
If, at any time, the constraints of this protocol are detrimental to the patient's health, and/or 
the patient no longer wishes to continue protocol therapy, the patient shall be 
withdrawn from protocol therapy.  Patients will also be withdrawn from study for the 
following reasons: 
1. Disease Progression: Any patient with disease progression should be 
removed from study.  Details and tumor measurements should be 
documented on flow sheets. 
2. Patient is unable to tolerate the toxicity resulting from the study treatment, 
even with optimal supportive care, in the opinion of the Treating 
Physician. Adverse event(s) that, in the judgment of the investigator, may 
cause severe or permanent harm or which rule out continuation of study 
drug.  
3. The physician feels it is in the best interest of the patient to stop the 
treatment. 
4. Inter current illness that would, in the judgment of the Investigator, affect 
assessment of clinical status to a significant degree or require 
discontinuation of study treatment 
5. Non protocol chemotherapy or immunotherapy is administered during the 
study 
6. Noncompliance with protocol or treatment—major violation 
7. Suspected Pregnancy 
8. Patient is lost to follow-up 
9. Patient refuses to continue treatment (patient will continue to be followed 
for disease-free survival and overall survival) 
10. Death 
 
In this event notify:          
 
Study PI (contact information on cover page of protocol) 
Study Coordinator(contact information on cover page of protocol) 
Regulatory Coordinator(contact information on cover page of protocol) 
Clinical Trials Office: Phone:718-379-6861  AND e-mail:  
cpdmu-registration@montefiore.org 
             
*Document the reason(s) for withdrawal on flow sheets.  Follow the 
 
patient for survival  with follow-up forms as dictated by the protocol 


 
Version 1.7 Nov 5, 2014 
Page 46 
 
 
 
14.0    FOLLOW-UP: 
 
Subjects who undergo surgery will have a post-surgery follow-up visit 30 days (±3 days) 
after surgery. Subjects who do not receive surgery will have an end of treatment visit 30 
days (±3 days) after Post-Treatment Visit.  
Any adverse event occurred during the study treatment should be monitored by 
subsequent follow-up visits until resolves to grade 1 or less, or until a new therapy is 
started.  
Subjects who discontinue treatment for any reason, will be followed for survival. In 
addition off study evaluations will be done when treatment is discontinued -Section 7.0. 
 
15.0   REGULATORY CONSIDERATIONS: 
 
15.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate.  Preparation of the consent 
form is the responsibility of the Investigator and must include all elements required by 
CFR 21 Part 50.25 and the local IRB. 
 15.2 Compliance with the Protocol and Protocol Revisions 
 
The study must be conducted as described in this approved protocol. The participating 
sites should not make any changes or revision to the protocol.  
Any changes or revisions to the protocol must be provided to Dr. Cheng, Montefiore 
Medical Center and Astellas.  The Investigator should not implement any deviation or 
change to the protocol without prior review and documented approval/favorable opinion 
from the IRB/IEC of an Amendment, except where necessary to eliminate an immediate 
hazard(s) to study patients. 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) 
must be sent to Astellas.  If the revision is an Administrative Letter, Investigators must 
inform their IRB(s)/IEC(s).  
 
The Investigator must ensure that patients or their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate.  Preparation of the consent 
form is the responsibility of the Investigator and must include all elements required by 
CFR 21 Part 50.25 and the local IRB. 
 
 


 
Version 1.7 Nov 5, 2014 
Page 47 
 
 
16.0   DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION: 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 
 
The Montefiore Medical Center, as coordinator of this study, is responsible for ensuring 
proper conduct of the study with regard to protocol adherence and the validity of the data 
recorded on the case report forms. The Principle Investigator (Haiying Cheng, MD.) will 
monitor this study. The case report forms will be monitored every 3 months against 
submitted support documents for accuracy, completeness, adherence to the protocol and 
regulatory compliance.  
 
U.S. FDA regulations (21CFR312.62[c] require all records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consents forms, laboratory test results and medication inventory 
records, must be retained by the Principal Investigator for 2 years after marketing 
application approval. If no application is filed, these records must be kept 2 years 
after the investigation is discontinued and the FDA and the applicable local health 
authorities are notified. Astellas will notify the Principle Investigator if an 
application is filed.  
 
 
17. 0   DATA SAFETY AND MONITORING BOARDS: 
 
All trials initiated by the Montefiore Medical Center are subject to oversight by the Data 
Safety Monitoring Board (DSMB).  This board meets once a month with any additional 
meetings scheduled when needed.  The responsibilities are as follows: 
 
 Familiarize themselves with the research protocol (s) 
 Review interim analyses of outcome data and cumulative toxicity data summaries 
to determine whether the trial should continue as originally designed, should be 
changed, or should be terminated based on these data.   
 The DSMB reviews trial performance information such as accrual information.   
 The DSMB also determines whether and to whom outcome results should be 
released prior to the reporting of study results. 
 All adverse events are reviewed by the committee with assurances that these have 
been in fact sent for review to all pertinent IRBs. 
 Review of reports of related studies to determine whether the monitored study 
needs to be changed or terminated. 
 Review major proposed modifications to the study prior to their implementation 
(e.g., termination, dropping an arm based on toxicity results or other reported trial 
outcomes, increasing target sample size). 
 


 
Version 1.7 Nov 5, 2014 
Page 48 
 
Following each DSMB meeting, provide the study leadership with written 
information concerning findings for the trial as a whole related to cumulative 
toxicities observed and any relevant recommendations related to continuing, 
changing, or terminating the trial.  The study leadership will provide information on 
cumulative toxicities and relevant recommendations to the local principal 
investigators to be shared with their IRB’s. 
 
 
18.0   STATISTICAL CONSIDERATIONS: 
18.1 Study Design/Analytic Plan 
 
• 
The primary statistical objectives of this single arm open label phase II study  to 
obtain preliminary estimates of the rate of mediastinal nodal clearance and the 
rate of complete pathologicl response in patients with stage III NSCLC with 
EGFR mutations who received neoadjuvant erlotinib and had surgical resection.  
Historical data from the neoadjuvant studies with chemotherapy or 
chemoradiotherapy in resectable NSCLC patients had mediastinal nodal clearance 
between 15-40%. We hypothesize that patients with stage III EGFR mutated 
NSCLC treated with neoadjuvant erlotinib therapy must have comparable rates of 
mediastinal down staging and complete path response for this strategy to evaluate 
further in this subset of NSCLC patients. 
 
• 
The mediastinal nodal clearance is defined as pathologicaly negative N2 disease 
in the final surgical resection specimen or mediastinoscopy. This can be 
objectively measured and has been confirmed as the best predictor of long term 
survival in patients with stage III NSCLC treated with neoadjuvant therapy and 
had surgical resection. 
 
• 
Secondary objectives are to estimate objective overall response rate [ORR, i.e., 
complete response (CR) + partial response (PR)],  disease control rate 
(CR+PR+SD), the surgical resection rate, the progression free (PFS) and overall 
survival (OS), and the safety of neoadjuvant erlotinib followed by surgical 
resection in patients with stage III EGFR mutated NSCLC.  
 
• 
PFS is defined as the time from randomization until documented tumor 
progression or death from any cause. PFS is censored at the date of the last 
follow-up visit for patients who are still alive and who have not progressed. OS is 
defined as the time from the date of randomization to date of death due to any 
cause.  
 
• 
Response rates will be summarized by computing proportions and corresponding 
95% confidence intervals. Time to event endpoints will be analyzed using 
standard survival analytic methods, including the Kaplan-Meier approach for 
estimating the survival distributions. Median time to event and 95% confidence 
intervals will be estimated from the Kaplan-Meier curves. All primary and 
secondary analyses will be based on the intent-to-treat principle. 


 
Version 1.7 Nov 5, 2014 
Page 49 
 
 
18.2 Sample Size/Accrual Rate 
 
• 
Our study patient population comprise of the patients with stage III NSCLC who 
have activating EGFR mutation.  
 
• 
Based on historical data, the mediastinal nodal clearance rate of 30% or higher 
will justify the further study of neoadjuvant erlotinib and the rate of 15% or less 
will be considered ineffective. 
 
• 
An optimal two-stage phase II study40 is designed to test the null hypothesis that 
the rate is 15% or less versus the alternative hypothesis that the response rate is at 
least 30%. 
 
• 
The total sample size if the study will be 55 patients 
 
• 
Nineteen (19) patients will be accrued in the first stage of phase II. If 3 or fewer 
responses are observed during the first stage then the treatment will be 
concluded early for lack of efficacy. Otherwise, 36 additional patients will be 
accrued for the second stage. If 12 or fewer responses among 55 patients are 
observed by the end of this phase II study, no further investigation of this 
treatment regimen is warranted.  
 
• 
The power under this design is 80% and the type I error is 0.05. The probability of 
early stopping at the first stage is 68.4% if the true response rate is 15%. If the 
true response rate is 30%, the probability of early stopping at the first stage is 
13.3%. 
 
• 
By the end of this study, response rate will be estimated and its exact 95% 
confidence interval will be calculated. A total of 55 patients ensure that the 95% 
confidence interval for the estimated response rate will be within +/- 15.7%. 
 
• 
The Montefiore Medical Center will initiate the study. Additional 4-5 sites will be 
subcontracted by Montefiore Medical Center to expedite accrual in the study. 
 
• 
With the initial anticipated accrual of 1-2 patients per month across 4-5 centers, it 
will take approximately 12 months for the first stage of the study. The total e 
accrual period is assumed to be approximately 24-36 months, with a follow-up 
period of an additional 12 months after the last patient is enrolled.  
18.3 Randomization and Stratification  
 
This will be a single arm phase II study and no randomization or 
stratifications will be involved 
 
 


 
Version 1.7 Nov 5, 2014 
Page 50 
 
     18.4 Evaluation of toxicity.   
 
 
All patients will be evaluated for toxicity from the time of their first treatment 
with erlotinib. All of the surgical procedures in the protocol are the usual 
standard of care in treating patients with stage III NSCLC. However, we will 
monitor and record all postoperative complications. Certain postoperative 
complications are expected after lung resection and/or mediastinoscopy. We 
will particularly monitor 30 day mortality, development of bronchopulmonary 
fistula or prolong wound healing. If the rate of these is more than what is 
expected as standard of care, the regulatory authorities will be reported and 
the trial will be suspended for toxicity. 
18.5 Evaluation of response.   
 
All patients who meet the eligibility criteria and have received at least one 
dose of treatment will be assessed for response to treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 51 
 
19.0    REFERENCES: 
 
1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. 
 
2. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 
2004;350:379 –392.  
 
3. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, 
Rusch V, Sobin L; International Association for the Study of Lung Cancer International Staging 
Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for 
the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM 
Classification of malignant tumours. J Thorac Oncol. 2007 Aug;2(8):706-14. 
 
4. Blackstock AW, Govindan R. 2007. Definitive chemo-radiation for the treatment of locally 
advanced non-small cell lung cancer. J Clin Oncol 25(26):4146-4152. 
 
5. Non-small Cell Lung Cancer Collaborative Group. 1995. Chemotherapy in non-small cell lung 
cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical 
trials. Br Med J 311(7010):899-909. 
 
6. Rolland E, Le Chevalier T, Auperin A Burdett S, Pignon JP on behalf of the NSCLC 
Collaborative Group. 2007. Sequential radio-chemotherapy (RT-CT) versus radiotherapy alone 
(RT) and concomitant RT-CT versus RT alone in locally advanced non-small cell lung cancer: 
Two meta-analysis using individual patient data from randomised clinical trials. J Thorac Oncol 
2(8 Suppl 4):S309. 
  
7. Auperin A, Rolland E, Curran WJ, Furuse K, Fournel P, Belderbos J, Clamon G, Ulutin HC, 
Stewart L, Le Pechoux C on behalf on the NSCLC Collaborative Group. Concomitant 
radiochemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung 
cancer (NSCLC). 2007. A meta-analysis using individual patient data from randomized clinical 
trials. J Thorac Oncol 2(8 Suppl 4):S310. 
 
8. Vokes EE, Herndon JE, Crawford J, Leopold KA, Perry MC, Miller AA, Green MR. 2002. 
Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction 
chemotherapy followed by followed by concomitant chemoradiotherapy for stage III non-small 
cell lung cancer: Cancer and Leukemia Group B Study 9431. J Clin Oncol 20(20):4191-4198.  
 
9. Hanna NH et al. Phase III trial of cisplatin plus etoposide plus concurrent chest radiation with 
our without consolidation docetaxel in patients with inoperable stage III non-small cell lung 
cancer: HOG LUN 01-24/USO-023. J Clin Oncol 2007; 25: 387s 
 
10. Vokes EE, Herndon JE, Kelly MJ, Cicchetti MG, Ramnath N, Neill H, Atkins JN, Watson 
DM, Akerley W, Green MR. 2007. Induction chemotherapy followed by chemoradiotherapy 
compared to chemoradiotherapy alone for regionally advanced unresectable stage III nonsmall- 
cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25(13):1698-1704. 
 
11. Kelly K et al. Updated analysis of SWOG 0023: A randomized phase III trial of gefitinib 
versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients 
with locally advanced stage III non-small cell lung cancer. J Clin Oncol 2007; 25: 388s 
 
12. Albain KS, Swann RS, Rusch VR, Turrisi AT, Shepherd FA, Smith CJ, Gandara DR, Johnson 


 
Version 1.7 Nov 5, 2014 
Page 52 
 
DH, Green MR, Miller RC, North American Lung Cancer Intergroup. 2005. Phase III study of 
concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection 
for stage IIIA (pN2) non-small cell lung cancer (NSCLC). Outcomes update of North 
American Intergroup 0139 (RTOG 9309). J Clin Oncol 23(16S):7014 
 
13. Jan P . van Meerbeeck , Gijs W. P. M . Kramer , Paul E . Y . Van Schil , Catherine Legrand , 
Egbert F . Smit ,Franz Schramel , Vivianne C . Tjan-Heijnen , Bonne Biesma , Channa Debruyne 
, Nico van Zandwijk ,Ted A. W . Splinter , Giuseppe Giaccone   Randomized Controlled Trial of 
Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non – Small-
Cell Lung Cancer J Natl Cancer Inst. 2007 Mar 21;99(6):442-50. 
14. Paul S, Mirza F, Port JL, Lee PC, Stiles BM, Kansler AL, Altorki NK. Survival of 
patients with clinical stage IIIA non-small cell lung cancer after induction therapy: age, 
mediastinal downstaging, and extent of pulmonary resection as independent predictors. J 
Thorac Cardiovasc Surg. 2011 Jan;141(1):48-58. 
15. Decaluwé H, De Leyn P, Vansteenkiste J, Dooms C, Van Raemdonck D, Nafteux P, 
Coosemans W, Lerut T. Surgical multimodality treatment for baseline resectable stage IIIA-N2 
non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on 
survival. Eur J Cardiothorac Surg. 2009 Sep;36(3):433-9.  
 
16. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the 
biology and treatment of cancer. J ClinOncol 2003;21: 2787–2799.  
 
17. Gridelli C, Maione P, Bareschino MA, Schettino C, Sacco PC, Ambrosio R, Barbato V, 
Falanga M, Rossi A. Erlotinib in the treatment of non-small cell lung cancer: current status and 
future developments. AnticancerRes. 2010 Apr;30(4):1301-10. 
 
18. Davies RL, Grosse VA, Kucherlapati R et al. Genetic analysis of epidermal growth factor 
action: Assignment of human epidermal growth factor receptor gene to chromosome 7. 
ProcNatlAcadSci U S A 1980;77:4188–4192. 
 
19.Olayioye MA, Neve RM, Lane HA et al. The ErbB signaling network: Receptor 
heterodimerization in development and cancer. EMBO J 2000; 19:3159 –3167. 
 
20. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358:1160 
–1174.  
 
21. Perez-Soler R: HER1/EGFR targeting: refining the strategy. Oncologist 9: 58-67, 2004. 
  
22. Ling YH, Li T, Yuan Z, Haigentz M Jr, Weber TK, Perez-Soler R.Erlotinib, an effective 
epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and 
nuclear translocation in association with cell growth inhibition and G1/S phase arrest in human 
non-small-cell lung cancer cell lines. MolPharmacol. 2007 Aug;72(2):248-58.  
 
23. Ling YH, Lin R, Perez-Soler R. Erlotinib induces mitochondrial-mediated apoptosis in human 
H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation 
through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK. 
MolPharmacol. 2008 Sep;74(3):793-8019  
 


 
Version 1.7 Nov 5, 2014 
Page 53 
 
24. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, 
Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston 
D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical 
Trials Group.Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 
14;353(2):123-32. 
 
25. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier 
O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN 
investigators.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a 
multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9.  
 
26. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, 
Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. 
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-
small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39.  
 
27. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical 
response to gefitinib therapy. Science 2004;304:1497-500. 
 
28.Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung 
cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and 
erlotinib. ProcNatlAcadSci U S A 2004;101:13306-11. 
 
29. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role 
in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009 Aug;28 Suppl 1:S24-31 
 
30. Ahn MJ, Park BB, Ahn JS, Kim SW, Kim HT, Lee JS, Kang JH, Cho JY, Song HS, Park SH, 
Sohn CH, Shin SW, Choi JH, Ki CS, Park CK, Holmes AJ, Jänne PA, Park K. Are there any 
ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung 
cancer? Clin Cancer Res. 2008 Jun 15;14(12):3860-6. 
 
31. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majern M, Lopez-Vivanco G, 
Isla D, Provencio M, Insa A, Massuti B, Gonzales-Larriba JL, Paz-Ares L, Bover I, Garcia-
Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo 
C, Bertran-Alamillo J, Molina MA, Sanchez JJ and Taron M: Screening for epidermal growth 
factor receptor mutations in lung cancer. N Engl J Med 361: 958-967, 2009. 
 
32. D'Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, Zakowski MF, 
Rusch VW, Ladanyi M, Kris MG.  Incidence of EGFR exon 19 deletions and L858R in tumor 
specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011 May 
20;29(15):2066-70.  
 
33. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, 
Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, 
Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma.Sep 3;361(10):947-57. Epub 2009 Aug 19. 
 
34. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, 
Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, 
You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR 


 
Version 1.7 Nov 5, 2014 
Page 54 
 
mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-
label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. Epub 2011 Jul 23. 
 
35. R. Rosell, R. Gervais, A. Vergnenegre, B. Massuti, E. Felip, F. Cardenal, R. Garcia Gomez, 
C. Pallares, J. M. Sanchez, R. Porta, M. Cobo, M. Di Seri, P. Garrido Lopez, A. Insa, F. De 
Marinis, R. Corre, M. Carreras, E. Carcereny, M. Taron, L. G. Paz-Ares, Spanish Lung Cancer 
Group; Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) 
patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the 
European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Lancet Oncol. 
2012 Mar;13(3):239-46. doi: 10.1016/S1470-2045(11)70393-X   
36. P. A. Janne, X. F. Wang, M. A. Socinski, J. Crawford, M. Capelletti, M. J. Edelman, M. A. 
Villalona-Calero, R. A. Kratzke, E. E. Vokes, V. A. Miller. Randomized phase II trial of erlotinib 
(E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers 
with advanced lung adenocarcinoma: CALGB 30406. J ClinOncol 28:15s, 2010 (suppl; abstr 
7503) 
 
37. Weber B, Sorensen BS, Knap MM, Madsen HH, Nexo E, Meldgaard P. Complete pathologic 
response in lung tumors in two patients with metastatic non-small cell lung cancer treated with 
erlotinib. J Thorac Oncol. 2011 Nov;6(11):1946-9. 
 
38. [NCI] National Cancer Institute. 2006. Cancer therapy evaluation program common 
terminology criteria for adverse events, version 3.0. Available at 
http://ctep.cancer.gov/reporting/ctcnew.html, accessed 4 February 2008. 
 
39.Investigator brochure erlotinib 
 
40.  Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 
1985; 69: 1375-1381. 
 
41. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228-47. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 55 
 
APPENDIX A 
MODEL INFORMED CONSENT 
 
 
Montefiore Medical Center 
Albert Einstein College of Medicine of Yeshiva University 
 Individual's Informed Consent to Participate as a Subject in Clinical Research 
 
TITLE OF STUDY 
EValuation of Erlotinib as a Neoadjuvant Therapy in stage III NSCLC patients 
with EGFR mutations (EVENT trial) 
 
 
PRINCIPAL   
 Haiying Cheng, MD  
INVESTIGATOR:  
 
 
 
 
TELEPHONE NO.: 718-405-8404 
OFFICIAL 
 
1695 EASTCHESTER ROAD 
 
ADDRESS: 
 
Bronx, NY 10461 
 
 
IRB PROTOCOL NO.:                                    
 
INTRODUCTION  
                                          
By signing this form you have voluntarily agreed to participate as a subject in the 
research study referenced above. 
 
You are being asked to take part in this research study because you have a type of lung 
cancer called Non-Small Cell Lung Cancer (NSCLC). Your physicians have determined 
that you have stage III disease and your tumor tested positive for a mutation in a gene 
called epidermal growth factor receptor (EGFR). The treatment for stage III lung cancer 
is complex and the standard treatment includes a combination of chemotherapy and 
radiation followed by surgery. This study will examine the effectiveness of an oral 
targeted therapy called erlotinib followed by surgery for your particular type of lung 
cancer. You are being offered this study because your physician thinks that your body is 
in good condition to receive this treatment followed by surgery to control your cancer.  
 
This is a clinical trial (a type of research study).  Clinical trials include only patients who 
choose to take part.  Please take your time to make your decision and discuss it with your 
friends and family. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this study is to develop more effective treatments for patients with stage 
III lung cancer like you by using effective novel targeted therapy prior to surgery. You 
are being asked to participate because your tumor has spread to the lymph nodes and 
hence determined to have stage III disease. The standard treatment options for your 


 
Version 1.7 Nov 5, 2014 
Page 56 
 
condition will usually includes a combination of chemotherapy and radiation either alone 
or followed by surgical resection, chemotherapy followed by surgery or in rare cases 
surgery followed by chemotherapy and radiation. 
 
Recent advances in molecular medicine has enable the physicians to identify the changes 
in the cancer causing genes called oncogenes in the tumor and develop medicine against 
these targets. About 15-20% of patients with the type of lung cancer that you have a 
mutation in a gene called epidermal growth factor receptor (EGFR). Erlotinib (Tarceva®) 
is an oral medication that targets EGFR. Erlotinib is available as a once a day oral pill. 
Erlotinib has proven clinical benefit in patients with advanced lung cancer when it is used 
alone as a single agent. The U.S. Food and Drug Administration (FDA) approved them 
for commercial use for patients with NSCLC who have failed one prior regimen of 
chemotherapy in 2004, as a maintenance therapy after chemotherapy in 2010 and recently 
approved as first line therapy in patients with stage IV disease (where the tumor is 
spread) and have EGFR mutation.   
 
Recent studies have shown that in patients with advanced lung cancer (where the tumor is 
spread) with EGFR mutation, single agent erlotinib is more effective than standard 
chemotherapy in reducing the size of the tumor and delaying the growth of tumor. 
However, if one drug is used alone, the majority of these tumors develop resistance to 
this drug over a period of 9-12 months. In addition, the role of erlotinib, in patients with 
stage III disease, like you, has not been studied. 
 
This study will examine the effectiveness of erlotinib giving prior to surgery in stage III 
patients with EGFR mutation. You are being offered participation in this study because 
your physicians have determined that you have stage III disease and your tumor tested 
positive for EGFR mutation. You will receive two months of treatment with daily oral 
erlotinib and then be evaluated for surgery. If there is significant shrinkage of the tumor, 
you will be offered surgery to completely remove your tumor.  
 
This will be a single arm study and all the patients in the study will receive the same kind 
of treatment.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
A total of 55 patients with stage III NSCLC with EGFR mutation will take part in this 
multi-institution study.   
 
WHAT IS INVOLVED IN THE STUDY 
 


 
Version 1.7 Nov 5, 2014 
Page 57 
 
Procedures and Tests Prior the Start of the Study 
 
If you give consent to take part in this study by signing this form, you will have certain 
tests and procedures (called “screening”) to determine that you are not at increased risk 
for side effects and you are eligible to receive treatment with erlotinib (Tarceva®) 
followed by surgical resection. If your tumor has not been previously tested for EGFR 
mutation, your physician will have you signed a separate consent form for testing. This 
testing is NOT covered by the study. 
 
At this “screening” visit the following will be done. These are part of regular cancer 
care:  
 Your study doctor will record your medical history, including your smoking 
habits, medication list, and perform a physical examination.  
 Your medication will be reviewed and your doctor might advise you to avoid 
some medications during your participation in the study. 
 About two (2) tablespoons of blood will be drawn from one of your veins to 
conduct laboratory tests of blood cell counts (numbers of each type of blood 
cell), chemistries (elements and minerals in your blood), and blood clotting.  
 You will have a PET/CT scan and MRI of the brain, if not already done as a 
part of your standard work up, to determine the extent of your disease and 
stage. 
 
If you are a woman who could get pregnant, you will be required to have a pregnancy test 
prior to entering the study and again after you stop taking erlotinib (Tarceva®). Patients, 
both females and males with reproductive potential (i.e. menopausal for less than one 
year and not surgically sterilized) must practice contraceptive measures throughout the 
study, 
Your researcher will review with you all medications that you are taking as some may 
interact with your therapy and may need to be discontinued. 
It is possible that after these tests are reviewed, you will not be able to take part in the 
study.  There may also be other reasons why you cannot participate which will be 
discussed with you by your doctor. 
 
Treatment 
If the screening tests show that you are eligible to participate in the study, you will be 
asked to return to the clinic once every two week during the treatment with erlotinib. You 
will be taking erlotinib treatment for about two months then be evaluated for surgery. It is 
important to understand that taking part in this study requires a commitment from you to 
visit the clinic for the regular appointments. 
 
Procedures and Tests during the Study 
 


 
Version 1.7 Nov 5, 2014 
Page 58 
 
The following examinations and tests will be performed at the clinic during study 
treatment. These are part of regular cancer care: 
: 
 Your doctor will examine you in the clinic every two weeks while you are on 
treatment with erlotinib. 
 About two (2) tablespoons of blood will be drawn from one of your veins to 
conduct laboratory tests of blood cell counts (numbers of each type of blood 
cell), chemistries (elements and minerals in your blood), and blood clotting on 
the first day of each treatment cycle and once every week during the first 
treatment cycle. 
 If you are taking anticoagulation medicine such as coumadin (warfarin), you will 
need more frequent blood tests to check blood clotting (PT/INR) as 
determined by the study doctor (e.g. weekly for first month and weekly for a 
minimum of 2 weeks following discontinuation of Tarceva® (Erlotinib).  
 After 2 months of erlotinib treatment, you will have a PET/CT scan to determine 
whether you are responding to the treatment (i.e. whether or not the tumor 
shrunk or remains stable) or not.  You will then be evaluated by a surgeon for 
surgical removal of the remaining tumor. You will continue to take erlotinib 
until 1day prior to the surgery. 
 Your treatment after the surgery will be determined by your treating physician 
and it will be influenced by your response to treatment with erlotinib. 
 
LABORATORY RESEARCH STUDIES 
 
If you participate in this study, your tumor tissue collected from a previous biopsy or 
surgery will be sent to researchers to determine several molecular and cellular 
biomarkers in the tumor.  Researchers hope this research will help them understand how 
your disease responds to the treatment. At the end of this consent, you will also be asked 
if your blood and a skin biopsy may be collected and used for other laboratory research 
studies. These additional research studies are optional. Even if you decline the additional 
research studies below, your tumor tissue will still be sent 
for the molecular and cellular tests.  
The results of the laboratory research studies will not be sent to you or your doctor, will 
not be placed in your medical records, and will not affect your care. These tests are for 
research purposes only. 
Drug Treatment 
The treatment will be administered in the outpatient clinic. You will not need to be 
hospitalized to participate in this study unless you experience a serious side effect. 
 
You will take erlotinib (Tarceva®) at a dose of 150 mg daily for approximately two 
months. After 2 months of erlotinib treatment, you will have a PET/CT scan to determine 
whether you are responding to the treatment (i.e. whether or not the tumor shrunk or 


 
Version 1.7 Nov 5, 2014 
Page 59 
 
remains stable) or not.  You will then be evaluated by a surgeon for surgical removal of 
the remaining tumor. You will continue to take erlotinib until 1day prior to the surgery. 
Your treatment after the surgery will be determined by your treating physician and it will 
be influenced by your response to treatment with erlotinib.  
 
Tarceva® (Erlotinib) 
Tarceva® (Erlotinib) 150 mg in tablet form is to be taken by mouth once daily. Your 
doctor may reduce the dose of Tarceva® (Erlotinib) if he or she is concerned that you 
have any significant side effects. The tablet should be taken in the morning with a glass 
of water.  It should be taken at least one hour before or two hours after a meal. Patients 
should avoid grapefruit juice while on Tarceva® (Erlotinib). If you forget to take your 
daily dose of Tarceva® (Erlotinib) in the morning you can take the dose later during the 
day. If you forget to take the tablet one day, you must NOT take the missed tablet the 
next day.  
 
You will be provided with Tarceva® (Erlotinib) free of charge for the entire time that you 
are on the study. You will be asked to complete a pill diary for Tarceva® (Erlotinib). We 
will provide you with the diary. Every dose of medication must be recorded on this diary 
in order to assure that you are taking the drug properly. You should bring this diary with 
you on each visit for collection by the research staff.  
 
If you experience serious side effects on either treatment, your doctor may consider 
reducing your dose or stopping treatment. 
 
Genetic Research 
The tests conducted under this research study may reveal genetic information in your 
tumors. Since the significance of these tests is not known for you and it is not likely to 
affect your family members, we will not disclose the results of the genetic testing. No 
formal genetic counseling will be provided under this research study.   
GENETIC COUNSELING INFORMATION: You may wish to obtain professional 
genetic counseling prior to signing the informed consent. A genetic counselor is a person 
qualified to provide information about what the results of this type of test may mean to 
you and your family. You or your insurance company will be responsible for the cost of 
these services.  
Please also see the "Study Plan Schema" at the end of this document that outlines this 
study for you. 
HOW LONG WILL I BE IN THE STUDY? 
You will receive erlotinib treatment for about two months followed by surgery. You will 
then be followed on regular basis for about 5 years. 
Your treatment in this study will continue as long as six conditions are met: 
 You continue to agree to take part in the study and follow the instructions.  


 
Version 1.7 Nov 5, 2014 
Page 60 
 
 Your disease does not become worse.   
 If your medical condition changes during treatment and continuing in the 
study do not appear to be in your best interest, you will be told, the treatment 
will be stopped, and other options for your medical care will be discussed with 
you. 
 No severe or life-threatening side effects develop.  The drug will be stopped if 
such side effects develop and appropriate medical care will be provided. 
 Your study doctor, the Sponsor, and the Supporters agree to continue to 
conduct the study and to continue your participation in the study. There may 
be safety issues or regulatory requirements that would cause the end of your 
participation in the study or that would end the study altogether. 
 For women, you do not become pregnant. 
 
You may stop participating at any time. However if you decide to stop participating in 
this research study we encourage you to talk to the study doctor first.  
 
POST-SURGICAL FOLLOW-UP 
After your surgery, you will be seen in the clinic for post-surgical follow up.  At this 
visit, the following procedures will be performed: 
 A physical examination and your vital signs will be recorded. 
 Your study doctor will also ask you about any medications you are taking, and 
about any side effects or symptoms you are having. 
 Blood samples (about 2 tablespoons) will be drawn for blood counts, 
chemistries, and clotting tests. 
 X-rays and/or other imaging scans to evaluate your disease may be repeated.  
 If you are a woman of childbearing potential, a pregnancy test may be 
performed if your study doctor believes it is necessary. 
 
After this visit, your study doctor will follow your disease status as needed.  
WHAT ARE THE RISKS OF THIS RESEARCH STUDY 
 
Based on the side effects seen in other lung cancer patients after receiving erlotinib 
(Tarceva®), we can predict some, but not all of the side effects you may have. You may 
experience some, all, or none of the side effects.  You should discuss these side effects 
with your doctor. You will be watched closely for side effects, and the drug will be 
stopped if serious side effects develop.  Other drugs will be given to make some of the 
side effects less serious and less uncomfortable. Many side effects go away shortly after 
the treatment is stopped, but in some cases, side effects can be serious, long lasting, 
permanent, or life threatening. Death is a rare but possible complication of this treatment. 
 
Tarceva® (Erlotinib) Risks and Discomforts 
 


 
Version 1.7 Nov 5, 2014 
Page 61 
 
Tarceva® (Erlotinib) may affect several organs or parts of your body in addition to the 
potential side effects it may have on cancer cells.   
 
The most common side effects of Tarceva® are rash and diarrhea.  These can be 
controlled with medication or if they become too severe, the Tarceva® treatment may 
have to be interrupted or the dose reduced.  If you have a rash that is bothersome, you 
should seek advice from your study doctor. In some cases, diarrhea accompanied by 
nausea, loss of appetite or vomiting may lead to dehydration (loss of too much body 
fluid) which could cause decreased kidney function.  If you have diarrhea that is severe or 
lasts more than 3 days you should seek advice from your study doctor. 
 
The side effects of Tarceva® may include but are not limited to:  
 
In more than 20% of patients: 
 
 Skin rash 
 Diarrhea (this may be treated with anti-diarrhea drugs) 
 Loss of appetite 
 Tiredness or fatigue 
 New or worse shortness of breath 
 Cough 
 Nausea 
 Vomiting 
 Infections 
 Weight loss (observed in the erlotinib+gemcitabine treatment for 
pancreatic cancer) 
 Dry skin  
 
In 5%-20% of patients: 
 
 Depression (observed in the erlotinib+gemcitabine treatment for 
pancreatic cancer) 
 Headache 
  Inflammation of mucous lining of mouth, mouth sore, or mouth ulcer 
 Itching 
 Dry, red, irritated eyes  
 Back pain 
 Chest pain 
 Joint pain 
 Musculoskeletal pain 
 Dehydration (loss of too much body fluid) 
 Nail infection 
 Fever 
 Abdominal or stomach pains 
 Wind, heartburn or upset somach 


 
Version 1.7 Nov 5, 2014 
Page 62 
 
 Neuropathy (nerve damage resulting in numbness or tingling) 
 Nosebleeds 
 Hair loss or thinning 
 Constipation 
 
In less than 5% of patients: 
 
 Changes in liver function tests which may indicate liver damage 
 Isolated reports of liver failure, including deaths 
 Irritation or damage to the cornea (clear part on the front of the eye) 
which may lead to changes in vision 
 Isolated reports of corneal ulcer or perforation 
 Irritation of stomach or bowel which may lead to ulcers (lining 
breakdown) or bleeding 
 ILD (Interstitial lung disease). An irritation of the lungs which rarely 
may be severe and may result in death  
 Decreased kidney function 
 Isolated reports of low potassium levels and kidney failure, including 
deaths 
 Changes in the sense of taste 
 Severe infections  
 Increased risk of bleeding which may be worse in patients who have 
low platelet count, are taking blood thinners, or are taking certain 
drugs for pain called NSAIDs such as aspirin or ibuprofen 
 Fingernail/toenail changes, and/or irritation of skin around nails 
 Possible cracking of skin, especially of fingers and toes 
 Isolated reports of increased body hair growth or eyelash/eyebrow 
changes. 
 Increased risk of gastrointestinal perforation, especially in patients 
with a history of ulcers or diverticulitis or who are taking NSAIDs, 
corticosteroids, or certain types of chemotherapy called taxanes or 
types of chemotherapy that target blood vessels 
 Isolated reports of conditions causing severe blistering or peeling of 
the skin, including deaths 
 Darkening of the skin color in isolated areas (hyperpigmentation) 
 
There is also a possibility of interaction between Tarceva® and statin, a cholesterol 
reducing drug, which may increase the risk of statin-related muscle problems which on 
rare occasions can lead to serious muscle breakdown resulting in kidney damage. 
Therefore, if you are also taking a statin, you should tell your doctor immediately if you 
experience unexplained muscle pain, tenderness, weakness or cramps. Your doctor may 
need to interrupt your treatment.   
 
We do not know all the side effects of the study drug or side effects due to a combination 
of Tarceva® with other drugs or alcohol. Therefore, you should always discuss the use of 


 
Version 1.7 Nov 5, 2014 
Page 63 
 
alcohol or any drugs (over-the-counter), prescription, illegal) with your doctor while you 
are in this study. 
Anticoagulants 
If you are taking or you have been prescribed a blood thinner (anticoagulants) at any time 
during the study, it is important that you immediately inform your study doctor. The 
study drug, Tarceva® (Erlotinib), may increase the risk of bleeding if you are taking 
blood thinners called coumadin or warfarin.  Until further related information is 
available, your doctor will closely follow up with blood tests to control this situation.  If 
you are visiting any other doctor at another site or office, who prescribes you 
anticoagulants, it is important that you inform him/her about your participation in this 
study.   
Other Potential Risks Include: 
 
Risks Associated with Blood Tests 
Side effects associated with blood tests may include infection, bruising, redness, 
discomfort or bleeding at the injection site. 
 
There may be additional side effects or risks that are not yet known.  Please tell your 
study doctor if you have any new or worsening health problems.  Your study doctor will 
watch you closely during this study. 
 
Women who are pregnant or breast feeding cannot take part in this study because we do 
not know what effect the treatment will have on an unborn child or if the study drug can 
be passed to an infant through the mother’s milk. If you are a woman capable of having 
children, you will be given a pregnancy test before you begin the study.  If there is a 
chance you could become pregnant during this study, you should not participate in the 
study or you must use a highly effective means of birth control [birth control pills, 
intrauterine device (IUD), or barrier device such as a condom] while you are taking part.  
If you become pregnant while you are taking part in this study, you must notify one of the 
doctors listed on this form immediately so that management of the pregnancy and the 
possibility of stopping treatment can be discussed. 
 
Any male patient whose partner is capable of having children should also use an effective 
means of birth control (condoms, abstinence) while taking part in this study, because we 
do not know what effect the treatment may have on the sperm and what effect this would 
have upon the development of an unborn child.  
 
Risks Associated with surgical procedures 
As a part of your treatment for your stage III lung cancer, you will be required to have 
certain surgical procedures done either as part of your treatment or to determine whether 
or not you have a good response to treatment. All the surgical procedures in the protocol 
are the usual standard of care in treating patients with your type and stage of lung cancer. 
There are potential side effects and risks associated with these procedures. Your surgeon 


 
Version 1.7 Nov 5, 2014 
Page 64 
 
will discuss with you all the risks and benefits associated with those procedures prior to 
the surgery. It is your right to accept or decline a procedure that is offered to you. The 
effect of taking erlotinib, prior to a surgical procedure, is not completely understood. 
However, the prior studies with erlotinib prior to surgery in lung cancer showed no 
increase in surgical complications.   
 
ARE THERE ANY BENEFITS TO TAKING PART IN THIS RESEARCH 
STUDY? 
 
If you agree to take part in this study, there may or may not be direct medical benefit to 
you.  Although it is not possible to predict or guarantee whether any personal benefit will 
result from your participation in this study, one possible benefit is decreasing the size of 
your tumor by erlotinib followed by complete surgical resection. Although this does not 
guarantee cure, it may likely increase your chances of being cured or  live longer.  We 
also hope the information learned from this study will benefit other patients with NSCLC 
cancer in the future. 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Your study doctor is very willing to discuss the benefits and side effects of alternative 
treatments. Instead of being in this study, you have these options: You may receive 
chemotherapy and radiation alone, chemotherapy and radiation followed by surgery, 
chemotherapy followed by surgery or surgical resection followed by either chemotherapy 
alone or chemotherapy and radiation. Other investigational protocols with chemotherapy 
and radiation may be available for your disease. You may receive no further cancer 
therapy and best supportive care measures to relieve your symptoms only. Please ask any 
questions you may have and take as much time as you need to make your decision. 
 
New Information 
 
Sometimes during the course of a research project, new information becomes available 
about the treatment/drug that is being studied.  If this happens, your study doctor will tell 
you about it and discuss with you whether you want to continue in the study. If you 
decide to withdraw, your study doctor will make arrangements for your care to continue.  
If you decide to continue in the study you will be asked to sign an updated consent form.   
 
Also, on receiving new information your research doctor might consider it to be in your 
best interests to remove you from the study.  He/she will explain the reasons and arrange 
for your care to continue. 
 


 
Version 1.7 Nov 5, 2014 
Page 65 
 
 
 
CONFIDENTIALITY (WHO MAY SEE YOUR RECORDS?) 
 
The records of this study will be kept confidential and you will not be identified in any 
written or verbal reports. Your research records will be kept in a secured area and locked 
in a file cabinet at Albert Einstein Cancer Center, Montefiore Medical Center. Only those 
directly involved with the conduct of the study will have access to your medical records. 
Representatives from Astella Pharmaceuticals, Inc. (Astella, the maker of Tarceva®) or 
their agents Independent Ethics Committees (IECs), the U.S. Food and Drug 
Administration (FDA), and certain Drug Regulatory Authorities may review information 
from the study that contains your identity.  Any such review will be held strictly 
confidential, so as to protect your privacy. You will also be asked to sign a document 
called an Authorization to use and disclose your Protected Health Information. This 
document allows you to give your permission for your health information to be 
collected, used, and disclosed as necessary to conduct the research study.   
 
Your research study records may also be inspected by the Montefiore Medical Center 
Institutional Review Board (IRB), the Albert Einstein College of Medicine Committee on 
Clinical Investigations (CCI). 
 
COST OF PARTICIPATING  
 
There is no cost to you for erlotinib (Tarceva®). However, you or your insurance 
company will be paying for the costs of other necessary medications for your disease, 
routine blood tests, x-rays, scans, other laboratory tests, surgical procedures and your 
routine medical care. You will not be charged for any research related studies like the 
laboratory and future research done on your blood tumor or skin biopsy, if you agree. 
 
Insurance companies and Medicare may not pay for costs associated with some requested 
studies.  If your insurance company does not cover the cost of routine care, then you will 
have to pay these costs. You have the right to ask what it will cost you to take part in this 
study or to have other treatments. You will not be paid for your participation in this 
study. One or more of the research personnel is receiving fees for giving presentations on 
this drug. 
INFORMATION ABOUT RESEARCH RELATED INJURY 
If you are injured as a result of the research procedures during the course of the study, 
you should immediately contact your study doctor.  If you are injured as a result of this 
research, only immediate, essential, short-term medical treatment, as determined by the 
participating hospital or sponsoring company, will be available for the injury without 
charge to you personally.  No monetary compensation will be offered. 


 
Version 1.7 Nov 5, 2014 
Page 66 
 
WILL ANY OF THE SAMPLES (TISSUE, BLOOD) TAKEN FROM ME BE 
USED FOR RESEARCH STUDIES? 
OPTIONAL BLOOD RESEARCH STUDIES 
 
This study includes one or more laboratory tests that will analyze a small amount of your 
blood. If you agree to participate in this laboratory research study, 1-2 teaspoons of blood 
will be collected before you begin treatment and after you have been on Tarceva® 
(Erlotinib) for at least two weeks. The samples will be collected at the same time blood is 
being collected for tests used to monitor your health.  An additional stick will not be 
necessary to collect these specimens.  
The specimens will be sent to a laboratory, where researchers will study lung cancer cells 
which may be in the blood. Researchers will perform these tests in order to understand 
your disease, the response your disease may have to the treatment, and the effect the 
treatment may have on patients. You may participate in the therapy portion of this 
research study without participating in the additional laboratory (blood) portion. 
 
Please review the points listed in the “Voluntary Participation and Withdrawal” section, 
then read the question below and circle “Yes” or “No”. 
I agree to participate in the blood laboratory research studies that are being done as 
part of this clinical trial. 
                          Yes    _________Initial                         No   __________Initial 
 OPTIONAL SKIN BIOPSY 
A skin biopsy is also being requested of you to determine the patients who will have 
better response to treatment.  
A biopsy is a surgical procedure in which an area is numbed with local anesthetic, and a 
small sample of skin in the upper back trunk is withdrawn. When the local anesthesia is 
given, you may initially feel a burning sensation for several seconds. During the actual 
procedure itself, you may temporarily feel pressure and/or pain of varying degrees. If 
necessary, you may ask your physician for additional local anesthesia or a medication to 
ease your stress. You also may experience bleeding, and/or bruising after the procedure is 
completed and you may experience soreness in the area for a few days afterwards. Rarely 
an infection can develop. A skin biopsy will be done before you begin your treatment and 
after you have been on Tarceva® (Erlotinib) for at least two weeks. You may participate 
in the therapy portion of this research study without participating in the biopsy portion. 
 
Please review the points listed in the “Voluntary Participation and Withdrawal” section, 
then read the question below and circle “Yes” or “No”. 
 
I agree to participate in the skin biopsy research studies that are being done as part 


 
Version 1.7 Nov 5, 2014 
Page 67 
 
of this clinical trial. 
                          Yes    _________Initial                         No   __________Initial 
FUTURE RESEARCH 
USE OF DE-IDENTIFIED SPECIMENS FOR FUTURE RESEARCH 
 
In addition to the research you are consenting to under this research study, Dr  Haiying 
Cheng or other researchers at this or other institutions may wish to study the samples in 
future research, including genetic analysis. These samples, taken from your body, would 
NOT be linked back to you. No one will know your name or protected health 
information.   
 
At this time, the researcher does not know what the future studies will be.  Your 
specimens may also be submitted to a tissue/cell/DNA bank.  The specimens may be kept 
for a long time and may exceed 50 years.   
 
In some research using human blood or tissue, the specimens and their parts may enable 
researchers to develop medical tests or treatments that have commercial value.  You will 
not receive any money that may result from any such commercial tests or treatments.   
 
Your specimens may be used for future research, even though the purpose of the future 
research is not known at this time.   
 
PARTICIPANT:  PLEASE INDICATE YOUR CHOICE BY INITIALING  
ONE (1) OF THE FOLLOWING OPTIONS   
 
___  I consent to have my specimens used for future research studies. 
 
 
 
___  I consent to have my specimens used for future research studies only for the study of 
 
________________________________________________________. 
 
___  I do NOT consent to have my specimens used for future research studies.  The 
specimens will be destroyed at the end of the study. 
 
WHO TO CONTACT 
 
In the event of a research-related injury or if any questions arise related to this research 
project, you may call the supervisor of this study Dr. Haiying Cheng at (718) 405-8404.   
 
If you have any questions about your rights as a research subject, you may also call 
Montefiore Medical Center Institutional Review Board (IRB) at (718) 798-0406, Monday 
through Friday between 9am and 5pm. or the Albert Einstein Committee on Clinical 
Investigations (CCI) at (718) 430-2253.  
 
WHERE CAN I GET MORE INFORMATION? 


 
Version 1.7 Nov 5, 2014 
Page 68 
 
 
• You may call the National Cancer Institute’s (NCI’s) Cancer Information 
Service. 
Voice: 1-800-4-CANCER (1-800-422-6237) 
TTY: 1-800-332-8615 
• Visit the NCI’s Web site: http://www.cancer.gov or CancerNet: 
http://cancernet.nci.nih.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You will get a copy of this form. If you want more information about this study, ask your 
study doctor. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
 
It is entirely up to you to decide whether or not to take part in this study.  If you do decide 
to take part you will be required to sign this consent form.  You are free to choose not to 
participate in this study or to withdraw from this study at any time and without giving 
reason.  If you choose not to be in the study, wish to withdraw, or if you are asked to 
leave the study there will be no penalties.  In other words, you will not be denied any 
treatments you may need and it will not affect the standard of care you receive.     
You will be asked to complete the procedures described in the section titled “End of 
Treatment/Follow-up”. 
 
IF YOUR STUDY DOCTOR OR SPONSOR(S) CHANGE THEIR MINDS 
 
Your study doctor or the company sponsor(s) may stop your treatment at any time, 
without your consent if it is determined that you need other treatment, if you have a 
study-related illness or injury or for any other reason. 
 
You will get a copy of this form. 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 69 
 
 
 
 
SUMMARY 
 
You have asked all the questions you want to ask, after reading and listening to an 
explanation of the following information. If you do not understand English, or if you are 
unable to read English, this information has been explained to you orally. You have been 
given a copy of this form whether or not you have agreed to participate in this study. 
 
SIGNATURES 
 
 
___________________________________________________________________________ 
Name of Participant                                                                            Date 
 
 
_____________________________________________________________________ 
Signature of Participant                                                                      Date 
  
_____________________________________________________________________  
Name of Person Conducting the                                                        Date 
Informed Consent Process 
          
___________________________________________________________________________ 
Signature of Person Conducting the                                                  Date 
Informed Consent Process 
 
 


 
Version 1.7 Nov 5, 2014 
Page 70 
 
 
 
 
 
 
 
STUDY SCHEMA 
 
 
 
You are diagnosed with 
Stage III NSCLC 
Your tumor  will be tested 
for EGFR mutation  
If EGFR mutation positive 
You will be treated with 
Erlotinib 150mg PO daily for 
2 months. 
Treatment response will be 
evaluated with a PET/CT 
scan and you will be 
evaluated for surgery 
If you can have surgery 
surgery 
You may require additional 
chemotherapy or radiation 
based on your preference or 
your physician’s 
recommendation 
If surgery cannot be done 
You may continue erlotinib 
or  change to chemotherapy 
or radiation based on your 
preference or your 
physician’s recommendation 
If your tumor gets worse 
You may change to 
chemotherapy or radiation 
based on your preference or 
your physician’s 
recommendation 
If EGFR mutation negative, 
You cannot participate in the 
study 


 
Version 1.7 Nov 5, 2014 
Page 71 
 
APPENDIX B 
ELIGIBILITY CHECKLIST FOR PATIENT REGISTRATION 
 
EValuation of Erlotinib as a Neoadjuvant Therapy in stage III NSCLC patients 
with EGFR mutations (EVENT trial) 
 
Eligibility Criteria: The answers to the following questions must be 
‘yes’ in order for the patient to be eligible. N/A should only be 
answered if description within question allows.  
INCLUSION CRITERIA 
YES 
NO N/A 
Pathologically proven (either histologic or cytologic) diagnosis of Stage 
IIIA or IIIB non-small cell lung cancer [according to AJCC Staging, 7th 
edition; see Appendix E] within 4 weeks of registration. 
 
State Method of Dx:  _____________ State Date Dx:  _____________  
 
 
State Stage and TNM:  _______ Stage _____ T ___ N _____ M0  
 
 
 
 
Activating mutation in EGFR oncogene: 
check appropriate:  
exon 19 deletion ____  
exon 21 mutation ___  
others ____ (specify_____________________) 
 
 
 
No prior chemotherapy or radiation for lung cancer 
 
 
 
Patients may be potentially resectable or unresectable: 
check appropriate:  
resectable ________  
unresectable ______  
 
 
 
Mediastinoscopies or EUS/EBUS to evaluate N3 disease. (Please 
complete the below) 
Mediastinoscopy:   Yes: ____       No: _____    
Date (if yes) _____    
 
Endoscopic ultrasound (EUS) : Yes: ____   No: ___     
Date (if yes) _____  
 
Endobronchial ultrasound (EBUS) : Yes: ____ No: ___   
Date (if yes) _____ 
 
Pathological confirmation of N3 nodes: Yes  ____    date: __________ 
   
 
 
 
    
   No  _____ 
 
 
 
 
Stage III A or B disease, including no distant metastases- based on 
following diagnostic workup: 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 72 
 
Eligibility Criteria: The answers to the following questions must be 
‘yes’ in order for the patient to be eligible. N/A should only be 
answered if description within question allows.  
INCLUSION CRITERIA 
YES 
NO N/A 
History/physical examination prior to registration. 
           
Date: __________             
 
 
 
CT Scan of the chest or PET/CT Scan within 28 days of study entry 
 
Date: __________            State Method: ______________  
 
 
 
 
CT Scan or MRI of abdomen or PET Scan within 28 days of study entry 
 
Date: __________            State Method: ______________  
 
 
 
An MRI of the brain or Head CT Scan with contrast within 28 days of 
study entry 
 
Date: __________            State Method: ______________  
 
 
 
PFT’s:. Must be done within 8 weeks of study entry. 
 
Date: __________             
 
 
 
EKG: Must be done within 6 weeks of study entry. 
Date: __________             
 
 
 
Patient  must have measurable or evaluable disease. 
 
 
 
ECOG performance status 0-2, 
                       ECOG PS (0-2): Numerical Value ____ 
 
 
 
 
State age in years____ 
                       Date of Birth ______ 
 
 
 
 
The following minimum required laboratory data must be done within 
14 days of treatment. 
 
 
 
Absolute neutrophil count >1,500 cells/ul:  
 
Numerical value   _________              Date of test     __________ 
 
 
 
Platelets > 100,000 cells/ul  
 
Numerical value   ________                Date of test     __________ 
 
 
 
Hemoglobin > 9.0 g/dl  
 
Numerical value________                   Date of test     __________  
 
 
 
Serum creatinine <  1.5 x ULN  
 
Numerical value______  
 
Institution ULN ______                Date of test    _________ 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 73 
 
Eligibility Criteria: The answers to the following questions must be 
‘yes’ in order for the patient to be eligible. N/A should only be 
answered if description within question allows.  
INCLUSION CRITERIA 
YES 
NO N/A 
Total Bilirubin < 2.0 x institutional upper limits of normal  
 
Numerical value________    
 
Institution ULN ___________            Date of test     ________ 
 
 
 
AST and ALT < 2.5 x the ULN  
 
Numerical value_____  
 
Institution ULN _____                        Date of test     ________ 
 
 
 
For women of Child-bearing potential: 
A negative serum or urine pregnancy test (sensitivity  25IU HCG/L) 
within 72 hours prior to the start of study drug administration 
 
Beta HCG: State results: ______ 
Date of test_____  
State date of Rx_____ 
 
 
 
 
Persons of reproductive potential must agree to use and utilize an 
adequate method of contraception throughout treatment and for at 
least 4 weeks after study drug is stopped. Prior to study enrollment, 
men and women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the 
potential risk factors for an unintentional pregnancy. 
 
Does patient agree to use adequate method of contraception? 
 
 
 
Ability to take oral medication  
 
 
 
Patient signed the study specific informed consent. (The patient 
must be aware of the neoplastic nature of his/her disease and 
must willingly consent after being informed of the procedure to 
be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and 
discomforts.) 
Date signed: _______ 
 
 Version:  _________ 
 
 Expiration date of ICF: ________ 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 74 
 
The support documentation, per the requirements under the study parameters 
section of each the protocol, as well as the consent form and this checklist, must be 
faxed to the Montefiore Medical Center, Central Protocol Office at the time of 
registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or 
check if "Not Applicable."  
 
a. Signed Consent Form     Enclosed   ______ Not Enclosed   
 
 
  Not Applicable   ___ 
 
b. Eligibility Form               Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
c.  Pathology Report(s)       Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
d. EGFR mutation Results Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
  
e.  Lab Report(s)                  Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
f.  Cat Scan/MRI Report(s)Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
g.  PET/CT Report(s)         Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
  
h.  PFT                                 Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
i.   EKG                                Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
j.   Surgical Evaluation       Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
k.  Mediastinoscopy report Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
  
l.    EUS/EBUS report         Enclosed _________Not Enclosed    
 
_ Not Applicable   
 
 
m.  Specimens (as applicable): Date Sent      Type of Specimen  
 
 Sent To __________ 
n.  Other  
 
 
Enclosed   
Not Enclosed   
 
 
 
 
 
 
 
IRB approval date of protocol:   
 Hospital where patient will be treated:    
 
 
 
Date patient will begin treatment:  
 
  Primary Physician:  
 
 
 
 
 
The patient (full name)   
 
 
 has met the above protocol criteria on  
 
 
 
and is assigned  the  sequence number  
 
 
 
 
Your signature:   
 
 
 
 
 
 
 
 
 
 
 
 
Please e-mail this form along with registration worksheet provided by Montefiore to 
cpdmu-registration@montefiore.org. Please copy the regulatory and study 
coordinator at Montefiore Medical Center, along with the Principal Investigator at 
Montefiore. 
 
   
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 75 
 
 
 
 
 
 
APPENDIX C 
 NCI CTCAE Version 4.0 
 
Toxicity will be scored using NCI  CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from 
http://ctep.info.nih.gov.  All appropriate treatment areas have access to a copy of the 
CTC Version 4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 76 
 
APPENDIX D 
 
ECOG PATIENT PERFORMANCE STATUS 
 
 
 
STATUS 
SCALES 
KARNOFSK
Y 
ZUBROD-
ECOG-
WHO 
 
STATUS 
No complaints 
100 
0 
Normal activity 
 
Able to carry on normal 
activities 
90 
1 
Symptoms, but fully 
ambulatory 
Normal activity with effort 
80 
 
 
 
Cares for self.  Unable to carry 
on normal activity or to do 
active work 
 
 70 
2 
Symptomatic, but in bed 
<50% of the day 
Requires occasional 
assistance, but able to care for 
most of his needs 
 
60 
 
 
Requires considerable 
assistance and frequent 
medical care 
 
50 
3 
Needs to be in bed >50% 
of the day, but not 
bedridden 
Disabled, requires special care 
and assistance 
 
40 
 
 
Severely disabled.  
Hospitalization indicated 
though death non imminent 
 
30 
4 
Unable to get out of bed 
Very sick.  Hospitalization  
Necessary.  Active support 
treatment necessary 
 
20 
 
 
Moribund 
 
10 
 
 
Dead 
0 
 
 
From: Minna J.D., Higgins G.A and Glapstein E.J.  Cancer of the lung:  In: DeVita V, 
Hellman S., Rosenberg S., (Eds.).  Cancer: Principles and Practice of Oncology, 
Lippincott, Philadelphia, 1984, p. 536. 


 
Version 1.7 Nov 5, 2014 
Page 77 
 
APPENDIX E 
 
Case Report Forms 
 
 
Please see attached CRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version 1.7 Nov 5, 2014 
Page 78 
 
APPENDIX F   AJCC TNM staging system for lung cancer (7th edition, 2007)