Phase II Study of Erlotinib for Patients With Malignant Peritoneal Mesothelioma (MPeM) Exhibiting EGFR Mutations
Phase: PHASE2
Conditions: Malignant Peritoneal Mesothelioma
Sponsor: University of Chicago

Protocol #: 12-0032 
 
 
TITLE:  Phase II study of erlotinib for patients with malignant peritoneal 
mesothelioma (MPeM) exhibiting EGFR mutations. 
 
 
Coordinating Center: 
 
The University of Chicago Medical Center 
 
Principal Investigator: 
 
Hedy L. Kindler, MD 
5841 S. Maryland Avenue, MC 2115 
Chicago, IL 60637-1470 
Telephone: 773-702-0360 
Fax: 773-702-3163 
E-mail: hkindler@medicine.bsd.uchicago.edu 
 
Co-Investigators: 
 
 
 
Ravi Salgia, MD, PhD 
5841 S. Maryland Avenue, MC 2115 
Chicago, IL 60637-1470 
Telephone: 773-702-4399 
Fax: 773-702-3002 
E-mail: rsalgia@medicine.bsd.uchicago.edu 
 
Rajani Kanteti, PhD 
900 East 57th Street 
KCBD Building 7240 
Chicago, IL 60637 
Telephone: 773-702-7875 
Fax: 773-702-9268 
Email: rkanteti@medicine.bsd.uchicago.edu 
 
 
 
Statistician: 
 
Study Coordinator: 
 
Theodore Karrison, PhD 
Tamika Harris 
 
5841 S. Maryland Avenue, MC 2007 
5841 S. Maryland Ave, MC 1140 
 
Chicago, IL 60637-1470 
Chicago, IL 60637-1470 
 
Telephone: 773-702-9326 
Telephone: 773-702-4367 
 
Fax: 773-702-1979 
Fax: 773-834-5800 
       tkarrison@health.bsd.uchicago.edu 
              tharris@medicine.bsd.uchicago.edu 
 
 
 
Responsible Research Nurse: 
 
Responsible Data Manager: 
 
Jennifer Shouldis 
Peter Ostiguy 
 
5841 S. Maryland Avenue, MC 2115 
5841 S. Maryland Avenue, MC 2115 
 
Chicago, IL 60637-1470 
Chicago, IL 60637-1470 

 
 
ii
 
Telephone: 773-834-3137  
Telephone: 773-834-1472 
 
Fax: 773-834-1798 
Fax: 773-834-1798 
 
jshouldi@medicine.bsd.uchicago.edu 
postiguy@medicine.bsd.uchicago.edu 
 
 
Astellas Pharmaceuticals Supplied Agent:  
 
Erlotinib (Tarceva)   
 
 
Protocol Type / Version # / Version Date: 
Original/Version #3 -02/06/2013 
 
 
 

 
 
i
 
SCHEMA 
 
 
 
 
 

 
 
ii
 
TABLE OF CONTENTS 
 
SCHEMA ........................................................................................................................................ I 
 
TABLE OF CONTENTS ............................................................................................................ II 
 
1.OBJECTIVES ............................................................................................................................ 1 
1.1. 
Primary Objective ............................................................................................................ 1 
1.2. 
Secondary Objectives ....................................................................................................... 1 
1.3. 
Laboratory Objectives ...................................................................................................... 1 
 
2.BACKGROUND ........................................................................................................................ 1 
2.1. 
Malignant Peritoneal Mesothelioma (MPeM).................................................................. 1 
2.2. 
Erlotinib ............................................................................................................................ 3 
 
3.PATIENT SELECTION ........................................................................................................... 6 
3.1. 
Eligibility Criteria ............................................................................................................ 6 
3.2. 
Exclusion Criteria ............................................................................................................ 7 
3.3. 
Inclusion of Women and Minorities ................................................................................ 8 
 
4.REGISTRATION PROCEDURES .......................................................................................... 8 
4.1. 
General Guidelines ........................................................................................................... 8 
4.2. 
Registration Process ......................................................................................................... 8 
 
5.TREATMENT PLAN ................................................................................................................ 9 
5.1. 
Erlotinib Administration .................................................................................................. 9 
5.2. 
Drug Accountability....................................................................................................... 10 
5.3. 
Treatment Compliance ................................................................................................... 10 
5.4. 
General Concomitant Medications and Supportive Care Guidelines ............................. 10 
5.5. 
Duration of Follow-up ................................................................................................... 13 
5.6. 
Criteria for Removal from Study ................................................................................... 13 
 
6.DOSING DELAYS/DOSE MODIFICATIONS .................................................................... 13 
6.1. 
Dose Modifications ........................................................................................................ 13 
 
7.ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................. 15 
7.1. 
Definition of Adverse Drug Reaction ............................................................................ 16 
7.2. 
Definition of Adverse Event .......................................................................................... 16 
7.3. 
Evaluating and Reporting of Adverse Events ................................................................ 16 
7.4. 
Assessment of Adverse Events ...................................................................................... 17 
7.5. 
Serious Adverse Events .................................................................................................. 17 
7.6. 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) .................................. 18 
7.7.     Serious Adverse Event Reporting Requirements ........................................................... 19 
7.8. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments ......................... 21 
7.9. 
Expected Adverse Events ............................................................................................... 22 
7.10. 
Pregnancy and Breast Feeding ................................................................................... 22 
 

 
 
iii
 
8.LABORATORY CORRELATES .......................................................................................... 23 
8.1. 
EGFR .............................................................................................................................. 23 
8.2. 
Immununhistochemical analyses. .................................................................................. 24 
8.3. 
Serum biomarkers .......................................................................................................... 25 
 
9.STUDY CALENDAR .............................................................................................................. 26 
 
10.MEASUREMENT OF EFFECT .......................................................................................... 27 
10.1. 
Antitumor Effect – Solid Tumors ............................................................................... 27 
 
11.REGULATORY AND REPORTING REQUIREMENTS ................................................ 30 
11.1. 
Adverse Events Reporting Guidelines ........................................................................ 30 
11.2. 
Data Safety and Monitoring ....................................................................................... 31 
 
12.STATISTICAL CONSIDERATIONS ................................................................................. 31 
12.1. 
Study Design/Endpoints ............................................................................................. 31 
12.2. 
Sample Size/Accrual Rate .......................................................................................... 33 
12.3. 
Reporting and Exclusions ........................................................................................... 33 
 
REFERENCES ............................................................................................................................ 34 
 
APPENDIX A 
Performance Status Criteria ...................................................................................................... 37 
 
APPENDIX B 
CYP3A4 and CYP1A2 Inhibitors/Inducers .............................................................................. 38 
 
APPENDIX C 
PATIENT’S MEDICATION DIARY ...................................................................................... 39 
 
 

1 
1
1. OBJECTIVES 
 
1.1. 
Primary Objective  
 
To determine the objective response rate (CR + PR) of erlotinib in MPeM patients who have 
EGFR mutations. 
 
1.2. 
Secondary Objectives 
 
1.2.1. 
To determine the percentage of patients with MPeM who have EGFR mutations. 
 
1.2.2. 
To characterize asbestos exposure history and other clinical parameters of patients 
with MPeM who do or do not have EGFR mutations. 
 
1.2.3. 
To determine the disease control rate (CR + PR + SD) of MPeM patients who have 
EGFR mutations and are treated with erlotinib.  
 
1.2.4. 
To determine the progression-free survival (PFS) of MPeM patients who have 
EGFR mutations and are treated with erlotinib.  
 
1.2.5. 
To determine the median overall survival (OS) of MPeM patients who have EGFR 
mutations and are treated with erlotinib.  
 
1.2.6. 
To evaluate toxicity in MPeM patients who have EGFR mutations and are treated 
with erlotinib.   
 
 
1.3. 
Laboratory Objectives 
 
1.3.1. 
To characterize the specific EGFR mutations observed in MPeM patients. 
 
1.3.2. 
To correlate tumor markers (CA 125 and SMRP) with response rate, PFS, and OS 
in MPeM patients treated with erlotinib. 
 
1.3.3. 
To correlate immunohistochemical staining of EGFR, p-EGFR, MET, E-cadherin, 
vimentin, and CBL with EGFR mutational status and, if present, particular EGFR 
mutation noted. 
 
1.3.4. 
To correlate immunohistochemical staining of EGFR, p-EGFR, MET, E-cadherin, 
vimentin, and CBL with response rate, PFS, and OS in MPeM patients treated with 
erlotinib. 
 
2.  BACKGROUND 
 
2.1. 
Malignant Peritoneal Mesothelioma (MPeM) 
 
Malignant mesothelioma is a highly aggressive neoplasm of the serosal lining of the pleura, 
peritoneum, pericardium, or tunica vaginalis largely attributed to asbestos exposure1, 2.  It 

 
2 
affects about 2500 to 3000 Americans each year.  Malignant peritoneal mesothelioma (MPeM) 
is the second most common type of mesothelioma and represents approximately 15-20% of all 
new diagnoses of the disease2.   
 
Patients with MPeM generally present with non-specific abdominal complaints with pain 
and/or distention being the most common, though a significant minority of patients can also 
present with fever, weight loss, or infertility3.  The most common sign noted in MPeM patients 
is the development of ascites which can occur in up to 70% of patients and is produced by the 
multiple tumor nodules present on the peritoneal surface.  It is this fluid combined with tumor 
volume that is the major cause of morbidity in MPeM3, 4.   
 
Macroscopically, MPeM is characterized by thousands of tumor nodules of variable size and 
consistency which can coalesce to either form plaques, masses, or layer out evenly to cover 
the peritoneal surface4.  Computed tomography (CT) is the current standard to evaluate and 
characterize the disease and is superior to sonography5.  While magnetic resonance imaging 
(MRI) can also be helpful in evaluating patients with MPeM, the longer scan time, increased 
cost, and difficulty with respiratory motion and bowel peristalsis can interfere with image 
resolution3.  
 
While imaging is helpful in the diagnosis of MPeM, as with any malignancy, the definitive 
diagnosis is made by biopsy.  Cytological examination of ascitic fluid rarely results in a 
positive finding and most patients are instead diagnosed via histology, occasionally after a CT-
guided biopsy but, more frequently, with a biopsy performed during laparoscopy or 
laparotomy3, 4.  Tumor markers such as serum CA-125 and soluble mesothelin-related peptide 
(SMRP) can also be measured if findings are suspicious for mesothelioma as many patients 
with the disease will have increased levels.  Though none are sensitive or specific enough to 
either screen for or to confirm the diagnosis of mesothelioma, respectively, they have each 
been shown to decrease with treatment and increase with tumor growth and could thus be used 
to monitor for treatment response6-8.  CA-125 is a tumor antigen associated with ovarian 
cancer, but is also elevated in patients with MPeM6 while SMRP is a cell surface protein highly 
expressed in mesothelioma attached to the cell surface2, 7.  
 
The histopathological diagnosis of MPeM requires a series of immunohistochemical studies to 
distinguish it from adenocarcinoma.  Calretinin, cytokeratins 5/6, WT-1, thrombomodulin, and 
mesothelin are usually positive while B72.3, CEA, CD 15, Leu-M1, and BER-EP4 
immunostains are generally negative3.  There are a variety of histological subtype 
classifications though these can be grouped broadly into epithelial, sarcomatoid, or a 
combination of the two known as biphasic disease.  More than 75% of patients with MPeM 
have purely epithelial disease with 10-15% having a pure sarcomatoid histology3.  
Prognostically, patients with the epithelial subtype fare significantly better than their 
sarcomatoid or biphasic counterparts as is also seen with malignant pleural mesothelioma 
(MPM)2, 4, 9.  
 
Treatment for MPeM has traditionally relied upon cytoreductive surgery with chemotherapy 
delivered intraperitoneally and/or systemically10.  Cytoreductive surgery is the mainstay of this 
treatment as most patients will eventually die from obstruction due to tumor compression3, 4.  

 
3 
Surgery allows for a maximal debulkment of resectable tumor and the lysis of adhesions 
between bowel loops.  While rarely curative, this procedure minimizes tumor volume and 
future complications when the tumor begins to grow again.  Cytoreduction also allows for the 
more effective delivery of intraperitoneal chemotherapy3.  While a variety of regimens have 
been used, the chemotherapy used is generally heated as hyperthermia can have direct 
cytotoxic effects and there is greater depth of penetration of the chemotherapy agents into the 
tumors3, 4, 9.  Cytoreductive surgery followed by intraperitoneal chemotherapy has been 
associated with a median survival of 34-92 months and 5-year survival rates reported at 33-
59%9, 11, 12.  Once a patient is deemed to no longer be a surgical candidate, treatment often 
relies on systemic chemotherapy alone.  As with pleural mesothelioma, the most common 
regimen used is a combination of a platinum with pemetrexed13-15 though pemetrexed 
combined with gemcitabine has also been reported15.  The median survival reported for 
previously treated patients with a platinum/pemetrexed combination was 13 months13 while 
the median survival for the patients treated with first-line gemcitabine/pemetrexed was 26.8 
months15.  Once patients fail these regimens there are no standard therapeutic options. 
 
Prognostically, in MPeM, women fare significantly better than men.  This is likely 
multifactorial and could relate to the higher rates of epithelial disease in women compared to 
men3, 16.  However, an interesting distinction between the sexes is that men are much more 
likely to have an asbestos exposure history, and it has been postulated that it is the underlying 
cause of the disease which is the true prognostic factor.  In men, MPeM often has an aggressive 
disease course with a median survival of less than one year while women have a far more 
indolent disease with a median survival that ranges from 3 to 5 years16. 
 
While EGFR inhibition has been attempted in the treatment of pleural mesothelioma, there 
have been no significant clinical responses despite almost-universal over-expression of EGFR 
via immunohistochemistry in this disease17, 18.  This is felt to be secondary to the fact that 
EGFR mutations – a predictor of response in the first-line treatment of patients with non-small 
cell lung cancer (NSCLC) – appear to be non-existent in pleural mesothelioma19.  Recently 
reported data by Foster and colleagues suggests that MPeM, however, exhibits an increased 
rate of EGFR mutations – both previously undescribed mutations as well as the known L858R 
activating mutation – as high as 31%20, and it appears that these are activating mutations with 
sensitivity to EGFR TKIs21. This is far in excess of that seen in pleural mesothelioma and 
compares favorably with the rate seen in NSCLC in which such mutations have been reported 
in just 7-22% of Western-population patients, though noted in up to 50% of Asian patient 
populations22-24.   
     
2.2. 
Erlotinib 
 
Erlotinib (Tarceva, Astellas) is an orally active, potent, selective inhibitor of the epidermal 
growth factor receptor (EGFR) tyrosine kinase. Erlotinib was initially approved in November 
2004 by the United States Food and Drug Administration (FDA), and in September 2005 by 
the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of 
patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure 
of at least 1 prior chemotherapy regimen.  Erlotinib has since been FDA- approved for 
maintenance therapy in NSCLC and for first-line treatment of pancreatic cancer when 

 
4 
combined with gemcitabine.  NCCN guidelines now recommend erlotinib for first-line 
treatment of NSCLC in those patients who exhibit a mutation in the epidermal growth factor 
receptor. 
 
2.2.1. Summary of Erlotinib Safety  
 
The safety of single-agent erlotinib has been evaluated in healthy volunteers and/or cancer 
patients at doses ranging from 1 mg to 1600 mg and for durations greater than 24 months. 
There have been 10 single-agent studies completed in cancer patients and 10 single-agent 
studies completed in healthy volunteers. The most relevant data for safety evaluation of single-
agent erlotinib have been collected in the large randomized, double-blind, phase 3 study of 
erlotinib 150 mg/day compared with placebo conducted in patients who failed at least 1 prior 
chemotherapy regimen for advanced/metastatic NSCLC (BR.21)25.  This phase 3, placebo-
controlled study is the primary basis for evaluating the safety of single-agent erlotinib. 
 
The most frequent adverse events (AEs) observed in clinical trials and consistent among EGFR 
inhibitors are the development of dermatological manifestations including a rash, erythema, 
and dry skin, as well as diarrhea25, 26.  Other less frequent events include mild to moderate 
nausea, vomiting, anorexia, and asthenia. The incidence of rash ranges from 75%-85% of 
patients while diarrhea has been reported in over half of the erlotinib-treated patients in the 
BR.21 trial. Grade 3 or 4 adverse events were reported in 62% of patients in the erlotinib arm 
and 58% of patients in the placebo arm in Study BR.21. Grade 3 or 4 events in Study BR.21 
were events that are frequently associated with NSCLC; dyspnea and fatigue occurred at a 
similar rate in the 2 treatment arms. Treatment-related grade 3 or 4 events occurred in 5% of 
patients who received placebo and 23% of erlotinib-treated patients (primarily grade 3 rash 
and diarrhea)25. 
 
Less common AEs for which the incidence in the BR.21 erlotinib arm was at least twice the 
incidence in the placebo arm include stomatitis (17% vs 3%), conjunctivitis (12% vs 2%), 
keratoconjunctivitis sicca (12% vs 3%), and epistaxis (7% vs < 1%). Overall, data from clinical 
studies confirm that erlotinib is not associated with any significant myelotoxicity, even in 
patients with extensive prior chemotherapy. Liver function abnormalities, including elevated 
serum ALT, AST, and/or bilirubin, have been observed infrequently in the treatment of 
NSCLC with single-agent erlotinib at 150 mg/day. Dose reductions or discontinuation due to 
AEs occurred in 19% and 7% of erlotinib-treated patients, respectively25. 
 
As with other drugs in this class of agents, interstitial lung disease (ILD)-like events have been 
observed (see Section 7.8). There have been infrequent reports of serious ILD-like events 
(including fatalities) in patients receiving erlotinib for treatment of NSCLC, pancreatic cancer 
or other advanced solid tumors. In the single-agent study in patients with NSCLC, Study 
BR.21, the incidence of ILD-like events (0.8%) was the same in the placebo and erlotinib 
groups. In the combination study with gemcitabine in patients with pancreatic cancer, study 
PA.3, the incidence of ILD-like events was 2.5% versus 0.4% in the erlotinib plus gemcitabine 
versus the placebo plus gemcitabine groups, respectively. The overall incidence in erlotinib-
treated patients from all studies (including uncontrolled studies and studies with concurrent 
chemotherapy) is approximately 0.7% out of approximately 4900 patients. No imbalance was 

 
5 
noted in the incidence of ILD-like events between treatment groups in the single-agent, 
randomized, placebo-controlled Study BR.21, or in the 2 large first-line NSCLC studies (Study 
OSI2298g, Study BO16411), which utilized a standard platinum-based regimen with or 
without erlotinib. Since this was not the case when erlotinib was used concurrently with 
gemcitabine in the placebo-controlled study PA.3, a potential causal relationship between 
erlotinib exposure and the rare occurrence of ILD cannot be completely ruled out. For more 
information, refer to the erlotinib Investigator’s Brochure. 
 
2.2.2. Summary of Erlotinib Efficacy  
 
Phase 2 studies of single-agent erlotinib in the treatment of advanced solid tumors indicated 
antitumor activity in NSCLC, head and neck, and ovarian cancers. Study BR.21 was a multi-
center, randomized, double-blind, placebo-controlled, phase 3 study of single-agent erlotinib 
150 mg/day in patients with NSCLC. In this study, 731 patients with stage IIIB/IV NSCLC, 
after failure of at least 1 prior chemotherapy regimen, were randomized (2:1) to receive daily 
erlotinib or placebo. Statistically significant and clinically relevant prolongation in OS was 
observed for erlotinib compared with placebo (median 6.7 vs 4.7 months; HR 0.73; 95% CI, 
0.61 – 0.86, P < 0.001), indicating that erlotinib reduced the risk of death by 27% compared 
with placebo25.   
 
Secondary endpoints of progression-free survival (PFS) and response rate were also 
significantly greater for erlotinib. The planned quality of life analysis, time to deterioration of 
patient-reported symptoms, showed statistically significant and clinically meaningful benefit 
for patients randomized to erlotinib25.  
 
In pleural mesothelioma, despite over-expression of EGFR via immunohistochemistry, EGFR 
inhibition resulted in no significant clinical responses17, 18.  As noted earlier, EGFR mutations 
in pleural mesothelioma appear to be non-existent19. This lack of correlation between EGFR 
over-expression and response to EGFR-targeted therapy27, 28 is an important observation that 
has since evolved into the realization that the most important factor allowing for response when 
exposed to EGFR inhibition is the presence of activating mutations in the EGFR tyrosine 
kinase domain29, 30.   
 
Rationale 
 
In pleural mesothelioma (MPM), EGFR is highly over-expressed in most cell lines and 
tumors31. Although the EGFR tyrosine kinase inhibitor gefitinib inhibits mesothelioma in vitro, 
phase II trials of gefitinib and erlotinib in MPM by the Cancer and Leukemia Group B and the 
Southwest Oncology Group, respectively, reported no activity17, 18. Despite EGFR over-
expression via immunohistochemistry (IHC) in >90% of MPM patients, EGFR activating 
mutations have been rarely observed and the largest published series evaluating for such 
mutations detected none19.  There is significant as a lack of correlation between EGFR over-
expression and response to EGFR-targeted therapy has also been observed in non-small-cell 
lung cancer (NSCLC)27, 28 while activating mutations in the EGFR tyrosine kinase domain 
have instead been associated with clinically significant responses when targeted by an EGFR 
TKI29, 30.   

 
6 
 
Data from Foster and colleagues revealed that MPeM exhibits an increased rate of EGFR 
mutations – both previously undescribed mutations as well as known activating mutations such 
as the L858R mutation20.  Up to 31% of MPeM tumor samples exhibited these mutations and 
it appears that these are activating mutations with sensitivity to EGFR TKIs20, 21.  Erlotinib, an 
oral EGFR TKI, is currently FDA-approved for NSCLC but to-date has never been formerly 
investigated as treatment for MPeM32.   
 
It is noteworthy that of the EGFR mutations in MPeM, most have never been previously 
reported.  While well-described exon 19 deletions or L858R point mutations in exon 21 have 
shown increased response rates in patients with NSCLC who are treated with EGFR TKI’s, 
other mutations – in particular the secondary T790M mutation – in addition to MET 
amplification have demonstrated resistance to treatment with the same agents33, 34.  While some 
preliminary data shows that the EGFR mutations in MPeM are indeed activating mutations, 
this information is based on a small sample and it is not fully known how these and other 
potentially discoverable EGFR mutations will respond to erlotinib21.  As such, the different 
EGFR mutations noted in MPeM in this trial will be correlated with response to erlotinib in 
the final outcome analysis. 
 
3.  PATIENT SELECTION 
 
3.1. 
Eligibility Criteria 
 
3.1.1.  Histologically- or cytologically-confirmed malignant peritoneal mesothelioma 
(MPeM); epithelial, sarcomatoid, biphasic, multi-cystic, or well-differentiated 
papillary subtypes are allowed.   
 
3.1.2. 
A tumor block or 10 unstained slides must be available for determining EGFR 
mutational status. Only those patients who have a mutation of the EGFR tyrosine 
kinase domain will be able to enroll in this study. 
 
3.1.3. 
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm with conventional techniques or as >10 mm with spiral CT scan.  See 
Section 10 for the evaluation of measurable disease.  
 
3.1.4. 
No prior use of EGFR tyrosine kinase inhibitors or monoclonal antibodies; all other 
prior treatments are allowed if ≥ 4 weeks since treatment completed, including  
chemotherapy (systemic or intraperitoneal), radiation therapy,  and/or surgery.  
There is no limit on the number of previous treatments allowed.   
 
3.1.5. 
Age >18 years.  Because no dosing or adverse event data are currently available on 
the use of erlotinib in patients <18 years of age, children are excluded from this 
study but will be eligible for future pediatric single-agent trials, if applicable. 
 
3.1.6. 
Life expectancy of greater than 3 months. 

 
7 
 
3.1.7. 
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
Appendix A). 
 
3.1.8. 
Patients must have normal organ and marrow function as defined by the following 
required laboratory values obtained ≤ 14 days before enrollment: 
 
leukocytes  
 
>2,000/mcL 
absolute neutrophil count 
>1,500/mcL 
platelets 
 
 
>100,000/mcL 
total bilirubin  
≤ 1.5 X institutional ULN 
AST(SGOT)/ALT(SGPT) 
2.5 X institutional ULN 
creatinine  
 
≤ 2 X institutional ULN 
 
 
OR 
creatinine clearance 
>30 mL/min/1.73 m2 for patients with                        
 
creatinine levels 
above institutional                         
 
normal 
 
3.1.9. The effects of erlotinib on the developing human fetus at the recommended therapeutic 
dose are unknown.  For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should 
a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
 
3.1.10. Ability to understand and the willingness to sign a written informed screening and 
treatment consent. 
 
3.2. 
Exclusion Criteria 
 
3.2.1. 
Chemotherapy, radiotherapy, or surgery within 4 weeks (6 weeks for nitrosoureas 
or mitomycin C) prior to entering the study or those who have not recovered from 
adverse events due to agents administered more than 4 weeks earlier. 
 
3.2.2. 
Patients may not be receiving any other investigational agents. 
 
3.2.3. 
Patients with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
 
3.2.4. 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to erlotinib. 
 

 
8 
3.2.5. 
EGFR-mutation negative tumor tissue as determined by sequencing. If an individual 
tissue test result is inconclusive (unable to be determined), it will be considered 
negative for study eligibility purposes.  
 
3.2.6. 
History of previous malignancy excluding non-melanoma skin lesions and in-situ 
cervical cancer.  Patients with other malignancies are eligible if they have been 
disease free for ≥ 3 years. 
 
3.2.7. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  
 
3.2.8. 
Pregnant women are excluded from this study because it is unknown if erlotinib 
poses a potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with erlotinib, breastfeeding should be discontinued if the 
mother is treated with erlotinib. 
 
3.2.9. 
HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with erlotinib.  In addition, these 
patients are at increased risk of lethal infections.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when indicated. 
 
3.2.10.  Inability to tolerate or absorb an oral medication due to any cause, including but 
not limited to malabsorption syndromes. 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
4. REGISTRATION PROCEDURES 
 
4.1. 
General Guidelines  
 
Eligible patients will be entered on study centrally at the University of Chicago by the Study 
Registrar, Peter Ostiguy at 773-834-1472 or postiguy@medicine.bsd.uchicago.edu. 
 
Following registration, patients should begin protocol treatment within 7 days. Issues that  
would cause treatment delays should be discussed with the Principal Investigator. If a patient  
does not receive protocol therapy following registration, the patient’s registration on the  
study may be canceled. The Registrar should be notified of cancellations as soon as possible.  
 
4.2. 
 Registration Process  
 
All patients must be registered with the University of Chicago Registrar, Peter Ostiguy at least 

 
9 
48 hours prior to the commencement of treatment. The following documents should be 
completed by the research nurse and emailed postiguy@medicine.bsd.uchicago.edu or faxed 
773-834-1798 to the Registrar:  
 
 Provider of information  
 Treating Physician  
 Patient name and hospital ID number  
 Patient’s zip code of residence  
 Date & copy of signed screening and treatment informed consents  
 Race, gender, date of birth of patient  
 Diagnosis and date of initial diagnosis  
 EGFR mutational analysis results 
 Source documentation for eligibility and pre-study procedures  
 
The research nurse or data manager will then call 773-834-1798 or e-mail 
postiguy@medicine.bsd.uchicago.edu to confirm all selection criteria listed in Section 4.0. 
To complete the registration process, the Coordinator will:  
 
 
 Assign a patient study number  
 Register the patient on the study  
 Call the research nurse or data manager and verbally confirm registration 
 
5. TREATMENT PLAN 
 
A separate screening consent must be signed for the screening process for any patient to have 
his/her tissue evaluated for EGFR mutational status.  If the patient’s tumor exhibits an EGFR 
mutation, the patient will then be offered a separate treatment consent for enrollment in clinical 
trial allowing for the administration of erlotinib. 
 
5.1. 
Erlotinib Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications for erlotinib are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient’s malignancy. 
 
5.1.1. Formulation  
 
 
Astellas will supply tablets containing erlotinib hydrochloride equivalent to 150 mg, 100 mg, 
and 25 mg of erlotinib. All tablets are round, white, film-coated, and bi-convex with no imprint. 
Additional information can be found in the erlotinib Investigator’s Brochure.  
 
5.1.2. Packaging and Labeling  
 

 
10 
Study drug tablets will be supplied in blue-white, high-density, polyethylene bottles of 30 tablets 
each. The bottles will have a tamper-evident seal and a child-resistant cap.  Each bottle will have a 
unique identifier (bottle number).  
 
5.1.3. Storage and Handling  
 
Study drug tablets should be stored between 15°C and 30°C (59°F and 86°F).  
 
5.1.4. Administration  
 
Study drug therapy must start within 14 days of registration. The date the patient takes the first 
dose of study drug will be considered Day 1 of this study. Study drug tablets should be taken 
at approximately the same time each day, preferably in the morning. 
 
Each study drug dose is to be taken with up to 200 mL (~ 1 cup or 8 oz) of water, and should 
be taken either 1 hour before or 2 hours after a meal or medications, including vitamins and 
other supplements. The starting dose of erlotinib is 150 mg daily (see Table 6-1).  
Consumption of grapefruit and grapefruit juice should be avoided while on study drug therapy 
(see Section 5.4.3).  
 
 
The entire dose must be taken at one time. If the patient vomits after taking the tablet(s), the 
dose should be replaced only if the tablet(s) can actually be seen and counted. 
 
5.2. 
Drug Accountability  
 
Astellas requires that a drug accountability log be maintained. The information contained on the 
log should be sufficient to comply with applicable GCP regulations. Drug accountability log 
information may include, but is not limited to, the following: number of bottles and date the study 
drug was received, number of bottles dispensed to each patient (including bottle number, date 
dispensed/returned, patient identifier information, protocol number, dose, and lot/batch number) 
quantity of tablets returned by the patient, current balance, and the initials of the person who 
recorded the accountability log information.  
 
5.3. 
Treatment Compliance  
 
Compliance will be assessed by counting tablets at the scheduled patient visits. Data regarding 
missed or modified doses will be recorded in the case report form (CRF). 
 
5.4. 
General Concomitant Medications and Supportive Care Guidelines 
 
All concomitant medications will be recorded in patient record through Post-treatment.  
 
5.4.1. Permitted Concomitant Medications  
 
5.4.1.1 Anti-rash and Anti-diarrheal Therapies  
 

 
11 
Skin rash or dermatosis has been observed in many patients during treatment with erlotinib. 
There have been no clinical trials formally evaluating treatments for rash induced by erlotinib. 
 
Patients who develop a mild rash characterized by pustules or raised, red areas may be treated 
with topical therapy such as corticosteroids or topical clindamycin.  Oral tetracycline or oral 
minocycline may be used at the discretion of the investigator if more severe. (NOTE: 
minocycline is known to interfere with anticoagulants and oral contraceptives. Patients treated 
with minocycline who are taking anticoagulants and/or oral contraceptives should be 
monitored accordingly). Retinoids and other acne medications such as benzoyl peroxide are 
not recommended, given that the pathology of the rash is not related to acne pathology and 
that these agents are more likely to exacerbate the rash due to their drying effects on the skin.  
 
Guidance concerning modification of study drug dosing is provided in Table 6-2 while 
guidance concerning the treatment of rash is provided in Table 6-3. 
Anti-diarrheal medications may be introduced if symptoms occur. Previous trials have 
shown that the frequency and severity of diarrhea rarely hindered the administration of 
erlotinib and that the diarrhea could be managed with loperamide. The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until diarrhea-free 
for 12 hours. 
 
5.4.1.2 Anticoagulant Therapies  
 
Concomitant treatment with warfarin or a coumadin-derived anticoagulant is permitted 
provided increased vigilance occurs with respect to monitoring international normalized ratio 
(INR). INR elevations and/or bleeding events have been reported in some cancer patients 
taking warfarin while on erlotinib. For this study, patients taking warfarin or other coumadin-
derived anticoagulants while on study drug should be monitored as clinically indicated for 
changes in INR, especially when the study drug is being started or stopped.  
 
5.4.2. Prohibited Concomitant Medications  
 
5.4.2.1 Cytotoxic or Hormonal Therapy and Biological or Immune Response 
Modifiers  
 
No other cytotoxic therapy, EGFR inhibitor therapy, hormonal therapy, or biological or 
immune response modifiers for the treatment of cancer may be administered to patients while 
they are on study drug.  
 
5.4.2.2 Radiotherapy  
 
The need for radiotherapy will be considered indicative of disease relapse, and these 
patients will be discontinued from study drug and will enter the Post-treatment period of 
the study. 
 
5.4.2.3 Other Investigational Drug Therapies  
 

 
12 
Patients should not receive any other investigational drugs during the On-treatment period of 
the study.  
 
5.4.3. Potential for Drug Interactions  
 
Erlotinib is protein bound (92% to 95% in humans) and metabolized by hepatic CYP3A4 and 
CYP1A2 and pulmonary CYP1A1 enzymes. Therefore, a potential for drug-drug interaction 
exists when erlotinib is co-administered with drugs that are highly protein bound or that are 
CYP3A4 or CYP1A inhibitors/inducers (Appendix B).  
 
Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole) decrease erlotinib 
metabolism and increase erlotinib plasma concentrations. This increase may be clinically relevant 
as adverse experiences are related to dose and exposure. Therefore, caution should be used when 
administering CYP3A4 inhibitors to patients who are on study drug. Grapefruit and grapefruit 
juice contain a strong inhibitor of CYP3A4 that may increase exposure to erlotinib. Therefore, 
patients in this study should avoid consuming grapefruit and grapefruit juice while on study drug 
therapy.  
 
Pre-treatment with the CYP3A4 inducer rifampicin decreases erlotinib AUC by about two-thirds. 
Alternate treatments lacking CYP3A4 inducing activity should be considered. If still smoking, 
patients should also be advised to quit due to the induction effect of tobacco on the CYP1A2 
enzyme. For more information, refer to the erlotinib Investigator’s Brochure.  
 
As mentioned in Section 5.4.1.2, INR elevations and/or bleeding events have been reported in 
some cancer patients taking warfarin while on erlotinib. For this study, patients taking warfarin 
or other coumadin-derived anticoagulants while on study drug therapy should be monitored as 
clinically indicated for changes in INR, especially when the study drug is being started or stopped.  
 
5.4.4.  Ophthalmologic Considerations  
 
Patients with dry eyes should be advised to use an ocular lubricant. Patients who continue to 
wear contact lenses may have an increased risk of ocular AEs (eg, keratitis). Patients may 
continue to wear contacts but should discuss this issue with their treating oncologist before 
going on study. In addition, any elective ophthalmological surgery while the patient is taking 
study drug must first be discussed between the investigator. 
 
5.4.5. Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 
 Patient decides to withdraw from the study, or 

 
13 
 General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.5. 
Duration of Follow-up 
 
Patients will be followed until progression or until death, whichever occurs first.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse events 
 
5.6. 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
 
6.1. 
 Dose Modifications  
 
The dose of study drug will not be escalated above 150 mg/day for any reason. Doses of study 
drug may be reduced and/or delayed for toxicities at any time during the study. If a patient 
experiences several toxicities, dose modifications are to be made according to the body system 
showing the greatest degree of toxicity. Toxicities will be graded by using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Refer to the following website for the CTCAE manual or the CTCAE document:  
 
http://ctep.cancer.gov/reporting/ctc.html 
 
6.1.1. Dose Reduction and Re-escalation  
 
In the event of a toxicity that is not tolerated due to symptoms, disfigurement or interference 
with normal daily activities (regardless of severity), or is not controlled by optimal supportive 
care, the daily dose of study drug will be decreased according to the schedule below (Table 6-
1). If significant toxicity is still apparent, the dose may be reduced a second time. 
 
Patients who require a dose reduction must be evaluated at least monthly until the toxicity 
stabilizes or improves. Once determined to be stable, patients can resume evaluations 
according to the protocol-specified visit schedule. The following applies to dose reductions 
and re-escalations:  
 
Doses that have been reduced to 100 mg/day may be re-escalated to 150 mg/day, but only if 
the toxicity that led to the dose reduction has abated or returned to baseline severity, and the 
investigator believes it is in the best interest of the patient. 
 

 
14 
Doses that have been reduced to 50 mg/day may be re-escalated to 100 mg/day, but only if the 
toxicity that led to the dose reduction has abated or returned to baseline severity, and the 
investigator believes it is in the best interest of the patient. Doses that have been reduced to 
50 mg/day may never be re-escalated to a dose higher than 100 mg/day.  
 
If any dose is re-escalated, patient must be seen by investigator in 14 days to assess 
toxicity.  Patients whose dose is re-escalated must be then evaluated at least monthly to assess 
for toxicity. Once determined to be stable, patients can resume evaluations according to the 
protocol-specified visit schedule. Any patient who fails to tolerate treatment with 50 mg/day 
will be discontinued from study drug and enter the Post-treatment period of the study. 
Recommendations for dose modification are outlined in Table 6-2.  
 
Table 6-1: Dose reduction levels 
 
Dose Level 
Erlotinib Dose 
0 
150 mg/day 
-1 
100 mg/day 
-2 
50 mg/day 
 
 
Table 6-2: Dose modification guidelines 
 
Toxicity – CTCAE v 4.0 
Dose Modificationa 
Diarrhea 
 
Grade 1 or 2 
None. Initiate therapy with loperamide. 
Grade 3b or 4b 
Interrupt study drug until resolution to ≤ grade 2 and then 
restart 1 dose level lower. 
Rash 
 
Grade 1 
None. 
Grade 2 
None. If rash persists or worsens over 14 days despite 
treatment as outlined in table 6-3, then reduce by 1 dose 
level. 
Grade 3b 
Reduce by 1 dose level. If rash persists or worsens over 10-
14 days, then interrupt study drug until resolution to ≤ grade 
2 and then restart 1 dose level lower. 
Grade 4 
Permanently discontinue study drug. 
Interstitial Lung Disease 
 
Any Grade 
If ILD is suspected, study drug should be interrupted 
immediately pending diagnostic evaluation. If ILD is 
diagnosed, study drug should be discontinued permanently. 
Other Treatment-related 
Toxicities 
 
Grade 1 or 2 
None. 
Grade 3b,c 
Interrupt study drug until resolution to ≤ grade 2 and then 

 
15 
restart 1 dose level lower. 
Grade 4 
Permanently discontinue study drug. 
A     Doses that have been to reduced to 100 mg/day may be re-escalated to 150 mg/day, but only if the 
toxicity that led to the dose reduction has abated or returned to baseline severity, and the investigator believes 
it is in the best interest of the patient. Doses that have been reduced to 50 mg/day may be re-escalated to 100 
mg/day, but only if the toxicity that led to the dose reduction has abated or returned to baseline severity, and 
the investigator believes it is in the best interest of the patient. Doses that have been reduced to 50 mg/day 
may never be re-escalated to a dose higher than 100 mg/day. Any patient who fails to tolerate treatment with 
50 mg/day will be discontinued from study drug and enter the post-treatment period of the study.  
 
B     If the event does not resolve to ≤ grade 2 by ≤ 21 days, study drug will be discontinued. 
 
C     Only if  ≥ 2 grade level change from baseline. 
 
Table 6-3: Rash treatment guidelines. 
 
Rash Grade 
Recommended Treatment 
Grade 1 
No treatment or topical hydrocortisone 1% 
cream and/or clindamycin 1% gel at 
investigator’s discretion 
Grade 2 
Hydrocortisone 2.5% cream or clindamycin 
1% gel PLUS doxycycline 100 mg po bid or 
minocycline 100 mg po bida 
Grade 3 
Hydrocortisone 2.5% cream or clindamycin 
1% gel PLUS doxycycline 100 mg po bid or 
minocycline 100 mg po bida PLUS 
methyprednisolone dose pack 
Grade 4 
Per Institutional Guidelines. 
A     Minocycline is known to interfere with anticoagulants and oral contraceptives. Patients 
treated with minocycline who are taking anticoagulants and/or oral contraceptives should 
be monitored accordingly. 
Note:  Retinoids and other acne medications such as benzoyl peroxide are not recommende
given that the pathology of the rash is not related to acne pathology and that these agents a
more likely to exacerbate the rash due to their drying effects on the skin.  
 
6.1.2. Dose Interruption  
 
Patients who have a continuous interruption of dosing for ≤ 21 days in a row may have study 
drug re-started at the appropriate dose, provided any toxicities have improved as outlined 
above. 
 
Patients who have a continuous interruption of dosing for > 21 days in a row generally should 
not be allowed to re-start study drug therapy and should enter the Post-treatment period of the 
study. However, re-starting study drug after > 21 days of dose interruption may occur provided 
any toxicities have improved as outlined above AND the investigator believes it is in the best 
interest of the patient. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  

 
16 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting.   
 
7.1. 
Definition of Adverse Drug Reaction  
 
An adverse drug reaction (ADR) is any response to a medicinal product that is noxious and/or 
unintended and related to any dose. The phrase, “response to a medicinal product”, means that 
a causal relationship between the medicinal product and the AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out).  
 
7.2. 
Definition of Adverse Event  
 
An Adverse Event or adverse experience is any untoward medical occurrence in a patient or 
clinical investigation patient administered a medicinal product which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. Pre-existing conditions, 
which increase in frequency or severity or change in nature during or as a consequence of use 
of a drug in human clinical trials, will also be considered as adverse experiences. Adverse 
events may also include pre- or post-treatment complications that occur as a result of protocol-
mandated procedures (eg, invasive procedures such as biopsies).  
 
Any continuing medical condition or clinically significant laboratory abnormality with an 
onset date before the first date of study drug administration should be considered as pre-
existing and should be documented as baseline signs and symptoms in the CRF. 
 
An AE does not include:  
 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion). 
The condition that leads to the procedure is the AE;  
 Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery, social and/or convenience admissions);  
 Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the patient is hospitalized for observation.  
 
 
7.3. 
 Evaluating and Reporting of Adverse Events  
 
 
All AEs (ie, a new event or an exacerbation of a pre-existing condition) that occur in the 
course of the clinical study (ie, from the time of randomization until 30 days from the last 
dose of study drug) must be recorded as an AE or SAE on the appropriate page(s) of the 
CRF and SAE form, as applicable. All study drug-related SAEs occurring more than 30 
days after the last dose of study drug must also be reported. The evaluation of an AE should 
continue until the AE resolves, or until the investigator and/or sponsor determine the 

 
17 
patient’s condition is stable. All patients who have received at least 1 exposure to study 
therapy will be evaluated for safety of study treatment.  
 
7.4. 
Assessment of Adverse Events  
 
All AEs will be assessed by the investigator and recorded on the appropriate case report form 
(CRF), including the dates of onset and resolution, severity, relationship to study drug, 
seriousness, and whether the event caused the patient to withdraw from the study.  
 
Severity: Severity should be recorded and graded according to the NCI CTCAE, v4.0 (refer 
to the following website for the CTC manual or the CTC document): 
 
http://ctep.cancer.gov/reporting/ctc.html 
 
Relationship: The relationship to study drug should be assessed using the following 
definitions:  
Not Related: Evidence exists that the AE has an etiology other than the study drug (eg, pre-
existing condition, underlying disease, intercurrent illness, or concomitant medication);  
Related: A temporal relationship exists between the event onset and administration of the 
study drug. It cannot be readily explained by the patient’s clinical state, intercurrent illness or 
concomitant therapies. In case of cessation or reduction of the dose, the event abates or resolves 
and reappears upon rechallenge. It should be emphasized that ineffective treatment should not 
be considered as causally related in the context of AE reporting.  
 
These criteria, in addition to good clinical judgment, should be used as a guide for determining 
the causal assessment. If the event is not considered related to study drug, then an alternative 
explanation should be provided. 
 
7.5. 
Serious Adverse Events  
 
An SAE is defined as follows:  
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes:  
o Death;  
o Life-threatening situation (patient is at immediate risk of death);  
o Inpatient hospitalization or prolongation of existing hospitalization (excluding 
those for study therapy, disease-related procedures, palliative or hospice care, or 
placement of an indwelling catheter, unless associated with other serious events);  
o Persistent or significant disability/incapacity;  
o Congenital anomaly/birth defect in the offspring of a patient who received study 
drug;  
o Other: Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events are:  

 
18 
o Intensive treatment in an emergency room or at home for allergic bronchospasm;  
o Blood dyscrasias or convulsions that do not result in hospitalization;  
o Development of drug dependency or drug abuse.  
 
Clarification of SAEs  
 
o Death is an outcome of an AE and not an AE in itself. In reports of death due to 
“Disease Progression”, where no other information is provided, the death will be 
assumed to have resulted from relapse of the disease being treated with the study 
drug(s);  
 
o All SAEs, regardless of cause, must be reported for patients on study (≤ 30 days 
from last study drug dose);  
 
o All SAEs occurring more than 30 days after last study drug administration and 
considered at least possibly drug-related must also be reported;  
 
o “Occurring at any dose” does not imply that the patient is receiving study drug at 
the time of the event. Dosing may have been given as treatment cycles or 
interrupted temporarily before the onset of the SAE but may have contributed to 
the event; event as it occurred. This does not include an event that might have led 
to death, if it had occurred with greater severity;  
 
o Complications that occur during hospitalizations are AEs. If a complication 
prolongs hospitalization, it is an SAE;  
 
o “Inpatient hospitalization” means the patient has been formally admitted to a 
hospital for medical reasons, for any length of time. Presentation and care within 
an emergency department does not necessarily constitute an SAE;  
 
o The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
o  
7.6. 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
 
A serious adverse event is considered to be a suspected adverse reaction if there evidence to 
suggest a causal relationship to the study agent.  This may include a single occurrence of an 
event strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon is the study population, or an aggregate analysis 
of specific events occurring at greater frequency than expected from historical controls. 
 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, investigator brochure, FDA-approved package insert, or elsewhere in the current IND 
application.  This includes adverse events listed in the protocol, consent or IND as occurring 
within the class of drugs or otherwise expected from the drug’s pharmacological properties but 

 
19 
which have not been previously observed with this investigational agent. 
 
ALL SUSARS occurring on this clinical trial must be reported to the FDA.  Refer to 
Section 7.7 for reporting guidelines.  
 
7.7. 
Serious Adverse Event Reporting Requirements  
 
7.7.1. University of Chicago Reporting Guidelines 
 
All serious adverse events and protocol deviations must also be reported to the University of 
Chicago Comprehensive Cancer Center (UCCCC) Cancer Clinical Trials Office (CCTO). 
Relevant events will be reported to the University of Chicago Institutional Review Board 
(UCIRB) in accordance with their current policies. The Research Nurse or other designated 
individual should report the SAE/deviation to the UCCCC Quality Assurance (QA) Operations 
Manager by the end of the business day when s/he becomes aware of the event. Events 
occurring after business hours will be reported to the CCTO by 12pm (noon) the next business 
day. Events may be reported to the UCCCC QA Manager by phone at (773)-702-5149 or email 
(qaccto@bsd.uchicago.edu). 
 
The following information is required when reporting the event to the CCTO: 
• 
Reporter’s Name and Telephone Number 
• 
Patient Initials 
• 
Patient Medical Record Number 
• 
IRB Protocol Number 
• 
Name of study principal investigator 
• 
Attending Physician 
• 
Date of Event 
• 
Description of event (include grade of the event and if the event required 
hospitalization.) 
• 
Whether or not the event meets the IRB’s reporting criteria 
 
When appropriate, the IRB’s Unanticipated Problems electronic submission form must be 
completed by the research nurse or other designated individual and submitted by the 
investigatorvia the IRB’s electronic submission system within the IRB’s designated 
reporting timeframes. 
 
Details of the IRB’s current policy can be found on their website at: 
http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html 
 
7.7.2. Astellas Pharmaceuticals Reporting Guidelines 
 
OSI has requirements for expedited reporting of SAEs to worldwide regulatory authorities; 
therefore, the appropriate parties must be notified immediately regarding the occurrence of any 
SAE that occurs after the patient has registered for the On-treatment portion of the study.  
 
The procedures for reporting SAEs, regardless of causal relationship, are as follows:  

 
20 
 
o Complete the Serious Adverse Event Report Form;  
o Details of the actual SAE routing in each specific country/region will be provided 
as part of the study procedures manual;  
o Serious Adverse Event Report Form must be faxed ≤ 24 hours of the investigator’s 
knowledge of the event using the following fax numbers:  
 
Americas: +1 866 635 6805 
Asia Pacific Region: +61 298 888322 
Europe: +44 (0) 1628 540028 
 
o For fatal or life-threatening events, also fax copies of hospital case reports, autopsy 
reports, and other documents when requested and applicable.  
 
Astellas may request additional information from the investigator to ensure the timely  
completion of accurate safety reports. Refer to the study procedures manual for specific  
details on how to report SAEs. 
 
The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the patient’s CRF.  
 
7.7.3. FDA Reporting Requirements 
 
Per 21 CFR 312.32, the sponsor-investigator is required to notify the FDA and all participating 
investigators of potential serious risks within 15 calendar days of determining the information 
meets FDA reporting requirements.   
 
Unexpected fatal or life-threatening suspected adverse reactions must be reported to the FDA 
by the sponsor-investigator via phone or fax within 7 calendar days.   
 
Current FDA regulations require that all SUSARs (see definition in Section 7.6) occurring on 
this trial, other findings that suggest a significant risk to humans exposed to the investigational 
drug (e.g. information from pooled analysis of multiple studies), and any clinically significant 
increase in the rate of an expected serious adverse reaction be reported as an IND Safety 
Report.  Refer to Table A below for guidelines for reporting these events to the FDA. 
 
In order to meet these requirements, the sponsor-investigator will review all reported serious 
adverse events as they occur and will conduct a literature search to seek new safety information 
and review and analyze all safety information from this clinical trial at least annually and more 
frequently as appropriate. 
 
Table A:  Reporting Requirements 
 
Report Type 
Method of Report 
Responsible 
Timeline1 

 
21 
Party 
Fatal/Life-Threatening Event 
Yes 
No 
Individual Report 
Form 3500A (MedWatch)7 
RN/CRA 
4 calendar days5 
10 calendar days5 
Other Findings that 
Suggest 
Significant 
Risk2 
Narrative3 
PI 
4 calendar day6 
10 calendar days6 
Clinically Significant 
Increased Frequency of 
Suspected 
Adverse 
Reactions4 
Narrative 
PI 
4 calendar days6 
10 calendar days6 
1: Report Due to CCTO IND Coordinator according to the specified timeline regardless of whether or not all 
information regarding the event is available.  If applicable, a follow-up report should be provided to the IND 
Coordinator once additional information on the event is available.   
2: An IND Protocol Amendment is also required to describe any changes to the protocol, consent, or overall conduct 
of the study made as a result of this information.  All revised documents should be made available to the CCTO 
IND Coordinator at the time of IRB submission. 
3: Copy of relevant publication(s) should be included if applicable.  
4: Details of individual cases should be included as appropriate 
5: From date event was reported to the sponsor-investigator 
6: After information is received by the investigator and determined to meet reporting criteria 
7: The MedWatch form only needs to be completed for events that require FDA reporting.   A copy of the completed 
form should be maintained in the subject research chart and master IND file in the CCTO.  
 
All other events (e.g. protocol deviations or other safety concerns) not meeting the 
requirements for IND Safety Reporting (per 21 CFR 312.32) but which require reporting to 
the IRB as an Unanticipated Problem will be reported to the FDA as an informational 
amendment or with the annual report as appropriate.   
 
7.8. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments  
 
Results from protocol-specified laboratory tests or unscheduled evaluations that are outside 
reference range, should not routinely be recorded as AEs unless the following occurs:  
 
The patient experiences signs and/or symptoms that are associated with a laboratory 
abnormality or the abnormality results in medical intervention (eg, anemia requiring 
transfusion, hypoglycemia that is symptomatic and/or requiring intervention, hypokalemia 
requiring potassium supplementation, or any abnormality that results in study drug dose 
modification); Other abnormal assessments (eg, echocardiogram, radiographs, vital signs) 
must be recorded as AEs (or SAEs) if they meet the definition of an AE (or SAE) as described 
above in Sections 7. 
 

 
22 
The investigator should assess the most severe laboratory result and evaluate the relationship 
of this to protocol treatment and the clinical condition. All clinically significant abnormal 
laboratory test results should be followed until they return to normal or become stabilized.  
 
7.9. 
Expected Adverse Events  
 
The Erlotinib Investigator’s Brochure contains a complete description of the safety information 
for erlotinib. An unexpected AE or ADR is any event for which the nature or severity is not 
consistent with the information contained in the erlotinib Investigator’s Brochure.  
 
Based on clinical results, dermatosis or rash, diarrhea, fatigue, nausea, vomiting, stomatitis, 
headache, cough, dyspnea, and infection were the most frequently observed undesirable effects 
in cancer patients following exposure to oral erlotinib. Hematological toxicity has not b een 
observed in patients receiving single-agent erlotinib treatment.  
 
Diarrhea (sometimes severe) has occurred in patients receiving oral erlotinib and was mostly 
managed by loperamide; however, reduction in the dose of erlotinib was occasionally 
necessary with continuous daily dosing. There have been rare reports of renal failure and 
hypokalemia and some were secondary to severe dehydration due to diarrhea, nausea, 
vomiting, and/or anorexia. In more severe or persistent cases of diarrhea that may lead to 
dehydration or in patients with aggravating risk factors of renal impairment, study drug therapy 
should be interrupted and appropriate measures should be taken including rehydration.  
 
There have been infrequent reports of serious ILD, including fatal events, in patients receiving 
erlotinib for treatment of NSCLC and other advanced solid tumors. In Study BR.21 in NSCLC 
patients, the incidence of ILD (0.8%) was the same in the placebo and erlotinib groups [12]. 
However, one cannot completely rule out a potential causal relationship between erlotinib 
exposure and the rare occurrence of ILD.  
 
In the event of acute onset of new or progressive, unexplained pulmonary symptoms such as 
dyspnea, cough, and fever, study drug should be interrupted pending diagnosticevaluation (see 
Table 6-2). If ILD is diagnosed, study drug should be discontinued and appropriate treatment 
instituted as necessary.  
 
For further details regarding AEs considered to be possibly associated with study drug, refer 
to the ‘Summary of Data and Guidance for the Investigator’ section of the erlotinib 
Investigator’s Brochure.  
 
7.10. Pregnancy and Breast Feeding  
 
Erlotinib should not be used during pregnancy or while breast feeding. Men and premenopausal 
women of child bearing potential will follow an approved, medically accepted birth control 
regimen or agree to abstain from heterosexual intercourse while taking study drug and for 30 
days following the last dose of study drug.  
 

 
23 
Pregnancy and lactation are exclusion criteria. If a female patient becomes pregnant while 
receiving study drug or within 90 days after the last dose of study drug, the sponsor must be 
immediately notified of the pregnancy. The patient must be followed during the entire course 
of the pregnancy with perinatal and neonatal outcomes  recorded, even if completely normal 
and without adverse events. At the time a site becomes aware of a pregnancy, a Pregnancy 
Report Form must be completed and submitted to the sponsor. 
 
8.  LABORATORY CORRELATES 
 
A tumor block or 10, 10-micron thick unstained slides must be available for study entry.  
These should be sent to: 
 
Rajani Kanteti, PhD 
900 East 57th Street 
KCBD Building 7240 
Chicago, IL 60637 
Telephone: 773-702-7875 
Fax: 773-702-9268 
Email: rkanteti@medicine.bsd.uchicago.edu 
 
 
8.1. 
EGFR 
 
8.1.1. Extraction of DNA  
 
 Three 10 um thick sections are cut from each paraffin embedded tissue block and 
placed into a microcentrifuge tube using clean forceps. Or 10, 10-micron unstained 
slides.  
 
 The microtome blade, tweezers and other equipments that could come into contact 
with the sample are carefully sterilized before processing each tissue block with care 
taken to minimize cross contamination. 
 
 The DNA extraction is carried out according to Sato et al. (2001) with minor 
modifications. 
 
 The tissue sections are resuspended  in 0.3 ml of digestion buffer ( 50mM Tris /Hcl, 
pH 8.5, 1 mM EDTA and 1% Tween 20 ).  
 
 The tube is tightly capped with a pinhole at the center. 
 
 High power microwave irradiation is carried out for 1 to 1.5 min with irradiation time 
split into 15 seconds segment to prevent over boiling. 
 
 The tubes are centrifuged while they are warm at 12000 x g for 10 minutes and placed 
on ice.  

 
24 
 
 Using a sterile tooth pick, the solid paraffin wax ring that is formed above the buffer 
is removed.  
 
 Proteinase K is added to each sample to get the final concentration of 0.5 mg /ml and 
the tubes are incubated at 550 C in a water bath for 48 hrs with constant shaking. 
 
 After two days of digestion with proteinase k,   Chelex –100 (Biorad) is added to each 
sample to final concentration of 5% and the mixture is vortexed and heated at 950 C 
for 10 minutes to inactivate the proteinase K.  
 
 The samples are then centrifuged for 5 minutes at 12000 x g and the sup containing 
DNA is transferred to a new tube and stored at –200 or 40 C.   
 
 The amount of DNA extracted is quantitated by running an aliquot on 0.8% Agarose 
using BGLO3 and BGLO4 primers as described and the expected product is 355 bp 
(Coates et al, 1991). 
 
 The above ensures the suitability of extracted DNA for amplification of specific genes.  
 
8.1.2. PCR 
 
 Exons 18 to 24 (inclusive) of EGFR are individually amplified by polymerase chain 
reaction (PCR). 
 
 PCR conditions are:   
 
o one cycle of 95ºC for 5 minutes; 
o 30 cycles of 95ºC for 30 seconds, 57 ºC for 30 seconds, 72ºC for 1 minute;  
o and one cycle of 72ºC for 7 minutes. 
 
 PCR products are treated with ExoSAP-IT (USB Corp., Cleveland, OH, USA) and 
sequenced by Big Dye Terminator Chemistry (Applied Biosystems, Weiterstadt, 
Germany).  
 
 Chromatograms are analyzed for mutations using Mutation Surveyor v2.61 
(Softgenetics). 
 
8.2. 
Immununhistochemical analyses. 
 
Immunohistochemistry for EGFR, p-EGFR, MET, vimentin, E-cadherin, CBL:  
 IHC staining will be performed using biotin-free HRP-labeled polymer complex 
bound to secondary antibody (DAKO Cytomation, Carpinteria, CA). 

 
25 
 We will utilize the slides provided to us from the frozen tissues, and they should be 5 
micron thick. We are requesting 10 slides per case.   
 The primary antibody will be applied at room temperature for 1 hour. For c-Met 
expression, primary antibodies will include anti-c-Met (Zymed mouse monoclonal).  
 For EGFR, the primary antibody will be the mouse monoclonal anti-human EGFR, 
clone 2-18C9 (Dako, Carpinteria, CA).  
 For CBL, we will use the CAB004350 antibody (www.proteinatlas.org).   
 The primary mouse will be the mouse monoclonal IgG2 antibody against E-cadherin 
(clone 36, BD Biosciences, Franklin Lakes, NJ). 
 For vimentin, we will use the CAB000080 antibody (www.proteinatlas.org).   
 Slides will then be developed for 5 min with 3-3’-diaminobenzidine (DAB) 
chromogen, counterstained with hematoxylin, and coverslipped.  
 Negative controls will be performed by substituting the primary antibody step with 
non-immune mouse immunoglobulins.  
 Results will be assessed qualitatively by light microscopy: Immunohistochemistry 
from tumor and adjacent normal tissue will be compared and grading will be for 
negative stain (0), weak stain (1+), moderate stain (2+), and strong expression (3+). 
 
8.3. 
Serum biomarkers 
  
8.3.1. SMRP 
   
 1 mL of blood is removed by phlebotomy and placed in red top tube. 
 Lab analysis performed by serology lab at the University of Chicago. 
 
8.3.2. CA 125 
   
 1 mL of blood is removed by phlebotomy and placed in red top tube. 
 Lab analysis performed by chemistry lab at the University of Chicago. 
 
 
 

 
26 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to administration of protocol 
therapy.  Scans and x-rays must be done within 4 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
 
Pre-study,     
pre-screena 
Pre-study, 
post-screenb 
Cy 1, 
D 1c 
Cy 1, 
D 8c 
Cy 1, 
D 15c 
Cy 1, 
D 21c 
Cy  2, 
D 1c 
Cy 3, 
D 1c 
D 1c, d  
Off 
studye 
Erlotinibf 
 
 
X ------------------------------------------------------------------- X 
 
Informed 
Consent 
(Screening) 
Xa 
 
 
 
 
 
 
 
 
 
Tissue analysis for EGFR 
X 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
(Treatment) 
 
Xb 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
X ------------------------------------------------------------------- X 
 
Physical exam 
 
X 
X 
 
X 
 
X 
X 
X 
 
Vital signs 
 
X 
X 
 
X 
 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
X 
 
X 
X 
X 
 
Performance status 
 
X 
X 
 
X 
 
X 
X 
X 
 
CBC w/diff, plts 
 
X 
X 
 
X 
 
X 
X 
X 
 
Serum chemistry, LFTsg 
 
X 
X 
 
X 
 
X 
X 
X 
 
Adverse event evaluation 
 
 
X ------------------------------------------------------------------- X 
 
Tumor measurements 
 
X 
Tumor 
measurements 
are 
repeated 
every 
2 
cycles. 
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
 
Radiologic evaluation 
 
X 
Radiologic measurements should be performed every 2 cycles 
(CT or MRI chest, abdomen, and pelvis) 
 
B-HCGh 
 
Xh 
 
 
 
 
 
 
 
 
CA-125 and SMRPi 
 
 
Xi 
 
 
 
 
Xi 
Xi 
 
a: Pre-study period prior to results of EGFR mutational analysis; patients are required to sign initial screening consent to have their 
tissue tested for EGFR mutations; treatment consent can not be signed until results have returned as positive for tumor exhibiting an 
EGFR mutation 
b: Pre-study period after results of EGFR mutational analysis; if no mutation noted, unable to enroll in treatment study; if mutation 
noted, must sign treatment consent to receive erlotinib on trial 
c. Office visits can be +/- 2 days from official date in cycle. 
d: Day 1 of each subsequent cycle 
e: Off study evaluation 
f: Erlotinib 150 mg daily; see section 6.1 for dose modifications as appropriate 
  g: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, 
total protein, SGOT[AST], SGPT[ALT], sodium.  
h: B-HCG: To be done ≤ 14 days before randomization for women of childbearing potential. Repeat while on study (through Post-
treatment) only if clinically indicated.   
i: Tumor markers (CA-125 and soluble mesothelin-related peptide (SMRP)) to be performed at baseline and then every 2 cycles at 
time of tumor radiologic evaluation. 
 
 

 
27 
10.  MEASUREMENT OF EFFECT 
 
10.1. Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8  weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee  version 
1.135.   
 
10.1.1. Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with erlotinib. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
10.1.2. Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not to be considered 
measurable.   
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  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 response. 

 
28 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
 
10.1.3. Methods for Evaluation of Measurable Disease 
 
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. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  These techniques 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. 
 
Ultrasound (US)  When the primary endpoint of the study is objective response evaluation, 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. 
 
Endoscopy, Laparoscopy  The utilization of these techniques 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 reference centers. However, such techniques may be useful 
to confirm complete pathological response when biopsies are obtained. 
 
Tumor markers  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.  Specific additional criteria for standardized usage of prostate-
specific antigen (PSA) and CA-125 response in support of clinical trials are being developed. 

 
29 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
10.1.4. 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 longest diameter (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. 
 
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in 
complete clinical response. 
 
Incomplete Response/ 
Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 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 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 

 
30 
confirmed at a later time by the review panel (or Principal Investigator). 
 
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 progressive disease the smallest 
measurements recorded since the treatment started).  The patient’s best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. From baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
36. In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
10.1.5. Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started.  
 
10.1.6. Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression. 
 
11.  REGULATORY AND REPORTING REQUIREMENTS 
 
11.1.  Adverse Events Reporting Guidelines 

 
31 
 
The descriptions and reporting system of adverse events is discussed in Section 7.0. 
 
 
 
 
 
Data Submission Guidelines 
 
For information regarding registration procedures, see section 4.0. 
 
Study data should be submitted every four (4) weeks to fax # 773-834-1798. Study data 
includes dosing/infusion records, laboratory results, radiology reports, adverse event (AE) log, 
MD visit notes, and when applicable hospitalization records. All SAEs should be reported 
within 24 hours (see Section 7.0 for details). 
 
11.2. Data Safety and Monitoring 
 
Data Safety and Monitoring will occur at the weekly University of Chicago Mesothelioma 
Conference meetings on Monday afternoons, which are lead by senior level medical 
oncologists. At each meeting, all active studies will be reviewed for safety and progress toward 
completion. Toxicities and adverse events will be reviewed at each meeting and a Data Safety 
and Monitoring form will be completed for each protocol and signed by either the principal 
investigator, the chairman of the section or by his designate if the chairman is not available. 
Auditing of 20% of patient charts will take place to ensure quality control and accuracy of 
documentation. 
 
12.  STATISTICAL CONSIDERATIONS 
 
12.1. Study Design/Endpoints 
 
Definition of primary outcome/endpoint:  
 
1. Objective response rate according to RECIST 1.1 criteria22 
 
Definition of secondary outcomes/endpoints:  
 
1. PFS – time from study enrollment until disease progression or death  
 
2. OS – time from study enrollment until death 
 
3. Toxicity – per NCI CTCAE criteria version 4.0   
 
4. Disease control rate – SD + PR + CR.   
 
5. The percentage of patients who have activating EGFR mutations among all screened 
patients, to be reported along with a 95% confidence interval. 

 
32 
 
Analytic plan for primary objective: 
 
The exact 95% confidence interval of the response rate will be reported. 
 
Analytic plan for secondary objectives: 
 
If the study proceeds to the second stage, progression-free and overall survival will be analyzed 
using the Kaplan-Meier method36.  The log-rank test as well as the Cox PH model will be 
applied to examine the association between the response status and survival.  The adjusted p-
values and 95% confidence interval will be reported. Analysis will be by intent-to-treat with 
the exception that patients who withdraw prior to receiving any medication will be declared 
non-evaluable and replaced.  Correlation of EGFR mutations with response, PFS, and OS will 
be exploratory in nature due to small sample size.  
 
Exploratory analytic plan for laboratory objectives: 
 
The aims of tumor tissue biomarker analyses include determining eligibility and exploring  the 
prognostic and predictive effects of differing EGFR mutations and other biomarkers from 
tissue and serum on response rate, PFS, and/or OS. Cox regression models for PFS and OS 
will be used to evaluate the effect of specific EGFR mutations noted on efficacy outcomes. 
Exploratory analyses of other biomarkers and combinations of biomarkers will be conducted 
using appropriate statistical methods in a data-dependent way. 
 
Sample size justification: 
 
The sample estimation is completed using the Simon’s optimal two-stage design method. A 
true 10% response rate would be uninteresting whereas a response rate of 30% would indicate 
that further study is warranted (i.e., p0=0.10 and p1=0.30 in the Simon terminology). Using an 
alpha level of 0.10 and 90% power, 12 patients will be enrolled in the first stage and if < 1 
responses are observed the trial will be terminated. Otherwise, an additional 23 patients will 
be enrolled for a total of 35 patients, and if < 5 responses are observed the agent will not be 
considered sufficiently active to warrant further study. If 6 or more responses are observed the 
drug will be considered worthy of further study.  This design provides a 65% probability of 
early stopping if, in fact, the true response rate is only 10%. 
 
As MPeM is a rare disease, however, and the true rate of EGFR mutations is unknown, we will 
institute an ‘early stopping rule’ which requires an evaluation of the rate of EGFR mutations 
noted after 24 patients have been screened.  Trial accrual is anticipated at 2 patients per month, 
24 patients per year.  If < 2 of those 24 patients are noted to have an EGFR mutation, the phase 
II trial will be discontinued and further screening for EGFR mutations will also cease.  
Observing 2 or fewer mutations in the first 24 patients is very unlikely (probability < 0.01) if 
the true rate is 31%; it is also unlikely even if the true rate is as low as 20% (probability = 
0.11).  A minimum 20% rate of EGFR mutations would be considered acceptable for the trial 
to proceed as the first stage of trial development requires 12 patients to be enrolled with EGFR 
mutations, requiring 2.5 years for completion at this rate.   

 
33 
 
However, despite this ‘early stopping rule’, any decision to terminate the trial will be 
undertaken in consultation with the sponsor, who may decide to continue enrollment if it 
appears that a positive signal of drug activity has been observed.   
 
 
12.2. Sample Size/Accrual Rate 
 
The University of Chicago is one of the leading institutions in the world for the treatment of 
mesothelioma. The most conservative estimate based on our current numbers would support a 
projection of at least 2 patients/per month for evaluation of EGFR status.  Based on an expected 
mutation rate of 31%, 39 patients would need to be screened for 12 patients to be found with 
EGFR mutations for stage 1 of the trial and this would take 1.6 years.  
 
 
12.3. Reporting and Exclusions 
 
12.3.1. Evaluation of toxicity.   
 
All patients will be evaluable for toxicity from the time of their first treatment with erlotinib.. 
 
12.3.2. Evaluation of response.   
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one 
of the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  
By arbitrary convention, category 9 usually designates the “unknown” status of any type of 
data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the exception of those who received no 
study medication) should be included in the main analysis of the response rate.  Patients in 
response categories 4-9 should be considered to have a treatment failure (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.   
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed 
on the basis of a subset of patients, excluding those for whom major protocol deviations have 
been identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  

 
34 
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gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin 
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mesothelioma. Lung Cancer 2004;45 Suppl 1:S125-7. 
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cell lung cancer. Oncologist 2009;14:1116-30. 
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Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene 
mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin 
Cancer Res 2006;12:5764-9. 
35. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
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Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer 
Statist Assn 1958;53:457-81. 
 

 
36 
 

 
37 
  
APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

 
38 
Appendix B 
 
CYP3A4 and CYP1A2 Inhibitors/Inducers 
 
CYP3A4 Inhibitors  
CYP3A4 Inducers  
Delaviridine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
 
Amiodarone 
Aprepitant 
Chloramphenicol 
Cimetidine 
Ciprofloxacin 
Clarithromycin 
Diethyl-dithiocarbamate 
Diltiazem 
Erythromycin 
Fluconazole 
Fluvoxamine 
Gestodene 
Itraconazole 
Ketoconazole 
Mibefradil 
Mifepristone 
Nefazodone 
Norfloxacin 
Norfluoxetine 
Verapamil  
 
Grapefruit juice  
Efavirenz 
Nevirapine 
 
Barbiturates 
Carbamazepine 
Glucocorticoids 
Modafinil 
Phenobarbital 
Phenytoin 
Rifampin  
St. John’s wort 
Troglitazone 
Pioglitazone 
Rifabutin  
 
 
CYP1A2 Inhibitors  
CYP1A2 Inducers  
Amiodarone 
Cimetidine 
Fluoroquinolones 
Fluvoxamine 
Furafylline 
Methoxsalen 
Mibefradil  
 
Insulin 
Methyl-cholanthrene 
Modafinil 
Nafcillin 
Beta-naphthoflavone 
Omeprazole  
Tobacco  
 
Refer to the following website for a complete list: http://medicine.iupui.edu/flockhart/table.htm 
 

 
39 
Appendix C 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________ 
Agent:   _______________________ 
Patient Name_____________________(initials acceptable)   Patient Study ID __________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2.     Erlotinib should be stored at room temperature. 
3. 
You will take erlotinib daily.   
4.     Erlotinib should be TAKEN WITH WATER ONLY IN THE MORNING, 1 HOUR BEFORE OR 2 HOURS AFTER 
MEALS.  
 
Total morning dose:   ___ mg erlotinib; Dosing:  __ 150 mg tablets, __ 100 mg tablets, and __ 25 mg tablets. 
3.     Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
4.      If you have any comments or notice any side effects, please record them in the Comments column.   
5.      Please bring this form and your bottles of study drug tablets when you return for each appointment. 
6.      Please record missed or skipped doses.  Do not share your study drug supply, and  wash your hands after touching 
 
Day 
 
Date 
 
Time of 
dose  
Erlotinib 
Comments 
Number 
of 
tablets 
Total Dose 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Patient’s signature______________________________________________________________________ 
 
Physician’s Office will complete this section: 
1. Date 
patient 
started 
protocol 
treatment
 ___________________________________________________________________________________________ 
2. Date 
patient 
was 
removed 
from 
study

 
40 
 ___________________________________________________________________________________________ 
3. Patient’s 
planned 
total 
daily 
dose
 ___________________________________________________________________________________________ 
4. Total 
number 
of 
tablets 
taken 
this 
month 
 ___________________________________________________________________________________________ 
5. Physician/Nurse/Data 
Manager’s 
Signature 
 ___________________________________________________________________________________________