Clinical trial NCT00871923
Conditions: Non-small Cell Lung Cancer Brain Cancer
Keywords: Non-small cell lung cancer NSCLC Brain Metastases Brain Cancer Lung Cancer Tarceva Erlotinib Hydrochloride OSI-774 Radiation Therapy Whole Brain Radiation Therapy WBRT
Sponsor: M.D. Anderson Cancer Center
Start date: 2009-03-26; Completion date: 2019-12-04
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn whether Tarceva (erlotinib hydrochloride), when given in addition to whole brain radiation therapy, is better to treat brain metastases in patients with Non-Small Cell Lung Cancer (NSCLC).

Detailed description:
The Study Drugs:

Erlotinib hydrochloride is designed to block the activity of a protein found on the surface of many tumor cells that may control tumor growth and survival. This may stop tumors from growing.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take the study drug on Days 1-6 before receiving radiation therapy. You will take 1 pill each day at least 1 hour before or 2 hours after eating. You will take the study drug while you are receiving radiation therapy. You will continue to take the study drug daily after the radiation therapy is complete for as long as the study doctor thinks it is necessary.

You will record at what time each day you take the study drug on a calendar that the will be provided to you. You will bring this calendar with you to each of your study visits.

During the time you are taking the study drug, you must tell the research staff if you have any changes in the drugs that you are taking. If you feel you are having any problems from the study drug before starting radiation therapy, you must tell the study doctor right away.

Radiation Therapy:

After Day 6 of taking the study drug, you will begin radiation therapy. You will receive radiation therapy 1 time each day (Monday through Fridays only) for a total of 14 days.

Once a week during radiation therapy:

* You will have a physical exam.
* You will complete a quality of life questionnaire (at the last week visit)
* You will complete a mini-mental status exam (at the last week visit)
* You will be asked about any changes in the drugs you may be taking
* You will be asked about how you are feeling and any side effects that you may be having
* You will have blood drawn (about 1/2 teaspoon) for lab tests if necessary.

One month after Radiation therapy follow up:

* You will have a follow up visit 1 month after radiation therapy is complete. The study doctor will decide if you will continue to take the study drug at the follow-up visit. The following tests and procedures will be performed:
* You will have a physical exam.
* You will have an MRI or CT of the brain.
* Your vital signs will be recorded.
* You will complete a quality of life questionnaire.
* You will complete a mini-mental status exam.
* You will be asked about any changes in the drugs you may be taking.
* You will be asked about how you are feeling and any side effects that you may be having.
* You will have blood drawn (about 1/2 teaspoon) for lab tests if necessary.

Follow-up Visits (While on Tarceva):

If, at the end-of-study visit, the doctor decides that you will continue to take the study drug, you will have a follow-up visit with the research nurse 1 time each month. At these visits, the following tests and procedures will be performed:

(If unable to return to MDACC, this visit will be conducted over the telephone and arrangements will be made to mail study Tarceva medication.)

* Your medical history will be reviewed.
* You will receive a 30-day supply of the study drug.
* You will bring in your study drug calendar for the nurse to review.
* You will be asked about how you are feeling and any side effects that you may be having.
* You will also be asked about any changes in the drugs you may be taking.
* Blood (about 1/2 teaspoon) may be drawn for routine tests.

The following tests and procedures will be performed every 3 months:

* You will have a physical exam.
* You will have an MRI or CT of the brain
* Your vital signs will be recorded.

Follow up visit (Discontinuation of Study Drug):

You will have a follow up visit with the research nurse 1 month after your last dose of the study drug, and the following will be performed:

(If unable to return to MDACC, this visit will be conducted over the telephone and arrangements will be made to have the study Tarceva medication and medication diary returned by mail.)

* Your medical history will be reviewed.
* You will be asked about how you are feeling and any side effects that you may be having.
* You will return your study drug calendar and any remaining Tarceva tablets to the research nurse.
* You will also be asked about any changes in the drug you may be taking
* Your vital signs will be recorded.

The following tests and procedures will be performed every 3 months (off Tarceva) for the first 2 years then every 6 months thereafter:

* You will have a physical exam.
* Your medical history will be reviewed.
* You will have an MRI or CT of the brain
* If you are unable to return for your follow up visits due to physical conditions, you will be contacted by phone.

Duration of Study Treatment:

You will remain on study for as long as the study doctor thinks you are benefitting from the study drug. You will be taken off study treatment early if the disease gets worse, you experience intolerable side effects, or your doctor thinks that it is no longer in your best interest to continue to receive treatment on this study.

This is an investigational study. Erlotinib hydrochloride is FDA approved and commercially available. It has not been FDA approved to treat NSCLC that has spread to the brain.

Up to 20 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Tarceva (Erlotinib hydrochloride) + Radiation Therapy. Tarceva 150 mg by mouth every day beginning Day 1. Whole Brain Radiation Therapy (WBRT) for total dose of 3500cGy in 14 daily fractions beginning after Day 6.
Interventions: intervention 1: Tarceva (Erlotinib hydrochloride) intervention 2: Radiation Therapy
Intervention descriptions: intervention 1: 150 mg by mouth every day beginning Day 1. intervention 2: Whole Brain Radiation Therapy (WBRT) for total dose of 3500cGy in 14 daily fractions beginning after Day 6.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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TITLE: 
 
A Phase II Study to Determine the Efficacy of Tarceva 
(Erlotinib Hydrochloride) with Concurrent Whole Brain 
Radiation Therapy in Patients with Brain Metastases 
from Non-Small Cell Lung Cancer  
 
PROTOCOL NO.  
2008-0170 (OSI-774UA2005) 
 
 
SPONSOR: 
M. D. Anderson Cancer Center (MDACC) 
 
Pharmaceutical: 
OSI Pharmaceuticals 
 
STUDY DRUG:               
Tarceva (Erlotinib Hydrochloride: OSI-774) 
 
PRINCIPAL INVESTIGATOR:    James Welsh, M.D. 
 
 
 
 
 
IND #: 
 
70,080 
 
EXPECTED  
START DATE: 
 
March 2009 
 
 


 
 
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TABLE OF CONTENTS 
 
1. Introduction 
  
1.1 Rationale  
 
2. Study Objectives 
2.1   Primary Endpoints 
2.2   Secondary Endpoints 
 
3. Study Design 
 
4. Eligibility Criteria 
 
4.1   Inclusion Criteria 
 
      4.2   Exclusion Criteria 
 
5. Study Medication 
      5.1   Description 
   5.2   Pharmacology 
   5.3   Adverse Events/Precautions 
      5.4   Packaging, Supply, and Labeling 
   5.5   Storage 
   5.6   Administration 
   5.7   Accountability 
 
6. Study Methods 
 
   6.1 Concomitant Medications 
 
   6.2 Study Discontinuation 
 
   6.3 Efficacy Evaluations 
 
   6.4 Dose Modification / toxicity Management  
 
7.  Radiation Therapy 
 
8.  Adverse Events 
    8.1 Severity of Adverse Drug Experiences 
    8.2 Serious Adverse Event Reporting (SAE) 
8.3   Investigator Communication with Supporting Companies 
        
9. Data Collection, Study Monitoring, and Data Disclosure 
9.1   Data Collection and Reporting 
9.2   Study Monitoring 
9.3   Data Disclosure and Patient Confidentiality 
 


 
 
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     10.  Administrative Considerations    
 
10.1   Regulatory Board Review 
 
10.2   Compliance with Protocol and Protocol Revisions 
 
10.3   Patient Informed Consent 
 
10.4   Patient Registration Procedure 
 
10.5   Data Management and Safety Monitoring 
                    
11. Statistics Consideration 
 11.1  Study Endpoints 
             11.2  Background 
             11.3  Sample Size 
             11.4  Patient Accrual 
             11.5  Data Analysis 
 
12.   References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1.0  Introduction 
 
Lung cancer is the leading cause of worldwide cancer mortality, and is responsible for 
more deaths annually in the United States than the combination of breast, colorectal, 
and prostate cancer, with an estimated 1.04 million new cases each year worldwide (1-
4).   Non–small cell lung cancer (NSCLC) accounts for approximately 75% of all lung 
cancers, and of these approximately one third will develop brain metastasis at some 
time during the course of their disease.  Additionally, 50% of all brain metastases are 
from lung primary tumors (5-7).  Unfortunately, for the vast majority of these patients 
this diagnosis is associated with significant impairment and morbidity and drastically 
shortened survival.  Present treatments for brain metastases include Surgery, Whole 
Brain Radiation Therapy (WBRT) and Stereotactic Radiosurgery (SRS).  These 
modalities are often quite effective in alleviating symptoms; however, median survival 
remains poor, at around 2-7 months, (8) clearly new treatments are greatly needed.  
1.1 Rationale: 
The process of cell division, growth, differentiation and death is a highly regulated 
process. Several classes of trans-membrane receptors play a pivotal role in this 
process.  Of these, epidermal growth factor receptor (EGFR) a member of Receptor 
Tyrosine Kinase (RTK) family is best known. This family is comprised of four receptors 
Erb B1/HER 1, Erb B2 / HER 2, Erb B3/ HER 3, and Erb B4 / HER 4.  Activation of 
these receptors typically occurs via specific ligand binding, resulting in the hetero- or 
homodimerization between receptor family members, with subsequent 
autophosphorylation of the tyrosine kinase domain.  This activation triggers a cascade 
of intracellular signaling pathways involved in both cellular proliferation (ras/raf/MAP 
kinase pathway) and survival (PI3kinase/AKT pathway). 
Aberrant signaling through the epidermal growth factor receptor (EGFR) is associated 
with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, 
angiogenesis and metastatic spread (9). The critical role that EGFR plays in cancer has 
led to an extensive search for selective inhibitors of the EGFR signaling pathway. The 
results of a large body of preclinical studies and the early clinical trials thus far 
conducted suggest that targeting the EGFR could represent a significant contribution to 
cancer therapy. Furthermore, continuous stimulation of the EGFR-mediates signal 
transduction pathway may not only confer a growth advantage to malignant cells, but 
also a survival advantage following a genotoxic insult such as ionizing radiation (anti-
apoptotic effects) (10). 


 
 
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Efficacy of this approach has been demonstrated in breast cancer with the blocking of 
the HER-2 receptor with the monoclonal antibody Herceptin. An alternate strategy is to 
inhibit EGFR TK activity using small molecules, like OSI-774 (Erlotinib, Tarceva™; OSI 
Pharmaceuticals) or ZD 1839 (gefitinib, Iressa™; Astra Zeneca ) approved for use in 
lung cancer.   Tarceva acts by reversibly inhibiting EGFR-TK thus inhibiting 
autophosphorylation of EGFR.  Initial trials of daily oral Tarceva 150 mg QD (Study 248-
1007) enrolled 56 patients with diagnosis NSCLC showed a 14.3% objective response 
rate and a 28.6% rate of disease stabilization.  Tarceva was well tolerated and 
demonstrated predictable pharmacokinetics. Additionally, Tarceva was assessed in a 
Phase III, randomized, double-blind, placebo-controlled trial in 731 patients with locally 
advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. In a 
2:1 randomization (Tarceva: Placebo), patients received Tarceva 150 mg or placebo 
orally once daily until disease progression or unacceptable toxicity. The primary study 
endpoint was survival with additional endpoints of response rate and progression free 
survival. The results of the study indicated a statistically significant improvement in 
survival for Tarceva treated patients (6.7 mo vs 4.7 mo). Both secondary endpoints 
(PFS and Response) also favored the Tarceva arm with p value  <0.001 (11). 
Given that Tyrosine Kinase Inhibitors (TKIs) have been shown to have efficacy in 
patients with Non-Small Cell Lung Cancer (NSCLC), one would postulate that 
metastases from NSCLC primaries would also likely respond.   NSCLC has a propensity 
to metastasize to the Central Nervous System (CNS).  One of the greatest barriers in 
treating CNS malignancies lies in the limited drug penetration through the blood brain 
barrier (making therapeutics such as mAB’s essentially useless in the brain).  However, 
Heimberger et al, at Duke has shown that small molecule TKIs (ZD1839) not only cross 
the BBB but produce a 105% increase in survival in animal models with brain tumors 
compared to untreated controls (12).  Furthermore, work published in our lab has 
demonstrated that the use of TKIs in vitro had a significant radiosensitizing effect and 
increased cell death when combined with external beam radiation (13).  Furthermore, 
this synergistic effect of combining  tyrosine kinase inhibitors and external beam 
radiation have been suggested by Bonner et al, work in head and neck cancer, that was 
recently presented in the Journal of Clinical Oncology (14).   Lastly, the safety of 
combining Tarceva and external beam radiation in treating Central Nervous System 
(CNS) tumors has been recently demonstrated in a phase I study (15).  In this dose 
escalation study with 20 patients with glioblastoma multiforme, Tarceva was dose 
escalated up to 200 mg per day, concurrently with external beam radiation of 60 Gy.   
Of the twenty patients, only one experienced a dose limiting toxicity of stomatitis.  Given 
that we will be using a lower dose of both Tarceva and radiation (150 mg and 30 Gy 
respectively), we feel that this is a safe regimen. 
 


 
 
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Based on these observations, we hypothesized that the synergistic properties of TKIs 
along with external beam radiation may prove to be a well tolerated and efficacious 
means of extending overall survival and decreasing morbidity in patients with brain 
metastasis from NSCLC. 
 
2.0  Study Objectives 
 
2.1 Primary Endpoints: 
To determine if Tarceva, given orally on a daily basis along with concurrent whole brain 
radiation therapy improves median survival of patients with brain metastases, compared 
with historical controls. 
 
2.2 Secondary Endpoints: 
2.2.1 To see if Tarceva along with concurrent WBRT, improves quality of life as 
assessed with the Spitzer Quality of Life Index (Appendix E) and the Folstein 
Mini-Mental Status Exam (Appendix F). Optional test will include Digit Span, 
Digit Symbol, Hopkins Verbal Learning Test, Controlled Oral Word 
Association, Trail Making Test Part A, Trail Making Test Part B, Grooved 
Pegboard, Barthel ADL Index, M.D. Anderson Symptom Inventory, and 
Functional Assessment of Cancer Therapy with Brain Module. As of July 18, 
2012- Optional tests will no longer be completed. 
2.2.2 To see if Tarceva along with concurrent WBRT, influences cause of death 
compared to matched controls, based on key attributes such as stage, age 
KPS, number of brain metastasis, etc.  
2.2.3 To see if Tarceva along with concurrent WBRT, increases time to progression 
of disease.  
2.2.4 To sequence the EGFR receptor of patients treated with Tarceva, in order to 
identify specific gene mutations that may correlate with favorable responses 
to Tarceva. 
2.2.5 To study downstream proteins involved in the EGFR cascade such as p-
EGFR, Raf, PKC, JNK, and p-AKT.  This information will be combined with 
other protein markers such as E cadherin that appear to increase the 
probability of response, in the hopes of developing a genetic signature of 
patients most likely to benefit from this regimen. 
2.2.6 To confirm the safety profile of Tarceva along with concurrent external beam 
radiation therapy, in the context of treating central nervous system 
malignancies.  
2.2.7 To provide evidence to support a much larger multi-institutional study. 
 


 
 
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3.0 Study Design 
 
Twenty patients will be collected from this M.D. Anderson based study and the data will 
be combined with an identical 20 patient study that Dr. James Welsh started while at the 
Arizona Cancer Center.  The Arizona study has enrolled 15 of the planned 20 patients 
(as of August 2008), and by combining these two studies we will have a total of 40 
patients for final analysis.   
 
 
Study Schema 
 
 
 
 
 
 
 
 
Patients must have radiographic evidence of brain metastases, proven with CT or MRI 
so that we can stratify patients by the number of brain metastases.  Additionally, they 
must have no prior history of cranial radiation (other than stereotactic radiosurgery).  
Once enrolled, patients will receive Tarceva (150mg PO QD) for at least 6 days prior to 
starting and during whole brain radiotherapy (WBRT).  External beam radiation will 
consist of opposed laterals to a total dose of 3500cGy in 14 daily fractions.   
 
Upon completion of external whole brain radiation, patients will continue taking Tarceva 
(150mg PO QD) until documentation of disease progression (unless treating physician 
feels that stopping Tarceva would adversely affect the patient) or if patients are unable 
to tolerate study drug due to toxicities.  Patients will be allowed to stop taking Tarceva at 
any time during this trial.  Following completion of WBRT patients will have a repeat 
MRI or CT at 1 month after completion of WBRT, and then at 3 month intervals, or 
sooner if indicated by symptom progression.  Additionally, during active treatment 
period of this trial, patients will not be allowed to have surgical debulking of CNS 
tumors, or stereotactic radiosurgery of CNS lesions, as this need would correlate with 
progression of disease.  Patients will be allowed to receive palliative radiation if needed 
to address symptoms. Patients will be allowed to dose reduce down to 50mg per day, 
and may also take a treatment break of up to seven days.   
 
Survival will be compared to a database of patients with similar histologies and stratified 
according to their Recursive Partitioning Analysis (RPA) class and the number of brain 
metastases, at time of diagnosis (16).  The RPA is a predictive tool used to estimate 
survival based on age, performance status, and presence of extracranial metastasis.  
Enrolled 
into study 
Tarceva loading 
at least 6 days 
prior to WBRT 
 
Radiation and 
Tarceva concurrent 
Maintenance 
Tarceva alone until 
progression of 
disease 


 
 
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The vast majority of patient will either be and RPA class I or II, which predicts for a 
survival of 7.1 and 4.2 months respectively. Patients that elect for tumor protein 
expression analysis will go on to have their tumors tested for EGFR expression along 
with receptor sequencing, if possible.  This will serve to identify if specific gene 
mutations may correlate with favorable responses to Tarceva.  Additionally, we will also 
study proteins thought to predict anti-EGFR response such as Vimentin, E-Cadherin, 
Fibronectin, PTEN, PKC, c-Met and p-AKT.  This information will be use to determine if 
a genetic signature of patients most likely to benefit from this regimen can be identified. 
 
 
 
 
 
 
4.0 Eligibility Criteria 
 
4.1 Inclusion Criteria 
4.1.1  Histological confirmation of non-small cell lung cancer 
4.1.2  Patients who have been treated in the past with Stereotatic radiosurgery, 
Stereotactic Radiotherapy, GliaSite or surgical resection will be allowed to 
enroll in this study  
4.1.3  A diagnostic contrast-enhanced MRI or CT scan must be performed, 
demonstrating brain metastases 
4.1.4  Age 18-70 
4.1.5  Patients must have KPS > 70 
4.1.6  Patients cannot be treated on any other treatment related clinical protocols 
within 30 days prior to study entry or during participation in the study 
4.1.7  No uncontrolled or symptomatic major medical illnesses or psychiatric 
impairments, such as Alzheimer’s or schizophrenia  
4.1.8  Screening Clinical Laboratory Values: ANC >1500/ul, Platelets >80,000/ul, 
baseline AST and/or ALT within normal limits (within 30 days of starting 
protocol treatment).   
4.1.9 
All women of childbearing potential (A woman of child-bearing potential is a 
sexually mature woman who has not undergone a hysterectomy or who has 
not been naturally postmenopausal for at least 24 consecutive months [i.e., 
who has had menses at any time in the preceding 24 consecutive months]) 
and male participants must practice effective contraception (abstinence, oral, 
injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine 
device; barrier contraceptive with spermicide; or vasectomized partner) 
throughout the study. All women of child-bearing potential must have a 
negative serum pregnancy test and practice birth control while on study.  
4.1.10  Patients must provide verbal and written informed consent to participate in 
the study 


 
 
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4.2 Exclusion Criteria 
4.2.1 Prior cranial radiation therapy, other than stereotatic radiosurgery, Stereotactic 
Radiotherapy or GliaSite.  
4.2.2 Patients with known Acquired Immune Deficiency (AIDS), as regimens with 
tyrosine kinase inhibitors may pose a safety risk related to excess toxicity or 
interference with anti-viral effectiveness 
4.2.3 Women who are pregnant or lactating, due to possible adverse effects on the 
developing fetus or infant due to study drug 
4.2.4 Patients with active connective tissue disorders, such as lupus or scleroderma  
 
 
 
 
5.0 Study Medications 
 
5.1 Description 
Tarceva (Eroltinib Hydrochloride): 
Tarceva is a quinazolinamine with the chemical name N-(3-ethynylphenyl)6,7 
bis(2methoxyethoxy)-4-quniazolinamine and contains Erlotinib 2 Clinical Formulations.  
In addition to the active ingredient, Tarceva tablets contain lactose (hydrous), 
microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, and 
magnesium sulfate.  The molecular weight of Tarceva (Erlotinib) is 429.90. It is slightly 
soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, 
acetone, ethyl acetate and hexane.  
 
5.2 Pharmacology 
The mechanism of clinical antitumor activity of Tarceva is not fully characterized. 
Tarceva inhibits the intracellular phosphorylation of tyrosine kinase associated with the 
epidermal growth factor receptor (EGFR). 
 
Bioavailability of Tarceva following a 150mg oral dose is about 60% and peak plasma 
levels occur 4 hours after dosing.  Food increases bioavailability substantially to almost 
100%. Tarceva’s half life is about 36 hours and it is cleared predominantly by CYP3A4 
metabolism. Time to reach steady state plasma concentration is 7-8 days and no 
significant relationship has been observed of clearance to patient’s age, body weight or 
gender. Smokers have a higher rate of Tarceva clearance than non-smokers.  Tarceva 
is predominantly cleared by the liver. No data are currently available regarding the 
influence of hepatic dysfunction or hepatic metastases on the pharmacokinetics of 
Tarceva. Since Tarceva is predominantly metabolized by CYP3A4, inhibitors or 
inducers of CYP3A4 would be expected to increase and decrease exposure, 
respectively. A potential for drug-drug interaction exists when Tarceva is co-


 
 
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administered with drugs that are highly protein bound or that are CYP3A4 and CYP1A2 
inhibitors/inducers.   
 
For patients who are being concomitantly treated with a potent CYP3A4 inhibitor, a 
dose reduction should be considered in the presence of severe adverse events.  For 
patients who are being concomitantly treated with a potent CYP3A4 inducer, alternative 
treatments that lack potent CYP3A4-inducing properties should be considered.   
 
Patients taking an enzyme-inducing anti-convulsant medication (phenytoin, 
carbamazepine, phenobarbital, Mysoline, Trileptal).  It should be discontinued and 
converted to a nonenzyme-inducing anti-convulsant (Keppra, Depakote, Topamax, 
Lamictal or Neurontin) prior to the first dose of Tarceva.  
 
In addition, altered coagulation parameters and bleeding have been reported in patients 
receiving Tarceva alone and in combination with other chemotherapeutic agents and 
concomitant warfarin-derivative anticoagulants.  The mechanism for these alterations is 
still unknown.  When warfarin is coadministered with Tarceva (anytime after Day 5), 
international normalized ratio (INR) and prothrombin time should be closely monitored 
(weekly until stabilized) and the anticoagulant dose should be adjusted as clinically 
indicated. 
 
5.3 Adverse Events/Precautions 
The most common adverse reactions in patients receiving Tarceva monotherapy and in 
combination with chemotherapy are rash and diarrhea. Grade 3-4 rash and diarrhea 
occurred in 9% and 6%, respectively in Tarceva treated patients. Rash and diarrhea 
each resulted in study discontinuation in 1% of Tarceva treated patients. The median 
time to the onset of rash was 8 days and the median time to onset of diarrhea was 12 
days. 
 
There have been infrequent reports of ILD (interstitial lung disease) in patients receiving 
Tarceva for the treatment of NSCLC and other advanced solid tumors. In the 
randomized single agent study, the incidence of ILD (0.8%) was the same for both the 
placebo and Tarceva groups. The overall incidence of ILD from all studies was 
approximately 0.6%. If ILD is diagnosed, Tarceva should be discontinued and 
appropriate treatment instituted as necessary. There are no adequate and well 
controlled studies of Tarceva in pregnant women. Women of childbearing potential 
should be advised to avoid pregnancy while on Tarceva, and will need to practice brith 
control while on study, if premenopausal.  
 
Asymptomatic increases in liver transaminases have been observed in patients on 
Tarceva; therefore, periodic liver function testing should be considered. Also, patients 
taking warfarin or other coumarin-derivative anti-coagulants should be monitored for 


 
 
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changes in prothrombin time or INR. NCI-CTC grade 3 conjunctivitis and keratitis have 
been reported infrequently in patients receiving Tarceva therapy.  Corneal ulcerations 
may also occur. 
 
5.4 Packaging, Supply, and Labeling 
Tarceva (Erlotinib) will be supplied by OSI at no cost for each study patient.   The 
pharmaceutical preparations of Tarceva are formulations containing the hydrochloride 
salt (OSI 774 01).  Tarceva is supplied as tablets containing erlotinib hydrochloride 
equivalent to 150 mg, 100 mg, and 25 mg of erlotinib.  All tablets are round, white, film-
coated, bi-convex tablets without markings.  Each bottle will be labeled with the drug 
name, pill dose, number of pills, manufacture date, Lot # and expiration date. 
 
5.5 Storage 
Tarceva tablets should be stored between 15°C and 30°C (59°F and 86°F).  
 
5.6 Administration 
Patients will receive only a 30-day supply of drug at a time, from the Investigational 
Pharmacy.  The patient will be seen by the nurse once approximately every 30 days (+/- 
7 days) to review number of pills taken during the previous 30 days (+/- 7 days), and to 
receive another 30 days of medication. If patients are unable to return for their follow up 
visits, we will review their mediations and current drug logs over the phone and their 
Tarceva refills will be mailed to them via the investigational pharmacy.  
 
Patients will begin taking Tarceva at least 6 days before their first dose of radiation, 
daily during radiation therapy, and then daily until progression is documented (unless 
treating physician feels that stopping Tarceva would adversely affect the patient), 
adverse events warrant discontinuation or the patient decides to stop taking the 
medication.  
 
Tarceva tablets should be taken once daily.  Each Tarceva dose is to be taken with up 
to 200 mL (~ 1 cup or 8 oz) of water, and should be taken 1 hour before or 2 hours after 
meals or medications, including grapefruit juice, vitamins, and iron supplements.   
 
For patients residing outside the U.S:  Patients will receive a 90 day supply of Tarceva 
at a time, from the Investigational Pharmacy; The study PI will have physician-to-
physician communication regarding protocol enrollment; a letter (Appendix G) will be 
sent to the home physician outlining the subject's participation and requesting the home 
physician agreement to supervise the subjects care. The home physician will be 
requested to provide any patient medication diaries, progress notes, hospitalization 
records, toxicities, tests, and procedures to the study PI or his research staff at MD 
Anderson within 48 hours.  The home physician will be asked that any questions related 
to the study drug dosing, schedule, or side effects be directed to study PI. All life 


 
 
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threatening clinical events must be reported by the home physician to the study PI 
within 24 hours of documented occurrence. The home physician will be provided with 
study contact numbers for business and non-business hours.  
Protocol required evaluations outside MDACC will be documented by telephone, fax or 
e-mail. Fax and/or e-mail will be dated and signed by the MDACC physician, indicating 
that they have reviewed it. 
 
Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
 
A copy of the informed consent, protocol abstract, treatment schema and evaluation 
during treatment will be provided to the local physician. 
Patients will return to MDACC every 3 months for evaluation. 
 
 
 
5.7 Accountability 
In accordance with current Good Clinical Practices (GCPs), the investigational site will 
account for all supplies of Tarceva.  Details of receipt, storage, administration, and 
return or destruction will be recorded in the study drug accountability record according 
to the standard operating procedure of the investigational site.  The drug will be 
delivered to and distributed by the investigational pharmacy of MD Anderson for clinical 
investigations.  
 
All unused supplies of Tarceva (from the study and unused drug from patients) will be 
destroyed after completion of the trial, as per pharmacy SOPs.  Copies of the study 
drug accountability record will be provided to OSI Pharmaceuticals. Patients unused 
drug will be returned to the research nurse.  
 
6.0 Study Methods 
 
Study Calendar 
Assessment 
Screening
Baseline 
(1-3 days 
prior to 
day 1 of 
Tarceva) 
Weekly 
During 
treatment 
One 
Month 
Post 
RT  
(+/- 7 
days) 
 
Follow-up for 
patients on 
Tarceva 
(+/- 7 days) 
 
Follow-up for 
patients off 
Tarceva 
(+/- 14 
days)m,n,o 


 
 
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Histological 
confirmation of 
NSCLC 
X 
 
 
 
 
 
CT/MRI of brain 
and report  
Xb 
 
 
X 
Xm 
 
X 
CBC/Differential
Xb 
 
 
 
 
 
Platelet 
Xb 
 
 
 
 
 
Complete 
Metabolic 
panel) 
Xb 
 
 
 
 
 
Repeat sodium 
level 
 
 
Xe 
 
 
 
CT or PET of 
Liver 
Xc 
 
 
 
 
 
Medical History  
X 
Xd 
 
 
Xd,f 
 
Xd 
Physical 
Examination 
Xb 
 
X 
X 
 
Xm 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
Xa,f, 
 
 
Serum 
Pregnancy test, 
if applicable 
 
X i 
 
 
 
 
 
 


 
 
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Assessment 
Screening
Baseline 
(1-3 days 
prior to 
day 1 of 
Tarceva)
Weekly 
During 
treatment
One 
Month 
Post RT  
(+/- 7 
days) 
 
Follow-up 
for patients 
on Tarceva 
(+/- 7 days) 
 
 
Follow-up for 
patients off 
Tarceva 
(+/- 14 
days)m,n,o 
Document 
steroid dose 
 
X 
X 
X 
 
 
Spitzer Quality 
of Life Index  
 
Xk 
Xl 
 
 
 
 
Folstein Mini-
Mental Status 
Exam 
 
Xk 
Xl 
 
 
 
Optional 
neurocognitive 
tests p 
 
Xk 
 
 
 
 
Consent for 
EGFR 
expression 
testing 
(Optional) 
X 
 
 
 
 
 
Informed 
Consent 
X 
  
  
  
  
 
Vital Signs 
  
X 
  
X 
Xm 
X 
Adverse Event 
Check g 
  
  
X 
X 
 Xf 
 
X 
PT/INR if 
patient on 
Coumadin   
X 
 
Xh,j 
Xh 
Xh 
 
 
X 
 
a = until 30 days after last dose of Tarceva 
b = within 30 days of starting treatment 
c = within 3 months of starting treatment  
d = update only 
e = Patient will have repeat sodium on RT day 7 and RT day 14 if baseline sodium < 135 mg/dl 
f=  Patients will be seen by the research nurse monthly while on Tarceva (+/- 7 days), and/or 
one month post last dose of Tarceva (+/- 7 days). Patients on Tarceva, who are unable to 
return for their follow up visits and 1 month post last dose of Tarceva visit, will be contacted 
by the research nurse by phone to review/asses the following; Update of medical history, 
assessment of AE’s concurrent medications. They will return their unused Tarceva 
medication along with their medication diaries to the research nurse via mail. 


 
 
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g=  All adverse events will be collected until 30 days after the last study dose of Tarceva or 30 
days post RT visit (whichever is last), then only neurocognitive decline will be captured. 
 h = Only if patient has abnormal values during initial screening testing  
 i= within 7 days of starting protocol treatment 
 j= weekly until stable 
 k= Prior to radiation 
 l = During last week of radiation therapy (+/- 7 days) 
m= every 3 months (+/- 14 days) for 2 years then every 6 months after 
n= patients with deteriorating conditions who are unable to return may be followed up by 
telephone. MRI brain, physical exam, mini-mental exam, QOL Index and neurocognitive 
testing may be excluded. 
o= for patients with progressive CNS disease we will record survival only. 
p= Optional neurocognitive tests will include Digit Span, Digit Symbol, Hopkins Verbal Learning 
Test, Controlled Oral World Association, Trail Making Test Part A, Trail Making Test Part B, 
Grooved Pegboard, Barthel ADL Index, M.D. Anderson Symptom Inventory, and Functional 
Assessment of Cancer Therapy with Brain Module. As of July 18, 2012- Optional tests will 
no longer be completed. 
 
 
6.1 Concomitant Medications 
The Investigator will be permitted to prescribe treatment(s) at his or her discretion, 
which must be recorded on the Case Report Form (CRF).  All concomitant meds will be 
tracked until 1 month post last dose of Tarceva. 
 
6.2 Study Discontinuation 
Once enrolled in this study, patients will be allowed to discontinue Tarceva at anytime 
during this study, before, during or after radiation and be considered“off active 
treatment’.  If for any reason a patient wishes to discontinue taking Tarceva they will be 
allowed to do so.  Patients will also be allowed to stop radiation at anytime as well; 
however, doing so will preclude them from continuing to receive Tarceva.  Patients will 
be allowed to have a drug break of up to seven days: however, longer breaks may lead 
to removal from the study based on the discretion of principal investigator.  Additionally 
the principle investigator may choose to discontinue a patient at any time.  All reasons 
for discontinuation of treatment must be documented. Patients will be considered “on 
active treatment” while they are taking Tarceva. Once Tarceva is stopped patients will 
be defined as “off active treatment” and will still undergo routine follow up and screening 
as per the study calendar (see section 6.0). If after disease progression the patient’s 
treating physician feels it is in the best interest of the patient to continue Tarceva, they 
may do so and the patient may also receive other therapies while continuing the study 
drug Tarceva without having the patient terminated from the study.  Monitoring and 
follow up will continue as per the study calendar (see section 6.0). 
 


 
 
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6.3 Efficacy Evaluations 
MRI, or CT, Spitzer Quality of Life Index (Appendix E), Folstein Mini-Mental Status 
Exam (Appendix F) will be done every three months. As of 2-14-13, MMSE and Spitzer 
QOL evaluations will no longer be completed.  
 
6.3.1 Optional Neurocognitive tests:  As of July 18, 2012, we will no longer be 
completing optional neurocognitive testing. 
 
The characteristics of a clinical trial battery to assess cognitive function, 
symptoms, and QOL must include the following: (20) brief ,i.e., able to be 
completed within 45 minutes by most patients, including those feeling ill, (21) 
sensitive to changes in patient function with results uninfluenced by  prior 
exposure to the tests ,and (22) inexpensive.  We have developed such a battery; 
the time to complete the cognitive assessment is on average 23 minutes and we 
have demonstrated that the assessment is practical in terms of cost and burden to 
patient, and is insensitive to repeated administration (20).  
 
 
Neuropsychological assessments will be conducted prior to treatment and at 
designated intervals.  Based on similar studies, we anticipate that more than 90% 
of patients will be willing to participate.   Patients who have progressive disease 
will be followed as long as they are receiving treatment for their disease.  At each 
time point, the test battery described below will be repeated and correlative 
studies will be obtained.   
 
The following tests were selected because they are widely-used standardized 
psychometric instruments that have been shown to be sensitive to the neurotoxic 
effects of cancer treatment in other clinical trials.  The tests have published 
normative data that takes into account age, and where appropriate, education and 
gender.  The tests were also selected to minimize the effects of repeated 
administration.   Data obtained on other studies reveals that patients tend to 
perform normally on tests of attention span, reflecting adequate effort is being put 
forth, and that mood disturbance does not correlate with the results of the 
cognitive portion of the battery.  The memory test has six alternate forms.  The 
other tests measure motor and information processing speed and are relatively 
resistant to the effects of practice.  The total time for test administration, including 
the QOL and symptom measures, is less than 40 minutes. 
 
Cognitive Function 
 
 
Test                            
  
Attention span       
 
Digit Span (21)                                                 


 
 
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Graphomotor speed 
 
Digit Symbol (21)                                               
Memory  
 
 
Hopkins Verbal Learning Test (22)                   
  
Verbal fluency  
 
Controlled Oral Word Association (23)             
  
Visual-motor speed 
 
Trail Making Test Part A (24)                            
  
Executive Function 
 
Trail Making Test Part B (24)                            
  
Motor dexterity  
 
Grooved Pegboard (24)        
 
 
  
 
Symptoms 
Activities of daily living 
 
Barthel ADL Index (25) 
 
 
 
 
Symptoms 
 
           M.D. Anderson Symptom Inventory (26) 
     
 
 
           
QOL 
Quality of life 
 
 
Functional Assessment of Cancer Therapy   
 
 
 
 
 
with Brain Module (27) 
Statistical Considerations 
We will determine the difference between the pre-treatment baseline and follow-up 
assessment scores by the reliable change (RC) index (28).  This index is derived 
from the standard error of measurement (SEM) for each test in the battery.  One 
advantage of this statistic is that the baseline level of performance of a given 
individual is accounted for, since these values may vary from patient to patient.  
 
 
 
The SEM is calculated from the test-retest reliability (r) and the standard deviation 
of test scores (SD): SEM=SD(1-r)½.  The standard error of difference is then 
calculated:  SEdiff=[2(SEM2)]½.   A reliable change (RC) in test scores from 
baseline to follow-up is considered significant if it falls within a 90% confidence 
interval that does include zero.  For each subject the difference between the pre-
treatment baseline and each follow-up assessment will be coded (according to the 
RC index) as 1 (deterioration), 2 (no change), and 3 (improved).  Cross 
tabulations between this variable, time, and possibly treatment group (to account 
for multi-arm studies) will be used to examine the percentages of  patients in each 
treatment group that show meaningful losses or gains in the various test domains 
over the course of the study. 
 
 


 
 
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One  disadvantage of using the RC approach, however, is that the magnitude of 
change is not captured.  Therefore, we plan to supplement our repeated measures 
analysis using raw scores. 
 
 
6.4 Dose Modification / Toxicity Management 
Anti-diarrheal and anti-rash medications may be introduced if clinically indicated.  
Previous Phase I and II studies have demonstrated the frequency and severity of 
diarrhea can 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 resolves for 12 
hours. 
 
Skin rash or dermatosis has been observed during the first several days of treatment 
with Tarceva in many patients and has been noted to diminish in severity despite 
continued treatment.  No controlled clinical trials have been conducted to allow definitive 
recommendations on the treatment of Tarceva -related rash. 
 
Patients who develop a rash characterized by pustules or raised red areas may be 
treated with oral minocycline (100 mg BID for 7 – 10 days to a maximum of 150 mg BID 
for 7 – 10 days as clinically indicated) at the discretion of the Investigator.  Minocycline 
is known to interfere with anticoagulants and oral contraceptives.  Patients treated with 
minocycline who are taking anticoagulants and/or oral contraceptives  will be instructed 
to use a second barrier contraceptive while on Minocycline and should be monitored 
accordingly. 
 
Dose adjustments may be made for toxicity and are to be made based on the greatest 
degree of toxicity. The initial dose reduction is from 150 mg/day to 100 mg/day. If 
significant toxicity is still apparent, the dose may be reduced a second time to 50 
mg/day. Significant toxicity will be defined as any grade 3 or 4 toxicity that the patient 
find unbearable.  Any patient who fails to tolerate treatment of 50 mg/day will be allowed 
to have a drug holiday for up to 7 days.  Any patient requiring a treatment break longer 
than seven days may be withdrawn from the study based on the discretion of the 
principal investigator.  Patients may resume drug or increase a previously decrease 
dosage based on the discretion of their medical oncologist. For analysis and monitoring 
patients on any dose of drug will be considered “on active treatment”. 
 
Tarceva dosing should be discontinued for any grade 3 or greater toxicity that does not 
respond to treatment or failure to recover from hematological toxicity within 14 days. 
 
For patients that are off Tarceva for more than 30 days the only toxicities that will be 
reported and recorded in PDMS will be neurocognitive decline. 
 


 
 
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7.0 Radiation Therapy 
Radiation therapy will be given once per day, five days a week for 14 days.  Radiation 
will be given at a dose of 250 cGy per day for 14 fractions for a total dose of 3500 cGy. 
Radiation will be delivered with 6MV photons using opposed lateral beams dosed to mid 
plane.  
 
8.0 Adverse Events  
All adverse events will be graded according to NCI CTC version 3.0 
 
Adverse drug experience means any adverse event associated with the 
use of a drug in humans, whether or not considered drug related, including 
the following:  an adverse event occurring in the course of the use of a 
drug product in professional practice; an adverse event occurring from 
drug overdose, whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action (21 CFR 
314.80). 
 
An adverse event is any adverse change from the subject’s baseline condition, including 
any clinically significant laboratory test value abnormality that occurs during the course 
of the clinical study after the informed consent is signed, whether the adverse event is 
considered related to the treatment or not. 
 
All adverse events will be collected until one month post last day of Tarceva or radiation 
(whichever is last).  This may require obtaining clinical blood samples for appropriate 
laboratory tests until their values return to baseline levels or performing follow-up 
physical examinations until resolution of identified abnormalities. 
 
The most common adverse reactions in patients receiving single-agent TARCEVA 150 
mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, 
respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study 
discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients 
needed dose reduction for rash and diarrhea, respectively. The median time to onset of 
rash was 8 days, and the median time to onset of diarrhea was 12 days. 
 
 
 
 
 


 
 
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TARCEVA 150 mg 
N = 485
Placebo 
N = 242
NCI CTC Grade
Any
Grade
Grade
3
Grade
4
Any
Grade
Grade
3
Grade
4
MedDRA Preferred Term
%
%
%
%
%
%
Rash  
75  
8  
<1  
17  
0  
0  
Diarrhea  
54  
6  
<1  
18  
<1  
0  
Anorexia  
52  
8  
1  
38  
5  
<1  
Fatigue  
52  
14  
4  
45  
16  
4  
Dyspnea  
41  
17  
11  
35  
15  
11  
Cough  
33  
4  
0  
29  
2  
0  
Nausea  
33  
3  
0  
24  
2  
0  
Infection  
24  
4  
0  
15  
2  
0  
Vomiting  
23  
2  
<1  
19  
2  
0  
Stomatitis  
17  
<1  
0  
3  
0  
0  
Pruritus  
13  
<1  
0  
5  
0  
0  
Dry skin  
12  
0  
0  
4  
0  
0  
Conjunctivitis  
12  
<1  
0  
2  
<1  
0  
Keratoconjunctivitis sicca  
12  
0  
0  
3  
0  
0  
Abdominal pain  
11  
2  
<1  
7  
1  
<1  
 
 
Rare, But Serious  
In some patients taking erlotinib and oral blood thinners INR have been 
reported abnormally elevated.  The elevation of INR was associated with 
bleeding. 
 
 Some patients (less than 1%) taking erlotinib can get ‘interstitial lung 
disorder’ or ‘interstitial pneumonia’. This can cause worsening of 
existing lung problems or causes new lung problems, such as 
sudden onset of shortness of breath, fever, cough, and/or problems 


 
 
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Page 21 
 
with oxygen getting through the lungs to the blood. In some patients, 
this lung disease has been fatal.   
  
 Inflammation of the lung, pulmonary fibrosis (scarring), and lung 
infiltrates may occur in patients on erlotinib.   
 Eye changes and blurred vision and corneal (lining of the eye) 
damage 
 Stroke 
 Blood clots 
 Weight loss 
 Confusion 
 Heart attack 
 
Serious side effects of erlotinib are infrequent. They are usually not severe enough 
to require discontinuing treatment. 
PDMS Recording Requirements 
 
AE’s will be recorded according to Phase II protocols. 
Recommended Adverse Event Recording (PDMS) Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
  
  
  
  
Unrelated 
Phase I 
 Phase I 
 Phase I             
Phase II   
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
Unlikely 
Phase I 
 Phase I 
 Phase I             
Phase II   
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
Possible 
Phase I           
Phase II 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
Probable 
Phase I           
Phase II 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
Definitive 
Phase I           
Phase II 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
Phase I             
Phase II  
Phase III 
 
 
 
8.1  Severity of Adverse Drug Experiences 
Adverse drug experiences will be graded according to the criteria in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 


 
 
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(Appendix B).  The toxicity criteria can be accessed through the NCI website 
(ctep.cancer.gov/reporting/ctc.html). 
 
Clinical adverse events not classified by this scale will be categorized using the 
following definitions: 
 
MILD  
 
discomfort noted, but no disruption of normal daily activity 
 
MODERATE  
discomfort noted of sufficient severity to reduce or adversely  
affect normal activity 
 
SEVERE 
 
incapacitating, with inability to work or perform normal daily  
activity 
 
 
8.2 Serious Adverse Event Reporting (SAE) 
 
A serious adverse event is – any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above may also be considered serious 
adverse events. Any important medical event can and should be reported as an 


 
 
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SAE if deemed appropriate by the Principal Investigator or MDACC- Office of 
Research Education and Regulatory Management (ORERM). 
 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on Reporting Serious Adverse Events”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to ORERM, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
 All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution to the study drug, must have a written report submitted within 24 hours 
(next working day) of knowledge of the event to the Safety Project Manager in 
ORERM.   
 
 The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to ORERM.  
 
 Serious adverse events will be captured from the time the patient signs consent 
until 30 days after the last dose of study treatment. Serious adverse events must 
be followed until clinical recovery is complete and laboratory test have returned 
to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to ORERM. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by MDACC (Safety Project 
Manager ORERM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, MDACC’s guidelines, and Institutional Review 
Board policy. 
 
 
 
8.3  Investigator Communication with Supporting Companies 


 
 
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The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for all 
SAEs, and all SAEs will be faxed (within 24 hours of learning of the event) to: 
 
OSI Drug Safety 
    Fax number: 303-546-7706 
 
9.0 Data Collection, Study Monitoring, and Data Disclosure 
 
9.1 Data Collection and Reporting 
Data for each patient will be recorded in PDMS. 
 
10.  Administrative Considerations    
 
10.1 Patient Registration Procedure 
All subjects will be registered in Clinical Oncology Research System (CORe). 
 
 
11.0 Statistical Consideration 
Phase II study of 20 patients (40 in total when combined with the Arizona study) to 
determine the effect of combining whole brain radiation with Tarceva.  From what has 
been observed from the initial 15 patients enrolled at the Arizona Cancer Center, we 
would expect the vast majority of patients, to be in recursive partitioning analysis (RPA) 
class II, with the remaining falling into class I and a small percentage in class III. From 
the first 15 patients enrolled 4 remain alive, of the patients that passed away the median 
survival has been 9.5 months, while the RPA predicted survival was 4.2 months. While 
the initial result from the Arizona study are encouraging accrual has been longer than 
expected, which is why we have proposed to open a similar study here at MD 
Anderson. If this initial phase II study is successful it will serve as the foundation for a 
much larger multi-institutional phase III study.  
 
11.1 Study Endpoints 
Primary Endpoint: 
Median survival 
 
 
11.2 Background 
The primary objective of this study is to estimate the median survival of patients with 
brain metastases from non-small cell lung cancer treated with Tarceva combined with 
whole brain radiation therapy.  
 


 
 
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Gaspar et al. provides a definition of average survival for patients with brain metastases 
stratified into three classes based on age, KPS and control of primary disease.  This 
information came from an analysis of 1200 patients from three earlier RTOG trials.  
Based on this study one can expect the following survival. (9) 
 
Class 1 patients with KPS >70 and age <65yrs to live approximately 7.1 months 
Class 2 patients not meeting Class 1 or 3 criteria, have an average survival of 4.2 
months 
Class 3 patients with KPS < 70 have an average survival of 2.3 months 
 
This study will be conducted in parallel with an identical study at the University of 
Arizona that was started on March of 2006.  So far this study has accrued 15 of 20 
patients, as of 8/2008.  From these initial 15 patients the vast majority fall into RPA 
class II, with the reaming falling into class I and a small percentage in class III. From the 
first 15 patients enrolled the 4 remain alive, of the patient that have passed away the 
median survival has been 9.5 months, while the RPA predicted survival was 4.2 
months.  
 
The data from the Arizona study will be combined with this study (based at MD 
Anderson) which will accrue an additional 20 patients, producing a total of 40 patients 
for analysis.  Patients will be analyzed based on the intent-to-treat principle. We will also 
analyze the subset of evaluable patients. Evaluable patients are defined as those 
patients that have completed WBRT and Tarceva.  
 
11.3 Sample Size 
We assume that the true median survival for the historical control is 4.2 months 
(averaging to the historical value for class 2), and we assume that the true median 
survival will be increased by 43% to 6.0 months with this therapeutic approach. This 
represents a hazard ratio (experimental/historical) of 0.70. We assume uniform accrual 
over 24 months, an additional follow-up period of 9 months, exponentially distributed 
death times. The exponential MLE test for a single arm study at the one-sided 0.10 
significance level will yield 80% power to detect an increase in median survival from 4.2 
to 6 months with a sample size of 40 patients.  
 
 
 
11.4 Patient Accrual 
MD Anderson treated 250 patients with all forms of brain metastasis in 2007 alone, 
given that approximately 60% of all brain metastasis are derived from NSCLC we would 
expect about 150 cases to be attributed to NSCLC, which would result in 12.5 patients 
per month, as such an estimated accrual of 4-6 pts per month would lead to a 
completion time of 3-5 months.   


 
 
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11.5 Data Analysis 
We will use descriptive statistics to summarize the demographic and clinical 
characteristics of patients overall and by treating institution. 
 
11.5.1 Endpoint Analysis 
 
11.5.1.1 Survival  
We will use the product limit estimator of Kaplan and Meier (1958) to estimate the 
overall survival of all patients using the intent-to-treat principle. We will report the 
median survival and its associated 95% confidence interval. 
 
We will also estimate overall survival stratified by treating institution and class, as 
described above in section 11.2. 
 
We will compare the estimates of survival from this study with a recent reported phase 
III randomized RTOG trial, 0118, which randomized 332 patients to WBRT with or 
without Thalidomide (19).  Our patients will be compared to both the overall survival and 
CNS progression free survival from this study.   
 
We will tabulate cause of death by treating institution and by class, and we will compare 
the cause of death for patients in this study with patients from RTOG 01188. 
 
We will analyze progression-free survival (PFS) in the same manner as overall survival. 
 
We will use the methods described in Klein and Moeschberger (1997) to test for 
differences in survival between the matched pairs. To help us understand how 
similar/dissimilar patients from MDACC and Arizona are we will summarize the 
demographic and clinical characteristics of these patients separately. We will also 
estimate the survival of the 40 patients (20 from MDACC and 20 from AZCC) with the 
product-limit estimator of Kaplan and Meier (1958) stratified by study center (MDACC, 
AZCC), and we will use Cox (1972) proportional hazards regression to model survival of 
these 40 patients as a function of study center and estimate the hazard ratio 
(MDACC:AZCC) with a 95% confidence interval.  For the match control based variables 
we will use patients from a prior randomized whole brain radiation therapy (WBRT) 
study performed by the Radiation Therapy Oncology Group (RTOG) study (RTOG 
0118).  Patients will be matched based on age, KPS, number of brain metastasis and 
control of systemic disease. If there is more than one match available for a patient we 
will review all cases. 
 
 
11.5.1.2 Quality of Life 


 
 
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We will use descriptive statistics to summarize the scores on the Spitzer Quality of Life 
Index (SQLI) and the Folstein Mini-Mental Status Exam (FMMSE) at baseline, at the 
end of Radiation Therapy, monthly while on Tarceva and/or one month post last dose of 
Tarceva, and then once every 3 months. For patients who are unable to return for their 
monthly research nurse visit and their 1 month post last dose Tarceva visit, the Spitzer 
Quality of Life index and Folstein Mini-mental exam (with exception to the last four 
questions) will be conducted by the research nurse monthly over the phone. We will 
summarize these scores by class and by treating institution as well. We will similarly 
summarize the change from baseline in scores of the SQLI and the FMMSE. We will 
use mixed effects regression to model changes in SQLI and FMMSE over time with 
patient as a random effect and treating institution and class as fixed effects with a 
spatial variance-covariance structure. 
 
11.5.1.3 Mutational Analysis 
Tumor tissue will be acquired from the source used to establish the diagnosis of 
malignancy.   The EGFR receptor will be sequenced and evaluated for small deletions 
that affect amino acids 747 through 750 or point mutations, with the most commonly 
implicated replacement being of leucine by arginine at codon 858 [L858R] (18).  If the 
patient goes on to have their metastatic brain lesion surgically resected, we will also 
plan to evaluate protein level of other key mediators implicated in the EGFR pathway.  
Protein analysis will be carried out with western blots and/or immunohistochemistry 
techniques, proteins analyzed will include EGFR, p-AKT, PTEN, Vimentin, Fibronectin 
and E-Cadherin. 
 
11.5.2 Interim Reports 
Interim reports with statistical analyses are prepared every six months until the initial 
manuscript reporting the treatment results has been submitted. The reports contain: 
a) the patient accrual rate with a projected accrual completion date 
b) the pretreatment characteristics of accrued patients 
c) the frequency and severity of toxicities 
d) the results of any completed study chair modality reviews 
 
 
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