Clinical trial NCT00563784
Conditions: Non-Small Cell Lung Cancer Lung Cancer
Keywords: Non-Small Cell Lung Cancer Lung Cancer Squamous Cell Carcinoma Adenocarcinoma Bronchoalveolar Cell Carcinoma Large Cell Anaplastic Carcinoma Giant Cell Carcinoma Clear Cell Carcinoma Erlotinib Erlotinib Hydrocholoride OSI-774 Tarceva Carboplatin Paraplatin Paclitaxel Taxol NSCLC
Sponsor: M.D. Anderson Cancer Center
Start date: 2007-11-01; Completion date: 2018-05-30
Enrollment: 68 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to find out if erlotinib given with chemotherapy and radiation therapy can help to control NSCLC. The safety of this combination treatment will also be studied.

Researchers will also test the tissue from your earlier biopsy to measure the levels of epidermal growth factor receptor (EGFR). The purpose of EGFR testing is to learn about any link between various forms of EGFR and your response to treatment with erlotinib.

Detailed description:
Erlotinib is designed to block the activity of a protein called epidermal growth factor (EGFR). EGFR is found on the surface of many tumor cells that may control tumor growth and survival. This may stop tumors from growing.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in the study. You will have a FEV1 (breathing test). You will have a complete physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). Blood (about 2 tablespoons) will be drawn for routine tests. You will have a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to check the status of the disease. You will be required to have a positron emission tomography (PET) scan to locate the area of cancer outside the chest and lymph glands. You will have either a CT scan or an MRI to measure the size of the tumor(s). If there is positive finding of CT or MRI you will be taken off study. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). If you have a significant history of cardiovascular disease, you will have a MUGA scan and echocardiogram to test your heart function. Women who are able to have children must have a negative urine or blood (about 2 teaspoons) pregnancy test before starting treatment.

You will have PET scan 1 month after completion of consolidation chemotherapy.

If you are found to be eligible to take part in this study, you will take erlotinib every day for 7 weeks (except on the days you receive chemotherapy). The erlotinib tablets should be taken at the same time each day, at least 1 hour before or 2 hours after a meal, with a small glass (about 7 ounces) of water. If you are unable to swallow tablets, you may dissolve the tablets in distilled water to drink.

You will receive radiation every day (Monday through Friday) for 7 weeks. You will also receive chemotherapy through a needle in a vein once a week for 7 weeks. The chemotherapy will include carboplatin and paclitaxel. Receiving chemotherapy will take about 6 hours total.

You will receive consolidation therapy on weeks 11-17.

Treatment on this study will last 17 weeks. Once a week during that time, you will have blood (about 2 tablespoons) drawn for routine tests. You will also have a CT scan of the chest within about 4 weeks from beginning the study, 2 months after finishing therapy, and then every 6 months after that for 2 years. The CT scans are used to check the status of the disease.

You will be taken off study if the disease gets worse or intolerable side effects occur. In this case, you would not receive erlotinib anymore but would continue standard chemotherapy and radiation therapy.

You will be asked to come in to the clinic for follow-up visits to check on your recovery from treatment. The follow-up visits will be at the end of all treatment, 1 month after treatment, and then once a month for as long as your doctor feels it is necessary. Once your side effects have become less severe, you will be asked to come in to the clinic for follow-up visits every 3 months for 2 years, and then every 4 months for the following 2 years after that. You will have a physical exam, and your medical history will be recorded. You will be asked about any side effects you may have. Blood (about 2 tablespoons) will be drawn for routine tests. You will have a PET scan.

You have the right to leave the study at any time. If you choose to stop participating in this study, you should contact the study chair and/or research nurse. Your doctor may decide to take you off this study if your medical condition gets worse and/or you are unable to comply with study requirements.

At the end of the study you will not be automatically notified of the research findings. If you wish to learn about the results, however, you may request them from the study chair.

This is an investigational study. All three study drugs are commercially available. Carboplatin, and paclitaxel are FDA approved for the treatment of NSCLC, but their use in combination with erlotinib is not. Erlotinib is FDA approved for some uses, but it has not been approved by the FDA to treat lung cancer patients like yourself who have not yet undergone chemotherapy; however, the FDA has permitted its use in this research study. Carboplatin and paclitaxel are considered standard of care treatment and you would probably be treated with these drugs or similar drugs even if you decided not to be in the study. Up to 48 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: Oral Erlotinib 150 mg daily + Paclitaxel 45 mg/m\^2 by vein weekly + Carboplatin 2 AUC by vein weekly and Radiation Therapy 63 GY/35 fractions for 7 weeks cycles
Interventions: intervention 1: Erlotinib intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Radiation Therapy
Intervention descriptions: intervention 1: 150 mg by mouth daily for 7 Weeks intervention 2: 2 AUC by vein weekly for 7 Weeks intervention 3: 45 mg/m\^2 by vein weekly for 7 Weeks intervention 4: 63 GY/35 fractions for 7 weeks (+/- 5 days)

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1
Protocol Page
A Phase II Study of TARCEVA (erlotinib) in Combination with Chemoradiation in 
Patients with Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC)
2005-1023
Core Protocol Information
Short Title 
Tarceva
Study Chair: 
Ritsuko R. Komaki
Additional Contact:
David Leos
Toni Williams
Victoria Cox
Department:
Radiation Oncology
Phone:
713-563-2300
Unit:
97
Full Title: 
A Phase II Study of TARCEVA (erlotinib) in Combination with Chemoradiation in Patients with 
Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 04/13/2015
Version:
28
Submitted by:
Toni Williams--3/30/2015 6:16:32 PM
OPR Action:
Accepted by:  Virginia M Gonzales -- 4/3/2015 4:59:49 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Background
Background on Non-small Cell Lung Cancer (NSCLC) Therapy
Lung cancer is the second most common cancer diagnosed for both sexes in the
United States, second to prostate cancer for men and breast cancer for women.
Approximately 172,570 new cases are estimated for 2005. It is the leading cause of 
cancer deaths in both men and women, with approximately 163,510 deaths estimated 
for 2003.
1 Upon initial presentation, fewer than one-half of patients will have surgically 
resectable lung cancer with the potential for cure. Approximately one-quarter of patients 
will present with locally advanced disease involving either the ipsilateral mediastinal or 
subcarinal lymph nodes (American Joint Committee on Cancer [AJCC] Tl-3 N2 MO, 
Stage IIIA) or contralateral mediastinal, hilar or ipsilateral or contralateral scalene or 
supraclavicular nodes (AJCC Tl-2 N3 MO, Stage IIIB) without evidence of extrathoracic 
metastases. A smaller number of patients will have a centrally located primary tumor 
involving mediastinal structures (AJCC T4 Nx MO, Stage IIIB). These patients are 
generally not considered candidates for surgical resection. Until recently
the standard therapeutic approach for these patients was a four to six week course of 
thoracic radiation therapy (RT). This approach resulted in excellent control of tumor 
related thoracic symptoms such as hemoptysis, airway obstruction, dyspnea, and chest 
pain. However, with median survival times of 9-12 months and five-year survival rates of 
only 5-8% reported with this approach, exploration of alternative therapeutic choices is 
well justified. One approach involves the delivery of chemotherapy and/or radiotherapy 
in an attempt to render these tumors potentially resectable followed by thoracotomy and 
attempted surgical resection. Several pilot studies have yielded
encouraging results with such regimens; however, the majority of patients with stage III 
non-small cell lung cancer (NSCLC) have tumors, which will not be rendered resectable 
for cure with any pre-operative approach. For these patients, the current therapeutic 
challenge is to optimize available non-operative strategies.
Since the 1970's, a number of investigators sought to improve the survival results of 
stage III NSCLC patients by combining chemotherapy with thoracic RT. While early 
randomized trials failed to demonstrate any advantage of such regimens over thoracic 
RT alone, two developments led to clinical trial designs that have yielded a positive 
result. These developments included the availability of cisplatin-containing regimens and 
the recognition that patients with a more favorable performance status are more likely to 
benefit from aggressive therapy. There now have been four randomized trials published 
that demonstrate a statistically significant survival advantage of a cisplatin containing 
regimen with thoracic RT over thoracic RT alone.
2-5 Two of these trials used two cycles of 
pre-RT full dose cisplatin and vinblastine,
2-3 one trial alternated chemotherapy with RT,
4 
and the other delivered low dose daily and weekly single agent cisplatin during thoracic 
RT.
5 Based on somewhat incomplete analyses of patterns of tumor failure location, it 
appears that sequential chemoradiation reduces or delays the development of 
extra-thoracic metastases, while low dose concurrent cisplatin appeared to improve the 
control rate of intra-thoracic tumor, i.e., acted as a potentiator of the radiation effect. The 
goal of many investigators in recent years has been to take advantage of both the 
benefits of full dose chemotherapy and the sensitizing effects of concurrent 
chemoradiation.
The Radiation Therapy Oncology Group (RTOG) has conducted several phase II trials 


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seeking to exploit the advantages of both full dose chemotherapy and the concurrent 
delivery of chemotherapy and thoracic RT. The most promising of these trials combined 
two cycles of cisplatin and oral etoposide concurrently with twice-daily thoracic RT. A 
total of 76 patients were entered, and the estimated median survival time was a 
remarkable 19.6 months.
6 This compared with a median survival time of 9.6 and 11.4 
months with standard RT and 13.7 and 13.8 months with sequential chemoradiation in 
two previously cited randomized trials.2-3 The exciting phase II result led to the phase III 
trial (RTOG 94-10) that compared the regimen to an established sequential 
chemoradiation regimen of vinblastine and cisplatin followed by once-daily RT on Day 50 
and another concurrent chemoradiation regimen in which once- or twice-daily RT and 
the same chemotherapy were used.
7 Median survival times were 14.6 months for the 
sequential arm and 17 and 15.6 months for the concurrent arms with once-daily and 
twice-daily RT, respectively.
The West Japan Lung Cancer Group compared sequential to concurrent
chemoradiation using Mitomycin, vindesine, and cisplatin, (MVC) chemotherapy among 
320 patients with stage III NSCLC and demonstrated a survival advantage favoring the 
concurrent arm, with median survival times of 16.5 versus 13.3 months, respectively 
(P=0.047).
8
1.1
Epidermal Growth Factor Receptor Expression and Significance in Cancer 
The control of cell growth is mediated by a complex network of signaling pathways 
responsive to external influences, such as growth factors, as well as to internal controls 
and checks.  Epidermal growth factor (EGF) was one of the first growth factors to be 
described.  It was shown to be mitogenic, an effect mediated by the binding of EGF (or 
other ligands) to the cell surface EGF receptor (EGFR), stimulating autophosphorylation 
of the intracellular tyrosine kinase domain of the receptor.  Subsequent investigations 
revealed EGFR to be one of a family of closely related receptors that includes EGFR 
(HER1), HER2, HER3, and HER4.  
EGFR and other HER family members are considered to be important in the 
development, progression, and aggressive behavior of human epithelial malignancies 
and to be relevant therapeutic targets.  A number of human malignancies are associated 
with aberrant or over-expression of EGFR.
9  Stimulation of tumor cells via the EGFR is 
important for both tumor growth and tumor survival in vivo.  Over-expression of EGFR in 
certain human tumors, including non–small cell lung carcinoma (NSCLC), has been 
correlated with both chemo-resistance and poor prognosis.
10-22 Inhibitors of EGFR 
tyrosine kinase activity have been in development for a number of years, and although 
earlier compounds lacked specificity and potency, newer compounds have proven active 
in nonclinical and clinical studies.
Erlotinib (previously known as OSI-774) is an orally active, potent, selective inhibitor of 
the EGFR tyrosine kinase.  Early clinical data with Erlotinib indicate that the compound is 
generally safe and well tolerated at doses that provide the targeted effective 
concentration based on nonclinical experiments.  A recently completed, randomized, 
double-blind, placebo-controlled trial has shown that Erlotinib as a single agent 
significantly improves the survival of patients with incurable Stage IIIb/IV NSCLC who 
have failed standard therapy for advanced or metastatic disease.
23


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1.2
Erlotinib as an EGFR Tyrosine Kinase Inhibitor
Erlotinib is an EGFR tyrosine kinase inhibitor that has been investigated in several 
Phase III studies.  An overview of relevant nonclinical and clinical information is 
presented below; complete details are available in the Erlotinib Investigator Brochure.
1.2.1
Nonclinical Data
a.
Pharmacology
Erlotinib, a quinazoline, directly and reversibly inhibits the human EGFR tyrosine 
kinase with an IC50 of 2 nM (0.79 ng/mL) in an in vitro enzyme assay and 
reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 nM 
(7.9 ng/mL).  This potent inhibition is selective for the EGFR tyrosine kinase both 
in assays assessing the effects of Erlotinib on a variety of other isolated tyrosine 
kinases and in cellular bioassays designed to isolate this functional pathway.  
Erlotinib is designed to inhibit EGF-dependent proliferation of cells at 
submicromolar concentrations and blocks cell cycle progression in the G1 phase. 
Data on drug exposure and anti-tumor responses in human tumor xenograft 
models (HN5 and A431) were analyzed in order to estimate the plasma 
concentration of erlotinib associated with anti-tumor activity.  Based on these 
efficacy models, the minimum steady-state plasma concentration targeted for 
clinical activity in humans is projected to be 500 ng/mL.
b. Toxicology
Toxicology studies have been performed in mice, rats (up to 6 months), dogs (up 
to 1 year), and monkeys (1 week).  Treatment-related effects observed in at least 
one species or study included effects on the cornea (atrophy, ulceration), skin 
(follicular degeneration and inflammation, redness, and alopecia), ovary 
(atrophy), liver (necrosis), kidney (papillary necrosis and tubular dilatation), 
gastrointestinal tract (delayed gastric emptying and diarrhea), and embryo-fetal 
toxicity.  Red blood cell parameters were decreased, and white blood cells 
(primarily neutrophils) were increased.  There were treatment-related increases 
in ALT, AST and bilirubin; increases in bilirubin were likely caused by a 
treatment-related impairment of bilirubin metabolism. 
1.2.2
Clinical Experience with Erlotinib
As of April 2004, Erlotinib has been studied clinically in more than 4000 healthy 
subjects and patients (excluding patients exposed to placebo) in a number of 
Phase I, II, and III studies.  


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a.
Dose Selection for Single-Agent Trials of Erlotinib
Phase I trials of Erlotinib explored both schedule and dose to evaluate the 
safety, tolerability, and pharmacokinetic profile of the compound given as a 
single agent.  A number of pharmacokinetic trials in healthy subjects have been 
conducted, along with three classic Phase I trials in patients with advanced 
cancer.  The single-agent maximum tolerated dose (MTD) was estimated to be 
150 mg administered once daily.  
The primary toxicities of single-agent Erlotinib consisted of rash (dermatosis), 
diarrhea, nausea, fatigue, stomatitis, vomiting, and headache.  When given 
daily, dose-limiting toxicity (diarrhea) was observed at 200 mg/day.  At 150 
mg/day, diarrhea was manageable with the addition of loperamide therapy; this 
dose was considered the maximal tolerated dose. 
Rash (variously referred to as dermatitis, acneiform rash, or maculopapular 
rash) has been variable in onset, duration, and severity, but typically appears on 
the face, neck, scalp, chest, and back starting after ~1 week of treatment.  The 
mechanistic basis of the rash remains uncertain; histopathologic examination of 
biopsies of the rash demonstrated inflammatory cell infiltrate and mild epidermal 
hyperproliferation.  In some cases, the rash gradually improved despite 
continued dosing and, in general, resolved without sequelae following Erlotinib 
discontinuation.  The rash did not result in study discontinuation in patients with 
cancer in the Phase I trials.  
Laboratory abnormalities observed infrequently with single-agent Erlotinib 
involved primarily liver function tests, including elevation of ALT, AST, and/or 
bilirubin.
Selection of the 150 mg/day dose of Erlotinib for subsequent single-agent 
studies was based on pharmacokinetic parameters, as well as the safety and 
tolerability profile of this dose in Phase I trials in heavily pretreated patients with 
advanced cancer.  Drug levels seen in patients with cancer receiving the 150 
mg/day dose were consistently above the average plasma concentration of 500 
ng/mL targeted for clinical efficacy. 
b.
Pharmacokinetics
Oral Erlotinib is well absorbed and has an extended absorption phase, with 
mean peak plasma levels occurring at 3 hours after oral dosing of 150 mg/dL at 
steady state.  A study in healthy subjects provided an estimate of bioavailability 
of 59% (95% CI:  55%, 63%).  The time to reach steady-state plasma 
concentration was ~5 days.  The accumulation ratio with daily dosing of Erlotinib 
was estimated to be 2.0.  From a population pharmacokinetic analysis of 708 
patients, the median trough concentration (Cmin) 24 hours following the 
previous dose was 1041 (697) ng/mL.  Median AUC achieved during the dosing 
interval at steady state was 19,801 ng  hr/mL.  Exposure after an oral dose is 
increased by food.  
There is extensive binding of Erlotinib and metabolites to both serum albumin 
and AAG (alpha-1-acid glycoprotein), with total plasma protein binding for 


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Erlotinib and OSI-420 of ~95% and 91%, respectively.  Erlotinib is extensively 
metabolized in the liver by the hepatic cytochromes in humans–primarily by 
CYP3A4 and to a lesser extent by CYP1A2.  The primary metabolite of Erlotinib, 
OSI-420, has potency comparable to that of erlotinib, but is present at levels 
that are  10% of erlotinib levels.  Erlotinib is excreted predominantly via the 
feces ( 90%).  The elimination half-life after a 150-mg oral dose is ~30 hours.  In 
population-based data analyses, no relationships were identified between 
predicted steady-state trough concentration and patient age, body weight, sex, 
ethnicity, or creatinine clearance.
d.
Phase II and III Trials in Patients with Advanced Cancer 
Multiple Phase II trials evaluating the safety, tolerability, and antitumor activity of 
Erlotinib have been conducted in patients with advanced, refractory 
malignancies including cancer of the head and neck, lung, aerodigestive tract, 
ovary, breast, central nervous system (glioma), and others. Erlotinib has been 
evaluated both as a single agent and administered concurrently with 
conventional chemotherapy agents using various doses and schedules.    
Evidence of activity has been observed in squamous cell carcinoma of the head 
and neck, ovarian, breast and pancreatic carcinoma, non–small cell lung cancer 
(NSCLC), and glioblastoma multiforme (GBM).  Patients received 150 mg/day of 
Erlotinib in all of these studies except the GBM study where dose escalation 
was allowed until limited by rash and where a higher starting dose was tested in 
subjects receiving concomitant enzyme inducing anti-epileptic drugs.  Dose 
reduction was allowed in all studies in the case of intolerance.  Diarrhea was 
treated with loperamide therapy and/or dose reduction.  Rash was treated with a 
variety of agents, including oral and topical antibiotics, corticosteroids, and other 
agents.  
Patients receiving Erlotinib in combination with various chemotherapy agents 
have generally experienced the same type of adverse events (AEs) as with 
either agent alone.  
The first randomized placebo controlled trial to demonstrate a survival 
advantage for an EGFR inhibitor was the Phase III study, BR21.  This 
international trial, conducted by the National Cancer Institute of Canada Clinical 
Trial Group (NCIC CTG), included 731 patients with incurable Stage IIIb/IV 
NSCLC who have failed standard therapy for advanced or metastatic disease.  
Patients randomized in a 2:1 ratio to single-agent Erlotinib 150 mg/day obtained 
a 42.5% improvement in median survival over placebo, from 4.7 to 6.7 months.  
The one-year survival increased significantly (from 22% to 31%) as did the 
median and 6 month PFS, response rate, and the time to deterioration of tumor 
related symptoms of pain, cough, and dyspnea.
23
In BR-21, of the 727 patients evaluable for safety (485 Erlotinib, 242 placebo), 
the most common AEs in the Erlotinib arm were rash (75% Erlotinib, 17% 
placebo), diarrhea (54% Erlotinib, 18% placebo) and stomatitis (17% Erlotinib, 
18% placebo) events.  The majority of these events were mild to moderate in 
severity.  The incidence of interstitial lung disease (ILD) reported was the same 


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in the placebo and Erlotinib groups at 0.8% in each arm.
Two large, Phase III, randomized studies in first-line NSCLC patients evaluated 
Erlotinib in combination with platinum-based two-drug combination 
chemotherapy.  A total of 1079 previously untreated patients received 
carboplatin/paclitaxel with either Erlotinib or placebo in the TRIBUTE trial 
(OSI2298g) conducted in the United States.  An additional 1172 patients 
received cisplatin/gemcitabine plus either Erlotinib or placebo in the TALENT 
trial (BO16411) conducted in 27 countries in Europe and other ex-U.S. 
locations.  Neither study met its primary endpoint of improved overall survival or 
a secondary endpoint of improved time to disease progression or overall 
response rate.  Overall, the number of adverse events and serious adverse 
events were well balanced between the two arms of each study, with two 
exceptions.  As expected, rash and diarrhea occurred more frequently in the 
Erlotinib arms.  In the TRIBUTE study, more serious adverse events resulting in 
death were seen in the Erlotinib arm compared with the placebo arm (53 vs. 27).  
Most of the apparent imbalance was due to events reported as pneumonia or 
progression of underlying cancer.
24 
e. Patients with Hepatic or Renal impairment
The influence of hepatic metastases and/or hepatic dysfunction on the 
pharmacokinetics of Erlotinib is not yet known.  However, Erlotinib is cleared 
predominately by the liver, and caution should be used when administering 
Erlotinib to patients with hepatic dysfunction. Erlotinib is also a strong inhibitor of 
the UDP-glucuronosyltransferase UGT1A1 enzyme responsible for the 
glucuronidation of bilirubin.  Hyperbilirubinemia appears most often to be a side 
effect related to genetic polymorphisms of UGT1A1.  
No clinical studies have been conducted in patients with compromised renal 
function since Erlotinib and its metabolites are not significantly excreted by the 
kidneys.  
1.3 
Rationale
At the 2002 annual meeting of the American Society of Clinical Oncology (ASCO), 
preliminary results from the American College of Radiology (ACR) Locally Advanced 
Multi-Modality Protocol (LAMP) study, ACR 427, were presented.
25 This study enrolled 
patients with unresected stage III NSCLC and randomized them to one of three arms: 
sequential paclitaxel/carboplatin followed by RT (Arm 1); induction therapy with 
paclitaxel/carboplatin followed by concurrent paclitaxel/carboplatin/RT (Arm 2); or 
concurrent paclitaxel/carboplatin/RT followed by consolidation therapy with
paclitaxel/carboplatin (Arm 3). The preliminary survival data led to the termination of 
accrual to Arm 2, but were sufficiently promising to continue accrual to Arms 1 and 3. 
Recently, the Southwest Oncology Group (SWOG) published updated results of a study 
(SWOG 9504) of concurrent therapy followed by consolidation therapy.
26 Patients with 
stage IIIB NSCLC were treated with a regimen of concurrent cisplatin/etoposide/RT 
followed by consolidation with docetaxel. The results presented were compared to an 
earlier study using the same concurrent regimen, but without consolidation therapy. 
Median survival and one-, two-, and three-year survival rates were substantially 
increased with the addition of the consolidation therapy.


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Several agents designed to block the effects of the EGFR have undergone clinical 
testing in patients with NSCLC. At the 2001 ASCO meeting, the results of a phase II trial 
utilizing the oral EGFR tyrosine kinase inhibitor OSI-774 were reported.
27 In that trial of 
patients with recurrent NSCLC, 19% of patients had received > 3 prior chemotherapy 
regimens. Overall, 1.8% of patients achieved a CR, 10.5% PR, and 26.3% SD with OSI- 
774. Importantly, the duration of PR’s lasted 17-36 weeks. Subsequently, the results of a 
phase I study with OSI-774 in combination with docetaxel were reported at the 2002 
ASCO annual meeting.
28 This study included patients with NSCLC and, as of the time of 
the report, minor response and stable disease had been observed in NSCLC patients.
Also at the 2002 ASCO annual meeting, several studies of another EGFR tyrosine 
kinase inhibitor, ZD1839, were reported.
29-31 Two of the trials, designated IDEAL 1 37 
(n=210) and IDEAL 2 37 (n=216), evaluated the activity of oral, single agent ZD1839 in 
patients with NSCLC. Patients on the IDEAL 1 trial had failed one or two prior regimens, 
at least one containing a platinum compound while patients on IDEAL 2 had failed two or 
more previous regimens containing platinum and docetaxel. Response rates for the 
IDEAL 1 trial were 18.4% with a dose of 250 mg/day and 19% with a dose of 500 
mg/day. In terms of second and third line treatment, response rates were similar at 
17.9% and 19.8%, respectively. Toxicity was milder with the 250 mg/day dose, primarily 
rash, diarrhea, pruritus, and dry skin. The conclusion from the IDEAL 1 trial was that 
ZD1839 demonstrated clinically significant antitumor activity and a favorable safety 
profile. Response rates obtained with the IDEAL 2 trial were 11.8% (250 mg/day) and 
8.8% (500 mg/day). The duration of tumor response ranged from 3 to 7+ months, and 
median survival was 6.1 months for the 250 mg/day group and 6.0 months for the 500 
mg/day group. As with IDEAL 1, toxicity was mild in IDEAL 2, consisting mostly of 
diarrhea and skin rash. The results of IDEAL 2 indicated that ZD 1839 also had clinically 
significant anti-tumor activity in heavily pretreated patients with NSCLC. Additional 
evidence for the efficacy of single agent ZD 1839 in NSCLC came from a compassionate 
use study, in which potential benefit (partial response + minor response + stable 
disease) was observed in 26.6% of the patients enrolled.
31
In regard to the maintenance EGFR inhibitor, the gefitinib maintenance in pateint with 
inoperable stage III NSCLC treated with concurrent chemoradiotherapy did not improve 
the outcome compared to placebo maintenance according to the SWOG trial 0023.
34 
Therefore we are not using erlotinib maintenance.
The question of whether overexpression of EGFR correlates with response to EGFR 
inhibiting therapies also has been examined. An exploratory analysis using tumour 
biopsies taken prior to treatment from patients enrolled in two phase II studies of gefitinib 
in advanced NSCLC did not reveal any evidence of a correlation between the levels of 
membrane EGFR expression as measured and tumour response.
32
Clearly the precedent has been set for the use of anti-EGFR therapy in NSCLC with the 
oral tyrosine kinase inhibitor compounds OSI-74 and ZD1839, and it is a logical step to 
evaluate the activity of erlotinib in this disease. Baselga et al. have reported on three 
phase I erlotinib studies in which a total of eight patients with NSCLC were given 
erlotinib, two as single agent therapy and six in combination with cisplatin.
33 Although 
results were not reported by disease state, patients in all three studies experienced 
disease stabilization and erlotinib-associated toxicity was minimal.


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2.0 Objectives
2.1 
Primary Objective
Determine the efficacy of concurrent erlotinib and chemoradiation as measured 
by time to progression.
2.2 
Secondary Objectives
2.2.1 Safety as measured by the rate of grade 3 or worse non-hematological 
toxicities (dose limiting toxicity or DLT) occurring 
prior to the beginning of 
consolidation therapy (including all toxicities attributed to chemoradiation occurring 
within 90 days 
of the start of radiation therapy) .
2.2.2 Compliance defined to be completion of concurrent chemoradiation plus 
erlotinib with no more than minor variations as 
defined (See Section 6.10). 
2.2.3 Response rate (complete and partial response rates)
2.2.4 Overall survival rates (one and two year rates, median survival).
2.2.5    Disease local control rate 
2.2.6    Association between EFGR expression and toxicity, response, overall 
survival, and progression (exploratory analysis) 
2.2.7    Association between EGFR expression and response correlated with 
imaging study.
3.0 Study Design
This is a  phase II study of Erlotinib (erlotinib) in combination with chemoradiation in patients 
with stage IIIA/B non-small cell lung cancer (NSCLC). 48 patients will be treated with concurrent 
chemoradiation and Erlotinib followed by consolidation therapy of chemotherapy.
SCHEMA
NOTE: Erlotinib is not to be taken on the days of chemotherapy administration.
Concurrent Chemoradiation and Erlotinib 
 
Weeks 1-7: 
Erlotinib, 150 mg p.o. daily throughout the radiation, except for 
chemotherapy day  
 
+ 
Paclitaxel, 45mg/m², and Carboplatin, AUC=2, weekly, throughout the 
radiation, for up to 7 treatments.  
  
+ 
RT:  63 Gy/35 fractions/7weeks (+/- 5 days) 
 
(1.8 Gy/ fraction, a total dose of 63.0 Gy in 35 fractions over 7 weeks) 
 
Concurrent Chemoradiation should be completed within 9 weeks 


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3.2 Rationale for Study Design
At the 2003 ASCO annual meeting, the results of several phase II studies were reported 
regarding the combination of C225 with chemotherapy.
34 In a phase I/II study in untreated 
metastatic NSCLC combining C225 with paclitaxel and carboplatin (C225 loading dose of 
400 mg/m
2 then weekly 250 mg/m
2 maintenance; paclitaxel 225 mg/m
2 q 3 weeks; 
carboplatin AUC 6), 31 patients were accrued. The overall response rate (ORR) was 29% (9 
patients), time to progression was 5.4 months, and the median survival was 15.7 months. 
The most common toxicity was rash, with 9.7% (3 patients) having a grade 3/4 acne-like 
rash. The most common grade 3 toxicity was fatigue at 19.4% (6 patients).
A phase I/II study in untreated metastatic NSCLC combining C225 with gemcitabine and 
carboplatin accrued 35 patients and reported an ORR of 28.6% (10 patients); time to 
progression was 5.5 months, and median survival was 10.3 months.
35 The most common 
toxicity was rash at 80% (28 patients), with 20% (7 patients) experiencing a grade 3 
acne-like rash. These studies demonstrated the feasibility of combining C225 with systemic 
chemotherapy in NSCLC. Both regimens had acceptable safety profiles, and encouraging 
clinical activity.
NCI Canada clinical trials group conducted a study of Erlotinib in previously treated NSCLC. They 
conducted a randomized, placebo-controlled, double-blind trial to determine whether the epidermal growth 
factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line 
or second-line chemotherapy. Patients had stage IIIB or IV non-small-cell lung cancer, with performance 
status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients 
were stratified according to center, performance status, response to prior chemotherapy, number of prior 
regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral 
erlotinib, at a dose of 150 mg daily, or placebo. The median age of the 731 patients who underwent 
randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent 
had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and 
less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months 
and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively 
(hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 
months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients 
discontinued erlotinib because of toxic effects. They concluded that Erlotinib can prolong survival in 
patients with non-small-cell lung cancer after first-line or second-line chemotherapy. 
36
The present study is based upon a combination of the data from the studies described 
above. The use of concurrent chemoradiation therapy followed by consolidation therapy 
which is based upon Arm 3 of the LAMP study and the SWOG 9504 study. The addition of 
biologic therapy with erlotinib to the regimen hopefully will result in even better efficacy 
without increasing toxicity.


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Clearly this study is a logical next step in the attempt to find the optimal regimen for the 
treatment of advanced NSCLC.
3.3 Safety Plan
3.3.1
Adverse Events Using Erlotinib
To date, at least 4000 cancer patients have received Erlotinib at a dose of 150 
mg/day in previous clinical trials.  
Common adverse events associated with Erlotinib administration include rash and 
diarrhea.  Other common adverse events include nausea/vomiting, stomatitis, 
headache, and fatigue. 
A rash occurred in 75% of Erlotinib-treated NSCLC patients enrolled in BR.21.  A 
papular, pustular rash manifesting most often on the face and upper trunk was 
common across all studies, but rash was rarely the cause of study drug 
discontinuation. The rash may be associated with erythema, pain, pruritus, dryness, 
and less commonly, stomatitis, keratitis and nailbed changes.  Wearing of contact 
lenses while receiving Erlotinib therapy is not recommended.  The incidence of 
diarrhea in BR.21 was 54% of Erlotinib-treated NSCLC patients.  The median time to 
onset of skin rash was 8 days and median time to occurrence of first diarrheal 
symptom was 9 days. 
There have been infrequent reports of serious (including fatal) interstitial lung 
disease (ILD) in patients receiving Erlotinib for treatment of NSCLC or other 
advanced solid tumors.  In Study BR.21, the incidence of ILD (0.8%) was the same 
in the placebo and Erlotinib groups.  The overall incidence in Erlotinib-treated 
patients from all studies (including uncontrolled studies and studies with concurrent 
chemotherapy) is approximately 0.6%.  Included in this rate of ILD are reported 
diagnoses of pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative 
bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung 
infiltration, irrespective of investigator assessed causality.  Most of the cases were 
associated with confounding or contributing factors such as concomitant/prior 
chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic 
lung disease, or pulmonary infections.
Reversible renal impairment has been reported in association with dehydration 
associated with nausea, vomiting, and diarrhea.  There have been rare reports of 
renal failure in patients receiving Erlotinib in combination with platinum-containing 
chemotherapy regimens. Febrile neutropenia has been reported in patients receiving 
concomitant chemotherapy.  
Erlotinib is both protein bound (92%–95%) and metabolized by hepatic cytochromes 
CYP3A4 and CYP3A5 and pulmonary cytochrome CYP1A1.  Therefore, a potential 
for drug–drug interaction exists when Erlotinib is co-administered with drugs that are 
highly protein bound or that are CYP3A4 inhibitors/inducers.  
Co-administration of Erlotinib with an inhibitor of CYP3A4 metabolism (ketoconazole, 


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200 mg po BID for 5 days) resulted in increased exposure to Erlotinib as measured 
by an 86% increase in median Erlotinib AUC and a 69% increase Cmax, compared 
with administration of Erlotinib alone.
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 600 mg po 
QD for 7 days) resulted in a 69% decrease in the median Erlotinib AUC, compared 
with administration of Erlotinib alone.  However, the effect of rifampin on Cmax was 
negligible.  
International normalized ratio (INR) elevations and/or bleeding events have been 
reported in some cancer patients taking warfarin while on Erlotinib.
3.3.2
General Plan to Manage Safety Concerns
A number of measures will be taken to ensure the safety of patients participating in 
this trial, addressed through exclusion criteria and routine monitoring.  Patients will 
be evaluated for adverse events at each study visit for the duration of their 
participation in the study and for 30 days after the discontinuation of Erlotinib. 
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically.  Because secondary bacterial infections are common and can lead 
to more serious complications, topical or systemic antibiotics may be considered.  
Anecdotally, topical or a short course of systemic corticosteroids can be helpful.  See 
Section 4.3.3 and Table 2 for management guidelines, including Erlotinib dose 
reduction/interruption.
Diarrhea will be monitored and managed symptomatically.  Guidelines for 
management include administration of loperamide and Erlotinib dose 
reduction/interruption as described in Section 4.3.3 and Table 2.
Although quite rare, ILD can be life threatening.  Therefore, patients should be 
monitored closely for symptoms consistent with ILD, such as new onset dyspnea 
without an obvious cause.  In the event that ILD is suspected, Erlotinib treatment 
should be discontinued and the patient should receive appropriate medical 
management.  Although there is no proven therapy, systemic corticosteroids are 
often provided.  Erlotinib should not be restarted in those patients suspected of 
having drug-related ILD.  See Section 4.3.3 and Table 2 for management guidelines, 
including Erlotinib dose interruption.
Women of childbearing potential should have a negative pregnancy test prior to 
starting therapy with Erlotinib and should use adequate contraceptive methods 
during and for at least 4 weeks after Erlotinib therapy.  If a patient becomes pregnant 
despite precautions, she should be apprised of the potential risk of fetal morbidity or 
loss.
3.4 Administrative Structure
This is a sponsored trial performed with the support of Genentech, Inc. and OSI 
Pharmaceuticals. Ritsuko Komaki, MD will be the Principle Investigator. Patients will be 


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seen and enrolled at the University of Texas M. D. Anderson Cancer Center, Houston, TX.  
The University of Texas M.D. Anderson Cancer Center IND office will monitor the study 
investigators to assure satisfactory enrollment rate, data recording, and protocol adherence. 
4.0 Materials and Methods
4.1 Patients
4.1.1
Inclusion Criteria
4.1.1.1 Histologically or cytologically documented NSCLC, including squamous cell 
carcinoma, adenocarcinoma (including bronchoalveolar cell), and large cell 
anaplastic carcinoma (including giant and clear cell carcinomas) and poorly 
differentiated (not otherwise specified, NOS) non-small cell lung cancer; 
totally resected tumors are excluded.
 · Patients must be M0;
 · Patients with Tl or T2 disease with N2 or T3N1-2 disease (Stage IIIA) 
are eligible if they are deemed inoperable. Patients with T4 with any N 
or any T with N2 or N3 disease are eligible if unresectable. 
Radiographic evidence of mediastinal lymph nodes > 2.0 cm in the 
largest diameter is sufficient to stage N2 or N3 disease. If the largest 
mediastinal node is < 2.0 cm in diameter and this is the basis for stage 
III disease, then at least one of the nodes must be proven positive 
cytologically or histologically;
 · Measurable disease is required. See Section 4.5.2 for RECIST 
definitions of measurable disease.
4.1.1.2 Patients with tumors adjacent to a vertebral body are eligible as long as all 
gross disease can be encompassed in the radiation boost field. The boost 
volume must be limited to < 50% of the ipsilateral lung volume.
4.1.1.3 
Patients must be >18 years of age;
4.1.1.4 
Patients with Zubrod performance status 0-1 (See Appendix E);
4.1.1.5 
Adequate hematologic function defined as: ANC > 1,500/mm
3, platelets >
100,000/mm
3, and hemoglobin > 9 g/dL (prior to transfusions); adequate 
hepatic unction defined as: total bilirubin < 1.5 mg/dl, SGOT or SGPT < 3 x 
ULN, adequate renal function defined as a serum creatinine level < 2.0 
mg/dl, alkaline phosphatase < 2.5 x ULN, glucose < 2 x ULN;
4.1.1.6 
FEV1 with > 1000 cc;
4.1.1.7 
Patients with weight loss < 10% over the past 3 months;
4.1.1.8 
Patients with a pleural effusion that is a transudate, cytologically negative 
and nonbloody are eligible if the radiation oncologists feel the tumor can 
still be encompassed within a reasonable field of radiotherapy. If a pleural 
effusion can be seen on the chest CT but not on CXR and is too small to 
tap, the patient is eligible.
4.1.1.9 
If patients had exploratory thoracotomy, they must have recovered from the 
procedure. Exploratory Thoracotomy and beginning of treatment should be 
within one month.
4.1.1.10 
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]) 


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and male participants must practice effective contraception (oral, injectable, 
or implantable hormonal contraceptive; tubal ligation; intra-uterine device; 
barrier contraceptive with spermicide; or vasectomized partner) throughout 
the study and for four weeks after completion of treatment.
4.1.1.11
For women of childbearing potential, a urine or blood pregnancy test must 
be performed within 48 hours prior to the start of protocol treatment;
4.1.1.12
Medical Oncology and Radiation Oncology consults and approval.
4.1.1.13
Patients must sign a study-specific consent form prior to study entry.
4.2 Exclusion Criteria 
4.2.1 Prior systemic chemotherapy and/or thoracic radiotherapy for any reason and/or
surgical resection of present cancer;
4.2.2 Exudative, bloody, or cytologically malignant effusion or effusion that are exudative 
and/or bloody and are suggestive or malignant involvement.
4.2.3 Prior therapy with any other drug that targets the EGFR pathway, 
4.2.4 Active pulmonary infection not responsive to conventional antibiotics;
4.2.5 History of interstitial lung disease;
4.2.6 History of severe COPD requiring > 3 hospitalizations over the past year;
4.2.7 Significant history of cardiac disease, i.e., uncontrolled hypertension, unstable 
angina, uncompensated congestive heart failure, myocardial infarction within the 
past year, or cardiac ventricular arrhythmias requiring medication; patients with left 
ventricular ejection fraction (LVEF) below the institutional range of normal (50-70%) 
on a baseline multiple gated acquisition (MUGA) scan or echocardiogram.
4.2.8 Patients with > grade 1 neuropathy;
4.2.9 Evidence of malignancy in the past 3 years except for adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer, or other in situ cancers;
4.2.10 Women who are pregnant or breast feeding, as treatment involves unforeseeable 
risks to the participant, embryo, fetus, or nursing infant; women with a positive 
pregnancy test on enrollment or prior to study drug administration;
4.2.11 Women of childbearing potential and male participants who are unwilling or unable to 
use an acceptable method of contraception (oral, injectable, or implantable hormonal 
contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with 
spermicide; or vasectomized partner) throughout the study and for four weeks after 
completion of treatment or those who are using a prohibited contraceptive method 
(methods with unknown efficacy).
4.2.12 Patients who currently are participating in other clinical trials and/or who have
participated in other clinical trials in the previous 30 days. Clinical trials involving  
administration of investigational agents or interfering with the safe conduct of this  
trial. All clinical trials would exclude observational trials which would not interfere with 
the endpoints of our study.
4.3 Study Treatment
4.3.1
Formulation
Erlotinib oral tablets are conventional, immediate-release tablets containing erlotinib 
as the hydrochloride salt. In addition to the active ingredient, Erlotinib contains 
lactose 
(hydrous), microcrystalline cellulose, sodium starch glycolate, sodium lauryl 


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sulfate, and magnesium stearate.  
Tablets containing 25 mg, 100 mg, and 150 mg of Erlotinib are available. Each bottle 
will contain 30 tablets, a quantity sufficient for 4 consecutive weeks of dosing, with 
overage.  
For further details, see the Erlotinib Investigator’s Brochure
4.3.2
Dosage, Administration and Storage
Erlotinib will be self-administered in an open-label, unblinded manner to all patients 
enrolled in the study. During the treatment period, patients will receive single-agent 
Erlotinib, 150 mg/day.  Tablets should be taken at the same time each day with 200 
mL of water at least 1 hour before or 2 hours after a meal.  Patients who are unable 
to swallow tablets may dissolve the tablets in distilled water for administration.
Dose reductions for adverse events will be permitted (see Section 4.3.3).  Treatment 
is continued daily until disease progression or other reason for termination of study 
therapy (see Section 4.6).
Erlotinib tablets will be supplied for clinical trials in white, high-density polyethylene 
(HDPE) bottles with child-resistant closures and should be stored at temperatures 
between 15°C and 30°C (59°F and 86°F). 
Erlotinib is being provided from investigational supply and may have unknown 
differences from the commercial stock.
4.4
Concomitant and excluded Therapies
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is 
not permitted while participating in this study. 
Use of concurrent investigational agents is not permitted.
There are potential interactions between Erlotinib and CYP3A4 inhibitors and CYP3A4 
promoters.  Although caution and careful monitoring are recommended when use of 
these compounds is necessary, use of these compounds does not exclude patients from 
participating in this trial (see Appendix F for a list of CYP3A4 inhibitors).
Patients taking warfarin or other warfarin-derivative anticoagulants should be monitored 
regularly for changes in prothrombin time or INR.


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4.5
Study Assessments
a. 
Within 2 weeks prior to study treatment;
b. 
Pre Chemotherapy, per standard of care for this chemo regimen.
c. 
Within 4 weeks +/- 5 days prior to start of study treatment; perform CT scan of the 


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chest/upper abdomen at less than 1 cm slice thickness to include the lung apices 
through the adrenals. It is recommended that a consistent evaluation (CT scan of the 
chest/upper abdomen) be used throughout the study.
d. 
Weekly;
e. 
Assess weight only; recalculate the BSA if there has been > 10% weight loss;
f. 
At relapse;
g. 
Recommended every 6 months for 2 years, then annually;
h. 
For women of childbearing potential; within 48 hours prior to start of protocol 
treatment; 
i. 
Approval to proceed must be received prior to initiation of study treatment.
j. 
At 6 months after completion of consolidation therapy, then at 1 year
k. 
A pretreatment PET scan, rather than a bone scan, is permitted to rule out bone 
metastases.
l.
If indicated
m.
Weekly, if receiving anticoagulant agents (until Erlotinib completed)
n.
patient will return one month after treatment, once a month until recovery from 
treatment related toxicities, then every 3 months for 2 years, then every 4 months for 
2 years (total of 4 years)
o.
Specimen will be stored for analysis immunochemical staining to analyze EGFR 
status.
p.
Optional blood samples will be obtained for evaluation the last week of concurrent 
treatment, at the start of consolidation therapy, at the first post- treatment follow-up visit, and 
every three months up to 12 months in coordination with the follow up visits. Serum or 
plasma samples will be assessed using in-house assays or in collaboration with outside 
institutions/vendors.  All samples will be de-identified and will not be re-identified except 
through unique codes tied into clinical information for statistical analysis. All statistical 
analysis will be done at MD Anderson on a password protected clinical database.
q. 
PET scan will be performed 1 month after completion of consolidation chemotherapy.
4.5.1 Post-treatment Follow up
A follow-up evaluation will be performed approximately 30 days following 
completion of all protocol treatment. In addition, all patients will be followed for a 
minimum of 30 days after the last dose of study therapy or every 4 weeks until all 
study drug related toxicities have resolved, returned to baseline, or are deemed 
irreversible, whichever is longer. Thereafter, patients will be seen for follow up 
every 3 
months for 2 years, then every 4 months for 2 years (total of 4 years). 
Patients will be off 
study at the time of death or 4 years after treatment
4.5.2 Response Assessment (RECIST Criteria)
4.5.2.1 Measurement of Response :Response will be evaluated in this study using 
RECIST Version1.1 for all patients with measurable disease at baseline and 
completing at least  two weeks of concurrent chemoradiation.  (Please refer to 
the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1) [Eur J Ca 45:228-247, 2009] under Appendix M).


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4.6
Patient Discontinuation
Patients may discontinue study treatment at any time.  Any patient who discontinues 
treatment will be encouraged to return to the study center to undergo treatment 
discontinuation assessments.  The primary reason for discontinuation should be 
recorded.  Reasons for discontinuation of a patient by the investigator include, but are 
not limited to, the following:  
·
Documented disease progression   
·
Clinically significant deterioration of the patient’s condition prior to treatment 
discontinuation 
·
Patient noncompliance
·
Persistent (3 weeks) NCI-CTCAE version 3.0 Grade 3 or Grade 4 adverse event or 
any significant adverse event that compromises the patient’s ability to participate in 
the study 
·
Investigator determination that it is not in the patient’s best interest to continue 
participation
·
Pregnancy
4.7
Statistical Methods
4.7.1 Statistical Considerations
The primary objectives for this phase II study is to evaluate the efficacy of the 
combination therapy by adding erlotinib to the standard chemoradiation therapy for 
patients with stage IIIA/B NSCLC. In addition, we have built in a Bayesian toxicity 
monitoring plan to ensure the safety of the study regimen. If the toxicity exceeds the 
pre-specified boundaries, the trial will be stopped.  The maximum sample size for this 
study is 48.
4.8
Study Endpoints
4.8.1 Primary Endpoints: Efficacy of concurrent erlotinib and chemoradiation as 
measured by time to progression.  
4.8.2 Secondary Endpoints:
4.8.2.1   Safety as measured by the rate of grade 3 or worse non-hematological 
toxicities (dose limiting toxicity or DLT) occurring prior to the beginning of 
consolidation therapy (including all toxicities attributed to chemoradiation 
occurring within 90 days of the start of radiation therapy) 
4.8.2.2  Compliance defined to be completion of concurrent chemoradiation plus 
erlotinib with no more than minor variations as defined (See Section 
6.10).
4.8.2.3  Response rate (complete and partial response rates)
4.8.2.4  Overall survival rates (one and two year rates, median survival)
4.8.2.5 One and two year disease progression rates
4.8.2.6 Disease local control rate 
4.8.2.7 Association between EFGR expression and toxicity, response, overall 
survival, and progression (exploratory analysis) 
4.9
Sample Size


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We assume that the primary endpoint for the phase II study, time-to-progression, 
follows an exponential distribution. We hypothesize that the combination of 
erlotinib and chemoradiation can increase the median time to progression from 
15 months to 25 months (a 67% increase). Using a logrank test, a total of 48 
patients will yield 80% power with 10% one-sided type I error rate. The sample 
size calculation assumes the accrual rate is 3 patients per month with an 
additional 12 months of follow-up after the last patient is enrolled. We also factor 
in a 10% inevaluable rate due to drop-out or loss-to-follow up, etc. The total study 
duration is estimated to be 28 months (16 months of accrual plus 12 months of 
follow up) Socinski et al., JCO 2008: median survival: 24.3 months; median time 
to progression is 14.9 months. 
A 95% exact confidence interval will be computed to estimate the compliance rate under 
the assumption of a binomial distribution. With 65 evaluable patients, we will have a 
maximum confidence interval width of 25.3%. BMSO/ACR 427 had a compliance rate of 
84% for patients receiving at least 6 cycles. If the compliance rate is the similar as in 
BMSO/ACR 427 (i.e. 55 compliant cases out of the 65 analyzable, 85.0%) the width of 
the confidence interval will be 18.8%. If the observed compliance rate is at or no better 
than 34 cases out of 65 ( 52.3% with an exact 95% confidence interval of [39.5%, 
64.85%]) – where the upper bound of the confidence interval is less than 65% – the 
regimen will be considered unfeasible.
  
4.10 
Patient Accrual
We expect to see accrual of 3 patients per month. 
4.11
Bayesian Toxicity Monitoring Plan
Our prior experience shows that 30% to 50% of the patients may experience DLT with 
the standard chemoradiation therapy.  A DLT rate of greater than 60% is considered 
unacceptable.  A Bayesian toxicity monitoring plan is constructed such that if the 
probability of unacceptable toxicity (Prob(DLT) > 50%) is high ( > 80%), the trial will be 
stopped early.  With a prior distribution of beta(0.9, 2.1), the posterior distribution of the 
probability of unacceptable toxicity can be computed using the relationship between the 
beta and binomial distributions.  Based on these criteria, the trial will be stopped due to 
excessive toxicity when 8 in 10, 13 in 20, 18 in 30,  24 in 40, and 29 in 50 patients 
experience DLT.  
The following table lists the operating characteristics for the design based on 1,000 
simulation runs. As it can be seen, when the probability of true toxicity rate increases, 
the probability of early stopping also increases and the average sample size decreases.  
The percent of patients experiencing DLT is close to the true toxicity rate but is slightly 
higher because early stopping due to excessive toxicity can cause the estimator to have 
an upward bias. 
Our assumptions are based on the premise that a 30% to 50% of DLT are acceptable 
due to the fact that the most DLT’s are expected and manageable and the disease has a 
grave consequence. The operating characteristics show that when the true toxicity rate 
is 40%, only 4% of the time the trial will be stopped early and when the true toxicity rate 
is 50%, 32% of the time the trial will be stopped early. The corresponding average 
sample sizes are 68.0 and 57.5, respectively.  When excessive toxicity is shown (i.e., 
DLT rate is 0.60), the probability of early stopping is 86% with an average sample size of 


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34.2. 
True Toxicity (DLT) 
Rate
Probability of Early 
Stopping due to 
toxicity
Average Sample 
Size
Percent of Patients 
Experiencing DLT
0.40
0.04
68.0
0.41
0.45
0.13
64.4
0.47
0.50
0.32
57.7
0.53
0.55
0.62
45.6
0.60
0.60
0.86
34.2
0.66
4.12 
Analysis and Reporting Plans
4.12.1 Interim Analyses for Early Stopping Due to Severe or Excessive 
Nonhematologic Toxicities 
Accrual to this study will be suspended if any patient experiences a fatal 
treatment related toxicity. In the event that a patient has a fatal treatment 
related toxicity at any time, the study PI, will review the data and patient 
information to make appropriate recommendations about continuing the study. 
The rate of grade 3 or worse non-hematological toxicities within 90 days of the 
first day of radiation therapy will be closely monitored with the stopping 
boundaries listed in Section 4.11
4.12.2 Interim Analyses for Efficacy
There will be no interim analysis for efficacy.  We consider the early stopping 
due to futility is unnecessary because the chemoradiation therapy is the 
standard therapy for this patient population and adding erlotinib is not expected 
to decrease its efficacy.  Early stopping due to efficacy is also not 
recommended in this phase II evaluation.
4.13    Interim Analyses of Accrual and Toxicity Data
Interim reports will be prepared every 6 months until the initial manuscript 
reporting the treatment results has been submitted. The usual components 
of this report are:
a) The patient accrual rate with a projected completion date for the accrual 
phase;
b) The distribution of pretreatment characteristics;
c) The frequency and severity of the toxicities.
The statistician will report any problems identified to the IRB.
4.14    Analysis for Reporting Initial Treatment Results
This analysis will be done when all the patients accrued to the study have been
potentially followed for a minimum of 12 months. It will include:
a) Tabulation of all cases entered into the trial; exclusions with reasons;


2005-1023
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b) Distribution of important prognostic baseline variables;
d) Observed results for the endpoints listed in Section 4.8.1
All the time-to-event endpoints will be plotted using Kaplan-Meier estimate and the 
logrank test with a one-sided test against the null hypothesis.
Estimates of overall survival and time to progression at one and two years will be 
calculated along with their associated 95% confidence intervals. Response 
(determined two months after completion of consolidation chemotherapy) is taken to be 
complete response (CR) or partial response (PR) using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
[JNCI 92(3): 205-216, 2000]. Point and interval estimates of the proportion of patients 
with either PR or CR, using an exact 95% confidence interval, will be calculated. The 
exploratory analysis of EGFR expression and toxicity, response, and progression will 
be a chi-squared test for association after dichotomizing EGFR expression for each 
patient. The maximum reported toxicity for each patient will be dichotomized to > 
Grade 3 or < Grade 3; response will be categorized to CR, PR, or other than CR/PR;
and progression will be dichotomized to yes/no. Patients will be grouped according to 
their dichotomized EGFR expression level and survival in the two groups will be 
compared.
4.15    Analysis for Reporting Long-Term Results
This analysis, if necessary, will be done when all the patients accrued to the study 
have been potentially followed for a minimum of 30 months.
5.0 Specification of Safety Variables
ASSESSMENT OF SAFETY
5.1
Specification of Safety Variables 
Drug toxicities will be evaluated according to CTC version 3 (Appendix B).  Reporting of 
adverse events will be according to M.D. Anderson Guidelines for AE Reporting 
(Appendix A).
Serious adverse events will be delivered to ORERM and will be submitted to the FDA by 
the regulatory compliance coordinator according to 21CR 312.32.
Unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study and all subject deaths should be promptly reported by 
phone (301-619-2165), by email (hsrrb@det.amedd.army.mil), or by facsimile 
(301-619-7803) to the U.S. Army Medical Research and Materiel Command,  Human 
Subjects Research Review Board (HSRRB).  A complete written report should follow the 
initial notification.  In addition to the methods above, the complete report can be sent to 
the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-ZB-QH, 504 
Scott Street, Fort Detrick, Maryland 21702-5012.
5.1.1 Communication Between Principal Investigator and Genentech
The investigators will submit written reports of all SAEs, regardless of attribution, to 


2005-1023
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Genentech within 48 hours of learning of the events to the following:
 Genentech’s Drug Safety Department at:
(650) 225-4682
or 
(650) 225-5288
6.0 Sponsor and Investigator Requirements
Sponsors are responsible for selecting qualified investigators, providing them with the 
information they need to conduct an investigation properly, ensuring proper monitoring of the 
investigation(s), ensuring that the investigation(s) is conducted in accordance with the general 
investigational plan and protocols contained in the IND, maintaining an effective IND with 
respect to the investigations, and ensuring that FDA and all participating investigators are 
promptly informed of significant new adverse effects or risks with respect to the drug.
6.1
Informed Consent
All study participants must sign and date an informed consent form prior to study 
participation. The investigator will be responsible for designing the consent form using 
appropriate National or Regional Guidelines (equivalent to the American Federal 
Guidelines Federal Register July 27, 1981, or 21 CRF Part 50, or International 
Committee on Harmonization-Good Clinical Practice).  
The informed consent form must be approved by the IRB or Ethics Committee and 
USAMRMC HSRRB.  State and local laws, and/or institutional requirements may require 
the disclosure of additional information on the informed consent form.
Participants will be consented by the treating physician and the research nurse.  
Witnesses will be clinic nurses or other members present during the informed consent 
interview process.  Participants may request information and decide to enroll at a later 
date.  Follow-up will occur through the research nurse.  
Once consent has been obtained, a copy of the informed consent form will be given to 
the participant.  The investigator will keep each participant’s signed informed consent 
form on file for inspection by a regulatory authority at any time.
For a detailed description of the informed consent process see Appendix G.


2005-1023
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6.2
Institutional Review Board Approval
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated.  In 
addition, any advertising materials must be approved by the IRB.  The study will be 
conducted in accordance with U.S. FDA, applicable national and local health authority, 
and IRB requirements.
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case the IRB must be updated at least once a year for annual review. Copies of the 
annual review and final study report will also be submitted to the HSRRB and/or 
USAMRMC, Human Research Protection Office. The Principal Investigator must also 
keep the IRB informed of any significant adverse events.
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are 
considered possibly or probably related to the study drug by the investigator.  Some 
IRBs may have other specific adverse event requirements to which investigators are 
expected to adhere.  Investigators must immediately forward to their IRB any written 
safety report or update provided by Genentech (e.g., IND safety report, Investigator 
Brochure, safety amendments and updates, etc.).
6.3
Study Monitoring Requirements
The University of Texas M.D. Anderson Cancer Center IND office will monitor the study 
investigators to assure satisfactory enrollment rate, data recording, and protocol 
adherence. The investigator and staff are expected to cooperate and provide all relevant 
study documentation in detail at each site visit on request for review.  M.D. Anderson 
Cancer Center will monitor and/or audit the other participating sites to assure 
satisfactory protocol adherence and enrollment.
6.4
Data Collection
The investigator and other appropriate study staff will be responsible for 
maintaining all documentation relevant to the study. Such documentation 
includes:

Copies of all Serious AE reporting forms faxed to the USAMRMC, Human Research 
Protection Office.

Participant Files—should substantiate the data entered in PDMS with regard to 
laboratory data, participant histories, treatment regimens, etc.

Participant Exclusion Log—should record the reason any participant was screened 
for the study and found to be ineligible.

Drug Dispensing Log—should record the total amount of study drug received and 
returned to sponsor, and the amount distributed and returned or destroyed.  This 
information must agree with the information entered in PDMS.

Informed Consent Forms—completed consent forms from each participant must be 
available and verified for proper documentation.

Informed Consent Log—must identify all participants who signed an Informed 


2005-1023
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Consent Form so that the participants can be identified by audit.
The Investigator must keep on file protocols, amendments, IRB approvals, all copies of 
Form FDA 1572, all correspondence, and any other documents pertaining to the 
conduct of the study for a minimum of two (2) years. 
6.5
Study Medication Accountability
For the drug supplied for this study, an accountability ledger containing current and 
accurate inventory records covering receipt, dispensing, and the return of study drug 
supplies must be maintained.  Drug supplies must be kept in a secure, limited-access 
storage area under the recommended storage conditions. During the course of the 
study, the following information must be noted on the accountability ledger: the 
identification code of the subject to whom drug is dispensed, the date(s) and quantity of 
drug dispensed to the subject, and the date(s) and quantity of drug returned by the 
subject.  Patients should return empty containers to the investigator, with the return 
noted on the ledger. These Accountability Forms must be readily available for inspection 
and are open to FDA inspection at any time.
All study drug required for completion of this study will be provided by 
OSI-Pharmaceutical (manufacturer), in partnership with Genentech (unless otherwise 
noted).  The recipient will acknowledge receipt of the drug by returning the drug receipt 
form indicating shipment content and condition.  Damaged supplies will be replaced.
Study drug accountability records should be maintained by the site in accordance with 
the regulations.
The original drug supply request of Erlotinib will be submitted to Genentech along with 
the form “Approval for Drug Re-Supply”, indicating which personnel will be able to submit 
drug re-supply requests.
All subsequent drug re-supply requests will be directly submitted to 
OSI-Pharmaceuticals from the site.
At the time of study closure, the unused, used and expired study drug will be destroyed 
at the site per Institutional SOPs, or returned to the OSI-Pharmaceutical Drug Depot.
6.6
Disclosure of Data
Data will be reviewed by the collaborating biostatistician prior to publication.  HSRRB 
and/or USAMRMC, Human Research Protection Office will have 30 days to review all 
definitive publications, such as manuscripts and book chapters, and a minimum of 10-15 
days to review all abstracts.
Patient medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.
Upon the patient’s permission, medical information may be given to his or her personal 


2005-1023
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physician or other appropriate medical personnel responsible for his or her welfare.  This 
medical information must be made available to Genentech and authorized 
representatives of Genentech, upon request, for source verification of study 
documentation.  
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, local health authorities, M. D. Anderson Cancer Center, 
Genentech, Inc, OSI Pharmaceuticals and their authorized representative(s), 
collaborators and licensees, and the IRB for each study site, if appropriate.
6.7
Retention of Records
HSRRB and/or USAMRMC, Human Research Protection Office, M.D. Anderson or their 
representatives may have access to subject records.
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years after 
the study is discontinued and the U.S. FDA and the applicable national and local health 
authorities are notified. 
6.8
Medical Monitoring
The medical monitor will review all serious and unexpected adverse events associated 
with this protocol and provide an unbiased written report of the event within ten (10) 
calendar days of the initial report.  At a minimum, the medical monitor will comment on 
the outcomes of the adverse event (AE) and relationship of the AE to the study.  The 
medical monitor will also indicate whether he/she concurs with the details of the report 
provided by the study investigator.  This individual should be a qualified physician, other 
than the principal investigator, not associated with the protocol, able to provide medical 
care for research volunteers for conditions that may arise during the conduct of the 
study, and who will monitor the volunteers during the conduct of the study.  The medical 
monitor is required to review all serious and unexpected adverse events (per ICH 
definitions) associated with the protocol and provide an unbiased written report of the 
initial report.  At a minimum the medical monitor should comment on the outcomes of the 
adverse event (AE) and relationship of the AE to the test article.  The medical monitor 
should also indicate whether he/she concurs with the details of the report provided by 
the study investigator.  Reports for events determined by either the investigator or 
medical monitor to be possibly or definitely related to participation and reports of events 
resulting in death should be promptly forwarded to the HSRRB.
The medical monitor for this study will be James Welsh, MD:
James Welsh, M.D.
University of Texas M.D. Anderson Cancer Center
Department of Radiation Oncology
1515 Holcombe Blvd. - 97
Houston, Texas 77030 USA
Phone:  713/563-2300


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Fax:  713/563-5331
Email:  Jwelsh@mdanderson.org  
The medical monitor will forward reports to the U.S. Army Research and Material 
Command, ATTN:  MCMR-RCQ, 504 Scott Street, Fort Detrick, Maryland, 21702-5012.
6.9
Termination of Study 
The HSRRB and/or USAMRMC, Human Research Protection Office and 
M. D. Anderson will retain the right to terminate the study and remove all study materials 
from the study site at any time.  Specific instances that may precipitate such 
termination 
are as follows:

Unsatisfactory participant enrollment with regard to quality or quantity

Inaccurate and/or incomplete data recording on a recurrent basis

The incidence and/or severity of adverse drug events in this or other studies 
indicating a potential health hazard caused by the treatment
6.10 
Study Amendments
The investigator will only alter the protocol to eliminate apparent immediate hazards to 
the participant. If preliminary or interim statistical analysis indicated that the experimental 
design, dosages parameters, or selection of participants should be modified, these 
changes will be described in an amendment to be approved by the institution’s and other 
appropriate review committees after consultation with the statistician and Study 
Chairman.  Any amendments cannot be enacted unless approved by the HSRRB and/or 
USAMRMC, Human Research Protection Office.  All revisions made to protocols 
previously approved by the IRB will be submitted to the IRB for approval prior to 
implementation of the revision.  If the IRB decides to disapprove a research activity, it 
shall include in its written notification a statement of the reasons for its decision and give 
the investigator an opportunity to respond in person or in writing.  No changes to the 
protocol will be initiated unless also approved by the Human Subjects Research Review 
Board.
6.11
Protocol Violations
In the event of a protocol violation, the principal investigator will notify M.D. Anderson 
and the study Medical Monitor.  This notification will occur as soon as the violation is 
identified and will be included in the annual review and final study report.  Any violation 
that affects the safety or rights of the subject and/or integrity of the study data will also 
be reported promptly to the United States Army Medical Research and Materiel 
Command, Office of Research Protections, Human Research Protection Office 
(USAMRMC ORP HRPO)
6.12
Annual Review and Final Study Reports
The investigator must submit an annual review and final study report to the IRB or Ethics 
Committee for review and approval.  Copies of the annual review and final study report 
must also be submitted to the HSRRB.
6.13
Ethical and Legal Considerations
This study will undergo full approval in accordance with the human surveillance 


2005-1023
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Page 27
requirements of each institution.  Blood samples will be obtained for the evaluations as 
described in the protocol.  Tissue samples obtained at the time of prior surgeries will be 
reviewed before participant enrollment to confirm the participant’s diagnosis.  Measures 
will be taken to ensure confidentiality of participant information.  Tissue samples will be 
collected prospectively during the trial.  Data collected on paper forms will be stored in 
locked file cabinets with restricted access.  Data collected on electronic media will be 
stored in computer files with restricted password access.  All staff members in the study 
will be informed prior to employment and at regular intervals of the necessity for keeping 
all data confidential.  Computers will not be accessible to the public and will be located in 
locked offices.  Subjects will be assigned a separate study number to protect subject 
identification.  No patient identifiers will be used in any publications of this research.  
Data will be maintained indefinitely.  When the time comes to dispose of the data, all 
database files will be deleted, patient identifiers will be removed from all paper forms and 
documents will be shredded.
6.14
Risks/Benefits
Venipuncture may cause pain, bleeding, clotting, bruising at the injection site, and rarely 
infection.
Erlotinib may cause rash, diarrhea, fatigue, nausea, vomiting, abdominal pain, 
headache, stomatitis, anorexia, alopecia, pruritis, myalgias, bone pain, cough dyspnea, 
elevated liver enzymes, interstitial lung dz, ocular changes.
-
Renal impairment in combination with N/V/D or platinum containing chemotherapy  
regimens, febrile neutropenia with concomitant chemotherapy.
-
Warfarin drug interactions. Drug interactions with CYP3A4 inhibitors/inducers
-
Caution advised in combination with NSAIDS due to risk of GI bleed
-
Containdicated in subjects with hypersensitivity to components/drug or class
-
Unanticipated risks
-
Unknown risks 
Paclitaxel may cause Myelosuppression; Nausea and vomiting; diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis, increased
liver function tests (SGOT, SGPT, bilirubin, alkaline phosphatase); hepatic failure, 
hepatic 
necrosis; Arrhythmias, heart block, ventricular tachycardia,myocardial infarction 
(MI), 
bradycardia, atrial arrhythmia, hypotension, hypertension, lightheadedness; 
peripheral 
neuropathy, seizures, mood swings, hepatic encephalopathy, blurred 
vision, scintillating 
scotoma Anaphylactoid and urticarial reactions (acute); 
Stevens-Johnson Syndrome; 
flushing, rash, pruritus Alopecia, fatigue, arthralgia, 
myopathy, myalgia, infiltration 
(erythema, induration, tenderness, rarely 
ulceration); radiation recall reaction.
Carboplatin may cause Myelosuppression; Nausea and vomiting; hepatic toxicity; 
electrolyte imbalance; hypomagnesemia; hypercalcemia; Peripheral neuropathy, 
ocular 
changes; Ototoxicity, myalgia, fatigue, allergic reaction
Radiation Therapy may cause Mucositis, stomatitis, erythema, desquamation, 
alopecia, bone marrow toxicity, skin pigmentation and esophagitis; Radiation 
pneumonitis 
and subsequent fibrosis of the lung; radiation-induced myocarditis or transverse 
myelitis 
(rarely occur at doses lower than 50 Gy)


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Participants will not be financially responsible for any study-related tests outside of
accepted standard of care follow-up.  
Treatment on this study may help to control the disease.  Future patients may benefit 
from what is learned.  There may be no benefits for you in this study.
6.15 
Gender and Minority Inclusion
Women and minorities will be actively recruited to participate in the trial.  However, since 
only 42% of lung cancer participants and 22% of laryngeal cancer participants are 
female, we expect to have more male than female subjects on the study.  We expect 
that the ethnic distribution of the enrolled participants will reflect the local ethnic mixture 
of each institution’s surrounding community.
6.16
Roles and Responsibilities of Key Study Personnel
Dr. Ritsuko Komaki will serve as the Study Chairman for this protocol at M. D. 
Anderson Cancer Center.  She will assume primary responsibility for the study. 
Dr. Ray Meyn will serve as Study Co-Chairman of this protocol.  
Dr. George Blumenschein will serve as Study Co-Chairman of this protocol. 
Research Nurses will identify eligible patients, schedule patients for collection of tissue 
and/or blood samples, coordinate the activities of oncologists/technicians, and be 
responsible for follow-up of patients.
OSI/Genentech Pharmaceuticals will supply investigational study agent, erlotinib.
6.17
Recruitment Process
MD Anderson Cancer Center (MDACC):  Representatives from Thoracic/Head & Neck 
Medical Oncology (i.e., the principal investigator, the co-principal investigator, 
sub-investigators, and the research nurse) will screen and evaluate patients seen in the 
M.D. Anderson Thoracic Center to identify potential subjects. If a patient is outside of the 
institution, he/she may be directly referred by a physician and/or contact the 
research 
nurse directly by phone numbers provided by the MDACC website.  
7.0 Radiation Therapy
Intensity Modulated RT (IMRT) is allowed.
7.1 Doses  
Total dose of radiation will be as follows:
A total radiation dose of 63Gy at 1.8 Gy per fraction once a day .
All doses are to be prescribed and calculated assuming a homogeneous patient.  
7.1.1
At the center of the target area on the central ray for a single beam.
7.1.2
At mid-separation on the central ray for two opposed coaxial equally weighted 
beams.
7.1.3
At the center of the target area on the central ray for two opposed coaxial 
unequally weighted beams.


2005-1023
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7.1.4
At the point of intersection of the central rays for two or more intersecting 
beams which are not coaxial.
7.1.5
At the center of the rotation in the plane of rotation containing the central axis 
for rotation or arc therapy.
7.1.6
At the center of the target area for complex treatment arrangements which 
are not covered above.
7.1.7
At the depth of the 90% isodose line for single electron beams.  Select an 
electron beam energy which provides at least 90% dose at 3 cm depth.
Two different target volumes shall be considered, the initial large field target 
volume consisting of  the primary tumor and mediastinum and the boost 
target volume consisting of the primary tumor only.
In treating the initial fields, various sets of fields may be used, which may be 
coplanar but not coaxial or may not even be coplanar.
7.2 Irradiation Portals:  
The irradiated target volume must be defined by the individually
shaped ports with secondary lead blocking or tailor-made blocks.
7.2.1
Target volume of primary tumor:
a)  
Includes complete extent of visible primary or as defined 
radiographically with a minimum of 1.5 cm and a maximum of 2.0 cm 
around the mass.
b)
Entire lung may be included for extensive lesions if complicated by 
atelectasis or pneumonitis, which will be modified depending on FEV1 
and/or  other pulmonary function tests.  One endobronchial 
brachytherapy is allowed to open up total atelectasis before definitive 
radiation therapy plus chemotherapy.
7.2.2. Target volume of lymph nodes: 
The following nodes must be included:
a)   PTV :Take 3 mm beyond CTV .
b)   CTV :Take 5 mm margin beyond GTV (Node)
c)   GTV ( In the mediastinal, hilar or supraclavicular node(s): PET positive node
(SUV>5) ,positive node(s) according to MDACC
 
diagnostic Radiologist's intererpretation , largest diameter of the lymph node 
larger than 1.0 cm on CT of the chest if the PET negative or EBUS or 
medistenoscopy revealed pathologically positive node.
7.3 Technical Factors
7.3.1
Electron Beam Energy.  Megavoltage equipment is required with effective 
photon energies higher than 1 MeV.  Electrons with at least 90% dose at 3 
cm depth may be used to boost supraclavicular lymph nodes.
7.3.2
Treatment Distance.  Minimal treatment distance to skin should be 80 cm for 
SSD technique and minimum isocenter distance should be 80 cm for SAD 
techniques.
7.3.3
Blocking:
a)
In the case of x-ray beams, the primary collimation may be used, and 
blocking will be required only for shaping of the ports to exclude 
volumes of tissues that are not to be irradiated.
b)
With Cobalt 60, however, beam trimmers or secondary blocking must 
be used all the way around the ports.


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7.3.4
Compensating Filters or Wedges:
In the case of a large sloping contour, such as that usually encountered when 
treating Upper lobe tumors in large patients, compensating filters are 
recommended.  A wedge may also be used as a 2-dimensional tissue 
compensator.  If necessary, field size must be reduced appropriately to avoid 
excessive irradiation to critical structures.
7.3.5
Fractionation:
a)
Each field is to be treated every day.
b)
Adherence to the fractionation schemes is required, although slight 
deviations in the daily dose fraction are allowed (+ 5%).
7.3.6
Therapy Interruptions:
a)
If interruptions of therapy up to two weeks become necessary, 
irradiation should be completed to the prescribed doses.  Total 
number of fractions and elapsed days should be carefully reported.
b)
If more than two weeks, interruption is required, resumption of the 
treatment is at the discretion of the radiation oncologist.  The patient 
will be considered a major protocol deviation although follow-up will 
be continued.  
c)
If patients experience Grade 3 esophogitis radiation treatment should 
be continued without interruption.
d)
Interruption is required for Grade 4 in-field toxicities.
7.3.7
Treatment Planning:
a)
Treatment planning should be performed in accordance with the 
prescribing doses to each target volume, together with restrictions in 
dose to normal tissues as given in Section 7.1
b)
One set should be calculated without lung correction while the other 
should be calculated with lung correction.  Sagittal dose distributions 
are encouraged.  The lung correction reporting form must be 
completed, which requires both uncorrected and corrected 
calculations of the dose to the center of the target volume.  The lung 
correction can be calculated by any  method which the institution 
prefers.
c)
In addition to the isodose distributions, the following specific points of 
dose calculations, should be observed:
1)
Spinal Cord Dose:. Maximal spinal cord dose should not 
exceed 45 Gy at any level for patients . 
2)
Subcarinal Nodes:  Are assumed to be at mid-plane.
3)
Ipsilateral Normal Lung Dose:  This is to be calculated at the 
level of the central rays of the boost fields at the point of 
maximum dose in the lung which lies at least 2 cm outside the 
projected borders of the initial treatment fields in the ipsilateral 
lung.
4)
Contralateral Normal Lung Dose:  This is to be calculated at 
the level of the central rays of the boost field at the point of 
maximum dose in the lung which lies at least 2 cm outside of 
the projected border of the initial treatment fields in the 
contralateral lung.
5)
Maximum Normal Tissue Dose:  This is to be calculated at the 
level of the central rays of boost fields as the maximum total 
dose at least 2 cm outside of the target volume.


2005-1023
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7.3.8
Localization Films:
Localization films taken on simulators and/or on the treatment machine
will be necessary in all cases.  
 
7.4 Anticipated Side Effects or Toxic Effects:
7.4.1
Suggested Maximum Uncorrected Doses to Critically Sensitive Normal
Structures
The following maximum doses to normal structures are suggested:
Organ
     
Dose Schedules
Normal 
Ipsilateral
25 Gy
Contralateral (only if necessary) 
20 Gy
 
Spinal Cord (Maximum Dose)
45 Gy       
  
Heart
Entire Organ
45 Gy
Less than 50%
50 Gy 
Esophagus
     50%
60 Gy
     5 cm
66 Gy
7.4.2
The uncorrected dose to the spinal cord must be limited to 45 Gy .  A 
posterior spinal cord shield will not be an acceptable technique.  Patient must 
be treated with an oblique or lateral field.
7.4.3
Reversible alopecia, bone marrow toxicity, skin pigmentation and esophagitis 
are expected side effects of radiation therapy, while radiation-induced 
myocarditis or transverse myelitis rarely occur at doses lower than 50 Gy.  
Radiation pneumonitis and subsequent fibrosis of the lung will occur in 100% 
of all patients receiving 40 Gy to the lung, usually within the first six months after 
initiation of treatment, so it is essential to spare all normal lung possible.
8.0 Drug Therapy
8.2 
Paclitaxel
8.2.1 Formulation
Paclitaxel is a poorly soluble plant product from the pacific yew, Taxus brevifolia. 
Improved solubility requires a mixed solvent system with further dilutions of either 
0.9% sodium chloride or 5% dextrose in water. Vials will be labeled with shelf life. 
All solutions of paclitaxel exhibit a slight haziness directly proportional to the 
concentration of drug and the time elapsed after preparation, although when 
prepared as described above, solutions of paclitaxel (0.3-1.2 mg/ml) are 
physically and chemically stable for 27 hours.
8.2.2 Preparation
A sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial) in 
polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 
50%. The contents of the vial must be diluted just prior to clinical use. Paclitaxel 
for injection must be diluted before administration with 5% dextrose USP, 0.9% 


2005-1023
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sodium chloride USP, or 5% dextrose in Ringer’s injection to a final concentration 
of 0.3 to 1.2 milligrams/milliliter. This solution is stable for 27 hours under 
ambient temperature (25 degrees Celsius) and room lighting (Prod Info Taxol®, 
1997). Use 5% polyolefin containers due to leaching of diethylhexphthalate 
(DEHP) plasticizer from polyvinyl chloride (PVC) bags and intravenous tubing by 
the Cremophor vehicle in which paclitaxel is solubilized.
Each bag/bottle should be prepared immediately before administration. NOTE: 
Formation of a small number of fibers in solution has been observed after 
preparation of paclitaxel (NOTE: acceptable limits established by the USP 
Particular Matter Test for LVP’s). Therefore, in-line filtration is necessary for 
administration of paclitaxel solutions. In-line filtration should be accomplished by 
incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 
microns (e.g.: Millex-GV Millipore Products) into the IV fluid pathway distal to the 
infusion pump. Although particulate formation does not indicate loss of drug 
potency, solutions exhibiting excessive particulate matter formation should not be 
used.
8.2.3 Administration
Paclitaxel will be administered as a 60 minute IV infusion using non-PVC tubing 
and connectors, such as the IV administration sets (polyethylene or polyolefin) 
that are used to infuse parenteral nitroglycerin and/or fat emulsion. A 22 micron 
filter must be placed on the distal end of the infusion line. Nothing else is to be 
infused through the line where paclitaxel is being administered. Patients will 
receive prophylactic antiallergy premedication approximately 30 minutes prior to 
paclitaxel administration as follows:
During Weeks 1-7 (Concurrent Chemoradiation)
Ondansetron 8 mg PO
Dexamethasone: 10 mg IV in 50ml NS IVPB
Diphenhydramine: 25 mg IV in 50ml NS IVPB
Cimetidine: 300 mg in 50 mL NS IVPB
During Weeks 11-17 (Consolidation Therapy)
Ondanesetron 8 mg IV
Dexamethasone: 20 mg IV 
Cimetidine: 300 mg IV
Diphenhydramine: 50 mg IV
The premedication schedule can be altered at the discretion of the treating 
physician after the first paclitaxel dose
8.2.4 Storage
Paclitaxel vials should be stored between 2°-25°C (36°-77°F).
8.2.5 Adverse Effects:

Hematologic: Myelosuppression

Gastrointestinal: Nausea and vomiting; diarrhea, stomatitis, mucositis,
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis, increased 
liver function tests (SGOT, SGPT, bilirubin, alkaline phosphatase); hepatic 
failure, hepatic necrosis

Heart: Arrhythmias, heart block, ventricular tachycardia, myocardial 
infarction (MI), bradycardia, atrial arrhythmia, hypotension, hypertension, 
lightheadedness


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
Neurological: Sensory (taste), peripheral neuropathy, seizures, mood 
swings, hepatic encephalopathy, encephalopathy, sensation of flashing 
lights; blurred vision, scintillating scotoma

Allergy: Anaphylactoid and urticarial reactions (acute); Stevens-Johnson 
Syndrome; flushing, rash, pruritus

Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration 
(erythema, induration, tenderness, rarely ulceration); radiation recall 
reaction.
8.2.6 Supply
Paclitaxel is commercially available.
8.3 
Carboplatin
8.3.1 Formulation
Carboplatin is supplied as a sterile lyophilized powder available in a single-dose 
vial containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by 
intravenous infusion. Each vial contains equal parts by weight of carboplatin and 
mannitol.
8.3.2 Preparation
Immediately before use, the content of each vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP, according to the following schedule:
These dilutions all produce a carboplatin concentration of 10 mg/ml. When 
prepared as directed, Paraplatin solutions are stable for eight hours at room 
temperature; since no antibacterial preservative is contained in the formulation, it 
is recommended that Paraplatin solutions be discarded eight hours after dilution.
8.3.3 Administration
Carboplatin will be administered after paclitaxel as an IV infusion over 30 
minutes. The dose will be calculated based on the patient’s actual body weight at 
each treatment visit and the AUC (area under curve) dosing.
The dose of carboplatin is calculated (in mg, not mg/m2) as follows, using the 
modified Calvert formula based on creatinine clearance:
AUC dose = Target AUC* x (Creatinine clearance + 25)
The *Target AUC for carboplatin treatment is AUC=2 (concurrent therapy) or 
AUC=6
(consolidation therapy).
The creatinine clearance used to calculate the carboplatin dose will be 
estimated,
based on serum creatinine, using the Cockroft-Gault formula:


2005-1023
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8.3.4 Storage
Unopened vials of Paraplatin are stable for the life indicated on the package 
when 
stored at controlled room temperature and protected from light.
8.3.5 Adverse Events

Hematologic: Myelosuppression

Gastrointestinal: Nausea and vomiting; hepatic toxicity; electrolyte imbalance; 
hypomagnesemia; hypercalcemia

Neurological: Peripheral neuropathy, ocular changes

Other: Ototoxicity, myalgia, fatigue, allergic reaction
8.3.6 Supply
Carboplatin is commercially available.
8.4 
Dose Modifications
8.4.1 Paclitaxel and carboplatin infusions will not be concurrently withheld if erlotinib 
is withheld. Likewise, if paclitaxel, carboplatin, or RT are delayed or withheld, 
erlotinib will not be concurrently delayed or withheld.
8.4.2 Dose Levels
Patients will be treated at the following dose levels:


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8.4.3 Erlotinib Dose Modifications
As stated in Section 8.4.2, erlotinib dose reductions below the –2 dose level will 
not be allowed. All dose reductions are permanent; that is, there will not be any 
reescalation of erlotinib dose. If erlotinib is omitted for more than seven 
consecutive doses for toxicity due to erlotinib or for an intercurrent illness (e.g., 
infection) requiring interruption of therapy, the patient should be discontinued 
from further erlotinib therapy. If toxicities prevent the administration of erlotinib, 
the patient may continue to receive paclitaxel, carboplatin, and RT without 
erlotinib.
Dose reduction or interruption of Erlotinib for toxicity may take place at any time 
during the study.  Toxicity grading is based on NCI-CTCAE, v 3.0.  Dose level 
reductions are presented in Table 1.  If patients do not tolerate the second dose 
reduction, Erlotinib is to be discontinued. 
Dose modification guidelines are summarized in Table 2. 
Management of a tolerable Grade 2 or 3 rash should include continuation of 
Erlotinib at the current dose and symptomatic management.  If skin rash is 
intolerable, dose reduction according to Table 2 should be considered.  When 
skin toxicity improves by at least one grade level, the dose may be re-escalated 
as tolerated.  In Phase II trials, this approach enabled dose re-escalation for the 
majority of patients requiring dose reduction for skin toxicity.  Patients 


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experiencing Grade 4 skin toxicity should be discontinued from study treatment.    
For Grade 1 or 2 diarrhea, early intervention should include continuation of 
Erlotinib at the current dose and initiation of loperamide therapy as described in 
Table 2.  Grade 2 diarrhea that persists over 48–72 hours, despite optimal 
medical management, should be managed by dose reduction according to Table 
2.  Patients experiencing Grade 3 diarrhea should interrupt Erlotinib until 
resolution to Grade 1 and re-start at a reduced dose according to Table 2.  
Patients should be maintained at the reduced dose without attempt at dose 
re-escalation.  Patients experiencing Grade 4 diarrhea should be discontinued 
from study treatment.
Erlotinib should not be restarted in those suspected of having drug-related ILD.
Table 2
Dosage Modification Criteria and Guidelines for Management 
of Erlotinib-Related Toxicities


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8.4.3.1
Retreatment with Erlotinib Following Allergic/Hypersensitivity or 
Cytokine Release Reactions 
Once a erlotinib dose has been decreased due to an 
allergic/hypersensitivity or cytokine release reaction, it will remain 
decreased for all subsequent doses. If the patient has a second 
allergic/hypersensitivity or cytokine release reaction with the slower 
dose, the drug should be stopped, and the patient should receive no 
further erlotinib treatment. If a patient experiences a Grade 3 or 4 
allergic/hypersensitivity or cytokine release reaction at any time, the 
patient should receive no further erlotinib treatment. If there is any 
question as to whether an observed reaction is an 
allergic/hypersensitivity or cytokine release reaction of Grades 1 – 4, 
the Study Chair should be contacted immediately to discuss the 
reaction.
If the patient experiences recurrent isolated drug fever following 


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pre-medication and post-dosing with an appropriate antipyretic, the 
subsequent dosing should be 50% of the previous rate. If fever recurs 
following dose changes, the Investigator should assess the patient’s 
level of discomfort with the event and use clinical judgment to determine 
if the patient should receive further erlotinib therapy.
8.4.4 Dose Modifications During Concurrent Therapy
8.4.4.1
Paclitaxel/Carboplatin/Erlotinib Dose Modifications for Hematologic 
Toxicity
8.4.4.2
If paclitaxel and/or carboplatin doses must be withheld for greater than 
two consecutive weeks, the drug(s) will be held permanently for the duration of 
concurrent therapy.
8.4.4.3
Paclitaxel/Carboplatin/erlotinib Dose Modifications for Non-Hematologic 
Toxicity During Concurrent Therapy


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a 
For CTCAE Grade 2 non-hematologic toxicity not described above, excluding neuropathy, 
maintain dose level of all study. For neuropathy, follow the guidelines
listed above.
b 
Dose levels are relative to the starting dose in the previous cycle. For concurrent therapy, 
paclitaxel and carboplatin doses will not be adjusted.
c 
With the exception of allergic/hypersensitivity or cytokine release reaction (see Section 
8.4.3.1), acne-like rash (rash/desquamation), anorexia, and viral infections. See Table 2 
for treatment modifications for in-field GI and skin toxicity management.
d 
Radiation therapy should continued to be delivered for . Grade 3 non-hematologic 
toxicities in or outside the
radiation treatment field. RT should be held for all Grade 4 non-hematologic toxicity in or 
outside the treatment
field and resumed only when toxicity is < Grade 2.
e 
See Section 8.4.4.5 for further neuropathy details.
8.4.4.4
Carboplatin Dose Modifications for Renal Toxicity
A > 25% change in the serum creatinine, based on weekly calculated 
creatinine clearance, will warrant a recalculation of the carboplatin 
dose.
8.4.4.5 Paclitaxel for Neuropathy
If paclitaxel doses must be withheld for greater than two consecutive 
weeks, the drug will be held permanently for the duration of concurrent 
therapy.
8.4.4.6 If there is a decline in Zubrod performance status to > 2 for greater 
than 2 weeks while under treatment, radiotherapy should be held with 
no further chemotherapy administered. Re-evaluate patient after one 
week for resumption of radiotherapy.
8.4.4.7 Paclitaxel/Carboplatin/RT Dose Modifications for In RT Field, 
Non-Hematologic Toxicity During Concurrent Therapy


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8.4.4.8
For Grade 4 infield esophagitis, radiotherapy and chemotherapy 
should be interrupted as detailed in the table above. Re-evaluate 
patient weekly.
8.4.4.9
For Grade >/= 3 esophagitis/pharyngitis, dermatitis, or other in-field 
radiotherapyrelated toxicity, on day of chemotherapy administration 
during any treatment week, omit paclitaxel and carboplatin until toxicity 
resolves to grade </= 2 as detailed in the table above. For erlotinib skin 
toxicity management, follow the guidelines in Table 2.
8.4.4.10 Radiotherapy should be interrupted only for Grade 4 in-field toxicity 
and resumed when that toxicity has decreased to Grade 2 as detailed 
in the table above. If treatment is interrupted for > 2 weeks, the patient 
should be removed from study treatment. If the patient experiences 
esophagitis so that IV fluid support is needed, insertion of a feeding 
tube should be considered.
8.4.4.11 For Grade 3 esophagitis, radiotherapy can be continued with pain 
management and IV support, or radiotherapy can be held for </= 5 
days until symptoms are < Grade 3.
8.5. 
Paclitaxel/Carboplatin Dose Modifications for Non-Hematologic Toxicity During 
Consolidation Therapy


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a For . CTCAE Grade 2 non-hematologic toxicity not described above, excluding 
neuropathy, maintain dose level of all study drugs. For neuropathy, follow the 
guidelines above.
b Dose levels are relative to the worst toxicities in the previous cycle. For concurrent 
therapy, paclitaxel and carboplatin doses will not be adjusted.
c With the exception of allergic/hypersensitivity reaction (see Section 8.4.3.1), acne-like 
rash (rash/desquamation), anorexia, and viral infections. Table 2 for treatment 
modifications for in-field GI and skin toxicity management.
d Radiation therapy should continue to be delivered for < Grade 3 non-hematologic 
toxicities in or outside the radiation treatment field. RT should be held for all Grade 4 
non-hematologic toxicity in or outside the treatment field and resumed only when 
toxicity is < Grade 2.
e See Section 8.4.4.5 for further neuropathy details.
When a chemotherapy dose reduction is required during the consolidation course of therapy, 
re-escalation of the chemotherapy dose will not be allowed for subsequent doses during that 
specific course.
8.6 
Paclitaxel/Carboplatin Dose Modifications for Hematologic Toxicity During 
Consolidation Therapy


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a
Dose levels are relative to the worst toxicities in the previous cycle. For consolidation 
therapy, dose reductions of paclitaxel and carboplatin below the -1dose level will not be 
allowed. 
bRepeat lab work weekly and resume chemotherapy based on this table
cDose delays greater than 2 weeks will warrant discontinuation of chemotherapy for the 
consolidation cycles. 


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dWith the exception of allergic/hypersensitivity reaction (see Section 8.4.3.1), acne-like 
rash (rash/desquamation), anorexia, and viral infections. Table 2 treatment modifications 
for in-field GI and skin toxicity management. 
8.7
Duration of Treatment
8.7.1 Treatment Compliance
Trained medical personnel will administer study therapy. Treatment compliance 
will be monitored by drug accountability, as well as recording treatment 
administration in the patient’s medical record.
8.7.2 This study will utilize the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 for grading of all treatment related adverse events. 
8.8
Reporting Requirements
AE's should be reported in accordance with UTMDACC's policy (see appendix A)
9.0 Pathology
All patients need to have biopsy specimen and/or unstained histological slides available for 
review by Dr. Wistuba at UTMDACC for EGFR expression.  If original biopsy for EGFR is 
adequate a second biopsy is not necessary. However if the biopsy specimen is to small for 
EGFR status then a second optional biopsy is encouraged. The EGFR represents one of the 
most promising biomarkers studied to date with regard to clinical outcome in cancer. The results 
of current studies will expand and refine investigation of EGFR relationship to clinical outcome 
and may lead to identification of promising similar or new biomarkers with the goals of 1) 
identifying factors predictive of outcome such that patients may be better stratified in future 
trials, and 2) developing novel treatment strategies which target the molecular abnormalities 
identified. In this particular trial, we will gain specific information regarding any correlation 
between various forms of the EGFR (along with several downstream markers, such as 
phosphorylated MAPK, AKT, and Stat-3) and clinical outcome in patients who receive an EGFR 
inhibitory agent.
Strict patient confidentiality will be maintained.  Patient confidentiality will be respected at all 
times.  Patient’s name and medical record number will be removed from any stored data.  Only 
the collaborators and the research team of this study will have access to patient information, 
and only information relevant to this protocol will be examined.  All protected health information 
will be de-identified prior to releasing outcomes of the study outside the research team. Patient 
identifiers will be destroyed after data is analyzed. Until then, the database will be password 
protected on a limited access computer.
If you choose to stop participating in the study and would like to also remove your donated 
samples, you should tell the study chair or research nurse at the time of your request to leave 
the study.  The study chair or research nurse will request to dispose of all of your samples that 
have not already been used in research testing.
10.0 Investigational Centers
Patients will be seen and enrolled at the University of Texas M. D. Anderson Cancer Center, 
Houston, TX.  


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10.1
Investigator Contact Information
Principal Investigator:
Ritsuko Komaki, MD
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd., Unit 097
Houston, TX  77030
Phone:  713-563-2300
Fax:  713-563-2331
Email: rkomaki@mdanderson.org
Co-Principal Investigators:
George Blumenschein, MD
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd., Unit 432
Houston, TX  77030
Phone:  713-792-6363
Fax:  713-792-1220
e-mail:  gblumens@mdanderson.org
Ray Meyn, PhD
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd., Unit 066
Houston, TX  77030
Phone:  713-792-7328
Fax:  713-794-5369
e-mail:  rmeyn@mdanderson.org
Ignacio Wistuba, M.D.
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd., Unit 432
Houston, TX  77030
Phone:  713-792-6363
Fax:  713-792-1220
e-mail:iiwistuba@mdanderson.org
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