Clinical trial NCT00553800
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Fox Chase Cancer Center
Start date: 2007-07-05; Completion date: 2011-06-01
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the combination of bevacizumab and erlotinib in elderly patients with advanced non-small cell lung cancer.

Detailed description:
There is no definite evidence of a superior therapy for advanced non-small cell lung cancer in elderly patients. With the exception of one known study, single agent erlotinib has not been studied exclusively in the elderly and the combination of erlotinib and bevacizumab has never been studied exclusively in the treatment naive elderly. This is an important population that needs less toxic therapies.

Arms: arm 1: bevacizumab 15 mg/kg intravenous every three weeks and erlotinib pill 150 mg by mouth every day
Interventions: intervention 1: bevacizumab intervention 2: Erlotinib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
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Phase II Study of Bevacizumab and Erlotinib in Elderly Patients with Advanced Non-
Small Cell Lung Cancer 
 
Support Provided By 
Genentech, Inc. 
 
Principal Investigator 
Hossein Borghaei, DO 
Fox Chase Cancer Center 
333 Cottman Ave 
Philadelphia, PA 19111 
Phone: 215-214-4297 
Fax: 215-728-3639 
 
Co-Investigators 
Michael Millenson, MD 
Ranee Mehra, MD 
Scot Ebbinghaus, MD 
 
Statistician: Samuel Litwin, Ph.D. 
 
Open to Fox Chase Cancer Center Extramural Research Program (FER) 
  
Study Monitor: Beth Adaire-Halenda 
333 Cottman Avenue 
Philadelphia PA 19111 
Phone: 215-214-3704 
Fax: 215-214-1511 
 
 
 
 
 
Version  
 
02/06/07 
Amendment 1      
01/17/2008 
Amendment 2       
05/28/2009 
Amendment 3     
10/5/2009 
Amendment 4 
10/01/2012 


 
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Table of Contents 
Schema ..........................................................................................................................................6                        
1.0 
Background ....................................................................................................................7 
1.1 
Disease Background .......................................................................................................7 
1.2           Vascular Endothelial Growth Factor (VEGF) and Anti-angiogenic Therapy .........7 
1.3 
Epidermal Growth Factor Receptor and Tarceva ......................................................8 
1.4 
Bevacizumab:   Background and Clinical Experience ...............................................8 
1.4.1 
Bevacizumab in Unresectable Non-Squamous, Non-Small Cell Lung Cancer……9 
1.5 
Clinical Experience with Erlotinib .............................................................................10 
1.5.1 
Dose Selection for Single-Agent Trials of Erlotinib ..................................................10 
1.5.2 
Pharmacokinetics .........................................................................................................11 
1.5.3 
Phase II and III Trials in Patients with Advanced Cancer ......................................11 
1.5.4 
Patients with Hepatic or Renal impairment ..............................................................12 
1.6 
Avastin and Tarceva Combination Studies ...............................................................13 
1.7 
Study Rationale ............................................................................................................14 
2.0 
Objectives......................................................................................................................14 
2.1 
Primary .........................................................................................................................14 
2.2 
Secondary......................................................................................................................15 
3.0 
Study Design .................................................................................................................15 
3.1 
Description of the Study ..............................................................................................15 
3.2           Rationale for Study Design and Dosing .....................................................................15 
3.3           Outcome Measures.......................................................................................................16 
3.3.1        Primary Outcome Measures .......................................................................................16 
3.3.2        Secondary Outcome Measures ....................................................................................16 


 
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4.0 
Study Subjects  .............................................................................................................16 
4.1. 
Inclusion ........................................................................................................................16 
4.2. 
Exclusion .......................................................................................................................17 
5.0 
Discontinuation of Subjects Treatment or Assessment ............................................19 
5.1          Criteria for Discontinuation.........................................................................................19 
5.2  
Definition of Dose Limiting Toxicity (DLT)………………………………...………20 
6.0 
Treatments ....................................................................................................................20 
6.1 
Bevacizumab  ................................................................................................................20 
6.1.1 
Bevacizumab Formulation ..........................................................................................20 
6.1.2 
Bevacizumab Safety Profile ........................................................................................20 
6.1.3 
Bevacizumab Dosage and Administration  ................................................................26 
6.1.4 
Bevacizumab Storage...................................................................................................26 
6.1.5 
Bevacizumab Dose Modification and Toxicity Management...................................27 
6.2 
Erlotinib (Tarceva) ......................................................................................................31 
6.2.1 
Formulation ..................................................................................................................31 
6.2.2 
Erlotinib Safety Profile ................................................................................................31 
6.2.3 
Dosage and Administration .........................................................................................35 
6.2.4 
Drug Ordering and Accountability ............................................................................35 
6.2.5        Storage ..........................................................................................................................36 
6.2.6 
Dose Modification and Toxicity Management ..........................................................36 
7.0 
Concomitant and Excluded Therapies .......................................................................39 
8.0 
Clinical and Laboratory Evaluations .........................................................................41 
8.1 
Pre-Treatment Evaluation ..........................................................................................41 


 
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8.2           Evaluations During Treatment ...................................................................................41 
8.3 
End of study ..................................................................................................................42 
8.4  
Long Term Follow up Evaluations .............................................................................43 
9.0 
Registration  .................................................................................................................43 
10.0          Data Safety Monitoring Plan .....................................................................................43 
11.0 
Statistical Methods and Determination of sample size .............................................44 
11.1         Primary Endpoint:   .....................................................................................................45 
11.2 
Secondary Endpoints ...................................................................................................45 
11.3 
Tertiary Objective ........................................................................................................46 
12.0 
Efficacy Measurement .................................................................................................46 
12.1 
Response Evaluation Criteria in Solid Tumors (RECIST) ......................................46 
12.2         Guidelines for Evaluation of Measurable Disease ....................................................47 
12.3 
Response Criteria .........................................................................................................47 
12.4 
Confirmatory Measurement/Duration of Response .................................................48 
12.5 
Reporting of Results ....................................................................................................49 
12.6 
 Patient-Reported Outcomes (PROs) .........................................................................50 
12.6.1       Functional Assessment of Cancer Therapy-Lung (FACT-L) .................................50 
12.6.2       Collection of Records ..................................................................................................51 
12.6.3       Procedure for Missing Data .......................................................................................51 
13.0 
Adverse Event Reporting and Definitions .................................................................51 
13.1         Adverse Event (AE) Definitions ..................................................................................51 
13.1.1      Severity Ratings ...........................................................................................................52 
13.1.2       Relationship to Study Drug/Attribution ...................................................................52 


 
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13.2         Investigator Reporting Responsibilities  ....................................................................53 
13.3 
Reporting of Serious Treatment Emergent Adverse Events (STEAEs)  ................55 
14.0 
EGFR Testing ...............................................................................................................55 
References .....................................................................................................................................56 
Appendices 
A)  Study Flowchart .....................................................................................................................59 
B) NCI CTC  .................................................................................................................................60   
C) List of CYP3A4 Inhibitors .....................................................................................................61 
D)  ECOG Performance Status Scale .........................................................................................62 
E)  New York Heart Association Guidelines .............................................................................63 
F)  Procedure for Urine Protein/Creatinine Ratio ....................................................................64 
G)  FACT-L (Version 4) ............................................................................................................. 65 
H)  Charlson Co-Morbidity Index ..............................................................................................68 
I) Informed Consent form and HIPAA Consent Form ............................................................73 
 


 
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Schema: 
Bevacizumab 15 mg/kg IV Q 3wks 
Erlotinib:  150 mg PO daily 
 
Cycle length:  21 days 
 
Treatment continued until disease progression or intolerable toxicity 
 


 
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1.0 
Background 
 
1.1 
Disease Background 
 
Lung cancer is the number one cause of death from cancer in both men and women. In particular 
the elderly (age >65) comprise more than 45% of newly diagnosed advanced NSCLC, but are 
inadequately represented in the therapeutic literature – rarely more than 20% of the populations 
studied.  Based on the retrospective analysis of two large trials (SWOG 9509, SWOG 9308)1,2, 
elderly lung cancer patients tend to have more co-morbidities, increased toxicity to cytotoxic 
chemotherapy, and trend towards worsened overall survival.  It has been reported in the ELVIS 
trial3 that the fit elderly (Performance Status 0-1) appear to benefit from systemic therapy 
(compared to best supportive care) with respect to quality of life (QOL) and overall survival, but 
many older patients decline systemic chemotherapy because of the perceived increased toxicity.  
Less toxic and more effective alternatives are obviously needed in elderly patients with advanced 
non-small cell lung cancer (NSCLC). 
 
In the literature, there is no definite evidence of superiority for one systemic therapy over 
another.  But the introduction of new targeted therapies into clinical practice has lead to an 
improvement in the survival and overall response rates of patients with advanced lung cancer. 
This study, first of its kind, explores the response rate of combination treatment with 
bevacizumab and erlotinib in treatment-naïve elderly patients with advanced NSCLC – an 
important cohort that need less toxic therapies. 
 
1.2 
Vascular Endothelial Growth Factor (VEGF) and Anti-angiogenic Therapy 
 
Folkman and others have provided compelling evidence linking tumor growth and metastases 
with angiogenesis4.  Of the identified angiogenic factors, VEGF is the most potent and specific 
and has been identified as a crucial regulator of both normal and pathologic angiogenesis5.  
VEGF produces a number of biologic effects, including endothelial cell mitogenesis and 
migration, induction of proteinases, leading to remodeling of the extracellular matrix, increased 
vascular permeability, and maintenance of survival for newly formed blood vessels5.  The 
biologic effects of VEGF are mediated through binding and stimulation of two receptors on the 
surface of endothelial cells:  Flt-1 (fms-like tyrosine kinase) and KDR (kinase domain region)5,6. 
 
Increased expression of VEGF has been measured in most human tumors examined to date, 
including tumors of the lung, breast, thyroid, gastrointestinal tract, kidney, bladder, ovary, and 
cervix, as well as angiosarcomas and glioblastomas5.  Inhibition of VEGF by using an 
anti-VEGF monoclonal antibody blocks the growth of a number of human cancer cell lines in 
nude mice5.  In addition, the combination of anti-VEGF antibody and chemotherapy in nude 
mice injected with human cancer xenografts results in an increased antitumor effect compared 
with antibody or chemotherapy treatment alone7.    
 
To test the hypothesis that inhibition of VEGF in patients with cancer results in clinical benefit, a 
recombinant humanized version of a murine anti–human VEGF monoclonal antibody, named 
Avastin (bevacizumab; previously known as rhuMAb VEGF), was created8.  Based on results of 
non-clinical efficacy and toxicology studies, bevacizumab was advanced into clinical 


 
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development by Genentech, Inc. for use as a single agent and combined with chemotherapy to 
induce tumor shrinkage in patients with solid tumors. 
 
1.3 
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 to a 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 EGFR38.  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 NSCLC, has been correlated with both chemo-resistance and poor prognosis9-15. 
Inhibitors of EGFR tyrosine kinase activity (EGFR TKIs) have been in development for a 
number of years, and although earlier compounds lacked specificity and potency, newer 
compounds have proven active in non-clinical and clinical studies16,17. 
 
Tarceva (erlotinib hydrochloride; 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 non-clinical 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 disease18.  
 
1.4 
Bevacizumab:   Background and Clinical Experience  
 
Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF).  
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more than 
5000 patients and in multiple tumor types. In addition, data are available from 3,863 patients 
enrolled in two postmarketing studies in metastatic colorectal cancer (CRC).  Approximately 
130,000 patients have been exposed to bevacizumab as a marketed product or in clinical trials. 
The following discussion summarizes bevacizumab’s safety profile and presents some of the 
efficacy results pertinent to this particular trial. Please refer to the bevacizumab Investigator 
Brochure for descriptions of all completed Phase I, II, and III trials reported to date. 
 
These clinical trials have included patients with a number of tumor types, including colorectal, 
breast, lung, and renal carcinoma.19-22. 
 
In a large phase III study (AVF2107g) in patients with metastatic colorectal cancer, the addition 


 
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of bevacizumab, a monoclonal antibody directed against VEGF, to irinotecan/5-
fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically and statistically significant 
increase in duration of survival, with a hazard ratio of death of 0.67 (median survival 15.6 vs. 
20.3 months; p < 0.0001).  Similar increases were seen in progression-free survival (6.2 vs. 10.6 
months; p < 0.0001), overall response rate (35% vs. 45%; p < 0.01), and duration of response 
(7.1 vs. 10.4 months; p < 0.01) for the combination arm versus the chemotherapy only arm19.   
 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was 
designated for priority review and was approved on 26 February 2004 in the United States for 
first-line treatment in combination with IV 5-FUbased chemotherapy for subjects with 
metastatic colorectal cancer (CRC).  
 
Additional data from Phase III trials in metastatic CRC (E3200), nonsmall cell lung cancer 
(NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated clinical benefit 
from bevacizumab when added to chemotherapy.  In Study E3200, the addition of bevacizumab 
to FOLFOX chemotherapy resulted in improved overall survival compared with FOLFOX alone 
(13.0 vs. 10.8 months, respectively, HR  0.75; p  0.01) in a population of previously treated 
CRC patients.   
 
There was also improved overall survival in first-line NSCLC patients (E4599) treated with 
carboplatin/paclitaxel  bevacizumab compared with chemotherapy alone (12.3 vs. 10.3 months, 
respectively; HR  0.80; p = 0.003).  The results from this trial were the basis for FDA approval 
of bevacizumab for use in combination with carboplatin  paclitaxel as first-line treatment of 
patients with unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC in 
October 2006.  Finally, patients with untreated metastatic breast cancer (E2100) who received 
bevacizumab in combination with weekly paclitaxel had a marked improvement in PFS 
compared with chemotherapy alone (13.3 vs. 6.7 months, respectively; HR  0.48; p  0.0001) 
(see the Bevacizumab Investigator Brochure for additional details). 
 
 
1.4.1 Bevacizumab in Unresectable, Non-Squamous, Non-Small Cell Lung Cancer 
 
The safety and efficacy of Bevacizumab in patients with non-small cell lung cancer was 
investigated in a randomized Phase III trial conducted by the Eastern Cooperative 
Oncology Group (ECOG 4599)23.  
 
In this multicenter trial, more than 800 patients were randomly assigned to receive 
chemotherapy with standard doses of carboplatin and paclitaxel (PC) or the same regimen 
with the addition of bevacizumab every three weeks at a dose of 15 mg/kg IV (PCB) 
given on day one along with the chemotherapy. Patients were all treatment naïve, with 
locally advanced, recurrent or metastatic disease. Patients with squamous histology, 
evidence of brain metastasis, uncontrolled hypertension, on anticoagulation therapy, 
unstable angina or a history of hemoptysis (more than half a teaspoon) were excluded. 
After completion of chemotherapy, patients continued to receive bevacizumab alone 
every three weeks until disease progression or unacceptable toxicity. The primary 


 
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endpoint of the study was overall survival and secondary endpoints included response 
rate, time to progression and tolerability.  
 
Overall survival was statistically significantly better in the PC plus bevacizumab arm. 
The median overall survival was 12.3 months vs. 10.3 months in the control group 
(hazard ratio 0.80). Response rate (10% vs. 27%) and time to progression (4.5 mos vs. 
6.4 mos) also favored the bevacizumab arm. Toxicities included grade 4/5 neutropenia 
(16.4% vs. 24%); grade 3/4 thrombosis/embolism (3% vs. 3.8%); & hemorrhage (1.0% 
vs 4.1%). There were 11 treatment-related deaths (arm PC: 2; arm PCB: 9); 5 due to 
hemoptysis, all on the bevacizumab arm. Bases on this trial, in October 2006, the FDA 
granted approval of this regimen for patients with locally advanced or metastatic non-
squamous non-small cell lung cancer. 
 
1.5 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.24   
 
1.5.1 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 


 
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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.  
 
1.5.2 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 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. 
 
1.5.3 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 others25-29.  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.   
 


 
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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, BR.21.  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 progression-free survival, response rate, and the 
time to deterioration of tumor related symptoms of pain, cough, and dyspnea.18 . 
 
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 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 States30.  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. 
locations31.  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.30,31. 
 
1.5.4 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.  
Rare cases of hepatic failure (including fatalities) have been reported during the 
postmarketing use of erlotinib.  Confounding factors for severe hepatic dysfunction have 
included pre-exiting liver disease such as cirrhosis, viral hepatitis, hepatocellular 


 
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carcinoma, hepatic metastases, or concomitant treatment with potentially hepatotoxic 
drugs.   
 
A pharmacokinetic (PK) study (data on file) in patients with advanced solid tumors and 
moderate hepatic impairment according to the Child-Pugh criteria has been completed.  
In this study, 10 of the 15 patients died on treatment from progressive disease, one patient 
died from hepatorenal syndrome and one patient died from rapidly progressing liver 
failure.  Six out of the 10 patients who died had baseline total bilirubin > 3 ULN 
suggesting severe, rather than moderate, hepatic impairment, highlighting the limitations 
of utilizing the Child-Pugh criteria in an oncology patient population.  All patients had 
hepatic impairment due to advanced cancer with liver involvement such as hepatocellular 
carcinoma, cholangiocarcinoma, or liver metastases. 
 
Rare cases of myocardial infarction (including fatalities) have been reported during the 
postmarketing use of erlotinib. 
 
No clinical studies have been conducted in patients with compromised renal function 
since Erlotinib and its metabolites are not significantly excreted by the kidneys.   
 
1.6 
Bevacizumab and Erlotinib Combination Studies  
 
The strategy for combining therapeutic agents in cancer treatments has been successful in 
multiple tumor types, including NSCLC.  A new series of clinical studies are now being 
designed and conducted to evaluate the combination of bevacizumab with erlotinib, particularly 
in NSCLC and renal cell carcinoma32,33.  This approach has scientific rationale because the two 
agents target different pathways involved in tumor growth and non-clinical studies in xenograft 
models have demonstrated that the combination of bevacizumab and erlotinib results in greater 
efficacy than either agent alone.  Furthermore, because there is little to no overlap in toxicity 
profile between the two agents, the combination is expected to be well tolerated and may provide 
even greater benefit for patients who are unable to receive cytotoxic therapy.  
 
An investigator-sponsored Phase I/II trial (OSI2486s) has been conducted to evaluate the 
combination of bevacizumab and erlotinib in subjects with relapsed or refractory NSCLC with 
non-squamous histology32.  This Phase I study evaluated three dose combinations to determine 
tolerability and pharmacokinetic profile of each agent when combined.  Subjects whose disease 
had progressed following at least one chemotherapy regimen for advanced disease (Stage IIIb or 
IV) were treated with 100 mg/day erlotinib + 7.5 mg/kg Bevacizumab every 3 weeks, 100 
mg/day erlotinib + 15 mg/kg bevacizumab every 3 weeks, or 150 mg/day erlotinib + 15 mg/kg 
bevacizumab every 3 weeks.  A total of 12 subjects were enrolled and treated (3, 3, and 6 per 
cohort, respectively).  No dose-limiting toxicities were observed, and the pharmacokinetic 
profiles of both drugs did not appear to be affected by the combination.  
 
For the Phase II portion of the study, 22 subjects were evaluable for safety and efficacy, 
inclusive of the 12 subjects treated in Phase I.  The majority of the subjects had a good 
performance status (11 with a Karnofsky score of 90%), adenocarcinoma histology (14 of 22 
subjects), and fewer than two prior chemotherapy regimens (16 of 22).  The most common 


 
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adverse events were rash (20 of 22 subjects), diarrhea (14 of 22), proteinuria (11 of 22), and 
nausea (9 of 22).  All of the events were Grade 1 or 2.  There was one episode of Grade 1 
hemoptysis and one episode of Grade 3 hypertension.  Eleven of the 22 subjects (50%) 
experienced progressive disease after the first 6 weeks of therapy.  Four partial responses 
(18.8%) and seven instances of stable disease (31.2%) were reported.  Based on the preliminary 
data from this single-arm, Phase I/II study, it appears that the combination of bevacizumab and 
erlotinib is well tolerated by most subjects at maximum doses and has encouraging activity, 
supporting a larger, controlled study to assess the efficacy and tolerability of the regimen. 
 
At the recent ASCO meeting, Fehrenbacher presented an abstract from a study were patients 
with NSCLC were randomized to three different arms: chemo plus placebo, chemo plus 
bevacizumab and erlotinib plus bevacizumab (AT). In this population (not limited to the elderly), 
the serious adverse event rates were somewhat less common in the erlotinib plus bevacizumab 
arm compared to the other two arms. There was one case of a pulmonary hemorrhage in this arm 
vs. two in the chemo plus bevacizumab arm. Study discontinuation due to adverse events were 
also less frequent in the AT arm. Efficacy was similar to the chemo plus bevacizumab arm and 
better that the chemo alone group34.  Hence the safety of this regimen has been tested and 
validated in a broader population of patients with advanced NSCLC.  
1.7 
Study Rationale 
 
The elderly (age > 65) comprise more than 40% of newly diagnosed advanced NSCLC, but are 
inadequately represented in the published therapeutic literature – rarely more than 20% of the 
populations studied.  Based on the retrospective analysis of two large trials (SWOG 9509, 
SWOG 9308)1,2, elderly lung cancer patients tend to have more co-morbidities, enhanced toxicity 
to cytotoxic chemotherapy, and trend towards worsened overall survival.  It has been reported in 
the ELVIS3 trial that the fit elderly (PS 0-1) appear to benefit from systemic therapy (compared 
to best supportive care) with respect to QOL and overall survival, but many older patients refuse 
systemic chemotherapy because of the perceived increase in risk of toxicity.  Less toxic 
alternatives are obviously needed in elderly patients with advanced NSCLC who are chemo-
averse or who appear vulnerable or frail, even if their performance status technically is intact. 
 
In the literature, there is no definite evidence of superiority for one systemic therapy over 
another.  Erlotinib is a well-tolerated EGFR-TKI which has been extensively tested in advanced 
NSCLC patients, especially in heavily pre-treated patients.  With the exception of a pilot trial in 
Boston, single agent erlotinib has not been studied exclusively in the elderly; and the 
combination of erlotinib and bevacizumab has never been studied exclusively in the treatment-
naïve elderly.  This study, first of its kind, will explore the response rate in treatment-naïve 
elderly patients with advanced NSCLC –an important cohort that needs less toxic therapies. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary 
 
 
The primary objective of this Phase II study is to evaluate the progression free survival of 
combination bevacizumab and Tarceva (erlotinib) as first line therapy in elderly patients with 


 
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advanced non-small cell lung cancer. 
 
2.2 
Secondary 
 
 
 To evaluate overall survival of combination bevacizumab and Tarceva (erlotinib) as first line 
therapy in elderly patients with advanced non-small cell lung cancer. 
 To evaluate one year survival of patients treated with this combination 
 To evaluate the safety of combining bevacizumab with erlotinib in elderly patients with 
previously untreated advanced NSCLC 
 To evaluate the efficacy of combining bevacizumab with erlotinib in elderly patients with 
previously untreated advanced NSCLC, as measured by objective response rate, duration of 
response, and disease-related symptom improvement and time to symptom progression 
[based on quality of life assessments as measured by the seven-item Lung Cancer Subscale 
(LCS) symptom score of the Functional Assessment of Cancer Therapy-Lung (FACT-L)] 
(Appendix G)  
 To 
correlate 
survival 
with 
baseline 
co-morbidities 
(Charlson 
Co-Morbidity 
Index)35(Appendix H) 
 
3.0 
Study Design  
 
This is a phase II open label study for elderly patients with advanced NSCLC that have not 
received chemotherapy for advanced disease. All patients will be treated with the same regimen.  
 
3.1 
Description of the Study 
 
The dose of bevacizumab in this study is 15 mg/kg administered by IV infusion on the first day 
of each 3-week cycle.   
 
The dose of erlotinib is 150 mg/day orally starting on cycle 1 day 1.  Tablets should be taken at 
the same time each day with ~200 mL (68 ounces) of water at least 1 hour before or 2 hours 
after a meal.  
 
Quality of Life assessments using FACT-L will be collected at baseline and at the end of every 
second cycle of therapy (e.g. cycle 3 day 1, cycle 5 day 1).The FACT-L can be done after every 
3rd cycle after 1st 6 months. 
 
3.2 
Rationale for Study Design and Dosing 
 
Standard doses of both drugs are chosen for this trial. There is ample evidence in support of the 
dosage and scheduling of both of these drugs with adequate clinical experience with regards to 
potential toxicities and their management. The combination of two, well-tolerated and new 
targeted therapies with different mechanisms of actions could be potentially more active than 
either one alone. Obviously the toxicities and potential unwanted interactions are also possible 
but less likely based on the clinical experience with both drugs. Also, given the patient 
population chosen for this study, the choice of two easy to administer and relatively safe drugs is 


 
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important. 
 
3.3 
Outcome Measures 
 
3.3.1 Primary Outcome Measures 
 
The primary efficacy outcome measure for this study is progression free survival, defined 
as the time from registration to documented disease progression, as determined by the 
investigator using the Response Evaluation Criteria in Solid Tumors (RECIST; Section 
12), or death on study, whichever occurs first.  
 
3.3.2 Secondary Outcome Measures  
 
The secondary efficacy outcome measures are as follows: 
 
 Overall survival, defined as the period from the date of enrollment until the date of 
patient death from any cause. 
 One year survival of patients treated with this combination. 
 Time to symptom progression, defined as the period from the date of enrollment until 
the date of symptom progression, as measured by the seven-item Lung Cancer 
Subscale (LCS) symptom score of the Functional Assessment of Cancer 
Therapy-Lung (FACT-L) 
 Objective response, as determined by the investigator using RECIST 
 Duration of objective response, defined as the period from the date of partial or 
complete response (PR or CR) until the date of disease progression, as determined by 
the investigator using RECIST 
 Symptom improvement rate at baseline and at the end of every second cycle of 
therapy, or after every third cycle of therapy; after the first 6 months;  as measured by 
the seven-item LCS of the FACT-L (see Appendix G) 
 Evaluation of the relationship between molecular exploratory markers and efficacy 
outcomes 
 
4.0 
Study Subjects 
 
Patients are eligible for this first-line therapy study if they have advanced NSCLC.  Additional 
specific inclusion and exclusion criteria are listed below. 
 
4.1           Inclusion Criteria 
 
Patients must fulfill all of the following criteria to be eligible for study entry: 
 
 Female or male aged  65 years with cytologically or histologically confirmed NSCLC – 
locally advanced, stage IIIA or stage IIIB (malignant pleural or pericardial effusion or 
pleural implants) OR stage IV OR recurrence after primary surgery or radiotherapy 
 ECOG Performance Status 0-1 


 
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 Measurable disease by RECIST criteria (see section 12).  Previous irradiated tumor is 
acceptable as long as there is at least a 20% increase in the size of the previously 
irradiated lesion 
 ANC > 1500/mm³, platelets > 100,000/mm³ 
 Total bilirubin < = 1.5 mg/dl, SGOT (AST) and SGPT (ALT)< 5 x ULN 
 Serum creatinine < = 3.0 mg/dl  
 Serious, active infections must be controlled. Patients may be enrolled while still on 
antibiotics as long as clinical signs of active infection are absent. 
 Previous radiation allowed provided the patient has recovered from the side effects 
 Availability of archival diagnostic tissue (paraffin tissue block, cytospin block from a 
fine needle aspirate, or unstained slides from resected tumor, core biopsy, or fine needle 
aspirate) is desirable but not required. IHC and FISH for EGFR expression will be 
performed. Patient selection is not based on EGFR expression.  
 Able and willing to sign an informed consent and HIPAA authorization 
 Able and willing to swallow and absorb orally administered medications. 
 Women of childbearing potential (WOCBP) and men who are sexually active with 
WOCBP must agree to use effective methods of contraception during active treatment 
and for a minimum of 2 weeks after the last dose of study treatment. 
 
4.2     Exclusion Criteria 
 
Patients meeting any of the following criteria will be ineligible for study entry: 
 
 Urine protein: Proteinuria as demonstrated by UPC ratio of ≥ 1.0 based on a spot 
urinalysis (See Appendix F).  Urine dipstick is not permitted at baseline. 
 Prior treatment with an investigational or marketed inhibitor of the EGFR pathway or 
anti-angiogenesis agent (this includes thalidomide) 
 Prior treatment for advanced stage disease, with the exception of surgery or radiation (no 
chemotherapy for advanced disease allowed). Chemotherapy prior to the diagnosis of 
advanced disease, such as in the adjuvant setting, is allowed. 
 History of gross hemoptysis (defined as bright red blood of at least half a teaspoon per 
episode) within 1 month of enrollment unless definitively treated with surgery or 
radiation. Hemoptysis post bronchoscopy is not cause for exclusion 
 Evidence of significant bleeding diathesis or coagulopathy or other serious or acute 
internal bleeding (in the absence of therapeutic anticoagulation) within 6 months of 
enrollment 
 Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated 
and/or low molecular weight heparin).  May have been off treatment or on treatment at a 
sub-therapeutic level for any period of time.   
 Current or recent (within 10 days of first dose of study treatment) use of aspirin 
( 325 mg/day) or other non-steroidal anti-inflammatory drugs (NSAIDs) with anti-
platelet activity.  Treatment with dipyridamole, ticlopidine, clopidogrel, and/or cilostazol 
is also not allowed. PRN use of NSAIDs once the protocol treatment has been started is 
allowed.  Low dose ASA (≤ 325 mg/day) is allowable. 
 Prior malignancy within the past 3 years other than basal cell carcinoma, cervical in situ. 


 
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 History of hemorrhagic or thrombotic stroke, transient ischemic attach (TIA) or other 
CNS bleeding within the last 6 months.  Clinically significant peripheral vascular disease 
such as active, symptomatic PVD, peripheral arterial thrombosis, aortic aneurysm, 
requiring surgical repair within 6 months of enrollment. 
 Known CNS disease, except for treated brain metastasis.  Treated brain metastases are 
defined as having no evidence of progression or hemorrhage after treatment and no 
ongoing requirement for dexamethasone, as ascertained by clinical examination and brain 
imaging (MRI or CT) during the screening period.  Anticonvulsants (stable doses) are 
allowed.  Treatment for brain metastases may include whole brain radiotherapy (WBRT), 
radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed 
appropriate by the treating physician.  Patients with CNS metastases treated by 
neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be 
excluded. 
 Uncontrolled or unstable co-morbidities which would clearly preclude use of 
bevacizumab or erlotinib. 
 Lung carcinoma of squamous cell histology (mixed tumors will be categorized by the 
predominant cell type unless small cell elements are present, in which case the patient is 
ineligible).   Sputum cytology alone is acceptable. Patients with extrathoracic-only 
squamous cell NSCLC are eligible.  Patients with only peripheral lung lesions of any 
NSCLC histology will also be eligible.  A peripheral lesion is defined as a lesion in 
which the epicenter of the tumor is <2 cm from the costal or diaphragmatic pleura in a 
three-dimensional orientation based on each lobe of the lung and is >2 cm from the 
trachea, main, and lobar bronchi. 
 Current, recent (within 4 weeks of enrollment of this study), or planned participation in 
an experimental drug study other than a Genentech-sponsored bevacizumab cancer study 
 Blood pressure of 
150/100 mmHg, that cannot be ameliorated with standard anti-
hypertensives.  Antihypertensives may be started prior to enrollment to reduce BP to 
acceptable range.   
 Prior history of hypertensive crisis or hypertensive encephalopathy. 
 Unstable angina 
 New York Heart Association (NYHA) Grade II or greater congestive heart failure (see 
Appendix E) 
 History of myocardial infarction within 6 months of enrollment 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to enrollment, anticipation of need for major surgical procedure during the course of 
the study (Port insertion, thoracenteses or pericardiocenteses etc are acceptable) 
 Minor surgical procedures such as  fine needle aspirations or core biopsies within 7 days 
prior to enrollment 
 Pregnant (positive serum pregnancy test) or lactating 
 History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 6 months prior to enrollment 
 Serious, non-healing wound, ulcer, or recent non-pathologic bone fracture.  Bone 
fractures must be healed. 
 Known hypersensitivity to any component of bevacizumab. 
 Inability to comply with study and/or follow-up procedures 


 
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5.0       Discontinuation of Subjects from Treatment or Assessment 
5.1       Criteria for Discontinuation 
Subjects may be discontinued from study treatment and assessments at any time. Specific 
reasons for discontinuing a subject from this study are: 
 
 Voluntary discontinuation by the subject who is at any time free to discontinue 
participation in the study, without prejudice to further treatment. 
 Incorrect enrollment of the subject 
 Death 
 Administration of radiotherapy, non-protocol chemotherapy, biological therapy or 
major surgical intervention during the trial    
 Subject lost to follow-up 
 Objective progression of disease  
 Clinical or symptomatic deterioration 
 Need for a third dose reduction of erlotinib 
 Significant toxicities precluding study continuation: 
o Grade 4 hypertension or Grade 3 hypertension not controlled with medication 
o Reversible posterior leukoencephalopathy syndrome (RPLS) 
o Grade ≥ 2 pulmonary or CNS hemorrhage or any grade 4 hemorrhage, 
symptomatic Grade 4 venous thromboembolic event, requiring full dose 
warfarin or equivalent (i.e., unfractionated or low molecular weight heparin) 
o Nephrotic syndrome 
o Any grade arterial thromboembolic event 
o Grade 4 CHF 
o Gastrointestinal perforation 
o Gastrointestinal fistula formation, tracheoesophageal or other non-GI Grade 4 
fistula formation 
o Bowel obstruction that has not fully recovered despite medical or surgical 
intervention 
o Wound dehiscence requiring medical or surgical intervention 
o Interstitial Lung Disease (ILD) 
o All Grade 4 events thought to be related to bevacizumab by the investigator 
 Inability of subject to comply with study requirements 
 Determination by the investigator that it is no longer safe for the subject to continue 
therapy 
 Treatment interruption of one or both study drugs for more than three weeks (ie 1 
cycle)  
 Full dose anticoagulation therapy 
 
Patients who have an ongoing bevacizumab-related Grade 4 or serious adverse event at 
the time of discontinuation from study treatment will continue to be followed until 
resolution of the event or until the event is considered irreversible. 


 
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5.2 
Definition of DLT 
 
For the purposes of this study the following events would be considered DLT: 
 Any grade 4 hemorrhagic events 
 Grade 4 hypertension or hypertensive encephalopathy,  
 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
 Any arterial thromboembolic events 
 Any attributable grade 5 toxicity 
 Grade ≥ 2 pulmonary or CNS bleeding 
 Grade 4 CHF 
 Clearly attributable interstitial lung disease occurring on treatment 
 
6.0 
Treatments 
 
6.1 
Bevacizumab 
 
6.1.1 Bevacizumab formulation (supplied by Genentech) 
 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid 
concentrate for solution for intravenous (IV) infusion.  Bevacizumab may be supplied in 
5-cc (100-mg), 20-cc (400-mg), and 50-cc (1000-mg) glass vials containing 4 mL, 16 
mL, or 40 mL of bevacizumab, respectively (all at 25 mg/mL).  Vials contain 
bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection 
(SWFI), USP.  Vials contain no preservative and are suitable for single use only. 
For further details and molecule characterization, see the bevacizumab Investigator 
Brochure. 
 
6.1.2 Bevacizumab Safety Profile 
 
 In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety 
signals were identified: hypertension, proteinuria, thromboembolic events, and 
hemorrhage.  Additional completed Phase II and Phase III studies of bevacizumab as well 
as spontaneous reports have further defined the safety profile of this agent. Bevacizumab-
associated adverse events identified in phase III trials include congestive heart failure 
(CHF) primarily in metastatic breast cancer, gastrointestinal perforations, wound healing 
complications, and arterial thromboembolic events (ATE). These and other safety signals 
are described in further detail as follows and in the bevacizumab Investigator Brochure. 
 
Hypertension: 
An increased incidence of hypertension has been observed in 
patients treated with bevacizumab Grade 4 and 5 hypertensive events are rare. Clinical 
sequelae of hypertension are rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) (Ozcan 
et al., 2006; Glusker et al., 2006).  
 


 
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Reversible Posterior Leukoencephalopathy Syndrome: There have been rare reports 
of bevacizumab-treated patients developing signs and symptoms that are consistent with 
RPLS, a rare neurologic disorder that can present with the following signs and symptoms 
of headache, altered mental function, seizures, and visual disturbances / cortical blindness 
with or without associated hypertension. Brain imaging is mandatory to confirm the 
diagnosis of RPLS.  In patients who develop RPLS, treatment of specific symptoms, 
including control of hypertension, management of specific symptoms, and 
discontinuation of bevacizumab. (Glusker et al. 2006; Ozcan et al. 2006).  
 
There is no information on the effect of bevacizumab in patients with uncontrolled 
hypertension at the time of initiating bevacizumab therapy.  Therefore, caution should be 
exercised before initiating bevacizumab therapy in these patients.  Monitoring of blood 
pressure is recommended during bevacizumab therapy.  Optimal control of blood 
pressure according to standard public health guidelines is recommended for patients on 
treatment with or without bevacizumab.   
 
Temporary interruption of bevacizumab therapy is recommended in patients with 
hypertension requiring medical therapy until adequate control is achieved.  
If hypertension cannot be controlled with medical therapy, bevacizumab therapy should 
be permanently discontinued.  Bevacizumab should be permanently discontinued in 
patients who develop hypertensive crisis or hypertensive encephalopathy. 
 
Proteinuria:  An increased incidence of proteinuria has been observed in patients treated 
with bevacizumab compared with control arm patients. In the bevacizumab-containing 
treatment arms of clinical trials (across all indications), the incidence of proteinuria 
(reported as an adverse event) was up to 38% (metastatic CRC Study AVF2192g).  The 
severity of proteinuria has ranged from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria events have 
been grade 1. NCI-CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab-
treated patients, and Grade 4 in up to 1.4% of bevacizumab-treated patients.  The 
proteinuria seen in bevacizumab clinical trials was not associated with renal impairment 
and rarely required permanent discontinuation of Bevacizumab therapy.  Bevacizumab 
should be discontinued in patients who develop Grade 4 proteinuria (nephrotic 
syndrome). 
 
In study AVF2107g, none of the 118 patients receiving bolus-IFL plus placebo, three of 
158 patients (2%) receiving bolus-IFL plus bevacizumab, and two of 50 (4%) patients 
receiving 5-FU/LV plus bevacizumab who had a 24-hour collection experienced grade 3 
proteinuria (> 3.5 g protein/24 hr). Rare events of nephrotic syndrome have occurred, and 
bevacizumab should be discontinued in patients with nephrotic syndrome. 
 
Thromboembolic Events:  Both venous and arterial thromboembolic (TE) events, 
ranging in severity from catheter-associated phlebitis to fatal, have been reported in 
patients treated with bevacizumab in the colorectal cancer trials and, to a lesser extent, in 
patients treated with bevacizumab in NSCLC and breast cancer trials.  
 


 
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Venous Thromboembolism (including deep venous thrombosis pulmonary 
embolism, and thrombophlebitis:  In the phase III pivotal trial in metastatic CRC, 
there was a slightly higher rate of venous TE events in patients treated with bevacizumab 
plus chemotherapy compared with chemotherapy alone (19% vs. 16%). There was also a 
higher rate of arterial TE events (3% vs. 1%) such as myocardial infarction, transient 
ischemia attack, cerebrovascular accident/stroke and angina/unstable angina. A pooled 
analysis of the rate of arterial TE events from 5 randomized studies (1745 patients) 
showed that treatment with chemotherapy plus bevacizumab increased the risk of having 
an arterial TE event compared with chemotherapy alone (3.8% vs. 1.7%, respectively) 
(Skillings et al., 2005). Furthermore, subjects with certain baseline characteristics (age ≥ 
65 years and/or a history of a prior arterial TE event) may be at higher risk of 
experiencing such an event. . See the bevacizumab Investigator Brochure for additional 
information on risk factors. 
 
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, including 
deep venous thrombosis, pulmonary embolism, and thrombophlebitis, occurred in 15.2% 
of patients receiving chemotherapy alone and 16.6% of patients receiving 
chemotherapy  bevacizumab.  
 
The incidence of NCI-CTC Grade  3 venous VTE events in one NSCLC trial (E4599) 
was higher in the bevacizumab-containing arm compared to the chemotherapy control 
arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the bevacizumab-containing arm; no 
fatal events were reported in the carboplatin/paclitaxel arm (see Bevacizumab 
Investigator Brochure).  In metastatic CRC clinical trials, the incidence of VTE events 
was similar in patients receiving chemotherapy  bevacizumab and those receiving the 
control chemotherapy alone.  
 
In clinical trials across all indications the overall incidence of VTE events was 
2.8%17.3% in the bevacizumab-containing arms compared with 3.2%15.6% in the 
chemotherapy control arms.  The use of bevacizumab with chemotherapy does not 
substantially increase the risk of VTE event compared with chemotherapy alone.  
However, patients with metastatic CRC who receive bevacizumab and experienced a 
VTE event may be at higher risk for recurrence of VTE event. 
 
Arterial Thromboembotic Events:  An increased incidence of ATE events was 
observed in patients treated with bevacizumab compared with those receiving control 
treatment.  ATE include cerebrovascular accidents, myocardial infarction, transient 
ischemic attacks (TIAs), and other ATE.  In a pooled analysis of data from five 
randomized Phase II and III trials (mCRC [AVF2107g, AVF2192g, AVF0780g]; locally 
advanced or metastatic NSCLC [AVF0757g]; metastatic breast cancer [AVF2119g]), the 
incidence rate of ATE was 3.8% (37 of 963) in patients who received 
chemotherapy 
 bevacizumab compared with 1.7% (13 of 782) in patients treated with 
chemotherapy alone.  ATE led to a fatal outcome in 0.8% (8 of 963) of patients treated 
with chemotherapy 
 bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 2.3% of 


 
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patients treated with chemotherapy 
 bevacizumab and 0.5% of patients treated with 
chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients treated with 
chemotherapy 
 bevacizumab compared with 0.7% of patients treated with chemotherapy 
alone (see the Bevacizumab Investigator Brochure for additional details). 
 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of aspirin ≤ 
325 mg daily was allowed in the five randomized studies discussed above. Use of aspirin 
was assessed routinely as a baseline or concomitant medication in these trials, though 
safety analyses specifically regarding aspirin use were not preplanned. Due to the 
relatively small numbers of aspirin users and arterial thromboembolic events, 
retrospective analyses of the ability of aspirin to affect the risk of such events were 
inconclusive. However, similarly retrospective analyses suggested that the use of up to 
325 mg of aspirin daily does not increase the risk of grade 1-2 or grade 3-4 bleeding 
events, and similar data with respect to metastatic colorectal cancer patients were 
presented at ASCO 2005 (Hambleton et al., 2005). Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor types are 
ongoing. 
 
Gastrointestinal perforation: 
Patients with metastatic carcinoma may be at 
increased risk for the development of gastrointestinal perforation and fistula when treated 
with bevacizumab and chemotherapy. Bevacizumab should be permanently discontinued 
in patients who develop gastrointestinal perforation. A causal association of intra-
abdominal inflammatory process and gastrointestinal perforation to bevacizumab has not 
been established. Nevertheless, caution should be exercised when treating patients with 
intra-abdominal inflammatory processes with bevacizumab. Gastrointestinal perforation 
has been reported in other trials in non-colorectal cancer populations (e.g., ovarian, renal 
cell, pancreas, breast, and NSCLC) and may be higher in incidence in some tumor types. 
 
Fistula:  
Bevacizumab use has been associated with serious cases of fistulae 
including events resulting in death.  Fistulae in the GI tract are common (1%–10% 
incidence) in patients with metastatic CRC, but uncommon (0.1%1%) or rare (0.01%–
0.1%) in other indications.  In addition, fistulae that involve areas of the body other than 
the GI tract (e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been 
reported uncommonly (0.1%–1%) in patients receiving bevacizumab in clinical studies 
and postmarketing reports.  Events were reported at various timepoints during treatment, 
ranging from 1 week to  1 year following initiation of bevacizumab, with most events 
occurring within the first 6 months of therapy. 
 
Permanently discontinue bevacizumab in patients with tracheoesophageal fistulae or any 
Grade 4 fistula.  Limited information is available on the continued use of bevacizumab in 
patients with other fistulae.  In cases of internal fistula not arising in the GI tract, 
discontinuation of bevacizumab should be considered 
 
Wound healing complications:  
Wound healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an analysis of 


 
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pooled data from two trials in metastatic colorectal cancer, patients undergoing surgery 
28-60 days before study treatment with 5-FU/LV plus bevacizumab did not appear to 
have an increased risk of wound healing complications compared to those treated with 
chemotherapy alone (Scappaticci et al., 2005). Surgery in patients currently receiving 
bevacizumab is not recommended. No definitive data are available to define a safe 
interval after bevacizumab exposure with respect to wound healing risk in patients 
receiving elective surgery; however, the estimated half life of bevacizumab is 21 days. 
Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
 
Hemorrhage:  
Overall, grade 3 and 4 bleeding events were observed in 4.0% of 
1132 patients treated with bevacizumab in a pooled database from eight phase I, II, and 
III clinical trials in multiple tumor types (bevacizumab Investigator Brochure, October 
2005). The hemorrhagic events that have been observed in bevacizumab clinical studies 
were predominantly tumor-associated hemorrhage (see below) and minor mucocutaneous 
hemorrhage.  
 
Tumor-associated hemorrhage: Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  Life-threatening and 
fatal hemoptysis was identified as a bevacizumab-related adverse event in NSCLC trials.  
These events occurred suddenly and presented as major or massive hemoptysis.  Among 
the possible risk factors evaluated (including  squamous cell histology, treatment with 
anti-rheumatic/anti-inflammatory 
drugs, 
treatment 
with 
anticoagulants, 
prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, and/or 
tumors located in the center of the chest in close proximity to major blood vessels and 
cavitation of tumors during therapy), the only variables that showed statistically 
significant correlations with bleeding were bevacizumab therapy and squamous cell 
histology. 
 
Of patients experiencing pulmonary hemorrhages requiring medical intervention, many 
had cavitation and/or necrosis of the tumor, either preexisting or developing during 
bevacizumab therapy.  Patients developing lung cavitation on treatment should be 
assessed by the treating physician for risk-benefit. 
 
In ECOG-conducted study E4599, in which squamous cell carcinoma was excluded, the 
rate of any type of Grade ≥ 3 hemorrhage was 1.0% in the control arm 
(carboplatin/paclitaxel) versus 4.1% in the carboplatin/paclitaxel + bevacizumab arm23. 
 
GI hemorrhages, including rectal bleeding and melena have been reported in patients 
with CRC, and have been assessed as tumor-associated hemorrhages. 
 
Tumor-associated hemorrhages were also seen rarely in other tumor types and locations, 
including a case of CNS bleeding in a patient with hepatoma with occult CNS metastases 
and a patient who developed continuous oozing of blood from a thigh sarcoma with 
necrosis. 
 


 
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Mucocutaneous Hemorrhage: 
Across 
all 
bevacizumab 
clinical 
trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients treated with 
bevacizumab. These were most commonly grade 1 epistaxis that lasted less than 5 
minutes, resolved without medical intervention and did not require any changes in 
bevacizumab treatment regimen. There have also been less common events of minor 
mucocutaneous hemorrhage in other locations, such as gingival bleeding and vaginal 
bleeding.  
 
Congestive heart failure:  
In clinical trials CHF was observed in all cancer indications 
studied to date, but predominantly in patients with metastatic breast cancer.  These events 
varied in severity from asymptomatic declines in left ventricular ejection fraction (LVEF) 
to symptomatic CHF requiring hospitalization and treatment and most patients showed 
improved symptoms and/or left ventricular function following treatment.  CHF has been 
reported in bevacizumab clinical trials and may be increased in incidence in patients with 
prior exposure to anthracyclines or prior irradiation to the chest wall. In a phase III trial 
(AVF2119g) of capecitabine with or without bevacizumab for metastatic breast cancer, 7 
subjects (3.1%) who received capecitabine plus bevacizumab developed clinically 
significant CHF compared with 2 subjects (0.9%) treated with capecitabine alone; of 
note, all subjects in this trial had had prior anthracycline treatment. In addition, 2 subjects 
had a left ventricular ejection fraction < 50% at baseline and 2 others had prior left chest 
wall irradiation.      
 
In a randomized, Phase III trial of patients with previously untreated metastatic breast 
cancer (E2100), the incidence of LVEF decrease (defined as NCI-CTC Grade 3 or 4) in 
the paclitaxel  bevacizumab arm was 0.3% versus 0% for the paclitaxel alone arm.  
 
No information is available on patients with preexisting CHF of New York Heart 
Association (NYHA) Class IIIV at the time of initiating bevacizumab therapy, as these 
patients were excluded from clinical trials. 
 
Prior anthracycline exposure and/or prior radiotherapy to the chest wall may be possible 
risk factors for the development of CHF.  Caution should be exercised before initiating 
bevacizumab therapy in patients with these risk factors. 
 
A recently published phase II study in subjects with refractory acute myelogenous 
leukemia reported 5 cases of cardiac dysfunction (CHF or decreases to <40% in left 
ventricular ejection fraction) of 48 subjects treated with sequential cytarabine, 
mitoxantrone, and bevacizumab. All but one of these subjects had significant prior 
exposure to anthracyclines as well (Karp et al., 2004). Other studies are ongoing in this 
patient population. Patients receiving anthracyclines or with prior exposure to 
anthracyclines should have a baseline MUGA or ECHO with a normal ejection fraction. 
 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or infection 
with severe neutropenia (including some fatalities) have been observed in patients treated 
with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to 
chemotherapy alone23. 


 
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FER-TH-007 Amendment 4   October 1, 2012 
26
 
Additional Safety Signals:  
 
Other safety concerns seen to date—asthenia, pain, headache, fever, chills, rash, 
infection, epistaxis, and mouth ulceration—are not thought to be clinically significant in 
that they rarely or never required treatment or study drug discontinuation.  An additional 
SAE reported in patients receiving bevacizumab is Nasal Septum Perforation. 
 
Non-Gastrointestinal fistula formation has been reported in patients treated with 
bevacizumab (< 0.3%) some with fatal outcome.  Permanent discontinuation of 
bevacizumab in patients with fistula formation involving any internal organ is 
recommended in a recent addition to the WARNINGS section of the Avastin label. 
 
If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical procedure. 
Patients undergoing a major surgical procedure should not begin/restart bevacizumab 
until 4 weeks after that procedure (in the case of high risk procedures such as liver 
resection, thoracotomy, or neurosurgery, it is recommended that chemotherapy be 
restarted no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery). 
 
Additional Adverse Events: See the bevacizumab Investigator Brochure for additional 
details regarding the safety experience with bevacizumab. 
 
6.1.3 Bevacizumab Dosage and Administration 
 
Bevacizumab will be given at a dose of 15 mg/kg IV on day 1 of each 21 day cycle. 
 
Bevacizumab will be diluted in 0.9% Sodium Chloride Injection, USP, to a total volume 
of 100 mL.  Administration will be as an IV infusion.  Anaphylaxis precautions should be 
observed during study drug administration. The initial dose will be delivered over 9015 
minutes.  If the first infusion is tolerated without infusion-associated adverse events 
(fever and/or chills), the second infusion may be delivered over 6010 minutes.  If the 
60-minute infusion is well tolerated, all subsequent infusions may be delivered over 
3010 minutes.   
 
6.1.4 Bevacizumab Storage 
 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO NOT FREEZE.  
DO NOT SHAKE.   Vials should be protected from light. 
 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE ONLY.  
Vials used for 1 subject may not be used for any other subject.  Once study drug has been 
added to a bag of sterile saline, the solution must be administered within 8 hours. 
 


 
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6.1.5 Bevacizumab Dose Modification and Toxicity Management 
 
There are no reductions in the bevacizumab dose. If adverse events occur that require 
holding bevacizumab, the dose will remain the same once treatment resumes. Refer to 
Table 1 for dose delays. 
 
Any toxicities associated or possibly associated with bevacizumab treatment should be 
managed according to standard medical practice. Discontinuation of bevacizumab will 
have no immediate therapeutic effect. Bevacizumab has a terminal half-life of 21 days; 
therefore, its discontinuation results in slow elimination over several months. There is no 
available antidote for bevacizumab.  
 
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time during the 
study, treatment on study should be discontinued.  
 
Infusion Reaction Related to Bevacizumab:  
 
Infusion of bevacizumab should be interrupted for subjects who develop dyspnea or 
clinically significant hypotension. Subjects who experience a NCI CTCAE v. 3.0 Grade 3 
or 4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab treatment 
and 
removed 
from 
the 
study. 
 
Document 
the 
reason 
for 
removal 
as 
hypersensitivity/bevacizumab. 
 
The infusion should be slowed to 50% or less or interrupted for subjects who experience 
any infusion-associated symptoms not specified above. When the subject’s symptoms 
have completely resolved, the infusion may be continued at no more than 50% of the rate 
prior to the reaction and increased in 50% increments every 30 minutes if well tolerated. 
Infusions may be restarted at the full rate during the next cycle.  
 
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed 
in Table 1.  Infusion reactions are described in section 6.1.3 
 
Regardless of the reason for holding bevacizumab treatment, including the events in 
Table 1, the maximum allowable length of treatment interruption is three weeks. If > 
three weeks, discontinue treatment.  Treatment with erlotinib will continue during this 
period.  Protocol treatment will discontinue if any of the drugs are held for more than 
three weeks. 


 
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FER-TH-007 Amendment 4   October 1, 2012 
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Table 1 
Bevacizumab Dose Management Due to Adverse Events 
Event 
Action Taken 
Hypertension 
Grade 1 or 2 
No dose modifications 
Grade 3 
Hold bevacizumab and initiate additional or different anti-
hypertensive therapy.  Erlotinib may be continued during the hold 
interval.  Check BP weekly and resume bevacizumab once BP 
controlled to < 150/100.  The day bevacizumab is resumed will be 
day 1 of the next cycle.  Count the days that erlotinib was continued 
as part of the prior cycle.  If not controlled with medication within 3 
weeks, discontinue study treatment phase.  May continue on 
treatment with grade 3 hypertension once controlled. 
Grade 4 (including RPLS confirmed by MRI 
or hypertensive encephalopathy) 
Discontinue study treatment phase 
Hemorrhage 
Grade 1 Pulmonary or CNS hemorrhage 
Hold bevacizumab and evaluate for source of bleed.  Erlotinib may 
continue.  If resolved within 1 week, and no source, resume full-
dose bevacizumab. If recurrent, discontinue study treatment phase.  
For recurrent epistaxis that is mild and does not require intervention, 
treatment may continue. 
Grade > 2 Pulmonary or CNS hemorrhage 
Discontinue study treatment phase.  In subjects with hemoptysis, 
consider early use of bronchoscopy in identify the site of bleeding. 
Other/non-pulmonary or non-CNS grade 1 or 
2 events of hemorrhage 
No dose modifications 
Grade 3 
Non-pulmonary or CNS hemorrhage 
Hold bevacizumab.  May continue erlotinib.  In subjects with 
bleeding, consider full hemostasis evaluation, which may include 
additional INR, bleeding time measurements, and platelet 
aggregation, etc.  In subjects with GI bleeding, consider stool 
guaiacs and early use of endoscopy or other studies to identify the 
location of the bleeding. 
 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued study treatment phase. 
All other subjects will have bevacizumab held until all of the 
following criteria are met: 
o The bleeding has resolved and hemoglobin is stable +/- 1 
g/dl over 24 hours. 
o There is no bleeding diathesis that would increase the risk of 
therapy. 
o There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic event will be 
discontinued study treatment phase. 
 


 
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Table 1 (continued) 
Bevacizumab Dose Management Due to Adverse Events: 
Event 
Action Taken 
Grade 4 
Discontinue study treatment phase. 
Venous Thrombosis  
Grade 1 or 2 
No dose modifications 
Grade 3 or Grade 4 
Hold bevacizumab (continue erlotinib). If the planned duration 
of full-dose anticoagulation is <2 weeks, bevacizumab should 
be held until the full-dose anticoagulation period is over.  If the 
planned duration of full-dose anticoagulation is >2 weeks, 
bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria  are met: 
 The subject must have an in-range INR (usually 
between 2 and 3) if on warfarin; LMWH, warfarin, 
or other anticoagulant dosing must be stable prior 
to restarting bevacizumab treatment. 
The subject must not have had a Grade 3 or 4 hemorrhagic 
event while on anticoagulation. 
Arterial Thromboembolic event 
[new onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event] 
Any Grade 
Discontinue study treatment phase 
Event 
 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
Grade 1 or 2 
No dose modifications 
Grade 3 
Hold bevacizumab until resolution to Grade < 1.  May 
continue erlotinib at investigator’s discretion. 
Grade 4 
Discontinue study treatment phase 
Proteinuria 
Grade 1 or 2 
No dose modifications 
Grade 3 
(UPC > 3.5, urine collection> 3.5 g/24 
hr) 
Hold Bevacizumab until < Grade 2 
A UPC ratio of <3.5 or < 3.5 gm/dL in a 24 hr. urine collection  
Grade 4 
Discontinue study treatment phase 
Bowel Obstruction 
Grade 1 
Continue patient on study for partial obstruction NOT 
requiring medical intervention 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical 
intervention.  Erlotinib to be held if subject is NPO. 
Patient may restart bevacizumab upon complete resolution.  
Erlotinib can be restarted when oral intake is permitted (may 
dissolve tablets in distilled water) if within 3 weeks. 
Grade 3/4 
Hold bevacizumab for complete obstruction.  If surgery is 
necessary patient may restart bevacizumab after full recovery 
from surgery, and at investigator’s discretion 


 
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Table 1 (continued) 
Bevacizumab Dose Management Due to Adverse Events: 
 Event 
Action Taken 
Gastrointestinal perforation    
Any Grade 
Discontinue study treatment phase 
Fistula 
 
Any grade (TE fistula) 
Discontinue study treatment phase 
Grade 4 fistula 
Discontinue study treatment phase 
Reversible Posterior Leukoencephalopathy Syndrome (confirmed by MRI) 
Any Grade 
Discontinue study treatment phase 
Nasal Septum Perforation 
Any Grade 
Discontinue study treatment phase 
Wound dehiscence 
Requiring medical or surgical therapy 
Discontinue study treatment phase 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Hold bevacizumab until recovery to < Grade 1 
Grade 4 
Discontinue study treatment phase 
 
A number of measures will be taken to ensure the safety of patients participating in this 
trial.  These measures will be addressed through exclusion criteria (see Section 4.2) and 
routine monitoring as follows. 
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, blood pressure, and laboratory measurements.  Patients will be evaluated 
for adverse events (all grades), serious adverse events, and adverse events requiring study 
drug interruption or discontinuation at each study visit for the duration of their 
participation in the study.  Patients discontinued from the treatment phase of the study for 
any reason will be evaluated ~30 days (28–42 days) after the decision to discontinue 
treatment (see Section 5.0).  Specific monitoring procedures are as follows: 
 
 Hypertension will be monitored through routine evaluation of blood pressure prior 
to each bevacizumab treatment.  Optimal control of blood pressure is required.  
For blood pressure ≥ 150/100 mm/Hg on the day of treatment with bevacizumab, 
which can not be controlled with standard antihypertensive therapy, treatment 
with bevacizumab must be withheld.  
 If patients on treatment with bevacizumab require elective major surgery, they 
must be taken off study (section 5.1).  It is recommended that bevacizumab be 
held for 4-8 weeks prior to the surgical procedure. Patients undergoing a major 
surgical procedure should not begin/restart bevacizumab until 4 weeks after that 
procedure (in the case of high risk procedures such as liver resection, 
thoracotomy, or neurosurgery, it is recommended that chemotherapy be restarted 
no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery).  It is the 
treating physician’s discretion whether or not to resume bevacizumab but if 


 
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31
treatment is resumed it will be off study and no further drug will be supplied 
through this study. 
 In patients with bleeding, hemostasis evaluation should be performed as clinically 
indicated.   
 Proteinuria will be monitored through urinary protein/creatinine ratio or dipstick 
performed  at least every 6 weeks 
 Patients who have an ongoing bevacizumab-related Grade 4 or serious adverse 
event at the time of discontinuation from study treatment will continue to be 
followed until resolution or deemed irreversible. 
 
Erlotinib will continue as per protocol guidelines until toxicities resolve and bevacizumab 
is continued or until the patient is removed from the study. 
 
6.2 
Erlotinib (Tarceva) (supplied by Genentech) 
 
6.2.1 Formulation 
 
In addition to the active ingredient, Tarceva (erlotinib hydrochloride), tablets contain 
lactose (hydrous), microcrystalline cellulose, sodium starch glycolate, sodium lauryl 
sulfate, and magnesium stearate.   
 
Tablets containing 25 mg, 100 mg, and 150 mg of erlotinib are available.  The oral tablets 
are conventional, immediate-release tablets containing erlotinib as the hydrochloride salt.  
Each bottle will contain 30 tablets, a quantity sufficient for 4 consecutive weeks of 
dosing, with overage.   
 
For further details, see the erlotinib Investigator Brochure. 
 
6.2.2 Erlotinib Safety Profile 
 
Common adverse events associated with erlotinib administration include rash and 
diarrhea.  Other common adverse events include nausea/vomiting, mucositis/stomatitis, 
headache, and fatigue.  
 
A rash occurred in 75% of erlotinib-treated NSCLC patients enrolled in BR.21.  Similar 
incidence of rash have occurred when erlotinib was administered concurrently with 
chemotherapy including gemcitabine, paclitaxel/carboplatin, and gemcitabine/cisplatin.  
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. Other 
dermatologic manifestations reported in clinical studies or postmarketing use of erlotinib 
include nail changes, paronychia, painful fissures or cracking of the skin on the hands and 
feet, and hair growth abnormalities (alopecia, thinning hair, eyelash/eyebrow changes, 
hirsutism). 
 
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 


 
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32
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, 
radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial 
lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress 
syndrome, alveolitis, 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. 
 
Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal 
insufficiency have been reported. Some were secondary to baseline hepatic impairment 
while others were associated with severe dehydration due to diarrhea, vomiting, and/or 
anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in 
patients with contributing risk factors for renal failure (eg, pre-existing renal disease, 
medical conditions or medications that may lead to renal disease, or other predisposing 
conditions including advanced age), erlotinib therapy should be interrupted and 
appropriate measures should be taken to intensively rehydrate the patient. Periodic 
monitoring of renal function and serum electrolytes is recommended in patients at risk of 
dehydration. 
 
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 erlotnib with omeprazole, a proton pump inhibitor, decreased the 
exposure of erlotinib (AUC) by 46% and the maximum concentration (Cmax) by 61%. 
There was no change to Tmax or half-life.  Therefore, drugs that alter the pH of the GI 
tract may alter the solubility of erlotinib and hence its bioavailability. 
 
The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, and the 
maximum concentration (Cmax) by 17%, when erlotinib was co-administered with 
ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 
 
Erotinib clearance can be induced by smoking via CYP1A2 induction. Potential drug-
drug interaction is expected when erlotinib is taken with CYP1A2 inducers or inhibitors.  
In a single-dose study in healthy volunteers, the AUC was reduced by 64% in smokers 
when compared with nonsmokers.  In BR.21, current smokers achieved erlotinib steady-
state trough plasma concentrations, which were approximately 2-fold less than the former 


 
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33
smokers or patients who had never smoked. This effect was accompanied by a 24% 
increase in apparent erlotinib plasma clearance. Similarly, in a Phase I (N=35) dose 
escalation PK study in NSCLC patients who were current smokers, Pka at steady-state 
indicated a dose proportional increase in erlotinib exposure when the erlotinib dose was 
increased from 150mg to 300mg. However, the exact dose to be recommended for 
smokers is unknown. These data suggest that patients who continue to smoke may be 
under dosed when treated with the current approved erlotinib dosage of 150mg, therefore, 
warranting consideration of dose escalation.   Patients should be advised to stop smoking.  
If patients continue to smoke, a cautious increase in the dose of erlotinib, not exceeding 
300mg/day may be considered while monitoring the patient’s safety. If patients decide to 
stop smoking while on a higher dose, then the dose should be reduced immediately to the 
indicated starting dose.  Efficacy and long-term safety (>14 days) of a higher dose than 
the recommended starting dose has not been established in patients who continue to 
smoke.  Pretreatment or co-administration of erlotinib did not alter the clearance of a 
prototypical CYP3A4 substrate, midazolam.  Therefore, significant metabolic 
interactions with other CYP3A4 substrates are unlikely.  However, the oral 
bioavailability of midazolam decreased by up to 24% following erlotinib treatment, 
which was not attributed to a metabolic interaction. 
 
Pretreatment or co-administration of erlotinib did not alter the clearance of a prototypical 
CYP3A4 substrate, midazolam.  Therefore, significant metabolic interactions with other 
CYP3A4 substrates are unlikely.  However, the oral bioavailability of midazolam 
decreased by up to 24% following erlotinib treatment, which was not attributed to a 
metabolic interaction. 
 
Co-administration of erlotinib with an inhibitor of CYP3A4 metabolism (ketoconazole, 
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.  
In another study, rifampicin pretreatment followed by co-administration of rifampicin 
with a single 450 mg dose of erlotinib resulted in a mean erlotinib exposure (AUC) that 
was 57.6% of that observed following a single 150 mg erlotinib dose in the absence of 
rifampicin treatment.  Therefore, a potential for drug-drug interaction exists when 
erlotinib is co-administered with drugs that are highly protein bound or that are potent 
CYP3A4 inhibitors or inducers. 
 
International normalized ratio (INR) elevations and/or bleeding events have been 
reported in some cancer patients while on erlotinib alone and in combination with other 
chemotherapeutic agents, and concomitant NSAIDS or anticoagulants, including 
warfarin. 
 


 
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Cardiovascular Effects: Myocardial infarction  
Dermatologic Effects: Rash  
Gastrointestinal: Diarrhea, gastrointestinal hemorrhage, stomatitis, mucositis, anorexia, 
nausea, vomiting, weight loss 
Hematologic 
Effects: 
Deep 
venous 
thrombosis, 
neutropenia, 
and 
anemia,  
microangiopathic hemolytic anemia, with thrombocytopenia  
Hepatic Effects: Acute hepatitis, hyperbilirubinemia, increased liver enzymes 
Neurologic Effects: Cerebrovascular accidents, headache   
Ophthalmic Effects: Conjunctivitis, Keratitis, Keratoconjunctivitis sicca, Lower eyelid 
ectropion, Trichiasis, Trichomegaly  
Renal Effects: Renal failure, renal impairment  
Respiratory Effects: Cough, dyspnea, epistaxis, interstitial lung disease  
Other: Fatigue, infectious disease, teratogenicity/effects in pregnancy/breastfeeding  
 
Based on clinical results, rash (dermatosis), diarrhea, nausea, fatigue, stomatitis, vomiting 
and headache were the most frequently observed undesirable effects following exposure 
to single-agent erlotinib. Patients receiving erlotinib in combination with various 
chemotherapy agents have generally experienced the same type of AEs as with either 
agent alone. AEs considered study drug related that appear to occur more frequently 
when erlotinib is administered with chemotherapy, regardless of regimen, include nausea, 
vomiting, stomatitis, and anemia. 
 
 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 a minimum of 30 days after the discontinuation of erlotinib.  
 
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically.    The following agents may be used to treat rash:  diphenhydramine, 
topical or oral corticosteroids, and topical (clindamycin) or oral antibiotics (tetracycline, 
minocycline, doxycycline).  Topical drying agents are not recommended.   
 
Diarrhea will be monitored and managed symptomatically.  Guidelines for management 
include administration of loperamide and erlotinib dose reduction/interruption as 
described in Section 6.2.6.2. 
 
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 6.2.6.3 and Table 4 for 
management guidelines, including erlotinib dose interruption. 
 


 
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Liver function abnormalities, including elevated serum ALT, AST, and/or bilirubin, have 
been observed infrequently with single-agent erlotinib and occasionally with erlotinib in 
combination with concomitant chemotherapy.   Treatment with erlotinib should be used 
with extra caution in patients with total bilirubin > 3 x ULN.   Patients with hepatic 
impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely 
monitored during therapy with erlotinib.  Erlotinib dosing should be interrupted or 
discontinued if changes in liver function are severe such as doubling of total bilirubin 
and/or tripling of transaminases in the setting of pretreatment values outside normal 
range.   
 
Women of childbearing potential should have a negative pregnancy test prior to starting 
therapy with erlotinib. Men and women should use adequate contraceptive methods 
during and for at least 2 weeks after erlotinib therapy.  Treatment should only be 
continued in pregnant women if the potential benefit to the mother outweighs the risk to 
the fetus.  If a patient becomes pregnant despite precautions, she should be apprised of 
the potential hazard to the fetus or potential risk for loss of the pregnancy.  
 
It is not known whether erlotinib is excreted in human milk.  Because many drugs are 
excreted in human milk and because the effects of erlotinib on infants have not been 
studied, women should be advised against breast-feeding while receiving erlotinib 
therapy. 
 
 
6.2.3 Dosage and Administration  
 
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 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 6.2.6). Treatment is 
continued daily until disease progression or other reason for termination of study therapy 
(see Section 5.1). 
 
6.2.4  Drug Ordering and Accountability 
 
All study drug required for completion of this study will be provided by OSI-
Pharmaceutical (manufacturer), in partnership with Genentech and distributed through 
Biologics Inc. 
   
Following submission and approval of the required regulatory documents, the initial 
order may be placed.  Biologics drug order forms and ordering procedure will be 
presented at the site initiation meeting. 
 
It is the responsibility of the Investigator to ensure that a current record of investigational 


 
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FER-TH-007 Amendment 4   October 1, 2012 
36
product disposition is maintained at each study site where investigational product is 
inventoried and disposed.  Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 
Amount received and placed in storage area. 
Amount currently in storage area. 
 
Label ID number or batch number. 
Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
Amount dispensed to and returned by each patient, including unique patient identifiers. 
Amount transferred to another area for dispensing or storage. 
Non-study disposition (e.g., lost, wasted, broken). 
 
At the time of study closure, the unused, used and expired study drug will be destroyed at 
the site per Institutional SOPs. 
 
6.2.5 Storage 
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). 
 
6.2.6 Dose Modification and Toxicity Management 
Dose reduction or interruption of erlotinib for toxicity may take place at any time during 
the study.  The patient will remain on bevacizumab until toxicities resolve and erlotinib is 
resumed or until the patient is removed from the study.  Toxicity grading is based on 
NCI-CTCAE, v 3.0.  Dose level reductions are presented in Table 2.  If patients do not 
tolerate the second dose reduction, erlotinib is to be discontinued and the patient removed 
from the study.  
 
Regardless of the reason for holding treatment, the maximum allowable length of 
treatment interruption is 3 weeks.  If > 3 weeks, discontinue study treatment phase.    
 
Table 2 
Erlotinib Dose Level Reductions 
Starting Dose  
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
6.2.6.1 Dermatologic 
 
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 4 should be considered.  When skin 
toxicity improves by at least one grade level, the dose may be re-escalated to prior 
dose level 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.     
 
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 Table 3 for management guidelines, including erlotinib dose 
reduction/interruption. 
 
6.2.6.2 Gastrointestinal 
 
Diarrhea will be monitored and managed symptomatically.  Guidelines for 
management include administration of loperamide and erlotinib dose 
reduction/interruption as described in Table 3. 
 
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 3.  Grade 2 diarrhea that persists over 48 hours, despite optimal medical 
management, should be managed by one dose level reduction according to Table 
3.  Patients experiencing Grade 3 diarrhea should interrupt erlotinib until 
resolution to Grade 1 and re-start at one dose level reduction according to Table 
3.  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. 
 
6.2.6.3 Pulmonary 
 
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 interrupted and the patient should receive appropriate medical 
evaluation.   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 Table 3 for management guidelines, including 
erlotinib dose interruption.   If diagnosed with ILD, the patient will be removed 
from the study.  
 


 
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Table 3 
Dosage Modification Criteria and Guidelines for Management  
of Erlotinib-Related Toxicities 
NCI-CTCAE (v 3.0) 
Grade 
Tarceva Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours until free of 
diarrhea for 12 hours) 
Grade 2 
None, unless grade 2 diarrhea 
persists 
>48 
hours 
despite 
optimal medical management, 
reduce one level.  
Loperamide (4 mg at first onset, followed by 
2 mg q 2–4 hours until diarrhea free for 12 
hours) 
Grade  3 
Interrupt then reduce by one 
dose level.  Erlotinib should not 
be re-escalated. 
See above treatment. Interrupt until resolution 
to Grade 1, restart at next reduced dose. 
Other interventions as medically indicated. 
Grade 4 
Discontinue study treatment. 
As medically indicated. 
Pulmonary Events  
All Grades 
Temporarily interrupt erlotinib 
for diagnostic evaluation.  If 
assessed as related to erlotinib, 
discontinue from study 
treatment. Otherwise resume at 
prior dose level once resolved to 
≤ grade 1. 
Unexplained 
dyspnea, 
either 
new 
or 
progressive, should be aggressively evaluated.  
Pulmonary Events if possibly ILD 
All grades 
Erlotinib should not be restarted 
in those patients suspected of 
having drug-related ILD.  The 
patient should be removed from 
the study. 
Unexplained dyspnea, either new or 
progressive, should be aggressively evaluated.  
Although there is no proven therapy, systemic 
corticosteroids are often provided. 


 
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Table 3 (continued) 
Rash 
Grade 1 and 2 Tolerable 
rash.  
None 
Any of the following: oral antibiotics 
minocycline, tetracycline, 
doxycycline, topical clindamycin, 
diphenhydramine,or oral 
corticosteriods at discretion of 
investigator 
Grade 3 Intolerable rash 
Consider interruption and or 
one dose level reduction, if 
unresponsive to symptomatic 
management.  Re-escalation is 
allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
 
 
6.2.6.4 Other treatment related adverse events 
 
Treatment with both agents should be held for any other grade 3 or 4 toxicities 
except for alopecia, until resolution to grade ≤ 1. Erlotinib will be reduced by one 
dose level. 
 
7. 0 
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 C for a list of CYP3A4 inhibitors/inducers). 
 
Grapefruit juice is a CYP3A4 inhibitor, therefore, consumption of grapefruit or grapefruit juice 
should be avoided during erlotinib treatment. 
 
Patients who are taking erlotinib with an inhibitor of both CTP3A4 and CYP1A2 like 
ciprofloxacin, a dose reduction of erlotinib should be considered if severe adverse reactions 
occur.   
 
The solubility of erlotinib is pH dependent.  Erlotinib solubility decreases as pH increases. Co-
administration of erlotinib with omeprazole, a proton pump inhibitor, decreased the exposure of 
erlotinib (AUC) by 46% and the maximum concentration (Cmax) by 61%.  There was no change 


 
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to Tmax or half-life.  Therefore, drugs that alter the pH of the GI tract may alter the solubility of 
erlotinib and hence its bioavailability.   
 
Concomitant use of erlotinib with proton pump inhibitors should be avoided if possible.  The use 
of antacids may be considered in place of histamine 2 receptor blockers (H2 blockers) or proton 
pump inhibitors in patients receiving erlotnib. However, no clinical study has been conducted to 
evaluate the effect of antacids on erlotinib pharmacokinetics. If an antacid is necessary, the 
antacid dose and the erlotnib dose should be separated by several hours. 
 
The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, and the maximum 
concentration (Cmax) by 17%, when erlotinib was co-administered with ciprofloxacin, an 
inhibitor of both CYP3A4 and CYP1A2.  Patients who are taking erlotinib with an inhibitor of 
both CYP3A4 and CYP1A2 like ciprofloxiacin, a dose reduction of erlotinib should be 
considered if severe adverse reactions occur. 
 
Erlotinib clearance can be induced by smoking via CYP1A2 induction. Potential drug-drug 
interaction is expected when erlotinib is taken with CYP1A2 inducers or inhibitors.  Patients 
who continue to smoke may be under dosed when treated with the current approved Tarceva 
dosage of 150mg, therefore, patients should be advised to stop smoking.   
 
International normalized ratio (INR) elevations and/or bleeding events have been reported in 
some cancer patients taking warfarin while on erlotinib.  Patients taking warfarin-derivative 
anticoagulants should be monitored regularly for changes in prothrombin time or INR. 
 
Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial 
thromboembolic disease. Subjects developing signs of arterial ischemia or bleeding on study 
should be evaluated for possible bevacizumab discontinuation per Table 1, Bevacizumab Dose 
Management Due To Adverse Events. 
 
Treatment with hormones or other chemotherapeutic agents will result in the patient’s removal 
from the study, except for steroids administered for adrenal failure, septic shock, or as 
temporizing measure for symptomatic pain or breathing, rash, or at the treating physician’s 
discretion for symptom management, or hormones administered for non-disease related 
conditions, e.g., insulin for diabetes.  Glucocorticosteroids may be used as antiemetics and 
megestrol acetate may be used for appetite. 
 
Patients should receive full supportive care including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate.  The use of erythropoietin (i.e., Epogen, Procrit) 
is permitted. 
 
Bisphosphonates for bone pain and colony stimulating factors (i.e., G-CSF, GM-CSF, etc.) may 
be used according to ASCO guidelines.   
 


 
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8.0 
Clinical and Laboratory Evaluations 
 
8.1 
Pre-Treatment Evaluation 
 
Epidermal growth factor receptor testing of archival tissue should be done if sufficient tissue is 
available.  Results are not needed prior to initiation of treatment.    
 
The following evaluations should take place within 14 days of enrollment and may be used for 
C1D1 evaluations: 
 CBC with differential 
 Biochemistry including: electrolytes, renal function, liver function, LDH, Bilirubin 
 Serum B-HCG for WOCBP 
 PT/PTT/INR 
 Urine protein:creatinine ratio (See appendix F) 
 Charlson Co-Morbidity Index to be performed by treating MD or designee. (See 
appendix H) 
 FACT-L Assessment (See appendix G) 
The following evaluations should take place within 28 days of enrollment  
 CT/MRI brain, preferably with contrast  
 CT scan chest/abdomen, preferably with contrast (or MRI if abdominal CT not 
diagnostic)  
 PET scan in addition to CT scans is recommended by not mandatory 
 
8.1.1 Physical examinations 
 
Methods of assessment 
Full physical examinations will be performed within 14 days of enrollment and will 
include performance status (appendix D), heart rate and blood pressure, weight, height, 
concurrent medications, review of systems. 
 
8.2 
Evaluations During Treatment  
 
Performed on the first day of each three-week cycle. 
 
 
 Urine protein:creatinine ratio every other cycle (every 6 weeks) (may be done up to 7 
days before D1 if site unable to obtain same day results).  On treatment testing may be 
done by urine dipstick however if > 1+ treatment must be held until laboratory results are 
available. 
 CBC with differential (may be done within 24 hours prior to D1 if site unable to obtain 
results in time to treat) 
 Biochemistry including: electrolytes, renal function, liver function, LDH, Bilirubin (may 
be done up to 7 days before D1 if site unable to obtain same day results) 
 PT/PTT/INR if on low dose coumadin 
 Full physical exam with weight (calculate BSA each cycle), vital signs including blood 
pressure, performance status, concurrent medication and review of systems 


 
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 Adverse Event (with CTC v. 3.0 grading and causality) recording/monitoring 
 CT scans chest/abdomen after every 3rd cycle of treatment. 
 FACT-L Assessment after every two cycles of treatment.  May be completed on day one 
of subsequent cycle. The FACT L can be done after every third cycle of therapy; after 
first 6 months. 
 
8.3 
End of study   
 
Subjects who discontinue study treatment should be seen and assessed by an investigator(s). The 
reason for withdrawal and the date of withdrawal must be documented.  If possible, any diary 
cards, questionnaires (e.g. for Quality of Life assessments) and investigational products 
(erlotinib) should be returned by the subject.  Patient should undergo the following at the time of 
discontinuation from the study: 
 Full physical exam with performance status, vital signs, weight, review of systems  
 CBC with differential  
 Biochemistry including: electrolytes, renal function, liver function, LDH, Bilirubin  
 Urine protein:creatinine ratio 
 Attributable Adverse Event (with CTC grading)  recording/monitoring until resolved to ≤ 
grade I 
 FACT-L Assessment 
 
If the reason for withdrawal from the trial is the death of the subject, the two options for 
categorizing withdrawal are either progressive disease or an adverse event (AE); more than one 
AE may be documented as a reason for withdrawal.  Only one event will be captured as the 
cause of death.  Note that death is an outcome and not an AE.  
 
All deaths that occur within the trial period or within 30 days after administration of the last dose 
of trial drug must be reported primarily for the purposes of serious adverse event (SAE) 
reporting; however, deaths due unequivocally to progression are not SAE's. 
 
All subjects who have new or worsening CTC grade 3 or 4 laboratory values that are deemed to 
be at least possibly related at the time of withdrawal must have further tests performed and the 
results recorded appropriately until the lab values have returned to CTC grade 1 or 2, unless 
these values are not likely to improve because of the underlying disease.  In these cases, the 
investigators must record their opinions in the subject’s medical records.  Laboratory 
abnormalities should not be reported as serious adverse events unless any criterion for a SAE is 
fulfilled, the laboratory abnormality causes the subject to discontinue from the study, or the 
investigator insists the abnormality should be reported as an attributable AE. At withdrawal all 
on-going study-related toxicities and SAEs must be followed until resolution, unless in the 
investigator’s opinion, the condition is unlikely to resolve due to the subject’s underlying 
disease. 
 
Patients should be seen in the clinic or contacted by telephone to determine if any serious or non-
serious adverse events have occurred within 30 days (+3 days) of termination of study treatment. 
 


 
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8.4 
Long Term Follow up Evaluations 
 
Evaluations to be completed every three months for two years, then every six months for three 
years then annually until death.   
 Full physical exam with weight, vital signs, performance status, concurrent medication 
and review of systems 
 Attributable Adverse Event (with CTC grading)  recording/monitoring until resolved to ≤ 
grade I 
 CT scans chest/abdomen repeated every 12 weeks in patients who have not progressed. 
 
9.0 
Registration  
 
Subjects may be registered from 9:00 am to 5:00 pm by calling the FER Study Coordinator at 
215-728-2451.  The investigator or designee will then fax the completed registration form and 
eligibility checklist to 215-728-4784.  FER will notify the site by phone and fax when eligibility 
is confirmed and the sequence number has been assigned.  Subjects must be registered and have 
received a sequence number assigned by FER prior to the initiation of treatment.  Treatment 
should start within 14 days of registration.  If ≥ 30 days from time informed consent form (ICF) 
signed and subject is registered, subject will need to re-sign and date ICF as will treating MD.  
The following forms must be completed at the time of registration: 
 
 Signed and dated informed consent form 
 Signed and dated HIPAA consent form 
 Registration form 
 Signed eligibility checklist 
 
Exceptions to the current registration policies will not be permitted as well as: 
 
 Late registrations (after initiation of treatment) 
 Exceptions to eligibility requirements (unless by approved waiver) 
 Participation by an institution/member not identified as eligible 
 Non-Compliance with Regulatory paperwork 
 
10.0 
Data Safety Monitoring Plan   
 
All adverse events will be summarized 1) without regard to causal relationship and 2) by causal 
relationship to study drugs, based on the Investigator’s opinion.  Worst toxicity grades per 
patient will be tabulated for selected adverse events and laboratory measurements.  Any serious 
adverse event or adverse event resulting in premature and permanent discontinuation of any 
study drug will be described in detail. 
 
Adverse events and other symptoms will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 
 
A Data Safety Monitoring Plan has been implemented to monitor safety parameters during the 


 
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study.  Ongoing monitoring will confirm proper conduct of this study for each subject and 
identify any protocol violations and unreported adverse events in a timely manner.  Any events 
determined to be significant will be reported immediately to the principal investigator.  FER 
administrative staff will review data every six months with the principal investigator or his 
designee.  Data will be collected from individual case report forms (CRF) once the CRFs have 
been monitored and all queries are resolved.  The semiannual review will include complete 
accrual listing demographic information, response, toxicity tables, and summaries of incidence 
severity and resolution of adverse events, including laboratory results abnormalities, summary of 
any pertinent findings from monitoring/auditing visits and a description of all known or 
suspected protocol violations. 
 
Each participating practice must designate a single on-site principal investigator with primary 
responsibility for the conduct of the study in his practice.  This site specific principal investigator 
is responsible for identification of all adverse events at their site and must verify that appropriate 
procedures are being followed.  SAEs experienced by a subject participating in a clinical trial 
must be reported according to section 13.0 Adverse Event Reporting and Definitions.  FER is 
responsible for collecting and reporting serious adverse events to the study principal investigator 
and appropriate regulatory authorities and to other participating sites for IRB submission.  Each 
practice must designate an IRB for this study and follow any by-laws regarding the use of an 
IRB set forth by the terms of their employment or determined by the institution in which they 
practice.  Investigators must supply their designated IRB with ongoing progress reports for the 
study and a formal review of each study will be conducted at least every 364 days or more 
frequently as designated by the IRB.  The IRB may suspend, terminate or restrict the study as 
appropriate. 
 
FER will manage the flow of documents to participating sites and external agencies (including 
reports of serious adverse events) to facilitate ongoing and timely review of the protocol.  FER 
will monitor the medical and study records of each participant accrued at each site throughout 
the course of the study.  All serious adverse events (SAEs) will be reviewed on a real time basis 
first by the site PI and subsequently by Dr. Borghaei.  Regular teleconferences may be conducted 
with all principal investigators or their designees.  During these meetings, the participants will 
review documents summarizing baseline demographic characteristics, retention and disposition 
of participants, QA issues, regulatory issues, AEs and SAEs, and efficacy (response rates, time-
to-progression).  FER will supplement these meetings with routine written summary updates 
which will be distributed to the participating sites. 
 
Grade 4-5 serious adverse events must be reported to FER within 24 hours of awareness of the 
event (please refer to section 13).  FER will report this information immediately to the principal 
investigator, and appropriate regulatory authorities.  Participating site PIs will be notified 
according to section 13.0. 
 
11.0 
Statistical methods and determination of sample size 
 
A phase II investigation will be conducted in patients with advanced stage non small cell lung 
cancer, chemo-naïve patients, aged 65 years and older with PS 0-1  


 
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11.1 
Primary endpoint:  Progression Free Survival 
 
PFS will be the primary endpoint. We will test the null hypothesis that median PFS is 3 months 
versus the alternative that it is at least 5 months. A one sample, one-sided test based on 
exponentially distributed survival times will have 90% power and 5% type I error for a study of 
33 evaluable patients accrued over a period of 24 months and followed for an additional 12 
months. Follow up on all patients for progression and survival will continue until death. 
 
Toxicity is monitored for possible early stopping. If, at any point in time 5 patients experience 
attributable DLTs (DLT defined in section 5.2) among the first 17 patients treated, the study will 
be stopped. If at any later point any 8 patients experience attributable DLTs, treatment will be 
regarded as too toxic. If the chance of DLT is at least 30% then the chance of early stopping is at 
least 61% and the chance of declaring the treatment too toxic is at least 84%. If the chance of 
DLT is at most 15% then the chance of early stopping, in error, is 9.9% and the overall type I 
error is 15.5%. Early stopping, here, does not mean that accrual is stopped until the first 17 
patients complete 12 months of follow up. Since toxicity can occur at any time, 5 attributable 
DLTs among the first 17 patients requires stopping the study even if all 33 patients have started 
but before they complete treatment. All patients must, in that case, or in case of 8 attributable 
DLTs, experienced by any patient, be taken off study. 
 
One year and overall survival are secondary endpoints. We will test the null hypothesis that one 
year survival is at most 20% versus the alternative that it is at least 35%. A one-sided test based 
on the exponential distribution of survival time will have 86% power and 10% type I error to 
make this distinction. 
 
11.2 
Secondary Endpoints 
 
11.2.1 
Toxicity 
 
All toxicities relating to study drugs will be recorded for each patient during the study.  
Adverse Events will be recorded.  
 
11.2.2      Time to Progression  
 
Time to Progression will be assessed from the start of study treatment to the date when 
objective disease progression is observed.  Subjects without documented objective 
progression at the time of the final analysis will be censored at the date of their last tumor 
assessment. 
 
11.2.3      Overall Survival 
 
Survival will be assessed from the start of study treatment to the date of subject 
death, due to any cause, or to the last date the subject was known to be alive.  We 
will measure median survival, one-year and two-year survival rates.  


 
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11.3 
    Tertiary Objective     
 
11.3.1 Quality of Life 
 
At every other cycle, while patients are on-study or after the third cycle if the patient is 
on therapy for greater than 6 months; the FACT-L questionnaire will be used to assess 
quality of life. Quality of Life will be evaluated graphically and with descriptive 
statistics. Changes over time will be noted. 
 
12.0 
    Efficacy Measurement  
 
12.1 
Response Evaluation Criteria in Solid Tumors (RECIST) 
 
The Response Evaluation Criteria in Solid Tumors (RECIST) criteria will be used for objective 
tumor response assessment.  See Appendix A for the timing of the assessments.   
 
12.1.1 Definitions 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee36.  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions 
are used in the RECIST criteria.  Note: Lesions are either measurable or non-measurable 
using the criteria provided below.  The term “evaluable” in reference to measurability 
will not be used because it does not provide additional meaning or accuracy. 
 
12.1.2 Measurable Disease  
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
12.1.3 Non-measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm using spiral CT scan), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
12.1.4 Target lesions 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 


 
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measurements (either by imaging techniques or clinically). A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
 
12.1.5 Non-target lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
 
12.2 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
Lesions located solely in a previously irradiated area will only be considered measurable if there 
has been demonstrable progression in the region of prior irradiation since the time of radiation as 
defined by RECIST criteria. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
12.3 
Response Criteria 
 
12.3.1 Evaluation of target lesions 
 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the treatment 
started 
 
12.3.2 Evaluation of non-target lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits 


 
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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the PI. 
 
12.3.3 Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
Target Lesions 
Non-Target Lesions New Lesions 
Overall Response 
CR 
CR 
No 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
12.4 
Confirmatory Measurement/Duration of Response 
 
12.4.1 Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 


 
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response are first met.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks. 
 
12.4.2 Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Upon the subject’s withdrawal, the investigator should assign an overall best response for 
the subject based on the definitions given in Appendix and his or her clinical judgment. 
 
12.4.3 Duration of Stable Disease 
 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. 
 
12.4.4 Survival 
 
Survival will be assessed from the start of study treatment to the date of subject death, 
due to any cause, or to the last date the subject was known to be alive. 
 
12.4.5 Time to Progression 
 
Time to Progression (TTP):  will be assessed from the start of study treatment to the date 
when objective disease progression is observed.  Death will be regarded as a progression 
event in those subjects who die before disease progression.  Subjects without documented 
objective progression at the time of the final analysis will be censored at the date of their 
last tumor assessment.   
 
12.5     Reporting of Results 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  (Note: By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database). 
 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus an incorrect treatment schedule or drug administration 


 
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does not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
 
Sub-analyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc).  However, these sub-analyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.  The 95% confidence 
intervals should be provided. 
 
12.6 
    Patient-Reported Outcomes (PROs) 
 
The methods for collecting subject/Patient Reported Outcomes (PRO) data are presented below. 
Functional Assessment of Cancer Therapy – Lung, Version 4 (FACT-L v. 4) (secondary 
endpoint)  
 
12.6.1     Functional Assessment of Cancer Therapy-Lung (FACT-L)(Appendix G) 
 
Methods of Assessment  
Functional Assessment of Cancer Therapy – Lung, Version 4 (FACT-L v. 4) will be 
utilized for each patient prior to the start of therapy, on the first day of every other cycle, 
for the first 6 month, then after every third cycle of therapy and at the time of treatment 
discontinuation.  Please see Appendix G for FACT-L questionnaire. 
Administration of PRO questionnaires 
Each center must allocate responsibility for FACT-L administration to a specific 
individual (e.g., a Research Nurse).  The Fox Chase Cancer Center Extramural Research 
Program (FER) will provide training for relevant personnel in the administration of the 
FACT-L to help avoid the key problem of missing data.  It is also important that the 
significance and relevance of the data are explained carefully to participating subjects so 
that they are motivated to comply with data collection37. 
The date of completion of each FACT-L should be documented. 
The instructions for completion of the FACT-L are: 
 
 It must be completed in private by the subject in their own time 
 It must be completed by the subject before any investigations or discussions about 
their disease with the clinic staff 
 The subject should not receive help from relatives, friends or clinic staff 
 Only one answer to each question should be recorded  
 Immediately following completion of FACT-L, the Research Nurse or appointed 
individual must collect and review the FACT-L for completeness.  If items are 
missed, the form must be returned to the subject immediately for completion.  
 


 
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12.6.2 Collection of Records 
 
The entire FACT-L will be collected. We will assess patient-specific changes over time 
based on the 7 item lung cancer subscale (LCS) and treatment outcome index (TOI) 
composed of the sum of physical well- being (PWB), functional well-being (FWB), and 
LCS scores. 
 
12.6.3 Procedure for Missing Data 
 
For each subscale, if less than 50% of subscale items are missing, the subscale score will 
be divided by the number of non-missing items and multiplied by the total number of 
items on the subscale.  Hence, missing data will be imputed.  If at least 50% of the items 
are missing, that subscale also will be treated as missing.  The reason for any missing 
data will be identified.  If data are missing at random, the above techniques will be used.  
If there is evidence that the missing data is systematic, missing values will be imputed to 
ensure that any possible bias is minimized.  
 
13.0 
Adverse Event Reporting and Definitions 
 
In the event of an adverse event the first concern will be for the safety of the subject.   
 
Calculation or derivation of outcome variables  
Any new conditions reported during the study will be documented as an AE.  Only those 
findings that are in addition to the condition being treated will be documented as AEs, see 
Section 13 for recording of AEs.  
 
If the patient is withdrawn from the trial due to death, the two options for categorizing 
withdrawal are either progressive disease or an adverse event (AE); more than one AE may be 
documented as a reason for withdrawal).  Only one event will be captured as the cause of death.  
Note that death is an outcome and not an AE.  
 
All deaths that occur within the trial period or within 30 days after administration of the last dose 
of trial drug must be reported primarily for the purposes of serious adverse event (SAE) 
reporting; however, deaths due unequivocally to progression are not SAE's. 
 
Investigators are required to report to FER serious adverse event (SAE) as soon as 
possible.   
 
13.1 Adverse Event (AE) Definitions 
 
Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(NCI CTEP Guidelines January 2001). 
 


 
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Serious Adverse Event (SAE) is any sign, symptom or medical condition that emerges during 
protocol treatment or during a post-treatment follow-up period that (1) was not present at the 
start of study treatment and it is not a chronic condition that is part of the patient’s medical 
history, OR (2) was present at the start of study treatment or as part of the patient’s medical 
history but worsened in severity and/or frequency during therapy, AND that meets any of the 
following regulatory serious criteria: 
 
 Results in death  
 Is life-threatening  
 Requires or prolongs inpatient hospitalization  
 Is disabling  
 Is a congenital anomaly/birth defect  
 Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
13.1.1 
Severity Ratings The investigator will evaluate the severity of each adverse  
event.  NCI Common Terminology Criteria for Adverse Events Version 3.0 will be used to 
capture adverse events.  Severity is expressed in numerical grade using the following 
definitions if the AE is not clearly specified in the CTC 
 
Grade 1: Mild-noticeable to the patient, does not interfere with the patient’s daily activities, 
usually does not require additional therapy, dose reduction, or discontinuation of the study 
drug. 
Grade 2: Moderate-interferes with the patient’s daily activities, possibly requires additional 
therapy, but does not require discontinuation of study drug. 
Grade 3: Severe-severely limits the patient’s daily activities and may require discontinuation 
of the study drug. 
Grade 4: Life-threatening or disabling  
Grade 5: Fatal 
 
13.1.2 
Relationship to Study Drug/Attribution 
 
Definite –clearly related 
Probably Related-the event occurs within a reasonable time period following drug 
administration or follows a known response for the drug and cannot be reasonably explained 
by known patient characteristics (including use of concomitant medications). 
Possible –may be related 
Unlikely –doubtfully related 
Definitely Not Related - the event is not known to be caused by the study drug. 
Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 
Unexpected Adverse Event is one not identified in nature, severity, or frequency in the 
Investigator’s Brochure or the product package insert for the study drug. 
 
 


 
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13.2. Investigator Reporting Responsibilities: 
 
1. Upon identification of an AE, the investigator will utilize the above definitions to properly 
classify the event.  Each category listed above must be recorded for each event. 
 
2. Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that the study 
treatment caused or contributed to an adverse event.  The following general guidance may be 
used. 
 Yes:    if the temporal relationship of the clinical event to study drug administration 
makes a causal relationship possible, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed event. 
 No:       if the temporal relationship of the clinical event to study drug administration 
makes a causal relationship unlikely, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the observed event. 
 
3. All AEs and SAEs will be recorded in the case report forms on the “AE/Toxicity Form” with 
details about the grade and attribution of each episode.  The action taken with respect to the 
study drug and the patient’s outcome should be recorded in the remarks section of the 
“Treatment Flow Sheet”.  All events will be recorded on case report forms each cycle until 
they resolve. 
 
4. All SAEs will be recorded on “FDA Form 3500 MedWatch” and faxed to the Office of 
Extramural Research (FER) Study Manager at 215-728-4784.  FER will submit to 
Genentech.  After submitting the initial report it may be necessary to submit additional 
reports by the investigator should the event require further investigation. In addition to 
completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description of the MedWatch 
3500 form: 
 
 Treatment regimen (dosing frequency, combination therapy, lot numbers) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
5.  Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
 Adding to the original MedWatch 3500 report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500 form  
 Summarizing new information and faxing it to FER with a cover letter including subject 
identifiers (i.e. D.O.B., initials, subject number), protocol description and number, if 


 
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assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The subject identifiers are important so that 
the new information is added to the correct initial report.) 
 
6.  Each investigator is responsible to report all AEs/SAEs to IRB following guidelines set by 
that IRB.  FER reserves the right to request an event be reported to the IRB at their 
discretion.  Copies of all documentation of events reviewed by the IRB must be sent to the 
FER Regulatory Coordinator.  
 
Sites are responsible for forwarding copies of documentation of IRB review of the event to 
FER regulatory coordinator at: 
50 Huntingdon Pike, Second Floor 
Rockledge, PA 19046 
Phone: 215-214-3773 
Fax: 215-728-4784 
 
7.  Timelines for Reporting SAEs to FER: 
 Unexpected Event: Grade 2-3 with possible, probable, or definite attribution requires 
written report to FER within 3 working days. 
 Unexpected Grade 4-5 regardless of attribution requires report to FER by phone/fax/e-
mail within 24 hours and a written report within 3 working days.  This includes deaths 
within 30 days of last drug. 
 Expected Event: Grade 4-5 regardless of attribution requires report to FER by 
phone/fax/e-mail within 24 hours and a written report within 3 working days. 
 
8.  If the results of an investigator or FER investigation show an adverse event not initially 
determined to be reportable is so reportable, the investigator will report the event following 
the above guidelines based on the date the determination is made.  
 
10. Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the subject for whom an adverse event was reported.  
 
13.2.1 
FER Responsibilities 
 
1. Any serious or unexpected adverse event that is possibly, probably or definitely related to 
the study will be reported in writing to FER who will submit to Genentech and 
voluntarily to the FDA within 5 working days of notification of the event.  Death from 
any cause will be reported immediately to Genentech and participating sites.  The report 
will be distributed to all investigative sites within 15 working days of notification of the 
event for review by each respective IRB 
 
2. If the results of an investigator or FER investigation show an adverse event not initially 
determined to be reportable is so reportable, FER will report the event following the 
above guidelines based on the date the determination is made. 
 
3. FER will track all serious events and report them routinely to the Principal Investigator 


 
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FER-TH-007 Amendment 4   October 1, 2012 
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for review.   
 
4. FER will track all reports submitted to all investigative sites and ensure that all involved 
Institutional Review Boards (IRB) have reviewed the reports.  FER will collect 
documentation of all IRB review. 
 
13.3 
Reporting of Serious Treatment Emergent Adverse Events (STEAEs) 
 
 All STEAEs should be recorded on a MedWatch 3500 Form and faxed to: 
Study Coordination Center/Principal Investigator: Hossein Borghaei, DO 
Contact Information and fax # 
Holly Tuttle, RN, MSN 
50 Huntingdon Pike, 2nd Floor 
Rockledge, PA 19046 
Fax 215-728-4784 
 
 
Safety Reporting Requirements for IND Exempt Studies 
For Investigator Sponsored IND Exempt Studies, there are some reporting requirements for 
the FDA in accordance with the guidance set forth in 21 CFR 314.80. 
 
Postmarketing 15-Day “Alert Report”: 
FER will notify the FDA of any fatal or life-threatening adverse event that is unexpected and 
assessed by the investigator to be possibly related to the study treatment. An unexpected 
adverse event is one that is not already described in the Investigator Brochure. Such reports are 
to be submitted to the FDA (2 copies) at the following address: Central Document Room, 12229 
Wilkins Avenue, Rockville, MD 20852.  All Postmarketing 15-Day “Alert Reports” submitted to 
the FDA by FER will also be faxed to: Genentech Drug Safety  
 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Tel: 
1-888-835-2555 
Fax: 
(650) 225-4682 or (650) 225-5288  
 
14. EGFR Testing 
Patients with available tissue will have paraffin-preserved biopsy or surgical specimens from the 
primary or metastatic site utilized for detection of EGFR expression by IHC by the commercially 
available DakoCytomation EGFR pharmDx™ test kit.  This test scores samples based on 
positive/negative and 1-3+ to indicate intensity of staining.  Standard methodology will be 
applied.    
 
 


 
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16. 
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17. 
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Gordon AN, Finkler N, Edwards RP, et al: Efficacy and safety of erlotinib HCl, 
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Herbst RS, Prager D, Hermann R, et al: TRIBUTE: a phase III trial of erlotinib 
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Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 
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32. 
Herbst RS, Johnson DH, Mininberg E, et al: Phase I/II trial evaluating the anti-
vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the 
HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with 
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Hainsworth JD, Sosman JA, Spigel DR, et al: Treatment of metastatic renal cell 
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34. 
L. Fehrenbacher, V. O'Neill, C. P. Belani, et al: A phase II, multicenter, 
randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with 
either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with 
chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer., ASCO. 
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36. 
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the 
response to treatment in solid tumors. European Organization for Research and Treatment of 
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Fallowfield LJ, Baum M, Maguire GP: Addressing the psychological needs of the 
conservatively treated breast cancer patient: discussion paper. J R Soc Med 80:696-700, 1987 
 
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1995;19:183-232. 
 
 


 
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Appendix A 
Study Flowchart 
 
Baseline 11 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Every Cycle 
Till 
progression 
Off Study12 
Informed Consent 
X14 
 
 
 
 
 
 
H+ P and PS & Vitals 
X1 
X15 
X 
X 
X 
X 
X 
CT(C/A)13 
(MRI 
if 
needed)  
X7 
 
X5 
 
X 
X5 
X9 
CT or MRI brain  
X7 
 
 
 
 
 
 
Pathology 
X6 
 
 
 
 
 
 
CBC, Diff and Plt. 
X  
X15 
X 
X 
X 
X 
X 
Comprehensive Panel 
X2 
X15 
X 
X 
X 
X 
X 
PT/PTT/INR 
X 
X15,10 
X10 
X10 
X10 
X 
X 
UA 
for 
Protein: 
Creatinine Ratio 
X3 
 
X 
 
X 
 
X 
Toxicity Assessment 
X 
X15 
X 
X 
X 
X 
X8 
Serum β-HCG 
X4 
 
 
 
 
 
 
FACT-L Assessment 
X 
 
X5 
 
X 
X5 
X 
Charlson  
Co-Morbidity Index 
X16 
 
 
 
 
 
 
1. 
History to include documentation of prior treatments and rationale for treatment with this combination. 
2. 
Baseline Glucose, Bun, Creatinine, Uric Acid, Total Bilirubin, Alkaline Phosphatase, LDH, Total protein, Albumin, 
SGOT (AST), SGPT (ALT), Calcium. All ≤ 14 days prior to enrollment. 
3. 
Required prior to treatment with bevacizumab and then pre-treatment (D1) every other cycle.  Baseline must be calculated 
from UA, on treatment testing can be done by dipstick.   
4. 
For Women of childbearing potential. 
5. 
CT scans and FACT-L Assessment will be done after every two cycles. After the sixth cycle, disease imaging assessment 
will be done  every 12weeks. 
6. 
For EGFR through IHC and FISH (if feasible) 
7. 
Scans to be done within 28 days prior to enrollment 
8. 
Follow until resolved.  Patients should be seen in clinic or contacted by phone within 30 + 3 days of discontinuation of 
treatment for toxicity assessment. 
9.     Off study evaluations should not be repeated if they were just done and documented progression. Follow up evaluations in         
the absence of disease progression should be performed every three months-until death 
    10.    Repeat PT/PTT/INR every cycle if on low dose coumadin.  
   11.   All baseline studies to be done within 14 days of registration unless otherwise indicated 
12.   Long term follow up for survival and disease progression should be conducted every 3 months for 2 years, then every 6  
        months for 2 years, the annually until death 
 13.  PET/CT permitted, if that is what is available from initial workup, as baseline if CT component has readable measurable 
disease.  CT will be used to follow lesions. 
14. Informed consent must be obtained prior to any study related procedures.  If ≥ 30 days from time consent is signed and                    
subject is registered, subject must re-sign ICF. 
15. Baseline H&P, PS, CBC, Chem, coags, UA for protein:creat ratio, VS may be used for C1D1.  If used, patient must be 
seen by study coordinator to assess for changes in status.  For subsequent cycles, Day 1 CBC, Chem & UPC ratio may be 
done up to 2 days prior to D1. 
16. To be performed by treating MD or designee. 
 
 


 
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APPENDIX B 
National Cancer Institute Common Toxicity Criteria, Version 3 
Obtain from http://ctep.info.nih.gov/CTC3/ctc.htm  


 
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APPENDIX C 
List of CYP3A4 Inhibitors 
 
From http://www.georgetown.edu/departments/pharmacology/davetab.html 
 
The following are known inhibitors of CYP3A4: 
Delaviridine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir  
Amiodarone  
Cimetidine  
Ciprofloxacin  
Clarithromycin  
Diethyl-dithiocarbamate  
Diltiazem  
Erythromycin  
Fluconazole  
Fluvoxamine  
Gestodene ++  
Grapefruit juice  
Itraconazole  
Ketoconazole  
Mifepristone  
Nefazodone  
Norfloxacin  
Norfluoxetine  
Mibefradil  
Troleandomycin 
Atazanavir 
Indinavir 
Telithromycin 
Voriconazole 
 
 
 
The following are known inducers of CYP3A4:  
 
Rifampicin 
Phenytoin 
Rifabutin 
Rifapentine 
Carbamazepine 
Phenobarbital 
St. John’s Wort 
 


 
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APPENDIX D 
ECOG Performance Status Scale 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about >50% of 
waking hours 
3 
Capable of only limited self-care, confined to a bed or 
chair >50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care. 
Totally confined to bed or chair 
5 
Dead 
 


 
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APPENDIX E 
NEW YORK HEART ASSOCIATION GUIDELINES 
 class I no limitation of physical activity  
 class II slight limitation of physical activity  
 class III marked limitation of physical activity  
 class IV inability to carry out any physical activity without discomfort 


 
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APPENDIX F 
Procedure for Obtaining a Urine Protein / Creatinine Ratio 
 
1)  Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine)  
2)  Determine protein concentration (mg/dL)  
3)  Determine creatinine concentration (mg/dL)  
4)  Divide #2 by #3 above:      urine protein / creatinine ratio = protein concentration (mg /dL) / 
creatinine concentration (mg /dL) 
 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of 1 should be equivalent to 1g protein in a 24hr urine collection) 
Protein and creatinine concentrations should be available on standard reports of urinalyses, not 
dipsticks. If protein and creatinine concentrations are not routinely reported at an Institution, 
their measurements and reports may need to be requested. 
 


 
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APPENDIX G 
FACT-L (version 4.0) 
 


 
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APPENDIX H 
Charlson Co-Morbidity Index 
 
Instructions for completing THE COMORBIDITY RECORDING SHEET: 
To be completed by the treating MD at baseline. 
1. Refer to the protocol for assessments to be used as a basis for data collection. 
2. Complete all patient/institution information. 
3. Extract all comorbidity elements you can identify and note them on the Recording Sheet. 
Place the elements in the most appropriate category. Be comprehensive.  
4. Include past surgeries, diseases, smoking history, and functional problems, such as 
incontinence or constipation. 
5. If a functional problem appears to be related to tumor or treatment, place TR after the 
diagnosis. 
6. Include medications, and specify as much as possible the dose/frequency. The 
investigators may use this information to rate the severity of a disease. 
7. Include all pertinent baseline laboratory values in your assessment of comorbidity. 
8. Leave the scoring column blank. 
 
Instructions for completing THE CHARLSON COMORBIDITY INDEX: 
1. Complete all patient/institution information. 
2. Follow the “Rules for Completing The Charlson Comorbidity Index” in this appendix. 
3. Complete the Charlson Comorbidity Index by noting “yes” or “no” for each disease. 
 


 
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COMORBIDITY RECORDING SHEET 
Name/Number:__________________________________________________________ 
Patient Initials (Last, First):___________________ Number:___________________ 
Name of Person Completing Sheet:____________________________ 
Phone Number:_____________ 
Date Completed:__-___-_____ 
 
Comorbidities 
(Add TR if related to tumor or its treatment) 
Score 
 (Optional) 
Heart 
 
 
Vascular 
 
 
Respiratory 
 
 
Eyes and ENT 
 
 
Upper GI 
 
 
Lower GI 
 
 
Liver and Pancreas 
 
 
Renal (Creatinine:                  ) 
 
 
GU 
 
 
Musculoskeletal/Integument 
 
 
Neurological 
 
 
Endocrine/Metabolic and Breast 
(Weight:              Height:              ) 
 
 
Psychiatric 
 
 
 
Medications 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX H (continued) 
 
Rules for Completing the Charlson Comorbidity Index (CCI) 
 
Adaptation: Do not count non-melanotic skin cancers or in 
situ cervical carcinoma. 
(Charlson et al. J Chron Dis. 40:373-383, 1987) 
 
 
Myocardial infarct 
Hx of medically documented myocardial infarction  
Congestive heart failure 
Symptomatic CHF w/ response to specific treatment 
Peripheral vascular disease 
Intermittent claudication, periph. arterial bypass for 
insufficiency, gangrene, acute arterial insufficiency, 
untreated aneuvrysm (>=6cm) 
Cerebrovascular disease (except hemiplegia) 
Hx of TIA, or CVA with no or minor sequellae 
Dementia 
chronic cognitive deficit 
Chronic pulmonary disease 
symptomatic 
dyspnea 
due 
to 
chronic 
respiratory 
conditions (including asthma) 
Connective tissue disease 
SLE, polymyositis, mixed CTD, polymyalgia rheumatica, 
moderate to severe RA 
Ulcer disease 
Patients who have required treatment for PUD 
Mild liver disease 
cirrhosis without PHT, chronic hepatitis 
Diabetes (without complications) 
diabetes with medication 
Diabetes with end organ damage 
retinopathy, neuropathy, nephropathy 
Hemiplegia (or paraplegia) 
hemiplegia or paraplegia 
Moderate or severe renal disease 
Creatinine >3mg% (265 umol/l), dialysis, transplantation, 
uremic syndrome 
2nd Solid tumor (non metastatic) 
Initially treated in the last 5 years 
  exclude non-melanomatous skin cancers and in situ 
cervical carcinoma  
Leukemia 
CML, CLL, AML, ALL, PV 
Lymphoma, MM... 
NHL, Hodgkin's, Waldenström, multiple myeloma 
Moderate or severe liver disease 
cirrhosis with PHT +/- variceal bleeding 
2nd Metastatic solid tumor 
self-explaining 
AIDS 
AIDS and AIDS-related complex 
Suggested: as defined in latest definition 
 


 
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APPENDIX  H (continued) 
 
Name/Number:__________________________________________________________ 
Patient Initials (Last, First):___________________ Number:___________________ 
Name of Person Completing Sheet:_____________________________ 
Phone Number:_____________ 
Date Completed:__-___-_____ 
 
CHARLSON COMORBIDITY INDEX (CCI) 
 
 
Comorbidity 
 
Present 
 
Points 
 
Myocardial infarct 
 
 
 
1 
 
Congestive heart failure 
 
 
 
1 
 
Peripheral vascular disease 
 
 
 
1 
 
Cerebrovascular 
disease 
(except 
hemiplegia) 
 
 
 
1 
 
Dementia 
 
 
 
1 
 
Chronic pulmonary disease 
 
 
 
1 
 
Connective tissue disease 
 
 
 
1 
 
Ulcer disease 
 
 
 
1 
 
Mild liver disease 
 
 
 
1 
 
Diabetes (without complications) 
 
 
 
1 
 
Diabetes with end organ damage 
 
 
 
2 
 
Hemiplegia 
 
 
 
2 
 
Moderate or severe renal disease 
 
 
 
2 


 
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2nd Solid tumor (non metastatic) 
 
 
 
2 
 
Leukemia 
 
 
 
2 
 
Lymphoma, MM... 
 
 
 
2 
 
Moderate or severe liver disease 
 
 
 
3 
 
2nd Metastatic solid tumor 
 
 
 
6 
 
AIDS 
 
 
 
6 
Total points: ____________ 
Comments: 
 
 


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