Clinical trial NCT00436332
Conditions: Lung Cancer
Keywords: recurrent non-small cell lung cancer stage IIIB non-small cell lung cancer stage IV non-small cell lung cancer bronchoalveolar cell lung cancer adenocarcinoma of the lung
Sponsor: SWOG Cancer Research Network
Start date: 2007-07-01; Completion date: 2019-08-20
Enrollment: 84 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving erlotinib together with bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving erlotinib together with bevacizumab works in treating patients with stage III or stage IV non-small cell lung cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine overall survival of patients with stage IIIB or IV bronchioloalveolar carcinoma (BAC) or adenocarcinoma with BAC features treated with erlotinib hydrochloride and bevacizumab.

Secondary

* Determine the progression-free survival of patients treated with this regimen.
* Compare, preliminarily, response as assessed by RECIST criteria vs response as assessed by a central computer-assisted image-analysis system in patients with measurable disease treated with this regimen.
* Assess the frequency and severity of toxicities of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive oral erlotinib hydrochloride once daily on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for up to 2 years.

PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.

Arms: arm 1: None
Interventions: intervention 1: bevacizumab intervention 2: erlotinib hydrochloride
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
S0635 
Activation Date July 15, 2007 
Version Date 12/02/2011 
SWOG 
A PHASE II TRIAL OF THE COMBINATION OF OSI-774 (ERLOTINIB; NSC-718781) AND 
BEVACIZUMAB (RHUMAB VEGF; NSC-704865) IN STAGE IIIB AND IV BRONCHIOLOALVEOLAR 
CARCINOMA (BAC) AND ADENOCARCINOMA WITH BAC FEATURES (ADENOBAC)  
Page 
  1.0 
OBJECTIVES....................................................................................................................3 
 2.0 
BACKGROUND ................................................................................................................3 
  3.0 
DRUG INFORMATION .....................................................................................................5 
 4.0 
STAGING CRITERIA ......................................................................................................17 
 5.0 
ELIGIBILITY CRITERIA ..................................................................................................18 
 6.0 
STRATIFICATION FACTORS ........................................................................................21 
 7.0 
TREATMENT PLAN........................................................................................................21 
 8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ..........................23 
 9.0 
STUDY CALENDAR .......................................................................................................28 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS...................................29 
11.0 
STATISTICAL CONSIDERATIONS................................................................................32 
12.0 
DISCIPLINE REVIEW.....................................................................................................33 
13.0 
REGISTRATION GUIDELINES ......................................................................................33 
14.0 
DATA SUBMISSION SCHEDULE ..................................................................................34 
15.0 
SPECIAL INSTRUCTIONS.............................................................................................37 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS.....................................................45 
17.0 
BIBLIOGRAPHY .............................................................................................................51 
18.0 
MASTER FORMS SET ...................................................................................................54 
19.0      APPENDIX……………………………………………………………………………………...87 
PARTICIPANTS: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
STUDY COORDINATORS: 
AGENTS: 
Howard (Jack) West, M.D. (Medical Oncology) 
Bevacizumab for injection (Avastin®) 
Swedish Cancer Institute 
(NSC-704865, IND-100426); 
1221 Madison Street, Second Floor 
OSI-774 (Erlotinib, Tarceva®)        
Seattle, WA 98104 
(NSC-718781, IND-100426) 
Phone:  206/386-2424 
FAX:  206/386-2746 
E-mail:  howard.west@swedish.org 
BIOSTATISTICIANS: 
Derick H. M. Lau, M.D., Ph.D. (Radiology) 
James Moon, M.S.  
Division of Hematology/Oncology 
Mary Redman, Ph.D.  
Department of Internal Medicine 
Southwest Oncology Group Statistical Center 
UC Davis Cancer Center 
Fred Hutchinson Cancer Research Center 
4501 X Street, Room 3019 
1100 Fairview Avenue North, M3-C102 
Sacramento, CA  95817 
P.O. Box 19024 
Phone:  916/734-3863 
Seattle, WA  98109-1024 
FAX:  916/734-7451 
Phone:  206/667-4623 
E-mail:  derick.lau@ucdmc.ucdavis.edu 
FAX:  206/667-4408 
E-mail:  jmoon@fhcrc.org 
E-mail:  mredman@fhcrc.org 


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STUDY COORDINATORS (cont.): 
Fred Hirsch, M.D., Ph.D. (Translational Medicine) 
University of Colorado Cancer Center 
P.O. Box 6511, MS 8111 
Aurora, CO  80045 
Phone:  303/724-3858 
FAX:  303/724-3162 
E-mail:  fred.hirsch@uchsc.edu 
Antoinette J. Wozniak, M.D. (Medical Oncology) 
Karmanos Cancer Center 
Wayne State University 
4160 John R 3rd Floor 
Detroit, MI 48201 
Phone:  313/576-8752 
FAX:  313/576-8699 
Email:  wozniakt@karmanos.org 


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1.0 
OBJECTIVES 
The primary objective of this Phase II study is: 
1.1 
To assess overall survival in patients with BAC/adenoBAC who receive daily oral OSI-
774 (erlotinib) in combination with intravenous bevacizumab every 3 weeks. 
The secondary objectives are: 
1.2 
To assess progression-free survival in this group of patients treated with this regimen. 
1.3 
To investigate in a preliminary manner the level of agreement between response 
outcomes determined by RECIST and response outcomes as determined by a central, 
computer assisted image analysis system (CAIA) in the subset of patients with 
measurable disease. 
1.4 
To evaluate the frequency and severity of toxicities associated with this regimen. 
1.5 
To assess tissue collected from BAC/adenoBAC for EGFR and ras mutations as well as 
EGFR 
expression, 
plasma 
markers 
of 
angiogenesis, 
angiogenesis-related 
polymorphisms, and to perform exploratory analysis of the relationships between these 
features and the clinical outcomes of the present trial. 
2.0 
BACKGROUND 
BAC has a distinct clinical presentation, radiologic appearance and natural history compared to 
other types of non-small cell lung cancer (NSCLC).  (1) Nodal involvement and distant metastatic 
disease occur much less commonly than in other forms of NSCLC.  Instead, it generally follows a 
much more localized growth pattern and may be spread aerogenously.  (2,3)  Even for the subset 
of patients with advanced BAC, death is most typically from respiratory failure secondary to 
diffuse pulmonary involvement or intercurrent pulmonary infection rather than from disease 
spread to other organ sites.  Importantly, recent clinical trials targeting this population have 
included patients with both "pure" BAC and adenoBAC.  (4,5) 
While patients may be cured after resection of focal BAC, there is no optimal established therapy 
for multilobar or recurrent disease.  Conventional chemotherapy is widely perceived to have a 
minimal impact on clinical course.  The largest prospective trial of chemotherapy in BAC, 
Southwest Oncology Group protocol S9714, administered 96-hour paclitaxel infusion and was 
associated with a modest objective response rate of 14%, a median survival of 12 months and 
considerable toxicity that precluded the further study of this regimen for advanced BAC.  (6)  In 
contrast, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) ZD1839 
(gefitinib) and OSI-774 (erlotinib) have each been studied as single-agent therapy for first-line or 
previously treated BAC and have been associated with overall more favorable results, most 
notably in women, never-smokers and those who develop a rash.  (4, 5)  Each of the EGFR TKIs 
has been associated with a response rate in the 15-25% range in this setting, with a subset of 
patients demonstrating prolonged survival on ZD1839 (gefitinib), with a three-year OS of 23% for 
untreated patients, compared with an OS of 13% for prolonged-infusion paclitaxel on S9714; data 
with prolonged follow-up are not yet available for OSI-774 (erlotinib).  (4,6)  Significantly, in 
subset analyses of these trials, the beneficial effects of EGFR-based therapies have not been 
restricted to pure BAC but are comparable, if not superior, in patients with adenoBAC.  Franklin 
and colleagues reported that results on S0126 were similar among patients with invasive 
adenocarcinoma with BAC features compared to those with pure BAC, while Kris and colleagues 
noted that the response rate to erlotinib was 29% for adenoBAC compared with 11% for pure 
BAC.  (5,7) 


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Bevacizumab is an antibody to the vascular endothelial growth factor (VEGF) ligand and has 
antiangiogenic activity in multiple preclinical models and clinical settings. (reviewed in 8)  It has 
been approved in metastatic colon cancer, in which a highly statistically significant survival 
benefit has been seen when bevacizumab was combined with standard chemotherapy.  There 
has also been considerable interest in the integration of bevacizumab with treatment of advanced 
NSCLC.  A randomized Phase II trial demonstrated a very encouraging potential survival benefit, 
particularly for the dose of 15 mg/kg IV q 3 weeks when combined with standard carboplatin and 
paclitaxel.  (9)  This approach has been tested further in a randomized Phase III trial of standard 
chemotherapy with or without bevacizumab, in which a significant survival benefit has been 
shown to be conferred by the addition of bevacizumab in patients with nonsquamous histology in 
whom the median overall survival of the bevacizumab/chemotherapy combination was 12.5 
months compared to 10.2 months for chemotherapy alone.  (10)  
While the treatment of advanced BAC/adenoBAC may potentially include chemotherapy, single-
agent EGFR TKI therapy is very widely practiced as an early intervention, based on the two 
studies described above with ZD1839 (gefitinib) and OSI-774 (erlotinib) in this population. 
Moreover, with the highly positive results from the BR.21 trial, there is now greater focus on OSI-
774 (erlotinib) in this setting.  The combination of bevacizumab and OSI-774 (erlotinib), targeting 
both the tumor itself and its blood supply, provides the potential advantage of integrating the 
survival benefit conferred by anti-angiogenic therapy with an existing early (and potentially first-
line) treatment strategy.  A recent Phase I/II trial tested the combination of OSI-774 (erlotinib) 
with bevacizumab in the salvage setting.  (11)  This trial demonstrated a 20% response rate and 
a non-progression rate of 85%, a promising 12.6 month median survival, and a modest toxicity 
profile at the established Phase II dose.  Specifically, the most common adverse events (any 
grade) were rash (85%), diarrhea (65%), infection (29%), hematuria (32%), proteinuria (9%), and 
epistaxis (6%).  The only serious adverse events were pneumonia, and there were no treatment-
related deaths.  Based on these promising results, a larger randomized Phase III trial is being 
undertaken in the second-line NSCLC setting, comparing the combination of OSI-774 (erlotinib) 
and bevacizumab to OSI-774 (erlotinib) alone.  Of note, all of the bevacizumab trials in NSCLC 
currently exclude patients with squamous cell histology and those with brain metastases, 
exclusion criteria that will be applied in the current trial as well. 
Taken together, these data demonstrate that EGFR TKI therapy is a current standard of care for 
patients with advanced BAC/adenoBAC, that OSI-774 (erlotinib) has an established survival 
benefit in NSCLC overall, and that bevacizumab in combination with first-line chemotherapy is 
associated with improved survival compared to chemotherapy alone.  While the combination of 
OSI-774 (erlotinib) and bevacizumab has not been tested in these patient populations 
specifically, the combination has demonstrated safety and encouraging efficacy in early trials in 
the salvage setting. 
The current proposal is to examine in a Phase II multicenter trial the clinical benefit and the long-
term tolerability of daily OSI-774 (erlotinib) along with intravenous q3week bevacizumab at 15 
mg/kg in patients with advanced BAC or adenoBAC who have not previously received an EGFR 
TKI or bevacizumab.  This would integrate the potential benefit of bevacizumab, which has 
provided a survival benefit in combination with chemotherapy, with the FDA-approved agent 
erlotinib in the particular subsets of patients in whom erlotinib has demonstrated the greatest 
likelihood of clinical benefit. For the subset of patients with BAC/adenoBAC, the endpoints of this 
study may potentially be compared with the historical results of S9714 and S0126.  If the results 
from this study are promising, a subsequent Phase III trial comparing OSI-774 (erlotinib) to OSI-
774 (erlotinib)/bevacizumab in BAC/adenoBAC would be considered. 
Inclusion of Women and Minorities: 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects. 


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Revised 8/2/10 
Revised 12/2/11 
3.0 
DRUG INFORMATION 
3.1 
Bevacizumab (rhuMAb VEGF) (Avastin) (NSC-704865) (IND-100426) 
a.
DESCRIPTION
Bevacizumab is a recombinant humanized monoclonal antibody that inhibits 
vascular endothelial growth factor (VEGF) resulting in inhibition of angiogenesis. 
Of the identified angiogenic factors, vascular endothelial growth factor (VEGF; 
also known as vascular permeability factor) is the most potent and specific and 
has been identified as a crucial regulator of both normal and pathologic 
angiogenesis.  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, maintenance of survival 
for newly formed blood vessels, and, possibly, suppression of dendritic cell 
antigen presentation.  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)/VEGFR-1 and KDR (kinase domain region)/VEGFR-2. 
Increased levels of VEGF expression have been found in most human tumors 
examined to date, including tumors of the lung, breast, thyroid, gastrointestinal 
tract, kidney, bladder, ovary, and cervix, angiosarcomas, glioblastomas, as well 
as multiple myeloma, lymphoma, and AML.  Inhibition of VEGF using an 
anti-VEGF monoclonal antibody blocks the growth of a number of human cancer 
cell lines in nude mice.  The human cancers represented by these cell lines that 
are growth-inhibited by anti-VEGF antibody include non–small cell lung cancer 
(Calu-6), colorectal cancer (LS174T, HM-7, LSLiM6), breast cancer (MCF-7), 
prostate cancer (D-145), head and neck cancer (KB), ovarian cancer (SK-OV-3), 
and others. 
b.
TOXICOLOGY
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Bevacizumab (NSC #704865) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via AdEERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification.  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed 
on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 


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Amended 9/17/07 
Revised 8/2/10 
Revised 12/2/11 
Version 2.2, October 21, 20111 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Anemia (Gr. 3) 
Blood and 
lymphatic system 
disorders - Other 
(renal thrombotic 
microangiopathy)
Febrile 
neutropenia 
Febrile neutropenia 
(Gr. 3) 
CARDIAC DISORDERS 
Acute coronary 
syndrome 
Heart failure 
Left ventricular 
systolic 
dysfunction 
CARDIAC DISORDERS (contd.) 
Myocardial 
infarction 
Supraventricular 
tachycardia 
Supraventricular 
tachycardia (Gr. 3) 
Ventricular 
arrhythmia 
Ventricular 
fibrillation 
EAR AND LABYRINTH DISORDERS 
Vertigo 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Abdominal pain (Gr. 3) 
Colitis 
Colitis (Gr. 3) 
Constipation 
Constipation (Gr. 3) 
 Diarrhea 
Diarrhea (Gr. 3) 
Dyspepsia 
Dyspepsia (Gr. 2) 
Gastrointestinal 
fistula2 
Gastrointestinal 
hemorrhage3 
Gastrointestinal 
hemorrhage3 (Gr. 2) 
Gastrointestinal 
obstruction4 
Gastrointestinal 
perforation5  
Gastrointestinal 
ulcer6 


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Amended 9/17/07 
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Revised 12/2/11 
Ileus 
Mucositis oral 
Mucositis oral (Gr. 3) 
 Nausea 
Nausea (Gr. 3) 
 Vomiting 
Vomiting (Gr. 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 Fatigue 
Fatigue (Gr. 3) 
Infusion related 
reaction 
Infusion related reaction 
(Gr. 2) 
Non-cardiac chest 
pain 
Non-cardiac chest pain 
(Gr. 3) 
Pain 
Pain (Gr. 3) 
IMMUNE SYSTEM DISORDERS 
Allergic reaction 
Allergic reaction (Gr. 2) 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
Infection7 
Infection7 (Gr. 3) 
Infections and 
infestations - 
Other (peri-rectal 
abscess) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
Gastrointestinal 
anastomotic leak 
 Wound 
dehiscence 
Wound dehiscence (Gr. 
2) 
INVESTIGATIONS 
Alanine 
aminotransferase 
increased 
Alanine 
aminotransferase 
increased  
(Gr. 3) 
Alkaline 
phosphatase 
increased 
Alkaline phosphatase 
increased (Gr. 3) 
INVESTIGATIONS 
Aspartate 
aminotransferase 
increased 
Aspartate 
aminotransferase 
increased (Gr. 3) 
Blood bilirubin 
increased 
Blood bilirubin 
increased (Gr. 2) 
 Cardiac troponin I 
increased 
Neutrophil count 
decreased 
Neutrophil count 
decreased (Gr. 3) 
Weight loss 
Weight loss (Gr. 3) 
White blood cell 
decreased 
White blood cell 
decreased (Gr. 3) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr. 3) 


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Revised 12/2/11 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Arthralgia 
Arthralgia (Gr. 3) 
Musculoskeletal 
and connective 
tissue disorder - 
Other (bone 
metaphyseal 
dysplasia)8 
Myalgia 
Myalgia (Gr. 3) 
Osteonecrosis of 
jaw9 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Dizziness (Gr. 2) 
 Headache 
Headache (Gr. 3) 
Intracranial 
hemorrhage 
Ischemia 
cerebrovascular 
 Peripheral 
sensory 
neuropathy10 
Reversible 
posterior 
leukoencepha-
lopathy syndrome 
 Syncope 
RENAL AND URINARY DISORDERS 
Acute kidney 
injury 
 Hematuria 
 Hematuria (Gr. 3) 
Proteinuria 
Proteinuria (Gr. 2) 
Renal and urinary 
disorders - Other 
(Nephrotic 
Syndrome) 
Urinary fistula 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Reproductive system 
and breast disorders 
- Other (ovarian 
failure)11 
Vaginal fistula 
Vaginal 
hemorrhage 
Vaginal hemorrhage (Gr. 
3) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Allergic rhinitis 
Allergic rhinitis (Gr. 3) 
Bronchopleural 
fistula 
Bronchopulmonary 
hemorrhage 
Cough 
Cough (Gr. 3) 


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Revised 12/2/11 
Dyspnea 
Dyspnea (Gr. 2) 
Epistaxis 
Epistaxis (Gr. 3) 
Hoarseness 
Hoarseness (Gr. 3) 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(nasal-septal 
perforation) 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(tracheo-
esophageal 
fistula) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Pruritus 
Pruritus (Gr. 2) 
Rash maculo-
papular 
Rash maculo-papular 
(Gr. 2) 
Urticaria 
Urticaria (Gr. 2) 
VASCULAR DISORDERS 
Hypertension 
Hypertension (Gr. 3) 
Thromboembolic 
event 
Thromboembolic event 
(Gr. 3) 
Vascular disorders 
- Other (arterial 
thromboembolic 
event)12 
 
1 
This table will be updated as the toxicity profile of the agent is revised. 
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 
Gastrointestinal fistula may include: Anal fistula, Colonic fistula, 
Duodenal fistula, Esophageal fistula, Gastric fistula, Gastrointestinal 
fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC 
3 
Gastrointestinal hemorrhage may include:  Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices 
hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other 
sites under the GASTROINTESTINAL DISORDERS SOC. 
4 
Gastrointestinal obstruction may include:  Colonic obstruction, Duodenal 
obstruction, 
Esophageal 
obstruction, 
Ileal 
obstruction, 
Jejunal 
obstruction, Rectal obstruction, Small intestinal obstruction, and other 
sites under the GASTROINTESTINAL DISORDERS SOC. 
5 
Gastrointestinal perforation may include:  Colonic perforation, Duodenal 
perforation, 
Esophageal 
perforation, 
Gastric 
perforation, 
Jejunal 
perforation, Rectal perforation, Small intestinal perforation, and other 
sites under the GASTROINTESTINAL DISORDERS SOC. 
6 
Gastrointestinal ulcer may include:  Duodenal ulcer, Esophageal ulcer, 
Gastric ulcer, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 


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7 
Infection may include any of the 75 infection sites under the 
INFECTIONS AND INFESTATIONS SOC. 
8 
Metaphyseal dysplasia was observed in young patients who still have 
active epiphyseal growth plates. 
9 
Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer 
patients in association with bevacizumab treatment, the majority of whom 
had received prior or concomitant treatment with i.v. bisphosphonates. 
10 
Increased rate of peripheral sensory neuropathy has been observed in 
trials 
combining 
bevacizumab 
and 
chemotherapy 
compared 
to 
chemotherapy alone.  
11 
Ovarian failure, defined as amenorrhea lasting 3 or more months with 
follicle-stimulating hormone (FSH) elevation (≥30 mIU/mL), was 
increased in patients receiving adjuvant bevacizumab plus mFOLFOX 
compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of 
bevacizumab, resumption of menses and an FSH level <30 mIU/mL was 
demonstrated in 22% (7/32) of these women.  Long term effects of 
bevacizumab exposure on fertility are unknown. 
12 
Arterial thromboembolic event includes visceral arterial ischemia, 
peripheral arterial ischemia, heart attack, and stroke. 
Also reported on Bevacizumab (rhuMAb VEGF) trials but with the 
relationship to Bevacizumab (rhuMAb VEGF) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic 
system 
disorders 
- 
Other 
(idiopathic 
thrombocytopenia 
purpura); 
Disseminated intravascular coagulation 
CARDIAC DISORDERS - Pericardial effusion 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Gait disturbance; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other 
(aseptic meningitis) 
INVESTIGATIONS - Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Musculoskeletal and connective tissue disorder - Other (aseptic necrotic 
bone); Musculoskeletal and connective tissue disorder - Other (myasthenia 
gravis) 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral motor neuropathy; 
Seizure 
PSYCHIATRIC DISORDERS – Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Pneumonitis; Pneumothorax; Pulmonary 
hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar 
erythrodysesthesia syndrome; Skin ulceration 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused 
by the other agent, or the combination may result in events never previously 
associated with either agent. 


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Based on clinical trials with bevacizumab as monotherapy or in combination with 
chemotherapy, the most common adverse events of any severity include 
asthenia, pain, headache, hypertension, diarrhea, stomatitis, constipation, 
epistaxis, dyspnea, dermatitis and proteinuria.  The most common Grade 3-4 
adverse events were asthenia, pain, hypertension, diarrhea and leukopenia.  The 
most serious AEs include life-threatening or fatal hemorrhage, arterial 
thromboembolic events, gastrointestinal perforation and wound dehiscence; 
these events were uncommon but occurred at an increased frequency compared 
to placebo or chemotherapy controls in randomized studies.    
The following is a description of major adverse events associated with 
bevacizumab therapy.  Reference may also be made to the Investigators’ 
Brochure 
and 
the 
FDA 
package 
insert 
(www.fda.gov/cder/foi/label/2004/125085lbl.pdf).  
Infusion-Related Reactions:  Infusion reactions with bevacizumab were 
uncommon (< 3%) and rarely severe (0.2%).  Infusion reactions may include 
rash, urticaria, fever, rigors, hypertension, hypotension, wheezing, or hypoxia. 
Currently, there is no adequate information on the safety of retreatment with 
bevacizumab in patients who have experienced severe infusion-related 
reactions.  
Hypertension:  Hypertension is common in patients treated with bevacizumab, 
with an incidence of 20-30% across trials.  Initiation or increase of anti-
hypertensive medications may be required, but in most cases, blood pressure 
(BP) can be controlled with routine oral drugs.  However, incidents of 
hypertensive crisis with encephalopathy or cardiovascular sequelae have been 
rarely reported.  BP should be closely monitored during bevacizumab therapy 
and the goal of BP control should be consistent with general medical practice. 
Bevacizumab therapy should be suspended in the event of uncontrolled 
hypertension. 
Proteinuria:  Proteinuria has been seen in all bevacizumab studies to date, 
ranging in severity from an asymptomatic increase in urine protein (incidence of 
about 20%) to rare instances of nephrotic syndrome (0.5% incidence). 
Pathologic findings on renal biopsies in two patients showed proliferative 
glomerulonephritis.  NCI-CTCAE Grade 3 proteinuria (> 3.5 gm/24 hour urine) is 
uncommon, but the risk may be higher in patients with advanced RCC.  In the 
Phase II randomized study in RCC, 24-hour urine was collected in a subset of 
patients enrolled, and Grade 3 proteinuria was found in 4 patients in the 10 
mg/kg-arm (n=37), 2 patients in the 3mg/kg arm (n=35) and none in the placebo 
arm (n=38).  The safety of continuing bevacizumab in patients with moderate or 
severe proteinuria has not been adequately tested.   
Hemorrhage:  The incidence of hemorrhage is increased with bevacizumab 
therapy.  Epistaxis is common, occurring in 20-40% of patients, but it is generally 
mild and rarely requires medical intervention.  Life-threatening and fatal 
hemorrhagic events have been observed in bevacizumab studies and included 
pulmonary hemorrhage, CNS bleeding and gastrointestinal (GI) bleeding.  In a 
Phase II study in non-small cell lung cancer, 6 cases of life-threatening 
hemoptysis or hematemesis were reported among 66 patients treated with 
bevacizumab and chemotherapy; 4 of these events were fatal (Novotny et al., 
2001).  In the pivotal Phase III trial in advanced colorectal cancer, the rate of GI 
hemorrhage (all grades) was 24% in the IFL/bevacizumab arm compared to 6% 
in the IFL arm; Grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% 
for IFL.  Serious GI hemorrhage has also been observed in clinical trials with 
bevacizumab in patients with pancreatic cancer or varices treated with 
bevacizumab.  


S0635 
Page 10 
Arterial Thromboembolic Events:  The risk of arterial thromboembolic events is 
increased with bevacizumab therapy, and such events included cerebral 
infarction, transient ischemic attack (TIA), myocardial infarction and other 
peripheral or visceral arterial thrombosis.  In the pivotal trial in CRC (AVF2107), 
the incidence of arterial thromboembolic events was 1% in the IFL/placebo arm 
compared to 3% in the IFL/ bevacizumab arm.  A pooled analysis of five 
randomized studies showed a two-fold increase in these events (4.4% vs 1.9%). 
Certain baseline characteristics, such as age and prior arterial ischemic events, 
appear to confer additional risk (Schilling et al, ASCO 2005).  In patients ≥ 65 
years treated with bevacizumab and chemotherapy, the rate of arterial 
thromboembolic events was approximately 8.5%.  
Gastrointestinal Perforation/Fistula: GI perforations/fistula were rare but occurred 
at an increased rate in bevacizumab-containing therapies.  The majority of such 
events required surgical intervention and some were associated with a fatal 
outcome.  In the pivotal Phase III trial in CRC (AVF2107), the incidence of bowel 
perforation was 2% in patients receiving IFL/bevacizumab and 4% in patients 
receiving 5-FU/bevacizumab compared to 0.3% in patients receiving IFL alone. 
GI perforation has also been reported in patients with gastric/esophageal cancer, 
pancreatic cancer, ovarian cancer or comorbid GI conditions such as diverticulitis 
and gastric ulcer.  GI perforation should be included in the differential diagnosis 
of patients on bevacizumab therapy presenting with abdominal pain or 
rectal/abdominal abscess. 
Tracheoesophageal (TE) fistula:  In a Phase II trial of concurrent chemoradiation 
and bevacizumab in limited SCLC (concurrent irinotecan, carboplatin, 
radiotherapy, and bevacizumab, followed by maintenance bevacizumab), among 
the first 25 patients enrolled, there have been two confirmed cases of 
tracheoesophageal (TE) fistula (one fatal) and a third case of fatal upper 
aerodigestive tract hemorrhage, with TE fistula suspected but not confirmed.  All 
three events occurred during the bevacizumab maintenance phase (1.5 to 4 
months after completion of concurrent bevacizumab and chemoradiation).  The 
TE fistula rate in this trial was higher than expected with chemoradiation alone. 
While pulmonary fistula (including TE fistula) has also been observed in 
advanced NSCLC or SCLC patients receiving bevacizumab and chemotherapy 
(without radiation), the incidence was extremely low (<< 1%), and the 
relationships to treatment vs. tumor in those cases were unclear.  Experience is 
limited for bevacizumab administered sequentially after chemoradiation for either 
NSCLC or SCLC; in a study for chemoradiation followed by bevacizumab in 
SCLC, one of the 60 patients enrolled developed TE fistula. 
Wound Healing Complications:  Bevacizumab delays wound healing in rabbits, 
and it may also compromise or delay wound healing in patients. Bowel 
anastomotic dehiscence and skin wound dehiscence have been reported in 
clinical trials with bevacizumab.  The appropriate interval between surgery and 
initiation of bevacizumab required to avoid the risk of impaired wound healing 
has not been determined.  However, all clinical trials with bevacizumab have 
required a minimum of 28 days from prior major surgery; experience in the 
pivotal trial in advanced CRC suggests that initiation of bevacizumab 29-50 days 
following surgery should be associated with a very low incidence of wound 
dehiscence.  The optimal interval between termination of bevacizumab and 
subsequent elective surgery has not been determined either.  In the pivotal study 
in CRC, 40 patients on the IFL/bevacizumab arm and 25 patients on the 
ILF/placebo arm underwent major surgery while on study; among them, 
significant post-operative bleeding or wound healing complications occurred in 4 
of the 40 patients from the IFL/bevacizumab arm and none of the 25 patients 


S0635 
Page 11 
from the IFL alone arm.  Decisions on the timing of elective surgery should take 
into consideration the half-life of bevacizumab (average 21 days, with a range of 
11-50 days). 
Congestive Heart Failure:  The risk of left ventricular dysfunction may be 
increased in patients with prior or concurrent anthracycline treatment.  In Phase 
III controlled clinical trial in metastatic breast cancer (AVF 2119g) in which all 
patients had received prior anthracyclines, congestive heart failure (CHF) or 
cardiomyopathy 
were 
reported 
in 
7 
patients 
(3%) 
in 
the 
bevacizumab/capecitabine arm compared to 2 (1%) in the capecitabine-only arm. 
No increase in CHF was observed in CRC trials with bevacizumab in 
combination with IFL or 5-FU.   
Venous Thrombosis:  Venous thromboembolic events reported in bevacizumab 
trials included lower extremity deep vein thrombosis (DVT), pulmonary embolism 
and rarely, mesenteric or portal vein thrombosis.  In the pivotal Phase III trial of 
IFL ± bevacizumab (given at 5 mg/kg q 2 weeks), the overall incidences of G3-4 
venous thromboembolic events were comparable in the two arms (15.1 vs 
13.6%). 
Fertility and Pregnancy:  Clinical data are lacking regarding the immediate or 
long-term effect of bevacizumab on fertility and pregnancy.  However, 
bevacizumab is known to be teratogenic and detrimental to fetal development in 
animal models.  In addition, bevacizumab may alter corpus luteum development 
and endometrial proliferation, thereby having a negative effect on fertility.  As an 
IgG1, it may also be secreted in human milk.  Therefore, fertile men and women 
on bevacizumab studies must use adequate contraceptive measures and women 
should avoid breast feeding.  The duration of such precautions after 
discontinuation of bevacizumab should take into consideration the half-life of the 
agent (average 21 days, with a range of 11 to 50 days). 
Immunogenicity:  As a therapeutic protein, there is a potential for immunogenicity 
with bevacizumab.  With the currently available assay with limited sensitivity, high 
titer human anti-bevacizumab antibodies have not been detected in 
approximately 500 patients treated with bevacizumab.  
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome:  RPLS or clinical syndromes related to 
vasogenic edema of the white matter have been rarely reported in association 
with bevacizumab therapy (< 1%).  Clinical presentations are variable and may 
include altered mental status, seizure and cortical visual deficit.  HTN is a 
common risk factor and was present in most (though not all) patients on 
bevacizumab who developed RPLS.  MRI scans are key to diagnosis and 
typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images 
and hyposensitivity in T1 images) predominantly in the white matter of the 
posterior parietal and occipital lobes; less frequently, the anterior distributions 
and the gray matter may also be involved.  RPLS is potential reversible, but 
timely correction of the underlying causes, including control of BP and 
interruption of the offending drug, is important in order to prevent progression to 
irreversible tissue damage. 
Neutropenia:  When combined with chemotherapy, bevacizumab increased the 
risk of neutropenia compared to chemotherapy alone.  In a Phase III trial with IFL 
± bevacizumab in colorectal cancer, Grade 3-4 neutropenia was 21% in the 
bevacizumab + IFL arm vs. 14% in the IFL arm (Grade 4 neutropenia was 3 vs. 
2%).  In the Phase III trial with carboplatin and paclitaxel ± bevacizumab in 
metastatic NSCLC, the bevacizumab-containing arm was associated with 


Amended 9/17/07 
S0635 
Revised 12/11/07 
Page 12 
increased rates of Grade 4 neutropenia (26% vs. 17%), febrile neutropenia (5.4% 
vs. 1.8%) and an increased rate of infection with neutropenia (4.5 vs. 1.8%) with 
3 cases with fatal outcome in the bevacizumab + chemotherapy arm vs. 0 in the 
chemotherapy only control. 
c.
PHARMACOLOGY
Kinetics: In Study AVF0737g, the pharmacokinetics of bevacizumab appeared to
be linear for doses of ≥ 1 mg/kg, with a half-life of ~15 days.  A consistent profile
was seen in Study AVF0761g.  Co-administration of bevacizumab with cytotoxic
chemotherapy did not appear to result in a change in the systemic concentrations
of the cytotoxic agents.
How Supplied:  Bevacizumab is supplied as a clear to slightly opalescent, sterile
liquid ready for parenteral administration.  For Bevacizumab, each 400 mg (25
mg/mL – 16 mL fill) glass vial contains bevacizumab with phosphate, trehalose,
polysorbate 20, and Sterile Water for Injection, USP.
Preparation:  Vials contain no preservatives and are intended for single use only.
Place the calculated dose in 100 mL of 0.9% sodium chloride for injection.
Once the bevacizumab has been added to the bag with 0.9% Sodium Chloride
for Injection, the solution must be administered within 8 hours.  When the
bevacizumab IV bag is empty, an additional 50 ml of 0.9% Sodium Chloride for
Injection should be added to the IV bag and the infusion continued for a volume
equal to that of the tubing to insure complete delivery of the bevacizumab.  An
alternative method of flushing the infusion line would be to replace the empty
bevacizumab infusion bag with a 50 mL bag of 0.9% Sodium Chloride for
Injection and infuse a volume equal to that of the tubing to insure complete
delivery of the bevacizumab.  Note that this flush is not included in the infusion
times.
Storage and Stability:  Bevacizumab is shipped on blue ice for next day delivery.
On receipt, bevacizumab should be stored in the refrigerator (2o to 8oC) and
should remain refrigerated until just prior to use.  Do not freeze.  Do not shake.
Shelf-life studies of bevacizumab are continuing.  Investigators will be notified of
any dating extensions, when lots have expired, and how to handle disposition of
the agent.  The sterile single use vials contain no antibacterial preservatives.
Therefore, vials should be discarded 8 hours after initial entry.  Once diluted in
0.9% Sodium Chloride for Injection, solution of bevacizumab must be
administered within 8 hours.
Administration:  The route of administration is intravenous as a continuous
infusion.  The initial dose should be administered over a minimum of 90 minutes.
If no adverse reactions occur after the initial dose, the second dose should be
administered over a minimum of 60 minutes.  If no adverse reactions occur after
the second dose, all subsequent doses should be administered over a minimum
of 30 minutes.  If infusion-related adverse reactions occur, all subsequent
infusions should be administered over the shortest period that was well tolerated.
d.
SUPPLIER
Bevacizumab is investigational for this study and will be supplied free of charge
to patients by Genentech for distribution by Biologics.  Allow 7 business days
for shipment of drug from receipt of the Biologics Drug Request Form (see
S0635 
abstract 
page 
on 
the 
SWOG 
website
[https://swog.org/Members/ClinicalTrials/ViewProtocolDetails.asp?Protocol
ID=2065]).  Forms should be faxed to the number on the form. Orders
received before 4 p.m. E.S.T Monday through Thursday will be processed and
shipped for same day delivery.  Orders received after 4 pm E.S.T. Monday
through Thursday or anytime on Friday will be processed and shipped the next
business morning.  Shipments will be sent via Federal Express for Priority
Overnight delivery.  Biologics will be closed the following holidays:


S0635 
Page 13 
New Years Eve, New Years Day, Memorial Day, Independence Day, Labor Day, 
Thanksgiving, Thanksgiving Friday, Christmas Eve and Christmas Day.  The 
bevacizumab to be supplied for this protocol is intended for clinical trial use only 
and is not the commercially available Avastin®.  Investigational bevacizumab and 
commercially available Avastin® may be produced at separate facilities and some 
difference may exist between the two products, although both are required to 
meet similar product testing criteria and are expected to be very similar in safety 
and activity.  For further details and molecule characterization, see the updated 
bevacizumab Investigator Brochure. 
3.2 
OSI-774 (Tarceva®) (NSC-718781, IND-100426) 
a.
DESCRIPTION
Chemical Name:
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
quinazolinamine, monohydrochloride 
Other Names: 
CP-358, 774, USAN: erlotinib hydrochloride, Tarceva® 
Classification: 
Tyrosine kinase Inhibitor (EGFR) 
Molecular Formula: 
C22H23N3O4 
M.W.:  393.4 (free base) 
       429.9 (hydrochloride salt) 
Mode of Action: 
Direct inhibition of EGFR tyrosine kinase 
b.
TOXICOLOGY
Reported Adverse Events and Potential Risks:
Animal Data:
On chronic administration studies the following toxicities were observed:
Rat: increased ovarian atrophy (females)
Dog: salivation, ocular changes (tapedal fundus pigmentation not considered an
adverse finding), corneal ulceration
At the highest doses administered to dogs the following toxicities were observed:
bloody stools, ocular changes (palpebral and bulbar conjunctiva redness,
partially-closed eyes, lacrimation, purulent discharge, protruding nictitating
membranes, corneal opacities, edema, ulceration & corneal perforation),
discoloration of anterior chamber and/or cornea, abnormal corneal surface,
increased fibrinogen, increased cholesterol and triglycerides, decreased Na, Cl,
albumin, and Ca, dilatation and/or abnormal contents of gall bladder, enlarged &
pale cervical lymph nodes (1 female), microscopic findings: diffuse corneal
atrophy, corneal ulcers, degeneration of skeletal muscle, sinusal histiocytosis in
cervical lymph nodes
Genetic toxicology studies demonstrate that OSI-774 does not induce microbial
or mammalian cell gene mutations in vitro, and does not produce chromosomal
aberrations in vitro or in vivo.


Revised 10/15/08 
S0635 
Revised 5/11/09 
Page 14 
Revised 5/31/10 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Erlotinib (OSI-774, NSC 718781) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements'  
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers 
for further clarification. Frequency is provided based on 3622 patients. Below is 
the CAEPR for Erlotinib (OSI-774). 
Version 2.3, March 29, 20101 
 Adverse Events with Possible  
 Relationship to Erlotinib (OSI-774) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 EXPECTED AEs 
FOR ADEERS 
REPORTING  
Agent Specific 
Adverse Event List
(ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
Expected 
EYE DISORDERS 
Conjunctivitis 
 Conjunctivitis 
Dry eye 
 Dry eye 
Eye disorders - 
Other (eyelash in-
growth and/or 
thickening) 
Eye disorders - 
Other (corneal 
perforation) 
Keratitis 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
 Abdominal pain 
Diarrhea 
 Diarrhea 
Dry mouth 
 Dry mouth 
Dyspepsia 
 Dyspepsia 
Gastrointestinal 
hemorrhage2 
Gastrointestinal 
perforation3 
Mucositis oral 
 Mucositis oral 
Nausea 
 Nausea 
Vomiting 
 Vomiting 


Revised 10/15/08 
S0635 
Revised 5/11/09 
Page 15 
Revised 5/31/10 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
 Fatigue 
HEPATOBILIARY DISORDERS 
Hepatic failure 
INFECTIONS AND INFESTATIONS 
Skin infection4 
 Skin infection4 
INVESTIGATIONS 
Alanine 
aminotransferase 
increased 
 Alanine 
aminotransferase 
increased 
Alkaline 
phosphatase 
increased 
Aspartate 
aminotransferase 
increased 
 Aspartate 
aminotransferase 
increased 
Blood bilirubin 
increased 
 Blood bilirubin 
increased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
 Anorexia 
Dehydration 
 Dehydration 
NERVOUS SYSTEM DISORDERS 
Dysgeusia 
 Dysgeusia 
Headache 
 Headache 
Intracranial 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Cough 
 Cough 
Dyspnea 
 Dyspnea 
Epistaxis 
Pneumonitis 
 Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
 Alopecia 
Dry skin 
 Dry skin 
Erythema 
multiforme 
Nail loss 
 Nail loss 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Pruritus 
 Pruritus 
Rash acneiform 
 Rash acneiform 
Rash maculo-papular 
 Rash maculo-papular 
1 
This table will be updated as the toxicity profile of the agent is revised.  Updates will 
be distributed to all Principal Investigators at the time of revision.  The current version 
can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of 
the investigator, the protocol and the agent should be included in the e-mail. 
2 
Gastrointestinal 
hemorrhage 
could 
include 
Colonic 
hemorrhage, 
Duodenal 
hemorrhage, Gastric hemorrhage or hemorrhage of other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
3 
Gastrointestinal perforation includes Duodenal perforation, Gastric perforation, or 
perforation in other sites under the GASTROINTESTINAL DISORDERS SOC. 
4 
Includes infection of the skin (folliculitis or cellulitis) as complications of rash. 


S0635 
Page 16 
Revised 5/11/09 
Revised 5/31/10 
Also reported on erlotinib (OSI-774) trials but with the relationship to 
erlotinib (OSI-774) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); 
Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; 
Dysphagia; Esophagitis; Gastric ulcer; Gastritis; Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema 
limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; INR increased (in patients taking 
Coumadin); Lymphocyte count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hypocalcemia; 
Hypokalemia; 
Hypomagnesemia; 
Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL 
AND 
CONNECTIVE 
TISSUE 
DISORDERS 
- 
Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Ischemia cerebrovascular; 
Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
Note: Erlotinib (OSI-774) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
Note:  Erlotinib (OSI-774)-induced diarrhea and/or vomiting has been associated 
with dehydration, hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; 
hyponatremia; hypophosphatemia, increased creatinine, and renal failure. 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) 
have been reported during use of erlotinib (OSI-774) in patients with baseline 
hepatic impairment. 


S0635 
Page 16a 
Revised 5/11/09 
Revised 5/31/10 
Gastrointestinal Perforation: Patients receiving erlotinib are at increased risk of 
developing gastrointestinal perforation, which was observed uncommonly. Some 
cases had a fatal outcome.  Patients receiving concomitant anti-angiogenic 
agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who 
have prior history of peptic ulceration or diverticular disease, are at increased 
risk. Erlotinib should be permanently discontinued in patients who develop 
gastrointestinal perforation. 
Bullous and Exfoliative Skin Disorders: Bullous, blistering and exfoliative skin 
conditions have been reported, including very rare cases suggestive of Stevens-
Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal. 
Erlotinib treatment should be interrupted or discontinued if the patient develops 
severe bullous, blistering, or exfoliating conditions. 
Ocular Disorders: Very rare cases of corneal perforation or ulceration have 
been reported during use of erlotinib. Other ocular disorders including abnormal 
eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with 
erlotinib treatment and are known risk factors for corneal perforation/ulceration. 
Erlotinib therapy should be interrupted or discontinued if patients present with 
acute/worsening ocular disorders such as eye pain. 
Potential Drug Interactions:  OSI-774 is both protein bound (92% to 95%) and 
metabolized by CYP3A4.  Therefore, a potential for drug-drug interactions exists 
when OSI-774 is co-administered with drugs that are highly protein-bound or 
CYP3A4 inhibitors or inducers.  
There is a potential interaction between OSI-774 and warfarin. Patients have 
experienced elevated INRs and bleeding with this combination of drugs. Patients 
on warfarin and OSI-774 should have more frequent INR/PT determinations 
(e.g., weekly for the first month and weekly for a minimum of 2 weeks following 
discontinuation of OSI-774). 


S0635 
Page 16b 
Revised 5/11/09 
Proton Pump Inhibitor:  OSI-774’s solubility decreases as the pH increases. Co-
administration of omeprazole with OSI-774 will decrease the AUC and Cmax by 46% 
and 61%, respectively.  
H2-antagonist: Avoid concomitant use of OSI-774 with gastric acid reducing agents 
if possible.  When ranitidine 300 mg is given with OSI-774, OSI-774 AUC and Cmax 
decrease by 33% and 54%, respectively.  Increasing the dose of OSI-774 will not 
compensate the loss of exposure.  However, if an H2-antagonist receptor is needed, 
take OSI-774 at least 2 hours before or 10 hours following the H2-antagonist 
administration.  Dosing such, OSI-774 loss of exposure is minimized to AUC of 
15% and Cmax   of 17%. 
Patient Care Implications:  If the patient vomits after taking the tablets, the dose 
is replaced only if the tablets can actually be seen and counted. 
Patients should wear sun screen protection, hat, and long sleeves to avoid sun 
as it can exacerbate skin rash. 
Pregnancy and Lactation:  No information on pregnancy and lactation in humans 
is available yet. 
c.
PHARMACOLOGY
Total clearance of OSI-774 is similar to hepatic blood flow in dogs and rats.  At 
intravenous doses > 1 mg/kg the clearance decreases and the plasma drug 
exposure increases supra-proportionately in rats and dogs.  In vitro, the agent is 
slowly oxidized by liver microsomes.  OSI-774 is extensively metabolized in rats 
and dogs with only a small amount excreted unchanged in urine, bile and feces. 
In a rat model designed to study pulmonary first pass extraction, OSI-774 had a 
pulmonary extraction of approximately 48%.  In vitro studies have shown that the 
agent is metabolized by CYP1A1, which is expressed in lung tissue.  Several 
circulating metabolites have been identified in mouse, rat and dog and 
subsequently synthesized and demonstrated to be potent as EGFR inhibitors. 
Only one, OSI-420, a hydroxylated metabolite, was a major metabolite in 
systemic circulation with a metabolite: parent ratio of 1:4 in plasma from rats or 
dogs given oral doses.  This compound is as potent as OSI-774 in the in vivo 
tumor xenograft model. 
The enzymes responsible for formation of the major metabolite in humans were 
identified as cytochromes P450 3A4 and 3A5 (expressed in liver) and 1A1 
(expressed in lung). Studies on the inhibition potential of OSI-774 and its major 
metabolite, OSI-420, on the main human cytochrome P450 isoenzymes revealed 
a relatively strong inhibition of CYP 3A4 by OSI-774 (Ki 8 µM) and a weak 
inhibition of CYPs 1A2 and 3A4 by OSI-420 (Ki 20 µM). Further studies to 
evaluate the mechanism of inhibition are ongoing. 
Oral bio-availability was found to be 77% in rats and 88% in dogs.  Plasma 
protein binding is 92 - 95% in humans, rats, monkeys and mice, and was 85% in 
dogs. 
How Supplied:  OSI-774 is supplied as 25 mg, 100 mg, and 150 mg white film-
coated tablets.  In addition to the active ingredient, OSI-774, the tablets contain 
lactose, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, 
and magnesium stearate.  Tablets are unmarked and unscored.  The 25 mg 
tablets [1/4 inch diameter, 3 mm deep (formerly non-film coated)], 100 mg tablets 
(11/32 inch diameter, 5 mm deep), and 150 mg tablets (13/32 inch diameter, 5.1 
mm deep) are supplied 30 tablets/bottle. 


S0635 
Page 16c 
Revised 5/11/09 
Storage and Stability:  The intact bottles should be stored at controlled room 
temperature (15°C-30°C).  Shelf life surveillance studies of the intact bottle are 
on-going.  Current data indicates OSI-774 is stable for at least 3 years at room 
temperature. 
Administration:  OSI-774 is administered orally.  Tablets should be taken once 
daily preferably in the morning with up to 200 mL of water one hour before or two 
hours after food. 


S0635 
Page 17 
Amended 9/17/07 
Revised 12/7/09 
Administration through G-tube: The tablets required for the dose should be 
dissolved in 100 mL of sterile water.  The dissolved tablets should be shaken 
vigorously to form a uniform suspension.  The suspension should be drawn up 
into a syringe and administered through the G-tube port.  Repeat the syringe 
transfer until the entire volume has been administered.  A small volume (40 mL) 
of sterile water should be added to the container used to dissolve the tablets and 
the residual suspension should be shaken, aspirated into syringe, and 
administered. This last step should be repeated to ensure the entire dose is 
administered.  The total volume of delivery/rinse (as per procedure submitted to 
IND) is ~180 ml. 
d.
SUPPLIER
OSI-774 is investigational for this study and will be supplied free of charge to
patients by Genentech for distribution by Biologics.  Allow 7 business days for
shipment of drug from receipt of the Biologics Drug Request Form (see
S0635 
abstract 
page 
on 
the 
SWOG 
website
[https://swog.org/Members/ClinicalTrials/ViewProtocolDetails.asp?Protocol
ID=2065]).  Forms should be faxed to the number on the form. Orders
received before 4 p.m. E.S.T Monday through Thursday will be processed and
shipped for same day delivery.  Orders received after 4 pm E.S.T. Monday
through Thursday or anytime on Friday will be processed and shipped the next
business morning.  Shipments will be sent via Federal Express for Priority
Overnight delivery.  Biologics will be closed the following holidays: New Years
Eve, New Years Day, Memorial Day, Independence Day, Labor Day,
Thanksgiving, Thanksgiving Friday, Christmas Eve and Christmas Day.  For
further details and molecule characterization, see the updated Tarceva Package
insert.
4.0 
STAGING CRITERIA 
Patients must have selected Stage IIIB disease or Stage IV disease as outlined below (AJCC 
Cancer Staging Manual, 6th Edition, 2002): 
4.1 
Selected Stage IIIB 
•
T4 (cytology confirmed malignant pleural effusion, OR pleural tumor foci that are
separate from direct pleural invasion by the primary tumor)
•
Any N
•
M0
4.2 
Stage IV 
•
Any T
•
Any N
•
M1 (distant metastases present)
NOTE:  Any disease that is recurrent after surgery or radiation is classified as Stage IV. 


Amended 9/17/07 
S0635 
Revised 1/9/09 
Page 18 
5.0 
ELIGIBILITY CRITERIA 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S0635 Prestudy Form (Form #11652) and submit 
to the Data Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be 
addressed to the Data Operations Center in Seattle at 206/652-2267 prior to registration. 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28.
This allows for efficient patient scheduling without exceeding the guidelines.  If Day 7, 14, 28 or 42 falls 
on a weekend or holiday, the limit may be extended to the next working day. 
SWOG Patient No.   
Patient's Initials (L, F, M)   
5.1 
Patients 
must 
have 
biopsy-proven, 
incompletely 
resected 
or 
unresectable 
bronchioloalveolar carcinoma or BAC variants (adenocarcinoma with BAC features, BAC 
with invasive adenocarcinoma).  No component of squamous carcinoma can be present 
in any histologic sample. 
NOTE:  Cytology specimens, such as bronchial brushings, washings, or fine needle 
aspiration specimens alone are not acceptable for diagnosis of BAC or its subtypes. 
5.2 
Patients must be willing to provide prior smoking history as requested on the S0635 
Prestudy Form (Form #11652).  Patients with BAC who are designated as "Never-
Smokers" by their smoking history should be preferentially placed on trial S0636, which 
shares an identical plan, provided that this protocol is available for enrollment at the 
same institution. 
5.3 
Patients must have selected Stage IIIB (cytology-confirmed malignant pleural effusion) 
or Stage IV disease as defined in Section 4.0.  Tumors may be multi-focal or diffuse. 
Recurrences of BAC in a separate lobe after prior resection within the preceding five 
years or multifocal lesions in more than one lobe are considered Stage IV disease.   
5.4 
Patients must have measurable and/or non-measurable disease (see Section 10.1) 
documented by chest CT.  Measurable disease must be assessed within 28 days prior to 
registration.  Pleural effusions, ascites and laboratory parameters are not acceptable as 
the only evidence of disease.  Non-measurable disease must be assessed within 42 days 
prior to registration.  All disease must be assessed and documented on the Baseline 
Tumor Assessment Form (Form #848). 
5.5 
Patients must have no symptomatic brain metastases.  Patients may have treated, 
asymptomatic brain metastases as long as they do not require steroids for symptomatic 
management.  Patients must have EITHER a negative CT/MRI scan of the brain, OR (for 
patients with treated brain metastases) a stable or improved scan.  These scans must be 
performed within 42 days prior to registration.  The timeframe for having completed any 
radiation and/or surgery for brain metastases must conform to the 28-day rule as outlined 
in Sections 5.6 and 5.7. 
5.6 
Prior radiation is allowed provided that at least 28 days have elapsed since the 
completion of prior radiation therapy and patients have recovered from all associated 
toxicities at the time of registration.  Measurable or non-measurable disease must be 
present outside the previous radiation field or a new lesion inside the port must be 
present.  If the patient received palliative radiation, at least 14 days must have elapsed 
since completion and patients must have recovered from all associated toxicities at the 
time of registration. 


Amended 9/17/07 
S0635 
Revised 10/15/08 
Page 19 
Revised 1/9/09 
SWOG Patient No.   
Patient's Initials (L, F, M)   
5.7 
Prior surgery is allowed, provided that at least 28 days have elapsed since surgery 
(thoracic or other major surgeries) and patients have recovered from all associated 
toxicities at the time of registration. 
5.8 
Patients must not have had a fine needle aspiration or core biopsy within 7 days prior to 
registration. 
5.9 
Patients may have received prior systemic chemotherapy or biologic therapy.  Prior 
systemic therapy must have been discontinued at least 28 days prior to registration. 
Patients must not have received prior treatment with ZD1839 (gefitinib), OSI-774 
(erlotinib), or bevacizumab.  In addition, patients must not have received other targeted 
therapies against the EGFR or VEGF axes. 
5.10 
Patients must not have had hemoptysis ≥ ½ teaspoon within 28 days prior to registration. 
Patients with clinical history of pulmonary/upper respiratory hemorrhage ≥ Grade 2 (per 
CTCAE 3.0) within 6 months or Grade 1 within 28 days prior to registration are not 
eligible.  Patients must have no history of either thromboses or hemorrhage, including 
hemorrhagic or thrombotic stroke or other CNS bleeding. 
NOTE:  The treating physician is responsible for documenting the amount of blood at 
hemoptysis.   
5.11 
Patients may be on stable therapeutic anticoagulation, including warfarin or low 
molecular weight heparin, as needed, except for those with a history of bleeding 
complications on anticoagulation or an inability to establish a stable therapeutic regimen 
for anticoagulation. 
5.12 
Patients must have adequate hepatic function, as determined by the following tests 
measured within 28 days prior to registration: serum bilirubin ≤ 1.0 x the institutional 
upper limit of normal (IULN) and a SGOT or SGPT ≤ 2.5 x IULN  
5.13 
Patients must have adequate renal function, as determined by the following tests 
measured within 28 days prior to registration:  serum creatinine ≤ 1.5 x IULN or a 
calculated or measured creatinine clearance ≥ 50 ml/min using the following formula: 
Calculated Creatinine Clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x serum creatinine (mg/dl) 
5.14 
Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) 
ratio.  For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be 
< 1,000 mg for patient enrollment.  The urine protein used to calculate the UPC ratio 
must be obtained within 28 days prior to registration. 
NOTE:  UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion – a 
UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm.  UPC ratio is 
calculated using one of the following formulas: 
[urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
[(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
5.15 
Patients must have an ANC ≥ 1,500/mcl and a platelet count ≥ 100,000/mcl obtained 
within 28 days prior to registration. 


S0635 
Page 20 
Amended 9/17/07 
SWOG Patient No.   
Patient's Initials (L, F, M)   
5.16 
Patients with hypertension must have hypertension controlled on medication prior to 
enrollment. 
5.17 
Patients must have a Zubrod Performance Status of 0 - 2 (see Section 10.5). 
5.18 
All patients must be 18 years of age or older. 
5.19 
Institutions must offer patient participation in correlative science studies as outlined in 
Section 15.0. 
5.20 
Patients must not be currently receiving or planning to receive surgery or any other non-
protocol treatment (including chemotherapy, hormonal, biologic or radiation therapy) 
directed at the BAC. 
5.21 
Patients must not have a serious non-healing wound, ulcer, or bone fracture. 
5.22 
No other prior malignancy is allowed except for the following: adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II 
cancer from which the patient is currently in complete remission, or any other cancer from 
which the patient has been disease-free for five years. 
5.23 
Pregnant or nursing women are not eligible to participate in this trial due to the potential 
teratogenic or abortifacient effects of the study drug on the fetus or nursing infant. 
Women and men of reproductive potential must have agreed to use an effective 
contraceptive method. 
5.24 
Patients must be informed of the investigational nature of this study and must sign and 
give written informed consent in accordance with institutional and federal guidelines. 
5.25 
At the time of patient registration, the treating institution's name and ID number must be 
provided to the Data Operations Center in Seattle in order to ensure that the current 
(within 365 days) date of institutional review board approval for this study has been 
entered into the data base. 


Amended 9/17/07 
S0635 
Revised 3/29/11 
Page 21 
6.0 
STRATIFICATION FACTORS 
There will be no stratification in this protocol. 
7.0 
TREATMENT PLAN 
For treatment or dose modification questions, please contact Dr. West at 206/386-2424 or Dr. 
Antoinette Wozniak at 313/576-8752.  For dosing principles or questions, please consult the 
Southwest Oncology Group Policy #38 "Dosing Principles for Patients on Clinical Trials" at 
http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 
38). 
7.1 
Good Medical Practice 
The following tests (and/or assessments) are recommended within 28 days prior to 
registration in accordance with Good Medical Practice.  Results of these tests do not 
determine eligibility and minor deviations from normal limits would be acceptable if they 
do not affect patient safety in the clinical judgment of the treating physician.  If there are 
significant deviations in these tests/assessments that could impact patient safety, it is 
highly recommended that the registering investigator discuss the patient with the Study 
Coordinator prior to registering. 
a.
HGB ≥ 9 g/dl
b.
Albumin and LDH
c.
Alkaline phosphatase
d.
Bone scan, if clinically indicated
e.
PET scan, if clinically indicated
f.
Patients should not have psychological, familial, sociological or geographical
conditions that do not permit medical follow-up and compliance with the study
protocol.
g.
Except for cancer-related abnormalities, patients should not have unstable or
pre-existing major medical conditions.
h.
Patients should not have any immediate life-threatening complications of their
malignancies.
7.2 
Treatment 
AGENT 
DOSE 
ROUTE 
DAYS 
INTERVAL** 
OSI-774 
*150 mg/day
PO 
1 - 21 
Daily 
Bevacizumab 
15 mg/kg 
IV infusion 
1 
q 21 days 
over 90 ±  
15 minutes*** 
*
OSI-774 tablets are supplied as 25 mg, 100 mg, and 150 mg tablets.  Tablets should
be taken in the morning with up to 200 mL of water 1 hour before or 2 hours after
food.
** A cycle of therapy is 21 days. 
*** If no adverse reactions occur, the second dose of bevacizumab should be given over 
a minimum of 60 minutes.  If no adverse event occurs, third and subsequent doses 
should be administered over a minimum of 30 minutes.  Infusions should be run in a 
volumetric infusion device.  Infusions should be run over the shortest period that is 
well-tolerated. 


Amended 9/17/07 
S0635 
Revised 3/29/11 
Page 22 
Revised 11/9/11 
NOTE:  Patients will be given a 30-day supply of OSI-774. Patients receiving full dose 
therapy will be supplied with 150 mg tablets and those reduced to a dose of 100 mg/day 
will be supplied with 100 mg tablets.  Patients dose reduced to 50 mg/day will be 
instructed to take two 25 mg tablets once a day. 
Administration through G-tube:  The tablets required for the dose should be dissolved in 
100 mL of sterile water.  The dissolved tablets should be shaken vigorously to form a 
uniform suspension.  The suspension should be drawn up into a syringe and 
administered through the G-tube port.  Repeat the syringe transfer until the entire 
volume has been administered.  A small volume (40 mL) of sterile water should be 
added to the container used to dissolve the tablets and the residual suspension should 
be shaken, aspirated into a syringe, and administered. This last step should be repeated 
to ensure the entire dose is administered.  The total volume of delivery/rinse is about 
180 mL. 
7.3 
Protocol treatment and parameters will continue on the same schedule until the patient 
has met any of the criteria listed in Section 7.6. 
7.4 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 19.2). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at 
the end of treatment for each cycle.  Calendar should be kept in the patient's clinic 
chart.  Note that the Intake Calendar is provided only as a tool for tracking patient 
compliance.  Sites may utilize institutional pill diaries or other source documentation in 
place of the Intake Calendar at the discretion of the treating physician. 
7.5 
Supportive Treatment 
Patients should receive full supportive care including transfusions of blood products, 
antibiotics, antiemetics, antidiarrheals, growth factor support, bisphosphonates, etc., 
when appropriate.  Use of G-CSF for patients being treated on this study is not 
anticipated to be necessary due to the low likelihood of significant hematologic toxicity for 
this combination.   Use of G-CSF for myelosuppression, per the ASCO guidelines 
(http://www.jco.org/cgi/content/full/18/20/3558), is at the discretion of the treating 
physician.  If used, it must be documented on the S0635 Treatment Form (Form #37277). 
The use of erythropoietin is also at the discretion of the treating physician.  If used, it 
must be documented on the S0635 Treatment Form (Form #37277). 
7.6 
Criteria for Removal from Protocol Treatment: 
a.
Progression of disease or symptomatic deterioration (as defined in Sections
10.2d and 10.2e)
b.
Unacceptable toxicity
c.
Development of any gross hemoptysis
d.
Treatment delay for both agents > 35 days, for any reason
e.
The patient may withdraw from the study at any time for any reason
f.
Physician’s discretion
7.7 
All reasons for discontinuation of treatment must be documented on the Off Treatment 
Notice (Form #28829). 
7.8 
All patients will be followed for a maximum of 3 years. 


S0635 
Page 23 
Revised 3/29/11 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
8.1 
Two different versions of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be used on this study. 
a.
Serious Adverse Event (SAE) reporting
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0
will be utilized for SAE reporting only. The CTCAE Version 4.0 is identified and
located at the CTEP website at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All
appropriate treatment areas should have access to a copy of the CTCAE Version
4.0. 
b.
Routine toxicity reporting
This study will utilize the CTCAE Version 3.0 for routine toxicity reporting. A copy
of the CTCAE Version 3.0 can be downloaded from the CTEP home page
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a
copy of the CTCAE Version 3.0.
8.2 
General Considerations 
a.
Dose modifications will be based on toxicities experienced during the previous
cycle of treatment.
b.
Once a dose is reduced, it will remain reduced for all subsequent administrations.
There are no dose re-escalations.
c.
If multiple toxicities are experienced, dose modifications will be based on the
toxicity requiring the largest dose reduction.
d.
Patients who must discontinue erlotinib or bevacizumab may continue on the
other agent and continue on study.
e.
Patient must be removed from protocol treatment if dose of both agents is
delayed > 21 days.
f.
NOTE:  In the event that treatment is held, therapy for that week cannot be made
up (i.e., the calendar is not stopped).
8.3 
If patients require radiation therapy for palliation in the absence of progressive disease, 
please contact Dr. West at 206/386-2424 to clarify the purpose of treatment. 
8.4 
Dosage Modification Criteria and Guidelines for Management of OSI-774-Related 
Toxicities 
a.
OSI-774 Dose Level Reductions
Starting Dose 
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
NOTE:  If a third dose level reduction is required, discontinue OSI-774.  The 
patient may continue on protocol treatment with single agent bevacizumab. 


S0635 
Page 24 
b.
Diarrhea
Grade 
OSI-774 
Dosage Modification 
Guideline for Management 
Grade 2 that is 
unacceptable 
to the patient 
Hold until resolution to 
≤ Grade 1, and 
subsequently re-start 
at the same dose.  If 
Grade 2 diarrhea 
recurs after re-
instituting treatment at 
the same dose, 
treatment should be 
held until resolution to 
≤ Grade 1 and re-
instituted at a one 
level dose reduction. 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2 - 4 hr until 
diarrhea free for 12 hr with a 
maximum of 16 mg/day). 
≥ 3 
Hold until resolution to 
≤ Grade 1, then re-
institute at a one level 
dose reduction. 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2 - 4 hr until 
diarrhea free for 12 hr with a 
maximum of 16 mg/day). 
c.
Rash
Grade 
OSI-774 
Dosage Modification 
Guideline for Management 
Grade 2 that is 
unacceptable 
to the patient 
Hold until resolution to 
≤ Grade 1, and 
subsequently re-start 
at the same dose.  If 
Grade 2 skin rash 
recurs after re-
instituting treatment at 
the same dose, 
treatment should be 
held until resolution to 
≤ Grade 1 and re-
instituted at a one 
level dose reduction.  
Administer any of the following:  
minocycline,1 topical tetracycline, 
topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral 
prednisone (short course), topical 
steroids. 
≥ 3 
Hold until resolution to 
≤ Grade 1, then re-
institute at a one level 
dose reduction. 
Administer any of the following:  
minocycline,1 topical tetracycline, 
topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral 
prednisone (short course), topical 
steroids. 
1 Recommended dose of minocycline:  200 mg po initially (loading dose) 
followed by 100 mg po bid x 7 - 10 days. 
d.
Pulmonary Toxicity/Pneumonitis
Pneumonitis and pulmonary toxicity have been reported with oral EGFR 
inhibitors such as ZD1839 and OSI-774.  Patients who continue to smoke 
tobacco products should be encouraged to discontinue their use due to a 
possible association between tobacco smoking and pulmonary toxicity.  All 
patients with new onset or worsening symptoms/signs of pneumonitis (i.e., 


Revised 10/15/08 
S0635 
Revised 5/11/09 
Page 25 
cough, dyspnea, fever) should have their treatment held pending investigation 
into the cause of their symptoms.  Patients found to have pneumonitis thought to 
be related to OSI-774 should be removed from treatment with OSI-774.  Patients 
with alternative explanations for their pulmonary symptoms may restart OSI-774 
without a dose reduction once symptoms return to Grade 1 or less. 
e.
Liver Function Abnormalities
Grade 
OSI-774 Dose Modification 
SGOT or SGPT 
 ≥ Grade 3 
OR 
Bilirubin 
≥ Grade 3 
Hold OSI-774.  Check weekly.  Upon 
resolution to ≤ Grade 2, re-start OSI-774 at 
one level dose reduction. 
f.
GI Perforation
In the event of bowel perforation, permanently discontinue erlotinib.
g.
Ocular Toxicities
If patient experiences acute/worsening eye pain, hold erlotinib until recovery and
then re-start at same dose.  If inflammation persists or if severe eye surface
damage occurs, permanently discontinue erlotinib.
h.
Other medically concerning toxicities
No dose reduction will be considered for any grade of alopecia.
For any other Grade 3 or greater toxicity, hold treatment until the toxicity resolves
to Grade 1 or less, then resume treatment at a reduced dose of 100 mg/day.  If
toxicity has not resolved to Grade 1 or less after 14 days off of treatment, call the
Study Coordinator to reconsider further therapy on this study.  If Grade 3 or
greater toxicity recurs after the patient has been already reduced to 100 mg/day,
hold treatment until the toxicity resolves to Grade 1, then resume treatment at a
dose of 50 mg/day.
8.5 
Treatment Modification Criteria and Guidelines for Management of Bevacizumab-
Related Toxicities 
There are no dose reductions for bevacizumab, only dose delays. If adverse events occur 
that require holding bevacizumab, the dose will remain the same once treatment 
resumes.  Adverse events requiring delays or permanent discontinuation of bevacizumab 
are outlined below.   
Patients who require discontinuation of bevacizumab for toxicity may continue to receive 
OSI-774. 
a.
Infusion-Related Adverse Events
If a patient experiences a Grade 1 or 2 bevacizumab infusion-related adverse
event, he or she may be premedicated for the next bevacizumab infusion;
however, the infusion time may not be decreased for the subsequent infusion.  If


S0635 
Page 25a 
Revised 5/11/09 
the next infusion is well tolerated with premedication, the subsequent infusion 
time may then be decreased by 30 ± 10 minutes as long as the patient continues 
to be premedicated.  If the patient experiences an infusion-associated adverse 
event with the 60-minute infusion, all subsequent doses should be given over 90 
± 15 minutes.  Similarly, if the patient experiences an infusion-associated 
adverse event with the 30 minute infusion, all subsequent bevacizumab doses 
should be given over 60 ± 10 minutes. 
In the event of Grade 3 or 4 infusion reaction, discontinue bevacizumab.* 
b.
For platelet counts < 50,000/mcl, hold bevacizumab.  If platelet count does not
recover within 21 days after discontinuation, the patient should be removed from
bevacizumab treatment.*


Revised 1/9/09 
S0635 
Revised 3/29/11 
Page 26 
c.
Hemorrhage
Any CNS hemorrhage 
Discontinue bevacizumab* 
Grade 2 hemoptysis 
Discontinue bevacizumab* 
Grade 2 other than 
Hold bevacizumab until both of the following criteria 
hemoptysis 
are met: 
•
The bleeding has resolved and hemoglobin is
stable
•
There is no anatomic or pathologic condition that
would 
significantly 
increase 
the 
risk 
of
hemorrhage recurrence
Grade 3 or 4 
Discontinue bevacizumab* 
d.
Venous Thrombosis
Grade 3 or 4 
Discontinue 
bevacizumab 
and 
initiate 
therapeutic 
anti-
coagulation* 
e.
Proteinuria
UPC ratio to be performed prior to every other bevacizumab treatment.  If UPC
ratio > 1 then a 24 hour urine protein must be obtained.  If at any point a patient
has a UPC ratio > 1 (including patients who have had UPC > 1 prior to Revision
#9) they do not need to undergo any further UPC ratio testing, but may proceed
directly to 24 hour urine protein test for all future timepoints.
Grade 3 
Hold bevacizumab until proteinuria improves to ≤ Grade 2 
(> 3.5 g/24 hr) 
Grade 4 
Discontinue bevacizumab* 
(nephrotic 
syndrome) 
f.
Hypertension
Grade 3 
If not controlled with medication, discontinue bevacizumab 
Grade 4 
Discontinue bevacizumab 
g.
Gastrointestinal perforation or dehiscence
If a patient experiences a GI perforation or wound dehiscence requiring medical
or surgical therapy, discontinue bevacizumab.*
h.
Bevacizumab should be held in patients with symptoms/signs suggestive of
reversible posterior leukoencephalopathy syndrome (RPLS), pending work-up
and management, including control of blood pressure.  Bevacizumab should be
discontinued upon diagnosis of RPLS.*


S0635 
Page 27 
Revised 3/29/11 
i.
Arterial thromboembolic events (including angina, myocardial infarction, transient
ischemic attack, cerebrovascular accident, or any other arterial thromboembolic
event)
Grade
Dose Modification 
Any Grade 
Discontinue bevacizumab* 
j.
Other non-hematological Grade 3 or 4 adverse events:  If a patient develops any
other Grade 3 toxicity (except for controllable nausea/vomiting) thought to be
related to bevacizumab or that would increase the risk of bevacizumab toxicity,
bevacizumab should be held until symptoms resolve to Grade 1 or less.  If Grade
3 toxicity persists for > 21 days or recurs after resumption of the therapy,
discontinue bevacizumab.*  For Grade 4 toxicities (except for controllable
nausea/vomiting), discontinue bevacizumab.*
*Patients are to continue on protocol treatment with single agent OSI-774 (per Section
8.2d). 
8.6 
For treatment or dose modification questions, please contact Dr. West at 206/386-2424 
or Dr. Antoinette Wozniak at 313/576-8752. 
8.7 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and NCI via AdEERS, and to the IRB per local IRB requirements. 


S0635, "A Phase II Trial of the Combination of OSI-774 (Erlotinib; NSC-718781) and Bevacizumab (Rhumab VEGF; NSC-704865) in Stage IIIB and IV Bronchioloalveolar Carcinoma (BAC) 
              and Adenocarcinoma with BAC Features (AdenoBAC)"
9.0    STUDY CALENDAR
√
REQUIRED STUDIES
PRE
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Follow-Up Prior
Follow-Up After
STUDY
1
2
3
4
5
6
7
8
9
10
11
12
 To Progression
  Progression
PHYSICAL
History and Physical Exam, including Blood Pressure
X
X
X
X
X ∆
Review Intake Calendar
X
X
X
Weight and Performance Status
X
X
X
X
X
Disease  Assessment  %
X
X
X%
Toxicity Notation
X
X
X
X
X#
X#
LABORATORY
CBC/Differential/Platelets
X
X
X
X
X
Bilirubin
X
X
X
X
SGOT or SGPT
X
X
X
X
Serum Creatinine Φ
X
X
X
X
X
Calculated or Measured Creatinine Clearance
X
X
X
X
X
Urine Protein Creatinine (UPC) Ratio*
X
X
X
SUGGESTED LABORATORY
Albumin and LDH  ß
X
X
X
X
Alkaline phosphatase  ◊ ß
X
X
X
X
SPECIMEN SUBMISSION
Tissue per Section 15.2 
X
Blood specimens and plasma per Section 15.2 
X
X
X
XҰ
X-RAYS & SCANS 
Chest CT  %
X
X
X%
Correlative Imaging Study  ‡
X
Brain CT/MRI 
X
Bone scan  £
X
PET  £
X
TREATMENT (see Section 7.0 for details)
OSI-774
X
X
X
X
X
X
X
X
X
X
X
X
Bevacizumab
X
X
X
X
Note:  Forms are found in Section 18.0.  Forms submission guidelines are found in Section 14.0.
%   To be performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years.  For patients who have not progressed by the two-year point, chest CT must be performed 
        once every 6 months until progression.  Disease must be assessed using the same technique as baseline and must be documented on the Follow-Up Tumor Assessment form.  A response
        must be confirmed by a second determination at least 4 weeks after a CR or PR has been noted.  
  ‡   If patient is removed from protocol treatment before Week 13, perform scan after discontinuation of treatment.  Prestudy and follow-up CT scans should be performed with the same CT scanner 
       (or identical brand and model) and techniques to allow for reliable comparison of response to be determined by central computer-assisted image analysis.  See Section 15.1 for Radiology Review
       Requirements.
∆    To be performed every 9 weeks until progression.
Φ    Not necessary if measured creatinine clearance is used.  
◊
Abnormalities in alkaline phosphatase levels should be appropriately followed to document the possibility of bone or hepatic metastases.
*
UPC ratio to be performed prior to every other bevacizumab treatment.  If UPC ratio > 1 then a 24 hour urine protein must be obtained.  If at any point a patient has a UPC ratio > 1 
(including patients who have had UPC > 1 prior to Revision #9) they do not need to undergo any further UPC ratio testing, but may proceed directly to 24 hour urine protein test for all future timepoints.
ß     Results of these tests do not determine eligibilty but are recommended prior to registration in accordance with Good Medical Practice (see Section 7.1) and are required during treatment and 
        throughout follow-up.
£   PET and/or bone scan is to be performed only if clinically indicated (per GMP).
∑    Protocol treatment and parameters will continue on the same schedule until patient has met any of the criteria in Section 7.6.  
√
After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years from initial registration.
#    Toxicity should be evaluated until resolution to ≤ Grade 1 of any adverse events.
Ұ    It is very important to obtain a blood specimen (approximately 10 ml) from any patient that is being removed from protocol treatment, regardless of the timepoint.
Cycle 1
Cycle 2
Cycle 4  ∑  
Cycle 3 
S0635
Page 28
Amended 9/17/07
Revised 1/9/09
Revised 3/29/11


S0635 
Page 29 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
10.1 
Measurability of lesions 
a.
Measurable disease:  Lesions that can be accurately measured in at least one
dimension by 1) medical photograph (skin or oral lesion), palpation, plain x-ray,
CT, MRI or other conventional technique with longest diameter 2 cm or greater in
the axial plane (bone lesions not included), or 2) spiral CT with longest diameter
1 cm or greater.  Ultrasound is suitable only for superficial disease (superficial
palpable nodes, subcutaneous lesions, thyroid nodules).
CT imaging is the preferred radiographic method for measuring response. 
Conventional CT or MRI slices are recommended to be 5 mm or smaller; spiral 
CT should be performed using a 5 mm contiguous reconstruction algorithm. 
b.
Non-measurable disease:  All other lesions including lesions too small to be
considered measurable, pleural or pericardial effusions, ascites, bone disease,
inflammatory breast disease, leptomeningeal disease, lymphangitis, pulmonitis,
abdominal masses not confirmed and followed by imaging techniques, cystic
lesions or disease documented by indirect evidence only (e.g., by lab values),
previously radiated lesions that have not progressed.
10.2 
Objective status at each evaluation:  Objective Status is to be recorded at each 
evaluation.  All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total, representative of all involved organs, should be identified as target lesions 
at baseline.  All measurable lesions not identified as target lesions are non-target lesions 
and are included as non-measurable disease.  Measurements must be provided for target 
measurable lesions, while presence or absence must be noted for non-target measurable 
and non-measurable disease. 
a.
Complete Response (CR):  Complete disappearance of all measurable and
non-measurable disease.  No new lesions.  No disease related symptoms.
Normalization of markers and other abnormal lab values.  All disease must be
assessed using the same technique as baseline.
b.
Partial Response (PR):  Applies only to patients with at least one measurable
lesion.  Greater than or equal to 30% decrease under baseline of the sum of
longest diameters of all target measurable lesions.  No unequivocal progression
of non-measurable disease.  No new lesions.  All target measurable lesions must
be assessed using the same techniques as baseline.
c.
Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.
All target measurable lesions must be assessed using the same techniques as
baseline.
d.
Progression:  One or more of the following must occur:  20% increase in the
sum of longest diameters of target measurable lesions over smallest sum
observed (over baseline if no decrease during therapy) using the same
techniques as baseline.  Unequivocal progression of non-measurable disease in
the opinion of the treating physician (an explanation must be provided).
Appearance of any new lesion/site.  Death due to disease without prior
documentation of progression and without symptomatic deterioration (see
Section 10.2e).
e.
Symptomatic deterioration:  Global deterioration of health status requiring
discontinuation of treatment without objective evidence of progression.  Efforts
should be made to obtain objective evidence of progression after discontinuation.


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f.
Assessment inadequate, objective status unknown:  Progression or
symptomatic deterioration has not been documented, and one or more target
measurable lesions have not been assessed or inconsistent assessment
methods were used.
g.
Objective status notes:
1.
Non-measurable and non-target measurable disease do not affect
objective status except in determination of CR (must be absent--a patient
who otherwise has a CR, but who has non-measurable or non-target
measurable disease present or not assessed, will be classified as having
a PR), and in determination of progression (if new sites of disease
develop or if unequivocal progression occurs in the opinion of the
treating physician).
2.
An objective status of PR or stable cannot follow one of CR.  Stable can
follow PR only in the rare case that tumor increases too little to qualify as
progression, but enough that a previously documented 30% decrease no
longer holds.
3.
In cases for which initial flare reaction is possible (hypercalcemia,
increased bone pain, erythema of skin lesions), objective status is not
progression unless either symptoms persist beyond 4 weeks or there is
additional evidence of progression.
4.
Lesions that appear to increase in size due to presence of necrotic tissue
will not be considered to have progressed.
5.
For bone disease documented on bone scan only, increased uptake
does not constitute unequivocal progression.
6.
Appearance or worsening of pleural effusions does not constitute
unequivocal progression unless cytologically proven of neoplastic origin.
7.
If CR determination depends on a lesion for which the status is unclear
by the required tests, it is recommended the residual lesion be
investigated with biopsy or fine needle aspirate.
10.3 
Best Response:  This is calculated from the sequence of objective statuses. 
a.
CR:  Two or more objective statuses of CR a minimum of four weeks apart
documented before progression or symptomatic deterioration.
b.
PR: Two or more objective statuses of PR or better a minimum of four weeks
apart documented before progression or symptomatic deterioration, but not
qualifying as CR.
c.
Unconfirmed CR:  One objective status of CR documented before progression or
symptomatic deterioration but not qualifying as CR or PR.
d.
Unconfirmed PR:  One objective status of PR documented before progression or
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.
e.
Stable/no response:  At least one objective status of stable/no response
documented at least 6 weeks after registration and before progression or
symptomatic deterioration, but not qualifying as anything else above.


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f.
Increasing disease:  Objective status of progression  within 12 weeks of
registration, not qualifying as anything else above.
g.
Symptomatic deterioration:  Objective status of symptomatic deterioration within
12 weeks of registration, not qualifying as anything else above.
h.
Inadequate assessment, response unknown:  Progression or symptomatic
deterioration greater than 12 weeks after registration and no other response
category applies.
10.4 
Computer-Assisted Image Analysis 
a.
A pre-study chest CT must show evidence of disease, and repeat CT scans must
be performed with the same CT scanner and techniques (e.g., slice width, the
use of contrast) used for subsequent evaluation of two follow-up CT scans to
assess response to therapy by computerized image analysis.  Chest CT scans
must be downloaded in DICOM format to CDs.
b.
For the purposes of computer-assisted image analysis, the following alternate
response definitions will be employed.
1.
Measurable disease:  Any lesion on CT measurable by computer-
assisted image analysis.
2.
Complete Response (CR):  Complete disappearance of all measurable
disease.  No new lesions.  All measurable lesions and sites must be
assessed using the same techniques as baseline.
3.
Partial Response (PR):  Greater than or equal to a 50% decrease in the
volume of lesions compared to baseline measured by computer-assisted
image analysis.
4.
Stable Disease (SD):  Does not qualify as CR, PR, or PD (below).
5.
Progressive Disease (PD):  30% increase in the volume of disease over
baseline, OR reappearance of any lesion that had disappeared, OR
appearance of any new lesion, OR failure to return for evaluation due to
death or deteriorating condition unless clearly unrelated to the underlying
cancer.
Exceptions:  (1) In cases for which initial tumor flare reaction is possible
(hypercalcemia, increased bone pain, erythema of skin lesions), either
symptom must persist beyond four weeks or there must be additional
evidence of progression.  (2)  Lesions, which appear to increase in size
due to presence of necrotic tissue, will not be considered to have
progressed.
6.
Unknown:  Progression has not been documented and one or more
measurable sites have not been assessed.


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10.5 
Performance Status:  Patients will be graded according to the Zubrod Performance 
Status scale. 
POINT 
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, office 
work.   
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours.   
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours.   
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair.   
10.6 
Progression-Free Survival:  From date of registration to date of first documentation of 
progression or symptomatic deterioration (as defined in Sections 10.2d - 10.2e), or death 
due to any cause.  Patients last known to be alive and progression-free are censored at 
date of last contact. 
10.7 
Time to Death:  From date of registration to date of death due to any cause.  Patients 
last known to be alive are censored at date of last contact. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
The accrual rate is expected to be 6-10 per month (conservatively) based on S0126 
accrual.  With emerging positive data for bevacizumab in NSCLC and the fact that this 
costly agent is being provided free-of-charge for this study, interest in this trial may lead 
to higher accrual rates. 
11.2 
The main objective of this study is to assess the overall survival of patients with 
BAC/adenoBAC who receive daily oral OSI-774 (erlotinib) in combination with 
intravenous bevacizumab every 3 weeks.  It is assumed that the regimen would not be 
promising if the true median survival were ≤ 12 months, but would be of considerable 
interest if the true median survival were ≥ 19 months.  Eighty eligible patients will be 
accrued over an estimated eight months.  With an additional 18 months of follow-up, we 
will have 86% power to rule out the null hypothesis of a 12-month median survival at a 
.05 level (indicating no further interest in the regimen) versus an alternative of a 19-month 
median survival.  An observed median survival of 16 months or longer will be considered 
evidence that this regimen warrants further testing in a Phase III setting providing other 
factors such as toxicity appear favorable.   
11.3 
The rate of Grade 4 or 5 hemorrhage will be closely monitored throughout this trial.  Once 
adverse event data becomes available on the first 30 eligible patients who receive 
protocol treatment, if the rate of Grade 4 or 5 hemorrhage exceeds or equals 10% of all 
eligible patients who have received protocol treatment, the trial will be stopped.  Eighty 
patients will be sufficient to estimate the probability of a particular toxicity to within ± 11% 
(95% confidence interval).  Any toxicity with at least 5% probability is likely to be seen at 
least once (98% chance).  


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Amended 9/17/07 
11.4 
Eighty patients are sufficient to estimate the progression-free survival rate at any time 
point (e.g. 12 months) to within ± 11% (95% confidence interval).  Assuming that 70% of 
patients will have measurable disease, then response will be assessed in approximately 
56 patients.  Fifty-six patients are sufficient to estimate the RECIST response rate 
(confirmed plus unconfirmed, complete plus partial) to within ± 13% (95% confidence 
interval). 
The level of agreement between response outcomes via CAIA versus response by 
RECIST will be preliminarily assessed among the subset of patients who have both 
measurable disease (as defined by RECIST) and CT images available for central review. 
11.5 
Molecular Correlative Statistical Considerations 
The relationship between clinical outcomes and EGFR and ras mutations, as well as 
EGFR and VEGF expression in tissue collected from patients with bronchioloalveolar 
carcinoma or BAC variants will be investigated.  Due to the limited sample size provided 
in a Phase II setting, these correlative studies will be considered exploratory in nature 
and will help generate hypotheses for future studies.  Assuming an 80% submission rate 
for specimens, we expect to have specimens from approximately 64 patients. 
11.6 
There is no formal data and safety monitoring committee for Phase II studies.  Toxicity 
and accrual monitoring are done routinely by the Study Coordinator, study Statistician 
and the Disease Committee Chair.  Response monitoring is done by the study Statistician 
and Study Coordinator.  Accrual reports are generated weekly, and formal toxicity reports 
are generated every 6 months.  In addition, the Statistical Center, Adverse Event 
Coordinator at the Operations Office, SAE Physician Reviewer, and Study Coordinator 
monitor toxicities on an ongoing basis. 
12.0 
DISCIPLINE REVIEW 
No formal discipline review will be performed in conjunction with this study. 
13.0 
REGISTRATION GUIDELINES 
13.1  
Patients must be registered prior to initiation of treatment (no more than seven working 
days prior to planned start of treatment). 
13.2  
For either phone or web registration, the individual registering the patient must have 
completed the appropriate Southwest Oncology Group Registration Form. The completed 
form must be referred to during the registration but should not be submitted as part of the 
patient data. 
The individual registering the patient must also be prepared to provide the treating 
institution's name and ID number in order to ensure that the current (within 365 days) 
date of institutional review board approval for this study has been entered into the data 
base.  Patients will not be registered if the IRB approval date has not been provided or is 
> 365 days prior to the date of registration. 
13.3  
Registration Procedures 
a.
You may register patients from Member, CCOP and approved Affiliate institutions
to a therapeutics study using the SWOG Registration program. To access the
Registration program go to the SWOG Web site (http://swog.org) and click on the
Logon 
link 
to 
go 
to 
the 
SWOG 
Members 
Area 
logon 
page


S0635 
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Revised 11/9/11 
(https://swog.org/visitors/logon.asp).  This Web program is available at any time 
except for periods listed under Down Times.  Log on as an Individual User using 
your SWOG Roster ID Number and individual web user password.  Help for the 
logon process may be found at https://swog.org/visitors/logonhelp.asp. After you 
have logged on, click on the Clinical Trials link and then the Patient Reg link to 
go to the Entry Page for the Patient Registration program. If you are a Registrar 
at an institution with Internet access you are encouraged to register this way.  For 
new users, the link to a "Starter Kit" of help files may be found by clicking on 
Starter Kit link at the logon page. 
To register a patient the following must be done (in order): 
1.
You are entered into the Southwest Oncology Group Roster and issued
a SWOG Roster ID Number,
2.
You are associated as an investigator or CRA/RN to the institution where
a registration is occurring, and
3.
You are granted permission to use the Patient Registration program at
that institution.
For assistance with points 1 and 2 call the SWOG Operations Office at 210/614-
8808.  For point 3 you must contact your Web User Administrator.  Each SWOG 
institution has one or more Web User Administrators who may set up Web Users 
at their institution and assign permissions and passwords to these users. For 
other password problems or problems with the Patient Registration program, 
please e-mail webreghelp@crab.org. Include your name, Roster ID Number, and 
telephone number, when the problem occurred, and exactly what you were 
doing. 
b.
If the Web Reg program is not used, the registration must be done by phone.
Member, Affiliate and CCOP Institutions
Registration by phone of patients from member, affiliate and CCOP institutions
must be done through the Southwest Oncology Group Data Operations Center in
Seattle by telephoning 206/652-2267, 6:30 a.m. to 4:00 p.m. Pacific Time,
Monday through Friday, excluding holidays.
13.4  
For either method of registration, exceptions to Southwest Oncology Group registration 
policies will not be permitted. 
a.
Patients must meet all eligibility requirements.
b.
Institutions must be identified as approved for registration.
c.
Registrations may not be cancelled.
d.
Late registrations (after initiation of treatment) will not be accepted.
14.0 
DATA SUBMISSION SCHEDULE 
14.1 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 


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Amended 9/17/07 
Revised 1/9/09 
Revised 11/9/11 
14.2 
Master forms are included in Section 18.0 and (with the exception of the sample consent 
form and the Registration Form) must be photocopied for data submission to the Data 
Operations Center in Seattle.  Data from approved SWOG institutions must be submitted 
on-line via the Web; see Section 14.3a for details.  Exceptions to online data submission 
are patient-completed (e.g. Quality of Life) forms and source documents (e.g. 
pathology/operative/lab reports). 
14.3 
Data Submission Procedures. 
a.
Southwest Oncology Group institutions must submit data electronically via the
Web by using the SWOG CRA Workbench.  To access the CRA Workbench, go
to the SWOG Web site (http://swog.org) and logon to the Members Area.  After
you have logged on, click on the CRA Workbench link to access the home page
for CRA Workbench website.  Next, click on the Data Submission link and follow
the instructions.  For new users, the link to a "Starter Kit" of help files may be
found by clicking on the Starter Kit link at the Members’ logon page.
To submit data via the web the following must be done (in order):
1.
You are entered into the Southwest Oncology Group Roster and issued
a SWOG Roster ID Number,
2.
You are associated as an investigator or CRA/RN at the institution where
the patient is being treated or followed, and
3.
Your Web User Administrator has added you as a web user and has
given you the appropriate system permissions to submit data for that
institution.
For assistance with points 1 and 2 call the Operations Office at 210/614-8808. 
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
b.
If you need to submit data that are not available for online data submission, the
only alternative is via facsimile.  Should the need for this occur, institutions may
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do
not use cover sheet for faxed data.
14.4 
WITHIN 14 DAYS OF REGISTRATION: 
Submit a copy of the following: 
a.
S0635 Prestudy Form (Form #11652).
b.
Baseline Tumor Assessment Form (#848).
c.
Pathology Report (for confirmation of histological diagnosis of bronchioloalveolar
carcinoma) must be faxed.
14.5 
SPECIMEN SUBMISSION: 
Submit specimens for correlative testing as outlined in Section 15.0. 


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Amended 9/17/07 
Revised 11/9/11 
14.6 
WITHIN 7 DAYS AFTER COMPLETION OF EACH CYCLE OF TREATMENT:  
Submit a copy of the following: 
a.
S0635 Treatment Form (Form #37277).
b.
S0635 Adverse Event Form (Form #34254).
NOTE:  One cycle = 21 days. 
14.7 
AFTER EVERY DISEASE ASSESSMENT WHILE ON PROTOCOL TREATMENT: 
Submit a copy of the Follow-Up Tumor Assessment Form (Form #38305). 
14.8 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
Submit a copy of the following: 
a.
Off 
Treatment 
Notice 
(Form 
#28829) 
documenting 
date 
of
progression/relapse/other reason and summarizing inclusive dates of treatment
and patient status.
b.
Final S0635 Treatment Form (Form #37277).
c.
S0635 Adverse Event Form (Form #34254).  If acute adverse events are not
resolved within 14 days of discontinuation of treatment, submit a final S0635
Adverse Event Form (Form #34254) after the date of the first visit or contact after
their resolution.
14.9 
WITHIN 30 DAYS AFTER THE WEEK 13 CT SCAN OR WITHIN 30 DAYS OF 
DISCONTINUATION OF TREATMENT: 
Submit a copy of the following: 
a.
Materials for Radiology Analysis per Section 15.1.
b.
A copy of the CAIA Radiology Submission Form (Form #58117) to the Data
Operations Center in Seattle.
14.10 
WITHIN 14 DAYS OF PROGRESSION OR RELAPSE: 
Submit a copy of the following: 
a.
Lung Carcinoma First Site(s) of Progression or Relapse Form (Form #9469).
b.
Follow-Up Tumor Assessment Form (Form #38305).
c.
If the patient is off protocol treatment, also submit the Lung Carcinoma Follow-Up
Form (Form #32426).
14.11 
ONCE OFF ALL PROTOCOL TREATMENT, EVERY 3 MONTHS FOR 1 YEAR AND 
THEN EVERY 6 MONTHS FOR A MAXIMUM OF 3 YEARS FROM REGISTRATION: 
Submit a copy of the following: 
a.
Copies of the Follow-Up Tumor Assessment Form (Form #38305) corresponding
to every disease assessment performed every 9 weeks until disease
progression.
b.
Lung Carcinoma Follow-Up Form (Form #32426).


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Revised 11/9/11 
14.12 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
Submit a copy of the following: 
a.
Lung Carcinoma Follow-Up Form (Form #32426).
b.
Notice of Death (Form #49467).
15.0 
SPECIAL INSTRUCTIONS 
15.1 
Radiology Analysis 
a.
The prestudy chest CT and first two follow-up scans (Week 7 and Week 13, or
end of treatment scan if off treatment prior to Week 13) must be performed using
the same scanner (or identical brand and model) and techniques to allow for
comparison by image analysis.  These scans will be submitted for central review
and analysis.
b.
Submit the chest CT scans in 16-bit images in DICOM format on CD with
accompanying radiology report and a copy of the CAIA Radiology Submission
Form (Form #58117) within 30 days after the Week 13 assessment or within 30
days of removal from protocol treatment to:
Dr. Derick H. M. Lau  
Division of Hematology/Oncology 
Department of Medicine 
UC Davis Cancer Center 
4501 X Street, Room 3019 
Sacramento, CA 95817-2229 
Phone:  916/734-3772 
It is strongly recommended that the pre-treatment and post-treatment CT 
scans be sent together rather than separately. 
An additional copy of the CAIA Radiology Submission Form (Form #58117) 
must be submitted to the Data Operations Center in Seattle each time 
submissions are made to Dr. Lau. 
c.
Image analysis of CT scans to assess responses will be performed with a
previously published method.  (17)
d.
Centralized testing will be performed only after study funding for these analyses
is obtained.
15.2 
Specimens for correlative studies and banking (submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201)(optional): 
a.
With patient’s consent, specimens must be collected at the following times and
submitted (see Section 9.0):
1.
Submit 1 - 2 paraffin-embedded tissue blocks or slides at time of
diagnosis (or subsequent, but prior to any previous treatment). If a tissue
block is unavailable or unable to be sent, 12 – 15 unstained slides are
acceptable as an alternative. Paraffin-embedded tissue blocks or slides
will be evaluated for expression of molecular targets relevant to the
activity of bevacizumab and OSI-774 (see Section 15.2d). Results will be
correlated with patient clinical data.


Amended 9/17/07 
S0635 
Revised 12/11/07 
Page 38 
Revised 11/09/11 
2.
Collect blood and plasma specimens in a 10 cc purple-top EDTA tube at:
a.
Prior to treatment
b.
Cycle 2 prior to treatment
c.
Cycle 3 prior to treatment
d.
It is very important to obtain a blood specimen (approximately 10
ml) from any patient that is being removed from protocol
treatment, regardless of the timepoint.
The tube of blood should be immediately centrifuged at approximately 
1,000 rpm for 10 minutes. Buffy coat cells should be removed and placed 
in labeled cryo tubes. Plasma should be separately removed and placed 
in two labeled cryo tubes. All tubes are then to be frozen. Store frozen at 
-70°C until shipped on dry ice as detailed on the specimen submission 
webpage (see Section 15.2b). These specimens will be used for protein 
and DNA assays. Blood Specimens will be examined for the presence of 
shed mutant tumor DNA (see Section 15.2d). Results will be correlated 
with patient clinical data. 
b.
Specimen collection and submission instructions can be accessed on the SWOG
Specimen Submission webpage
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via the
link on the S0635 protocol abstract page on the SWOG website (www.swog.org).
c.
Specimen collection kits are not being provided for this submission; sites will use
institutional supplies.
d.
Molecular Markers, Background, Hypotheses, Preliminary Studies and
Methods
1.
Expression of EGFR and HER-2/neu
Hypothesis: EGFR and/or HER-2/neu expression levels and/or activation
of signal pathway molecules will correlate with patient responses and/or
survival.


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Amended 9/17/07 
Revised 7/1/10 
Revised 3/29/11 
Revised 11/9/11 
This proposed trial provides an opportunity to prospectively re-examine 
this hypothesis, recently put into question by the poor predictive value of 
EGFR expression status in ZD1839 (gefitinib) trials.  For example, our 
data from S0126 showed that EGFR expression levels did not correlate 
with survival; instead it was phospho-MAPK (p-MAPK) and HER2 that 
significantly correlated with overall survival following treatment with 
ZD1839 (gefitinib).  (12)  Determining the status of these receptors will 
be part of a comprehensive analysis in delineating the contribution of 
signal transduction pathway elements in bronchioloalveolar carcinoma 
(BAC) patients treated with OSI-774 (erlotinib) plus bevacizumab.   
An objective and reproducible method for staining and scoring of 
immunohistochemical results developed by Dr. Franklin (University of 
Colorado) will be used for this trial and this aspect of the correlative 
science will be conducted under his direct supervision.  This is the same 
method used for analysis of BAC specimens from S9714 and S0126, 
providing continuity.  (7, 12)  The method consists of microscopically 
estimating the dominant intensity of staining of tumor cells on a scale of 


S0635 
Page 40 
0 to 4 with 0 being negative (no staining) and 4 intense staining.  The 
intensity of staining is then multiplied by the estimated percentage of 
tumor cells that stain positively.  The labeling scores thus range from 0-
400.  This grading scheme has the advantage that it does not depend on 
predetermined cut points, but is an objective estimation of the intensity of 
staining in the tissue section. Similar grading scales have been used in 
Leukocyte CD clustering workshops and were recently used to evaluate 
EGFR expression in the Iressa® Dose Evaluation in Advanced Lung 
cancer (IDEAL) trials for which Dr. Franklin was one of two reference 
pathologists.  (13, 15)  We have tested several series of NSCLC tumors 
using a monoclonal antibody from Zymed anti-EGFR monoclonal 
antibody 31G7.  From our studies, we estimate that approximately 60% 
of NSCLC patient tumors can be expected to exhibit staining levels of 
200 or more (IHC positive).  (24, 25)   In several studies with gefitnib, we 
have demonstrated a significant correlation between EGFR IHC levels 
and clinical outcome, both in terms of response and survival.  (24, 25) 
Likewise, in the Canadian BR-21 study with erlotinib an association was 
found between EGFR IHC and clinical outcome.  (26) 
Because of concerns regarding cellular phosphatase activity and tissue 
fixation, scoring of the phospho-specific antibody stains will be done only 
at the tissue periphery, where formalin (a known phosphatase inhibitor) 
is able to penetrate the tissue quickly and render the phosphatases 
inactive. (NOTE: Detailed methods for these correlative studies can be 
found below.) 
2.
Status of Downstream Signal Transduction Pathway Molecules
Hypothesis: 
Activated 
downstream 
components 
of 
the 
signal 
transduction cascade initiated by HER family receptor dimerization will 
allow identification of patient subsets responsive to treatment with OSI-
774 (erlotinib).  
Pertinent here will be examination of activated downstream molecules 
including p-MAPK (aka, ERK1/2), indicating activation of the proliferation 
associated RAS pathway, and p-AKT, indicating activated PI3-K/AKT 
survival associated pathway.  Similarly, low or absent basal levels of the 
cyclin-dependent kinase inhibitor p27 indicate activation of the EGFR 
pathways. 
As noted above, BAC patients with p-MAPK had significantly worse 
outcome following ZD1839 (gefitinib) therapy.  (7, 12)  However, the 
underlying mechanism for this observation remains unclear, particularly 
in other tumor types.  Because OSI-774 (erlotinib) has activity against 
EGFR, it is important to determine the status of multiple HER1/2-RAS-
MAPK-AKT pathway members in order to determine the relative 
contribution of each to clinical outcome. 
HER family signals induce cell proliferation through the RAS-MAPK 
(ERK) pathway.  These downstream markers can potentially serve as 
predictors for patient outcome following treatment with HER pathway 
inhibitors.  As mentioned above, p-MAPKn and pMAPKc significantly 
correlated with overall survival following treatment with ZD1839 (gefitinib) 
in BAC.  Furthermore, inhibition of the EGFR and HER-2 by antibodies 
and small molecules, such as OSI-774 (erlotinib), has been shown to 
induce G1 phase cell-cycle arrest.  Inhibition of EGFR by OSI-774 
(erlotinib) is not only associated with cell-cycle arrest, but also the 


S0635 
Page 41 
induction of apoptosis.  The particular mechanism and pathway(s) 
utilized are not established, but there is evidence implicating activation of 
the PI3K-AKT pathway and RhoB in reduced apoptosis associated with 
tumors overexpressing tyrosine kinase oncogenes such as EGFR.  One 
role ascribed to RhoB is in the increased ubiquitin-mediated degradation 
of the p27.  In in vitro models, increased levels of p27 are associated 
with both cell-cycle arrest and induction of apoptosis.  Loss of p27 has 
been shown to be a negative prognostic factor for lung and other tumor 
types, with loss of the protein found in approximately 70%.  Basal levels 
of p27, p-MAPK, and p-AKT will be assessed by immunohistochemistry 
(IHC) in pre-treatment tumor tissues or tumor aspirates.  
3.
EGFR Gene Mutations
Hypothesis: Mutations in the ATP-binding site/kinase domain of EGFR 
will correlate with response in patients treated with the small molecule 
EGFR inhibitor OSI-774 (erlotinib).  Further, we expect that this 
correlation will extend to overall patient survival and/or progression-free 
survival. 
One of the most recent exciting developments in cancer research is the 
finding that mutations in the EGFR gene are associated with response in 
NSCLC to a molecularly targeted small molecule inhibitor of EGFR.  Two 
groups have simultaneously reported similar results that responders to 
ZD1839 (gefitinib) have either missense point mutations or in-frame 
deletions in their tumors.  (14, 16)  The relevant mutations are now 
known to cluster within exons 19 and 21, and when one of both types of 
mutations were tested in vitro, they conferred gain-of-function or 
oncogenic activation to EGFR.  (14)   
Recently, analogous mutations in HER2 have been identified in lung 
cancers.  (18, 19)  In the latter study, HER2 mutations were found in 
1.6% of NSCLC but were absent in other types of cancers.  All HER2 
mutations were in-frame insertions in exon 20 and are in the identical 
corresponding region as for EGFR insertions (exon 19).  HER2 mutations 
were found to be significantly more frequent in never smokers (3.2%, 8 
of 248; P=0.02) and adenocarcinoma histology (2.8%, 11 of 394; 
P=0.003).  We will conduct an exploratory study of HER2 mutations in 
BAC from the specimens on this trial.      
Procedures to isolate tumor DNA and analyze it for mutations by PCR 
and sequencing have been established for many years in the laboratory 
of Dr. Gumerlock at UC Davis.  (21)  The specific primer sets needed to 
amplify EGFR exons 19 and 21, and the conditions for amplification will 
be as described in the recent publications.  These products will be 
directly sequenced using an automated DNA sequencing approach. 
Results will be correlated with patient clinical data.  (NOTE: Methods are 
summarized below.) 
Recently, acquired resistance to ZD1839 (gefitinib) has been shown to 
be associated with an additional mutation in EGFR exon 20.  (20)  Our 
group has recently identified a BAC patient from the S0126 trial that had 
this mutation de novo, prior to exposure to ZD1839 (gefitinib).  (21)  
Thus, it appears important to also examine pre-treatment specimens for 
this potential resistance factor to EGFR small molecule inhibitors. 


S0635 
Page 42 
4.
EGFR Gene Copy Number and/or Amplification
Hypothesis: That copy number and/or amplification of the EGFR gene 
will correlate with patients outcomes to OSI-774 (erlotinib) treatment. 
Hirsch et al from our group, have evaluated gene copy number and 
protein status of EGFR in micro-arrayed tumors from 183 NSCLC 
patients, including squamous cell carcinoma (89 patients).  (22)  Protein 
expression was assessed by immunohistochemistry on a scale from 0 to 
400 (percentage of positive cells x staining intensity).  Gene and 
chromosome 7 copy numbers were identified by fluorescent in situ 
hybridization (FISH).  Table 1 outlines the definitions used to interpret 
FISH results. 
Table 1: FISH definitions 
Group Definition: 
FISH Negative 
No or low level of genomic gain for the EGFR gene (≤ 4 copies of the 
gene in > 40% of cells) 
FISH Positive 
High level of polysomy (≥ 4 copies of the gene in ≥ 40% of cells) or gene 
amplification, defined by presence of tight gene clusters, a ratio 
gene/chromosome per cell ≥ 2, or ≥ 15 copies of the genes per cell in ≥ 
10% of analyzed cells. 
Patients with high polysomy and gene amplification were deemed 
to be FISH-positive: EGFR protein over-expression was observed in 
62% of the NSCLC (25% scored 201 to 300; 37% scored 301 to 400), 
more frequently in squamous histology than non-squamous (82% v 44%; 
P < 0.001), and in 80% of the bronchioloalveolar carcinomas. The 
prevalent FISH patterns were balanced disomy (40%) and trisomy (38%) 
for EGFR gene and chromosome 7 (40%), whereas balanced polysomy 
was seen in 13% and gene amplification was seen in 9% of the patients. 
Gene copy number correlated with protein expression (r = 0.4; P < 
0.001). 
Building on these results, these same investigators then proceeded to 
compare the relationship between EGFR gene copy number, EGFR 
protein expression, EGFR mutations, and Akt activation status as 
predictive markers for ZD1839 (gefitinib) therapy in advanced NSCLC. 
(24)  Tumors from 102 NSCLC patients (from an Italian study) treated 
daily with 250 mg of ZD1839 (gefitinib) were evaluated for EGFR status 
by FISH, DNA sequencing, and IHC and for Akt activation status 
(phospho-Akt [P-Akt]) by IHC.  Amplification or high polysomy of the 
EGFR gene (seen in 33 of 102 patients) and high protein expression 
(seen in 58 of 98 patients) were statistically significantly associated with 
better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 
to 50.3; P< 0.001), disease control rate (67% versus 26%, mean 
difference = 40.6%, 95% CI = 21.5 to 59.7; P< 0.001), time to 
progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% 
CI = 2.8 to 10.3; P< 0.001), and survival (18.7 versus 7.0 months, mean 
difference = 11.7 months, 95% CI = 2.1 to 21.4; P = 0.03).  EGFR 
mutations (seen in 15 of 89 patients) were also statistically significantly 
related to response and time to progression, but the association with 


S0635 
Page 43 
survival was not statistically significant, and 40% of the patients with 
mutation had progressive disease.  In multivariable analysis, only high 
EGFR gene copy number remained statistically significantly associated 
with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). 
Independent of EGFR assessment method, EGFR+/P-Akt+ patients had 
a statistically significantly better outcome than EGFR-, P-Akt-, or 
EGFR+/P-Akt- patients. These investigators concluded that high EGFR 
gene copy number identified by FISH may be an effective molecular 
predictor for efficacy of an oral EGFR tyrosine kinase inhibitor in 
advanced NSCLC.  Hirsch and colleagues have also reported from the 
prospective placebo-controlled ISEL trial that increased EGFR gene 
copy number detected by FISH was a strong predictor for clinical 
outcome on gefitinib therapy, with a hazard ratio (HR) for survival of 0.61 
in the FISH-positive group, compared with no reduction in HR in the 
FISH-negative group.  (9, 23) 
Similar results were observed when tumor tissue from 81 patients with 
advanced stage BAC treated with ZD1839 (gefitinib) 500 mg/day in the 
Southwest Oncology Group protocol S0126 were analyzed by FISH and 
classified in two main categories: FISH positive (high polysomy/gene 
amplification) and FISH negative (disomy, trisomy and low polysomy). 
(25)  Among 19 FISH positive patients, 12 (63%) had disease control 
(response or stable disease) versus 14/36 pts (39%) in the FISH 
negative group (exact p-value=0.099).  Eighty-one patients were 
evaluable for survival, and the median survival time for the FISH 
negative patients was 8 (95%CI 6-15) months.  While the median 
survival for the FISH positive pts has not yet been reached, it is 
approaching 18 months, with a hazard ratio of 2.02 (95%CI 1.03- 3.99; p 
= 0.042).  The median progression-free survival time for FISH negative 
patients was 4 (95%CI 2- 5) months versus 9 (3-20) months for FISH 
positive patients with a hazard ratio of 1.67 (95%CI 0.96- 2.91; p=0.072). 
EGFR copy number by FISH remained a significant predictive factor after 
accounting for smoking status, sex, histology and performance status. 
This study again demonstrated a strong association between increased 
EGFR gene copy number detected by FISH and sensitivity for ZD1839 
(gefitinib) treatment in patients with advanced NSCLC.  The results 
suggested that FISH methodology can be used to select patients for 
treatment with EGFR tyrosine kinase inhibitors. 
5.
Polymorphisms of the EGFR Gene
Hypothesis: Polymorphisms within the EGFR gene will correlate with 
response and/or patient outcome to OSI-774 (erlotinib). 
We hypothesize that either or both of two specific polymorphisms within 
the EGFR gene will correlate with response and/or patient outcome. 
Analyses will be done in tumor tissue initially, with analyses in a subset 
of patient PBMCs if interesting data on specific polymorphisms are found 
in the tumor tissues.  Blood will be collected from all consenting patients 
for the analysis of genomic DNA in peripheral blood mononuclear cells 
(PBMCs) for the EGFR polymorphisms that have been shown to 
correlate with prognosis or drug activity. 
EGFR polymorphisms of potential interest for activity of EGFR inhibitors 
will be evaluated as follows, with results compared to the predecessor 
study S0126.  One known EGFR polymorphism, positioned within exon 
sequences at codon 497, was shown to be easily detected using PCR- 
 


S0635 
Page 44 
SSCP.  (27)  This G to A transition results in a substitution of a lysine for 
an arginine (HER1-497K) and appears to be fairly common in the human 
population.  By comparison with the wild-type receptor, the HER1-497K 
exhibited a reduced induction of cell growth and downstream gene 
activation when stimulated by EGF or TGF-alpha.  (28)  Another 
polymorphism is an A to T change at position 2073 that is silent and 
does not change the encoded amino acid, but does generate a unique 
BsrI restriction site which provides an assay for its rapid detection.  (29, 
30)
Both the T and A alleles appear to be relatively common in the
population, although the exact frequencies have not been established. 
Both alleles have also been found in normal and tumor tissues, although 
there may be an increased association of the T allele with malignant oral 
keratinocytes.  No specific biological differences have yet been found for 
these alleles. 
Further, several new polymorphisms were recently reported in or near 
the ATP binding site by the two groups who were sequencing for 
mutations.  (14, 16)  Because these data will also be obtained during the 
sequencing here, any associations with patient clinical data will be 
evaluated.  
6.
Plasma Markers of Angiogenesis
Hypotheses:  The distribution of pro-angiogenic factors in patient plasma 
will be predictive of patient outcome in response to bevacizumab-
containing regimens.  Specifically, patients with higher levels of tumor or 
plasma PDGF and lower levels of sICAM and OPN will have 
comparatively superior outcomes.   
We will focus our investigations on plasma levels of three markers that 
we hypothesize will correlate with patient outcome: PDGF, sICAM and 
OPN.  Platelet-derived growth factor (PDGF) and its receptors (PDGFR-
alpha and beta) are variably expressed in NSCLCs.  In a study by 
Shikada et al, PDGF-AA correlated with VEGF expression and was a 
negative prognostic factor (Shikada CR 65:7241, 2005).  Further, their 
cell line modeling indicated that PDGF, a critical angiogenic switch, 
regulated expression of VEGF.  PDGF, while a negative prognostic 
indicator, may be a positive predictive factor for bevacizumab 
activity.  Although VEGF is the sole target of bevacizumab, PDGF may 
be a superior marker as it may better reflect tumor-mediated 
angiogenesis without the inter-patient variability that VEGF is subject 
to.  Furthermore, post-treatment changes in PDGF levels may serve as 
an early indicator of therapeutic activity; whereas post-treatment VEGF 
levels may be obfuscated by bevacizumab binding.  Using ELISA or 
Luminex, we will measure the major isoforms of PDGF (AA, AB and 
BB).  Pre-treatment plasma levels of VEGF will also be measured, and 
we hypothesize that PDGF levels will roughly correlate with VEGF levels, 
such that patients high in PDGF will also show elevated VEGF (although 
some patients low in PDGF may still have elevated plasma 
VEGF).  Tumor levels of PDGF and VEGF will be assessed by IHC in 
archival tumor material. 
We hypothesize that patients with lower baseline levels of soluble 
intercellular 
adhesion 
molecule-1 
(sICAM) 
will 
have 
superior 
outcomes.  Serum levels of sICAM are elevated in patients with NSCLC 
compared with healthy volunteers, and further correlate with the 
presence of metastatic disease (Grothrey et al, Br. J Cancer, 77:801, 


S0635 
Page 45 
1998).  Dowlati et al., reported at the 2006 ASCO Annual Meeting the 
correlative biomarkers assessed for the E4599 randomized phase II/III 
trial of carboplatin and paclitaxel with or without bevacizumab in patients 
with advanced NSCLC.  From these studies, sICAM emerged as a 
strong prognostic marker of patient outcome.  When stratified at the 
median, patients with lower levels of sICAM had significantly improved 
response rates and overall survival, regardless of treatment arm.  Further 
investigation revealed a potential correlation between lower baseline 
sICAM and improved progression-free survival due to the inclusion of 
bevacizumab.  The currently proposed trial provides an opportunity to 
validate these findings.  In serial blood draws, sICAM will be measured 
by ELISA in all patients, with results correlated to patient response, 
overall survival and progression-free survival. 
Tumor expression of osteopontin (OPN) was found to be associated with 
more aggressive phenotypes in advanced NSCLC patients (Hu et al 
CCR 11:4646, 2005).  We have found that OPN plasma levels showed 
substantial intra-patient variability and were highly prognostic for NSCLC 
patient response to therapy and overall survival (Mack ASCO 2006, 
manuscript in preparation).  However, the role of this factor has not been 
defined in the context of an anti-angiogenic therapy, and this study 
affords that opportunity.  OPN, a highly pleiotropic factor involved in 
metastasis and tissue remodeling, is produced under hypoxic 
conditions.  We hypothesize that patients with elevated OPN will be less 
responsive to bevacizumab as OPN may enhance tumor cell survival in 
low oxygen conditions and serve as an alternative to VEGF as a pro-
angiogenic stimulus, mediating against the effects of bevacizumab.   
Exploratory 
analysis 
of 
angiogenesis-associated 
plasma 
proteins.  As no biomarkers have been fully established to date as 
predictive for patient response and survival following treatment with anti-
angiogenic agents, the work proposed in this section is by its nature 
exploratory.  Furthermore, it is unlikely that any single marker will be 
completely informative in isolation.  At UC Davis we have established a 
panel of angiogenesis-related factors, measurable in patient plasma, 
which 
can 
be 
assessed 
simultaneously 
by 
multiplex 
analysis 
(Luminex).  This exploratory work is necessitated by the need to identify 
marker profiles predictive of response to anti-angiogenic agents.  A 
blinded comparison of VEGF plasma levels as measured by 
conventional ELISA vs Luminex showed a highly significant correlation 
between these assays (r2=0.9359; p <0.0001), providing validation for 
this high-throughput technique.   
7.
Angiogenesis-related polymorphisms
Hypothesis:  Polymorphisms in IL-8 (locus -251) and VEGF (locus 936) 
will be predictive of response to therapy. 
Work conducted in the laboratory of Dr. Heinz-Josef Lenz (University of 
Southern California) has identified associations between germline 
polymorphisms in the IL-8 and VEGF genes with response to 
bevacizumab plus cyclophosphamide in patients with recurrent or 
metastatic ovarian cancer (California Cancer Consortium trial phase II-
45, manuscript in preparation).  Specifically, analysis of -251 TÆA 
polymorphisms in IL-8 showed that patients homozygous T/T had a 
favorable response rate compared to heterozygous patients or those 
homozygous A/A (see adjacent figure; Fisher’s exact test: P=0.047; HJ 


S0635 
Page 46 
Lenz, personal communication).  Furthermore, patients with any T allele 
at the 936 locus of the VEGF gene had a median PFS of 17 months 
compared to 6.4 months for patients with the C/C genotype (log-rank 
test: P=0.041).  Patients with the C/C genotype comprised 73% of the 
population.  We will determine whether these markers retain their 
predictive value in lung cancer patients enrolled on this trial.  PBMCs will 
be collected from each patient and snap frozen for DNA extraction and 
polymorphism identification in collaboration with Dr. Lenz.  Circulating 
plasma levels of the pro-angiogenic cytokine IL-8 will also be measured 
and correlated with patient outcome, genotype and other plasma 
markers. 
8.
K-RAS Mutations and Resistance to EGFR Inhibition
Hypothesis: Tumors harboring K-RAS mutations will be less sensitive to
treatment with OSI-774 (erlotinib) than those with wild-type K-RAS.
One potential cause for activation of the MAPK pathway, high levels of p-
MAPK, and failure of response to EGFR inhibitors is the presence of a K-
RAS oncogene.  The RAS family of G proteins function as signal
transduction switches located downstream of receptor tyrosine kinases,
but upstream of MAPK.  Mutations in RAS at codon 12 result in
constitutive activation of this protein resulting in sustained signaling,
regardless of the status of upstream receptors.  Our examination of the
S0126 specimens has demonstrated this K-RAS mutation in 30% of BAC
tumors, more frequent association with smoking, and that the mutation is
a potential resistance marker to ZD1839 (gefitinib), as only 1/19 patients
(6%) with a K-RAS mutation responded.  (31)  Thus, we hypothesize that
tumors harboring K-RAS mutations will be less sensitive to treatment
with OSI-774 (erlotinib).  We have used highly sensitive PCR assays to
detect K-RAS 12th codon mutations, and will use those here to examine
pre-treatment, paraffin-embedded tumor tissues, and in exploratory
studies, DNA shed in patient plasma.  (32)  Results will be correlated
with patient outcomes.
0
10
20
30
40
50
60
A/A
A/T
T/T
%
Response to Bevacizumab+ Cyclophosphamide by IL-8 polymorphism


S0635 
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Revised 3/29/11 
9.
Proteomics and Other Pharmacogenomics
With the patient's consent, blood specimens will be banked for future
proteomic and pharmacogenomic analyses.
10.
Molecular Correlative Statistical Considerations
Due to the limited sample size provided in this setting, the correlative
studies will help generate hypotheses for future studies.
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
Drug Accountability 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
16.1 
Adverse Event Reporting Requirements 
a.
Purpose
Adverse event data collection and reporting, which are required as part of every
clinical trial, are done to ensure the safety of patients enrolled in the studies as
well as those who will enroll in future studies using similar agents. Adverse


S0635 
Page 48 
Revised 11/9/11 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. See also Appendix 
19.1 for general and background information about expedited reporting. 
b.
Reporting methods
This study requires that expedited adverse event reporting use the NCI’s
Adverse Event Expedited Reporting System (AdEERS). The NCI’s guidelines for
AdEERS can be found at http://ctep.cancer.gov. An AdEERS report must be
submitted to the SWOG Operations Office electronically via the AdEERS Web-
based application located at http://ctep.cancer.gov.
c.
When to report an event in an expedited manner
Some adverse events require 24-hour notification (refer to Table 16.1) via
AdEERS. When Internet connectivity is disrupted, a 24-hour notification is to be
made to the Operations Office by telephone at 210/614-8808.  Once Internet
connectivity is restored, a 24-hour notification that was phoned in must be
entered electronically into AdEERS by the original submitter at the site.
When the adverse event requires expedited reporting, submit the report within
the number of calendar days of learning of the event specified in Table 16.1.
d.
Other recipients of adverse event reports
The Operations Office will forward reports and documentation to the appropriate
regulatory agencies and drug companies as required.
Adverse events determined to be reportable must also be reported according to
local policy and procedures to the Institutional Review Board responsible for
oversight of the patient.
e.
Expedited reporting for investigational agents
Expedited reporting is required if the patient has received at least one dose of the
investigational agent(s) as part of the trial. Reporting requirements are provided
in Table 16.1. The investigational agents used in this study are bevacizumab and
OSI-774.  If there is any question about the reportability of an adverse event or if
on-line AdEERS cannot be used, please telephone or email the SAE Specialist at
the Operations Office, 210/614-8808 or adr@swog.org, before preparing the
report.


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Table 16.1: 
Phase II and III Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  AdEERS Expedited 
Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of the 
Investigational Agents Bevacizumab and/or OSI-774 in this Study 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 5
2 
Grades 
4 & 5
2 
Unexpected 
Expected 
Unexpected 
and 
Expected 
Unexpected Expected
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
Unex-
pected 
Expected 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required
10 Calendar
Days 
Not 
Required 
10 
Calendar
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required
10 Calendar
Days 
10 
Calendar 
Days 
10 
Calendar
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND or Non-CTEP IND require reporting as follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via email to adr@swog.org for agents in non-CTEP 
IND studies) followed by complete report within 5 calendar days for: 
•
Grade 4 and Grade 5 unexpected events
AdEERS 10 calendar day report: 
•
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
•
Grade 5 expected events
2  Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
March 2005   
Note:  All deaths on study require both routine and expedited reporting 
regardless of causality.  Attribution to treatment or other cause must be provided. 
•
Expedited AE reporting timelines defined:
¾
“24 hours; 5 calendar days” – The investigator must initially report
the AE via AdEERS within 24 hours of learning of the event followed
by a complete AdEERS report within 5 calendar days of the initial 24-
hour report.
¾
“10 calendar days” - A complete AdEERS report on the AE must be
submitted within 10 calendar days of the investigator learning of the
event.
•
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that
precipitates hospitalization (or prolongation of existing hospitalization)
must be reported regardless of attribution and designation as expected
or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions.
•
Any event that results in persistent or significant disabilities/incapacities,
congenital anomalies, or birth defects must be reported via AdEERS if
the event occurs following treatment with an agent under a CTEP IND.
•
Use the NCI protocol number and the protocol-specific patient ID
assigned during trial registration on all reports.


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Page 50 
Revised 3/29/11 
Revised 11/9/11 
f.
Additional Instructions or Exceptions to AdEERS Expedited Reporting
Requirements for Phase II and III Trials Utilizing an Agent under a CTEP-
IND or Non-CTEP IND:
1)
Group-specific instructions.
Within 10 calendar days, submit the following to the Operations Office
(mail address below, FAX: 210/614-0006):
•
Printed copy of the AdEERS report
•
Copies of clinical source documentation of the event
•
Copy of IRB notification of the event
•
If applicable, copies of Off Treatment Notice (Form #28829)
and Notice of Death (Form #49467).
g.
Reporting secondary AML/ALL/MDS
1.
All cases of acute myeloid leukemia (AML), acute lymphocytic leukemia
(ALL), and myelodysplastic syndrome (MDS) that occur in patients on
NCI-sponsored trials following chemotherapy for cancer must be
reported in AdEERS.
i.
In protocols using CTCAE Version 4.0 for SAE reporting, three
options are available to describe treatment-related events:
•
Leukemia secondary to oncology chemotherapy
•
Myelodysplastic syndrome.  NOTE:  The only grading option
for "Myelodysplastic syndrome" is Grade 4, life-threatening.
If reporting MDS that is other than Grade 4, use “Neoplasms
benign, malignant and unspecified (incl cysts and polyps) -
Other, (specify,__)” and insert MDS as the specify term.
•
Treatment related secondary malignancy
ii.
In protocols using CTCAE Version 3.0 for SAE reporting, the
event(s) can be reported as “Secondary malignancy-Other
(specify, ___)”.    Report MDS as “Myelodysplasia,” in the
BLOOD/BONE MARROW category.
iii.
Secondary malignancies other than AML/ALL/MDS that are
related to protocol treatment must also be reported in AdEERS.
iv.
Non-treatment related cases of AML/ALL/MDS must be reported
as follows:
In protocols using CTCAE Version 4.0 for SAE reporting, report
as “Neoplasms benign, malignant and unspecified (incl cysts and
polyps) - Other, specify”
In protocols using CTCAE Version 3.0 for SAE reporting, report
MDS as “Myelodysplasia” and Leukemias as “Blood/Bone
Marrow - Other (Specify, __)”
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_events
_adeers 


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Revised 3/29/11 
Revised 11/9/11 
2.
The following supporting documentation must also be submitted within
30 days:
•
a copy of the pathology report confirming the AML/ALL /MDS
diagnosis
•
(if available) a copy of the cytogenetics report
Submit the Report and documentation to: 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, TX 78229 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 


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17.0 
BIBLIOGRAPHY 
1.
Detterbeck FC, Rivera MP, Socinski MS, et al (Eds).  Diagnosis and treatment of lung cancer:  an
evidence-based guide for the practicing clinician, pp. 394-407, 2000.
2.
Donovan WD, Yankelevitz DF, Henechke CI, et al.  Endobronchial spread of bronchioloalveolar
carcinoma.  Chest 104(3):951-3, 1993.
3.
Hidaka N, Hidaka Y, Tajima Y, et al.  Bronchioloalveolar carcinoma presenting aerogenous
metastasis to the upper airway.  Eur J Cancer 32A(7):1261-2, 1996.
4.
West H, Franklin WA, McCoy J, Gumerlock PH, Vance R, Lau DHM, Chansky K, Crowley JJ,
Gandara DR.  Gefitinib in bronchioloalveolar carcinoma (BAC): Southwest Oncology Group study
S0126.  Clinical Oncol 24:1807-1813, 2006.
5.
Kris MG, Sandler A, Miller V, et al.  Cigarette smoking history predicts sensitivity to erlotinib:
Results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC).  J of Clinical
Oncology ASCO Annual Meeting Proceedings (Post-Meeting Edition) Vol. 22, No 14S (July 15
Supplement) A#7062, 2004.
6.
West HL, Crowley JJ, Vance RB, et al.  Advanced bronchioloalveolar carcinoma:  A phase II trial
of paclitaxel by 96-hour infusion (SWOG 9714).  Annals of Oncology 16:1076-1080, 2005.
7.
Franklin WA, Gumerlock PH, Crowley JJ, et al.  EGFR, HER2 and ERB-B Pathway Activation in
Bronchioloalveolar Carcinoma (BAC): Analysis of SWOG 9417 and Lung SPORE tissue
samples.  Proceedings of the American Society of Clinical Oncology 22:620 (Abstract #2493),
2003. 
8.
Herbst RS, Sandler AB.  Non-small cell lung cancer and antiangiogenic therapy: what can be
expected of bevacizumab?  Oncologist 9 (suppl 1):19-26, 2004.
9.
Johnson DH, Fehrenbacher L, Novotny WF, et al.  Randomized phase II trial comparing
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously
untreated locally advanced or metastatic non-small-cell lung cancer. J of Clin Onc Jun
1;22(11):2184-91, 2004.
10.
Sandler AB, Gray R, Brahmer J, et al.  Randomized phase II/III trial of paclitaxel (P) plus
carboplatin (C) with or without bevacizumab (NSC#704865) in patients with advanced non-
squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group
(ECOG) Trial – E4599. Journal of Clinical Oncology ASCO Annual Meeting Proceedings Vol. 23,
No 16S (June 1 Supplement) A# LBA4, 2005.
11.
Herbst RS, Johnson DH, Mininberg E, et al.  Phase I/II trial evaluating the anti-VEGF MAb
bevacizumab in combination with erlotinib, a HER1/EGFR-TK inhibitor, for patients with recurrent
non-small cell lung cancer. J of Clin Onc Apr 10: 23 (11), 2544-2555, 2005.
12.
Gandara DR, West H, Chansky K, et al.  Bronchioloalveolar carcinoma: A model for investigating
the biology of EGFR inhibition.  Clinical Canc Res 10:4205s-4209s, 2004.
13.
Gilks WR, Oldfield L, Rutherford A.  Statistical Analysis.  In: Knapp W, Dorken B, Gilks WR,
Rieber EP, Schmidt RE, Stein H, von dem Borne AEG Kr. (eds.), Leucocyte Typing IV, pp. 6-12.
Oxford: Oxford University Press, 1989.
14.
Lynch TJ, Bell DW, Sordella R, et al.  Activating Mutations in the Epidermal Growth Factor
Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib.  NEJM
350:online Apr 29, 2004.


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15.
Bailey R, Kris M, Wolff M, et al  Gefitinib monotherapy for pretreated advanced non-small cell
lung cancer in IDEAL 1 and 2:  tumor response is not clinically relevantly predictable from tumor
EGFR membrane staining alone.  Lung Cancer 41:571, 2003 (abstract 0-242).
16.
Paez JG, Janne PA, Lee JC, et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical
Response to Gefitinib Therapy.  Science (Express online) Apr 29, 2004.
17.
Lau D, Seibert A, Gandara D, Laptalo L, Geraghty E, Coulon C.  Computer-assisted image
analysis of bronchioalveolar carcinoma.  Clin Lung Cancer 6:281-286, 2005.
18 
Stephens P, Hunter C, Bignell G, et al.  Lung cancer: intragenic ERBB2 kinase mutations in
tumours.  Nature Sep 30;431(7008):525-6, 2004.
19.
Shigematsu H, Takahashi T, Nomura M, et al.  Somatic mutations of the HER2 kinase domain in
lung adenocarcinomas.  Cancer Res Mar 1;65(5):1642-6, 2005.
20.
Pao W, Miller VA, Politi KA, et al.  Acquired resistance of lung adenocarcinomas to gefitinib or
erlotinib is associated with a second mutation in the EGFR kinase domain.  PLoS Med.
Mar;2(3):e73. Epub 2005 Feb 22.
21.
Gumerlock PH.  Personal communication.
22.
Hirsch FR, Varella-Garcia M, Bunn P, et al.  Epidermal Growth Factor Receptor in Non–Small-
Cell Lung Carcinomas: Correlation Between Gene Copy Number and Protein Expression and
Impact on Prognosis. J of Clin Onc Vol 21, Issue 20: 3798-3807, 2003.
23.
Hirsch FR, Varella-Garcia M, McCoy J, et al.  Molecular analysis of EGFR gene copy number,
EGFR expressing and AK+ activation status in advanced non-small cell lung cancer treated with
gefitinib or placebo (ISEL trial). J of Clin Onc:  in press.
24.
Capuzzo F, Hirsch FR, Rossi E, et al.  Epidermal growth factor receptor gene and protein and
gefitinib sensitivity in non-small-cell lung cancer.  JNCI 4;97(9):643-55, 2005.
25.
Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, Bunn PA, Franklin WA,
Crowley JJ, Gandara DR.  Increased EGFR gene copy number detected by FISH is associated
with increased sensitivity to gefitinib in patients with bronchioloalveolar cardinoma (BAC)
(S0126).  J Clin Oncol 23:6838-6845, 2005.
26.
Tsao MS, Sakurada A, Cutz JC, et al.  Erlotimib in lung cancer-molecular and clinical predictors
of outcome.  NEJM 23:6838-45, 2005.
27.
Lopez ME, Kobrin MS, Moriai T, et al.  Single-strand conformation polymorphism analysis of the
epidermal growth factor receptor at codon 497.  Pancreas 12:216-220, 1996.
28.
Moriai T, Kobrin MS, Hope C, Speck L, Korc M.  A variant epidermal growth factor receptor
exhibits altered type alpha transforming growth factor binding and transmembrane signaling.
Proceedings of the National Academy of Sciences USA 91:10217-10221, 1994.
29.
Shintani S, Matsuo K, Crohin CC, et al.  Intragenic mutation analysis of the human epidermal
growth factor receptor (EGFR) gene in malignant human oral keratinocytes.  Cancer Research
59:4142-4147, 1999.
30.
Reiter JL, Eley G, James CD, et al.  Correspondence re: Shintani et al.  Intragenic mutation
analysis of the human epidermal growth factor receptor (EGFR) gene in malignant human oral
keratinocytes.  (Cancer Res., 59:4142-4147, 1999.)  Cancer Research 60:766-767, 2000.


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31.
Gumerlock PH, Holland WS, Chen HL, et al.  Mutational analysis of K-RAS and EGFR implicates
K-RAS as a resistance marker in the Southwest Oncology Group (SWOG) trial S0126 of
bronchioalveolar carcinoma (BAC) patients treated with gefitinib.  Proceedings of the American
Society of Clinical Oncology 24: Abstract #, 2005.
32.
Levi S, Urbano-Ispizua A, Gill R, et al. Multiple K-ras codon 12 mutations in cholangiocarcinomas
demonstrated with a sensitive polymerase chain reaction technique.  Cancer Research 51:3497-
502, 1991.


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Amended 9/17/07 
Revised 1/9/09 
18.0 
MASTER FORMS SET 
This section includes copies of all data forms that must be completed for this study.  These 
include: 
18.1 
Model Informed Consent Form.  This is preceded by "Notes for Local Institution Consent 
Form Authors" and "Notes for Local Investigators."  The study - as well as the local 
consent form meeting the guidelines noted in these documents - must be reviewed and 
approved by the Institutional Review Board prior to registration and treatment of patients 
on this study. 
18.2 
S0635 Registration Form (Form #47242) (10/1/07) and Coding Guidelines. 
18.3 
S0635 Prestudy Form (Form #11652) (3/1/09) 
18.4 
Baseline Tumor Assessment Form (Form #848).  (9/1/03) 
18.5 
0635 Treatment Form (Form # 37277) (10/1/07) 
18.6 
0635 Adverse Event Form (Form #34254).  (7/15/07) 
18.7 
Follow-Up Tumor Assessment Form (Form #38305).  (9/1/03) 
18.8 
Off Treatment Notice (Form #28829).  (6/15/06) 
18.9 
CAIA Radiology Submission Form (Form #58117) (7/15/07) 
18.10 
Lung Carcinoma First Site(s) of Progression or Relapse Form (Form #9469).  (3/15/01) 
18.11 
Lung Carcinoma Follow Up Form (Form #32426).  (9/1/02) 
18.12 
Notice of Death (Form #49467).  (9/1/03) 


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Informed Consent Model for S0635 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they may be justified in writing by the investigator and approved by the 
IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be forwarded to the Southwest Oncology Group Operations Office for approval 
before a patient may be registered to this study.   
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
Southwest Oncology Group Operations Office. 
Readability Statistics:   
Flesch Reading Ease 
61.2 (targeted above 55) 
Flesch-Kincaid Grade Level 8.6 (targeted below 8.5) 
•
Instructions and examples for informed consent authors are in [italics].
•
A blank line,  __________, indicates that the local investigator should provide the
appropriate information before the document is reviewed with the prospective
research participant.
•
The term "study doctor" has been used throughout the model because the local
investigator for a cancer treatment trial is a physician.   If this model is used for a
trial in which the local investigator is not a physician, another appropriate term
should be used instead of "study doctor".
•
The dates of protocol updates in the header and in the text of the consent is for
reference to this model only and should not be included in the informed consent
form given to the prospective research participant.
•
The local informed consent must state which parties may inspect the research
records. This includes the NCI, the drug manufacturer for investigational studies,
any companies or grantors that are providing study support (these will be listed in
the protocol's model informed consent form) and the Southwest Oncology Group.
The "Southwest Oncology Group" must be listed as one of the parties that may
inspect the research records in all protocol consent forms for which patient
registration is being credited to the Southwest Oncology Group.  This includes
consent forms for studies where all patients are registered directly through the
Southwest Oncology Group Data Operations Office, all intergroup studies for
which the registration is being credited to the Southwest Oncology Group (whether
the registration is through the SWOG Data Operations Office or directly through


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the other group), as well as consent forms for studies where patients are registered 
via CTSU and the registration is credited to the Southwest Oncology Group. 
•
When changes to the protocol require revision of the informed consent document,
the IRB should have a system that identifies the revised consent document, in order
to preclude continued use of the older version and to identify file copies.  An
appropriate method to identify the current version of the consent is for the IRB to
stamp the final copy of the consent document with the approval date.  The stamped
consent document is then photocopied for use.  Other systems of identifying the
current version of the consent such as adding a version or approval date are allowed
as long as it is possible to determine during an audit that the patient signed the most
current version of the consent form.
*NOTES FOR LOCAL INVESTIGATORS:
•
The goal of the informed consent process is to provide people with sufficient
information for making informed choices.   The informed consent form provides a
summary of the clinical study and the individual's rights as a research participant.
It serves as a starting point for the necessary exchange of information between the
investigator and potential research participant.  This model for the informed consent
form is only one part of the larger process of informed consent. For more
information about informed consent, review the "Recommendations for the
Development of Informed Consent Documents for Cancer Clinical Trials" prepared
by the Comprehensive Working Group on Informed Consent in Cancer Clinical
Trials for the National Cancer Institute.  The Web site address for this document is
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/
•
A blank line,  __________, indicates that the local investigator should provide the
appropriate information before the document is reviewed with the prospective
research participant.
•
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is
available for your patients.  The pamphlet is entitled: "If You Have Cancer…What
You Should Know about Clinical Trials".  This pamphlet may be ordered on the
NCI Web site at http://cissecure.nci.nih.gov/ncipubs/details.asp?pid=1035 or call
1-800-4- CANCER (1-800-422-6237) to request a free copy.
•
Optional feature for Local Investigators: Reference and attach drug sheets,
pharmaceutical information for the public, or other material on risks.  Check with
your local IRB regarding review of additional materials.
*These notes for authors and investigators are instructional and should not be included in the
informed consent form given to the prospective research participant.  


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S0635, "A PHASE II TRIAL OF THE COMBINATION OF OSI-774 
(ERLOTINIB; NSC-718781) AND BEVACIZUMAB (RHUMAB 
VEGF; NSC-704865) IN STAGE IIIB AND IV 
BRONCHIOLOALVEOLAR CARCINOMA (BAC) AND 
ADENOCARCINOMA WITH BAC FEATURES (ADENOBAC)" 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
You are being asked to take part in this study because you have a specific type of non-small cell 
lung cancer called bronchioloalveolar carcinoma, or "BAC", and your cancer is present in 
multiple areas of the lungs and cannot be surgically removed. 
Who is doing this study?
The Southwest Oncology Group (SWOG) is sponsoring this trial.  SWOG is an adult cancer 
clinical trials organization. SWOG is funded through the National Cancer Institute, and its 
network consists of almost four thousand physicians at almost three hundred institutions 
throughout the United States.  Your study doctor has met all requirements to be a member of 
SWOG and to perform National Cancer Institute-funded research through this Group. 
Why is this study being done? 
The purpose of this study is to find out what effects (good and bad) the combination of 
OSI-774 and bevacizumab has on you and your lung cancer.   
OSI-774 is an oral drug approved by the FDA to treat lung cancer in patients who have 
already received chemotherapy.  OSI-774 is investigational for this study. 
Bevacizumab is the common name for the commercial drug, Avastin®.  It is approved for
use in colon cancer and as a first-line treatment for patients with locally advanced 
metastatic or recurrent non-small cell lung cancer in combination with platinum-based 
chemotherapy.  Bevacizumab is considered investigational for this study.  The 
bevacizumab used in this trial may be made at locations different from those where 
Avastin® is made.  Although some differences may exist, bevacizumab for research use and
the commercial drug Avastin® are manufactured by a similar process, meet similar
standards for final product testing, and are expected to be very similar in safety and 
effectiveness. 


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It works against a protein that helps form new blood vessels in tumors.  As tumors grow 
bigger, they need their own blood supply.  Blocking the formation of these tumor blood 
vessels, which is what bevacizumab can do, may limit or even shrink the tumor.   
As part of this study, your tumor tissue samples and blood samples may be sent to a special 
laboratory.  They may be evaluated for various molecules that can help researchers to 
predict, in the future, which patients can best benefit from treatment with OSI-774.  You 
will not have to undergo any further biopsies, as the biopsy already used to diagnose your 
lung cancer will be used.  
This research is being done because we are still trying to find the most effective treatment 
for this type of cancer (BAC). 
How many people will take part in the study? 
About 80 people will take part in this study. 
What will happen if I take part in this research study? 
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
•
Medical history and physical examination
•
Blood tests for blood counts, blood chemicals and to test your kidney and liver
•
Urine tests to check your kidneys if blood test is not done
•
X-rays/scans to assess disease
•
Brain CT/MRI
•
Bone scan (if clinically indicated)
•
PET scan (if clinically indicated)
During the study…. 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will receive the following treatment: 
If you take part in this study, you will receive two drugs.  Bevacizumab will be given to you 
through an IV and may take 30 to 90 minutes depending on how you tolerate the treatment.  It 
will be given once every 21 days.  This 21-day period is called a "cycle".  In addition, you will  


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Revised 1/9/09 
take OSI-774 once a day by mouth.  You should take this drug daily (preferably in the morning) 
with up to 8 ounces of water, one hour before or two hours after food.  You will continue on 
these drugs until you have dangerous side-effects, your disease gets worse, or you and your 
doctor decide that you should stop taking the drug for other reasons. 
You will record the number of pills you take each day and any side effects you experience on a 
calendar.  You should bring your calendar with you each time you have an appointment.  During 
your visits, your calendar will be reviewed. 
You will also need the following tests and procedures.  They are part of regular cancer care.  
These tests will all be done in an outpatient setting. 
•
Medical history
Prestudy 
•
Physical exam
Prestudy and at the start of every cycle 
•
Complete blood counts
Prestudy and at the start of every cycle 
•
Blood chemistry (including tests to
Prestudy and at the start of every cycle 
check your liver and kidneys)
•
Urine tests (if kidney blood test not done) Prestudy and at the start of every cycle
•
X-rays/scans to assess disease
Prestudy and after every 2 cycles for first 
6 cycles, then after every 3-4 cycles up to 
2 years, then every 6 months (1/9/09) 
How long will I be in the study? 
You will be asked to take bevacizumab and OSI-774 until your disease gets worse or your side 
effects become too great.  After you are finished with the study treatment, you will need to come 
to the clinic for doctor visits and blood tests every three months for one year and then every six 
months for a maximum of three years from the time you started the study.  If your disease did not 
get worse on the treatment, you will also need CT scans and/or x-rays.  These will be done every 
6 weeks for 18 weeks, then every 9-12 weeks for 2 years, then every 6 months until your disease 
gets worse. (paragraph updated 1/9/09) 
Can I stop being in the study?
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you. 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 


Amended 9/17/07 
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Revised 8/2/10 
Revised 12/2/11 
What side effects or risks can I expect from being in the study? 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects that 
may happen.  Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking 
the OSI-774 and bevacizumab.  In some cases, side effects can be serious, long lasting, or 
may never go away.  There also is a risk of death. 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
OSI-774 can interact with many medications.  Please tell your study doctor or nurse about 
all medications that you are currently taking including any over the counter or herbal 
products.  OSI-774 potentially reacts with drugs that are dependent on the P450 
cytochrome isoenzyme. 
The side effects of the bevacizumab and OSI-774 include the following: 
Likely: 
•
(items moved to Less Likely 10/15/08)
•
Skin rash with the presence of macules (flat discolored area) and papules (raised
bump) (updated 5/31/10)
•
Diarrhea
•
(moved to Less Likely 12/2/11)
•
(moved to Less Likely 8/2/10)
•
(moved to Less Likely 8/2/10)
•
(item moved to Less Likely 10/15/08)
•
(moved to Less Likely 8/2/10)
•
(item moved to Less Likely 10/15/08)
•
(item moved to Less Likely 9/17/07)
•
(item moved to Less Likely 5/11/09)
•
(items moved to Less Likely 9/17/07)
•
(moved to Less Likely 8/2/10)
•
deleted 8/2/10)
•
High blood pressure
•
(moved to Less Likely 8/2/10)
•
(moved to Less Likely 8/2/10)
•
Fatigue or tiredness (updated 5/31/10)
•
(item moved to Less Likely 10/15/08)
•
(item moved from Less Likely 9/17/07) (deleted 5/31/10)
•
(moved to Less Likely 8/2/10)
•
(moved to Less Likely 8/2/10)
•
(moved to Less Likely 8/2/10).
•
(moved to Less Likely 8/2/10)
•
Loss of appetite (item moved from Likely 9/17/07) (item moved from Less Likely
10/15/08


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•
Vomiting  (item moved from Likely 9/17/07) (item moved from Less Likely 10/15/08)
•
(moved to  Less Likely 12/2/11)
•
Loss of the normal functioning of the ovaries in a woman that can result in
temporary or permanent menopause; the impact on fertility (temporary or
permanent) is unknown. (added 12/2/11)
Less Likely:  
•
Hair loss
•
Acne(updated 5/31/10)
•
Dry mouth
•
Taste changes
•
Dry eyes
•
(deleted 8/2/10)
•
(Item moved to likely 9/17/07)
•
Irritation or sores in the lining of the mouth (12/11/07) (updated 5/31/10)
•
Increased blood level of a liver or bone enzyme (alkaline phosphatase)  (12/11/07)
(updated 5/31/10) (updated 8/2/10)
•
Increased blood level of a liver enzyme (ALT/SGPT) (added 5/31/10)
•
Increased blood level of a liver enzyme (AST/SGOT) (added 5/31/10)
•
Increased blood level of a liver pigment (bilirubin) often a sign of liver problems
(updated 5/31/10)
•
(Item moved to likely 9/17/07)
•
(deleted 12/11/07)
•
(deleted 12/11/07)
•
(deleted 9/17/07)
•
Bleeding in the vagina  (added 9/17/07) (updated 8/2/10)
•
(deleted 12/11/07)
•
(deleted 9/17/07)
•
(deleted 9/17/07)
•
(Item moved to likely 9/17/07)
•
Formation of a blood clot that plugs the blood vessel; blood clots may break loose
and travel to another place, such as the lung (updated 8/2/10)
•
Reaction that can occur during or following infusion of the drug.  The reaction
may include fever, chills, rash, low blood pressure, and difficulty breathing
(updated 8/2/10)
•
Infection (item moved from Likely 9/17/07) (updated 8/2/10)
•
(deleted 10/15/08)
•
(item moved to Likely 10/15/08)
•
Heartburn  (item moved from Likely 9/17/07)
•
(item moved to Likely 10/15/08)
•
Cough  (item moved from Likely 9/17/07)
•
(deleted 8/2/10)
•
Lack of enough red blood cells (anemia) (added 9/17/07) (updated 8/2/10)


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Page 62 
Revised 10/15/08 
Revised 7/1/10 
Revised 8/2/10 
Revised 12/2/11 
•
Dry skin (item moved from Likely 10/15/08)
•
Itching  (item moved from Likely 10/15/08)
•
Belly pain (item moved from Likely 10/15/08)
•
Nose bleed (item moved from Likely 10/15/08)
•
(item deleted 5/11/09)
•
(item moved to Likely 10/15/08)
•
Headache or head pain (Moved from Likely 12/2/11)
•
Nausea or the urge to vomit (moved from Likely 12/2/11)
•
Fever associated with dangerously low levels of a type of white blood cell
(neutrophils) (added 12/2/11)
•
Blockage in an organ(s)/part(s) of the digestive tract (added 12/2/11)
•
Infection of the skin (added 10/15/08) (updated 5/31/10)
•
Loss of some or all of the finger or toenails (added 10/15/08) (updated 5/31/10)
•
Dehydration (when your body does not have as much water and fluid as it should)
(added 5/11/09) ) (updated 5/31/10)
•
(moved to Likely 8/2/10)
•
Eyelash in-growth and/or thickening (added 5/11/09) (updated 5/31/10)
•
Inflammation (swelling and redness) of the lungs (moved from Rare but Serious
5/11/09) (updated 5/31/10)
•
Bleeding  in some organ(s) of the digestive tract (added 5/31/10)
•
Shortness of breath (moved from Likely 5/31/10)
•
Inflammation (swelling and redness) of the conjunctiva (the outermost layer of the
eye and the inner surface of the eyelids).  Commonly called “pink eye” (added
5/31/10) (updated 7/1/10)
•
Fast heartbeat usually originating in an area located above the ventricles (added 8/2/10)
•
Feeling of spinning or whirling (added 8/2/10)
•
Inflammation (swelling and redness) of the large bowel (colon) (added 8/2/10)
•
Constipation (moved from Likely 8/2/10)
•
Partial or complete blockage of the small and/or large bowel. Ileus is a functional rather
than actual blockage of the bowel. (added 8/2/10)
•
Chest pain not heart-related (updated and moved from Likely 8/2/10)
•
Pain (added 8/2/10)
•
Allergic reaction by your body to the drug product that can occur immediately or may be
delayed. The reaction may include hives, low blood pressure, wheezing, swelling of the
throat, and difficulty breathing. (updated and moved from Likely 8/2/10)
•
Infection (collection of pus) around the rectum (added 8/2/10)
•
Premature opening of a wound along surgical stitches after surgery (updated and moved
from Rare But Serious 8/2/10)
•
Increased blood level of a heart muscle protein (troponin I) indicating damage to the
heart muscle (updated and moved from Rare but Serious 8/2/10)
•
Decreased number of a type of white blood cell (neutrophil/granulocyte) (updated 8/2/10)
•
Weight loss (moved from Rare but Serious 8/2/10)


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Revised 8/2/10 
Revised 12/2/11 
•
Decrease in total number of white blood cells (leukocytes) (updated and moved from Likely
8/2/10)
•
Joint pain (moved from Likely 8/2/10)
•
Muscle Pain (moved from Rare but serious 8/2/10)
•
Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) (updated and moved
from Likely 8/2/10)
•
Fainting (added 8/2/10)
•
(moved to Rare but Serious 12/2/11)
•
Blood in the urine (added 8/2/10)
•
More protein leaking into the urine than usual, often a sign of kidney disease (updated and
moved from Likely 8/2/10)
•
Destruction or death of jaw bone (added 12/2/11)
•
Inflammation (swelling and redness) or degeneration of the peripheral nerves (those
nerves outside of brain and spinal cord) causing numbness, tingling, burning (added
12/2/11)
•
Stuffy or runny nose, sneezing (updated and moved from Likely 8/2/10) (updated 12/2/11)
•
Hives (moved from Likely 8/2/10)
•
(deleted 12/2/11)
•
Hoarseness (updated and moved from Likely 8/2/10)
Rare but Serious:  
•
(moved to Less Likely 5/11/09)
•
(deleted 8/2/10)
•
(moved to less Likely 8/2/10)
•
(deleted 12/11/07)
•
(deleted 8/2/10)
•
(moved to likely 9/17/07)
•
Abnormal changes in the brain that can cause a collection of symptoms including
headache, confusion, seizures, and vision loss associated with MRI findings
(RPLS) (updated 8/2/10).
•
(deleted 8/2/10)
•
(deleted 12/11/07)
•
(item moved to Likely 9/17/07)
•
(item moved to Likely 9/17/07)
•
(deleted 12/11/07)
•
(deleted 8/2/10)
•
(moved to Less likely 8/2/10)
•
Leakage from the stomach due to breakdown of anastomosis (surgical connection
of two separate body structures)  (12/11/07) (updated 8/2/10) (updated 12/2/11)
•
Heart failure:  inability of the heart to adequately pump blood to supply oxygen to
the body (updated 8/2/10)


S0635 
Page 62b 
Revised 8/2/10 
Revised 12/2/11 
•
Heart attack caused by a blockage or decreased blood supply to the heart (updated
8/2/10)
•
Irregular heartbeat resulting from an abnormality in the one of the lower
chambers of the heart (ventricle) (updated 8/2/10)
•
Ventricular fibrillation:  irregular heartbeat that involves the lower chambers of
the heart (ventricles) that results in uncoordinated contraction of the heart; life
threatening and potentially fatal, needing immediate attention (updated 8/2/10)
•
Decrease in heart's ability to pump blood during the “active” phase of the
heartbeat (systole) (updated 8/2/10)
•
(deleted 8/2/10)
•
(deleted 8/2/10)
•
(deleted 8/2/10)
•
(moved to Less Likely 8/2/10)
•
(deleted 9/17/07)
•
(deleted 8/2/10)
•
(moved to Less Likely 8/2/10)
•
(deleted 12/11/07)
•
Gastrointestinal fistula:  Abnormal hole between an organ of the digestive tract
and another organ or tissue (updated 8/2/10)
•
Hole in a part(s) of the digestive tract (updated 5/31/10)
•
(deleted 12/2/10)
•
Abnormal hole between part of the urinary system and another organ or tissue
(added 9/17/07) (updated 8/2/10)
•
Severe reaction of the skin and gut lining  that may include rash and shedding or
death of tissue (added 10/15/08) (updated 5/31/10)
•
Swelling and redness of the skin on the palms of the hands and soles of the feet
(added 10/15/08) (updated 5/31/10)
•
Liver failure (added 10/5/08) (updated 5/31/10)
•
Bleeding in the brain (added 5/11/09) (updated 5/31/10)
•
Inflammation (swelling and redness) of the cornea (the transparent front cover of the
eye) (added 5/11/09) (updated 5/31/10)
•
Hole in the outer layer of the eye (added 5/11/09) (updated 5/31/10)
•
Damage of or clots in small blood vessels in the kidney that can cause
complications, some of which are serious including abnormal destruction of red
blood cells (hemolysis) of platelets (that help to clot blood) and kidney failure
(added 8/2/10)
•
Collections of signs and symptoms that indicate sudden heart disease in which the
heart does not get enough oxygen.  Sudden symptoms such as chest pain, shortness
of breath, or fainting could indicate heart disease and should be reported right
away.  Signs such as abnormal EKG and blood tests can confirm damage to the
heart (added 8/2/10)


S0635 
Page 62c 
Revised 8/2/10 
Revised 12/2/11 
•
Gastrointestinal perforation:  A tear or hole in the stomach or gut that can lead to
serious complications and may require surgery to repair (added 8/2/10)
•
Sore (ulcer) somewhere in the digestive tract (added 8/2/10)
•
Serious, life-threatening allergic reaction requiring immediate medical treatment
by your doctor.  The reaction may include extremely low blood pressure, swelling
of the throat, difficulty breathing, and loss of consciousness (added 8/2/10)
•
Stroke caused by decreased blood flow to the brain (added 8/2/10)
•
A condition in which the kidneys leak a large amount of protein into the urine that
can cause complications including swelling and kidney failure (added 8/2/10)
•
Abnormal hole between the vagina and another organ or tissue (added 8/2/10)
•
Abnormal hole between the lower breathing tube and the body cavity that
surrounds the lungs (added 8/2/10)
•
Bleeding from the lungs (added 8/2/10)
•
Hole in the wall that separates the nostrils of the nose (added 8/2/10
•
Blockage or narrowing of a blood vessel (artery) that can cause damage or loss of
function including  a heart attack or stroke (added 8/2/10)
•
Sudden decrease of kidney (moved from Less Likely 12/2/11)
•
(deleted 8/2/10)
•
Abnormal hole between the breathing tube (windpipe) and the tube that goes from
mouth to stomach through which food passes (esophagus).   This is life-threatening
and potentially fatal.  (updated 8/2/10)
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a 
baby while on this study.  It is important you understand that you need to use birth control 
while on this study.  Check with your study doctor about what kind of birth control 
methods to use and how long to use them.  Some methods might not be appropriate for use 
in this study.  
For more information about risks and side effects, ask your study doctor. 


S0635 
Page 63 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors hope the 
combination of OSI-774 and bevacizumab will be more useful against cancer compared to 
the usual treatment, there is no proof of this yet. We do know that the information from 
this study will help doctors learn more about this combination as a treatment for cancer.  
This information could help future cancer patients. 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
•
Getting treatment or care for your cancer without being in a study
•
Taking part in another study
•
Getting no treatment
•
Getting comfort care, also called palliative care.  This type of care helps reduce
pain, tiredness, appetite problems and other problems caused by the cancer.  It does
not treat the cancer directly, but instead tries to improve how you feel.  Comfort
care tries to keep you as active and comfortable as possible.
Talk to your doctor about your choices before you decide if you will take part in this study. 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
•
The Southwest Oncology Group
•
The National Cancer Institute (NCI) and other government agencies, like the Food and
Drug Administration (FDA), involved in keeping research safe for people
•
Qualified representatives of Genentech (the manufacturer for both study drugs)
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 


S0635 
Page 64 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
Administration of bevacizumab will be (provided free of charge/charged in the usual way).  The 
parts of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate).  (local institutions must choose the option that best fits the 
hospital's situation) 
Genentech will provide you with the drugs bevacizumab and OSI-774 at no cost to you while 
you are participating in this study.  However, if you should need to take the study agent much 
longer than is usual, it is possible that the free supply of study agent given through the study 
could run out.  If this happens, your study doctor will discuss with you how to obtain additional 
drug from the manufacturer and you may be asked to pay for it. 
You will not be paid for taking part in this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You 
can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   


S0635 
Page 65 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
Please note:  This section of the informed consent form is about additional research 
studies that are being done with people who are taking part in the main study.   
You may take part in these additional studies if you want to.  You can still be a part 
of the main study even if you say ‘no’ to taking part in any of these additional 
studies. 
You can say "yes" or "no" to each of the following studies.  Please mark your 
choice for each study.   
1.
Future Contact
I agree to allow my study doctor, or someone approved by my study doctor, to
contact me regarding future research involving my participation in this study.
Yes
No


S0635 
Page 66 
Amended 9/17/07 
2.
Specimen Submission for Study-Specific Testing
If you agree, samples of your cancer tissue (which were obtained at the time of your
biopsy or operation) will be obtained at registration and sent to a special laboratory for
scientific testing.  These studies are being done in order to better understand the
mechanisms of BAC and to try to predict who will be treated most effectively with this
type of treatment.
Additionally, blood specimens (approximately 6 teaspoons total) will be collected before
treatment and prior to the start of Cycles 2 and 3.  If you go off study or if your disease
gets worse prior to Cycle 2 or 3, blood will be collected at that time (approximately 2
teaspoons).
The results of the testing will not be given to you or your doctor.  Although the results
will not affect your treatment, the tests may help future patients.  Reports about research
done with your specimens will not be put in your health records.  Results from these tests
may be published, but you will not be identified in the publications.
My specimens may be used for the special testing described as part of this study.
(9/17/07)
Yes
No
3.
Storage and Use of Tissue and Blood for Future, Unspecified Research
You are going to have a biopsy (or surgery) to see if you have cancer. Your doctor will
remove some body tissue to do some tests. The results of these tests will be given to you
by your doctor and will be used to plan your care.  You have also had blood specimens
(approximately 2 teaspoons each) taken as part of this study before treatment and before
Cycles 2 and 3 of treatment.
We would like to keep some of the tissue and blood that is left over for future research. If
you agree, this tissue and blood will be kept and may be used in research to learn more
about cancer and other diseases. Please read the information sheet called "How are
Specimens Used for Research" to learn more about specimen research.
The research that may be done with your specimens is not designed specifically to help
you. It might help people who have cancer and other diseases in the future.
Reports about research done with your specimens will not be given to you or your doctor.
These reports will not be put in your health record. The research will not have an effect
on your care.


S0635 
Page 67 
Things to Think About  
The choice to let us keep the left over specimens for future research is up to you. No 
matter what you decide to do, it will not affect your care.  
If you decide now that your specimens can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your 
tissue. Then any specimens that remain will no longer be used for research.  
In the future, people who do research may need to know more about your health. While 
the Southwest Oncology Group may give them reports about your health, it will not give 
them your name, address, phone number, or any other information that will let the 
researchers know who you are.  
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families). Even if your tissue is used for this kind of research, the results will not be put 
in your health records.  
Your specimens will be used only for research and will not be sold. The research done 
with your specimens may help to develop new products in the future.  
Benefits  
The benefits of research using specimens include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records. We will 
do our best to make sure that your personal information will be kept private.  The chance 
that this information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No."  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1.
My specimens may be kept for use in research to learn about, prevent, treat
or cure cancer.
Yes No 


S0635 
Page 68 
2.
My specimens may be kept for use in research about other health problems
(for example: diabetes, Alzheimer's disease, or heart disease).
Yes No 
3.
Someone may contact me in the future to ask me to allow other uses of my
specimens.
Yes No 
If you decide to withdraw your specimens from a Southwest Oncology Group 
Specimen Repository in the future, a written withdrawal of consent should be 
submitted through your treating physician to the Southwest Oncology Group 
Operations Office.  Please designate in the written withdrawal whether you would 
prefer to have the specimens destroyed or returned to the treating physician. 
Where can I get more information? 
You may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
You may also visit the NCI Web site at http://cancer.gov/ 
•
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
•
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor. 
Signature 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
Participant  
Date _____________________________________ 


S0635 
Page 69 
Specimen Consent Supplemental Sheet 
How are Specimens Used for Research? 
Where do specimens come from? 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials. 
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by the Southwest Oncology Group.  Your doctor does not work 
for the Southwest Oncology Group, but has agreed to help collect specimens from many patients.  Many 
doctors across the country are helping in the same way.   
Why do people do research with specimens? 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
What type of research will be done with my specimen? 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease. 
How do researchers get the specimen? 
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact the Southwest Oncology Group and request samples for their studies.  The 
Southwest Oncology Group reviews the way that these studies will be done, and decides if any of the 
samples can be used. The Southwest Oncology Group gets the specimen and information about you from 
your hospital, and sends the specimen samples and some information about you to the researcher.  The 
Southwest Oncology Group will not send your name, address, phone number, social security number or 
any other identifying information to the researcher. 
Will I find out the results of the research using my specimen? 
You will not receive the results of research done with your specimen.  This is because research can take 
a long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, 
but they may be helpful to people like you in the future. 
Why do you need information from my health records? 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to 
the researcher may include your age, sex, race, diagnosis, treatments and family history.  This 
information is collected by your hospital from your health record and sent to the Southwest Oncology 
Group.  If more information is needed, the Southwest Oncology Group will send it to the researcher. 
Will my name be attached to the records that are given to the researcher? 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you are. 


S0635 
Page 70 
Amended 9/17/07 
Revised 11/9/11 
How could the records be used in ways that might be harmful to me? 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members. 
How am I protected? 
The Southwest Oncology Group is in charge of making sure that information about you is kept private. 
The Southwest Oncology Group will take careful steps to prevent misuse of records.  Your name, 
address, phone number and any other identifying information will be taken off anything associated with 
your specimen before it is given to the researcher.  This would make it very difficult for any research 
results to be linked to you or your family.  Also, people outside the research process will not have access 
to results about any one person which will help to protect your privacy. 
(section deleted 11/9/11) 
What if I have more questions? 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number). 


Southwest  Oncology  Group  Registration Form
10/1/2007
Activation Date:  July 15, 2007
Last Amended Date:  October 1, 2007
SWOG Study No.
S 0 6 3 5
Registration Step
1
Assigned Treatment Arm
1
Caller's SWOG Roster ID
SWOG Investigator Number
IRB Approval Date
/
/
SWOG Treating Institution Number
Projected Start Date of Treatment
/
/
Date Informed Consent Signed
/
/
INSTRUCTIONS: All of the information on this Registration Form and the Protocol Eligibility Section must be answered appropriately for
a patient to be considered eligible for registration.  This Registration Form must be entirely filled out and referred to during the
registration.  Do NOT submit this form as part of the patient data.
Date HIPAA Authorization signed:
/
/
A Phase II Trial of the Combination of OSI-774 (Erlotinib;
NSC-718781) and Bevacizumab (Rhumab VEGF;
NSC-704865) in Stage IIIB and IV Bronchioloalveolar
Carcinoma (BAC) and Adenocarcinoma with BAC
Features (AdenoBAC)
(Not required for non-American sites)
Patient's Name
SWOG Patient ID
Please indicate how the patient answered the following questions on the consent form:
1. My specimens
may be kept for use
in research to learn
about, prevent, treat
or cure cancer.
Yes
No
2. My specimens may be
kept for use in research
about other health problems
(for example: diabetes,
Alzheimer's disease, or
heart disease).
Yes
No
4. I agree to allow my study
doctor, or someone approved
by my study doctor, to contact
me regarding future research
involving my participation in
this study.
Yes
No
3. Someone may
contact me in the
future to ask me to
allow other uses of
my specimens.
Yes
No
Social Insurance Number:
-
-
Postal Code:
-
If a resident of Canada:
Country of Residence (if not USA):
Patient Social Security Number:
-
-
Patient's ZIP Code:
If a U.S. resident:
Black or African American
White
Native Hawaiian or Other Pacific Islander
Asian
American Indian or Alaska Native
Unknown
Patient's Race (select all that apply):
Patient Gender:
Female
Male
Patient's Date of Birth:
/
/
Method of Payment:
Patient's Ethnicity:
Southwest Oncology Group Data Operations Center
C/o Cancer Research And Biostatistics
1730 Minor Ave, Suite 1900
Seattle, WA 98101-1468
Patient Registration:
via WebReg at: http://swog.org
     (24 hours a day, 7 days a week, excluding downtimes for maintenance)
or call 206-652-2267 (Mon-Fri, 6:30am-4:00pm Pacific Time, excluding holidays)
Southwest Oncology Group Operations Office
14980 Omicron Drive
San Antonio, TX  78245-3217
Phone: (210) 450-8808
Fax: (210) 677-0006
5. My specimens may be
used for the special testing
described as part of this
study.
Yes
No
47242


10/24/2006 
Southwest Oncology Group Registration Form Code Sheet 
Patient’s race definitions: 
White or Caucasian:  a person having origins in any of the original peoples of Europe, 
Middle East, or North Africa. 
Black or African American:  a person having origins in any of the black racial groups 
of Africa. 
Native Hawaiian or Other Pacific Islander:  a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa and other Pacific islands. 
Asian:  a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent.  Including, for example, Cambodia, China, India, 
Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam. 
American Indian or Alaskan Native:  a person having origins in any of the original 
peoples of North, Central or South America, and who maintains tribal affiliations or 
community attachment. 
Patient’s ethnicity (Spanish/Hispanic Origin) options: 
Unknown 
Yes, Central American 
No (not Spanish) 
Yes, South American 
Yes, Mexican 
Yes, Other 
Yes, Puerto Rican 
Yes, NOS 
Yes, Cuban 
Method of Payment codes: 
Private 
No insurance (no means) 
Medicare 
Other, specify at registration 
Medicare and Private 
Unknown 
Medicaid 
Veterans Admin 
Medicaid and Medicare 
 
Military 
No insurance (self-pay) 
Other Group codes for use in the Web Registration program: 
9977 – ACOSOG 
9987 – MDACC 
9982 – CALGB 
9996 – NCCTG 
9976 – CTSU  
9981 – NCIC 
9995 – ECOG 
9983 – NSABP 
9984 – GOG  
9997 – RTOG 


SOUTHWEST ONCOLOGY GROUP
S0635 PRESTUDY FORM
Page 1 of 3
Patient Initials
(L, F M)
3/1/2009
SOUTHWEST ONCOLOGY GROUP
S0635 PRESTUDY FORM
Page 1 of 3
Physician
Institution / Affiliate
Patient Initials
(L, F M)
SWOG Patient ID
Instructions:  Submit this form within 14 days of registration.  All dates are MONTH, DAY, YEAR.  Explain any blank fields or blank
dates in the Comments section.  Place an    X    in appropriate boxes.  Circle AMENDED items in red and write AMENDED across top
of form.
3/1/2009
(PS0635)
PATIENT AND DISEASE DESCRIPTION
Performance status:
SWOG Study No. S 0 6 3 5
Registration Step 1
continued on next page
ELIGIBILITY VERIFICATION:
Each of the fields below corresponds to a criterion in Section 5 and must be completed for patient to be eligible.
Histology:
Adenocarcinoma with BAC features
Bronchioloalveolar carcinoma
Stage:
Selected IIIB
IV
Type of disease:
New diagnosis
Recurrent
Smoking history:
Current
Former (no smoking for 1 year or more)
Never (less than 100 cigarettes in lifetime)
Amount of hemoptysis:
.
teaspoons
Date hemoptysis assessed:
/
/
History of pulmonary/upper respiratory hemorrhage:
Yes, Grade 2* or worse
Yes, Grade 1*
No
Last date observed:
/
/
Last date observed:
/
/
* per CTCAE version 3.0
M:
M0
M1
N:
NX
N0
N1
N2
N3
T:
TX
Tis
T0
T1
T2
T3
T4
If Yes, date:
/
/
Did patient have a previous fine needle aspiration or core biopsy?
Yes
No
Date of pre-treatment scan of brain:
/
/
Method (select one):
CT
MRI
Is scan negative for brain metastases?
Yes
No
If No, does scan show stable or improving brain metastases following treatment for brain metastases?
Yes
No
SWOG Patient ID
11652


SOUTHWEST ONCOLOGY GROUP
S0635 PRESTUDY FORM
Page 2 of 3
Patient Initials
(L, F M)
3/1/2009
Hematologic:
ANC
Platelets
Hepatic:
Total bilirubin
Transaminase (select one)
Alkaline phosphatase
Renal:
Serum creatinine
Measured creatinine clearance
Calculated creatinine clearance
Urine Protein Creatinine (UPC) ratio
Collection date:
LABORATORY VALUES
Document values in units listed
SWOG Study No. S 0 6 3 5
Registration Step 1
continued on next page
Collection date:
mg/dL
.
mg/dL
.
/
/
ULN
SGOT
SGPT
U/L
ULN
U/L
/
/
mg/dL
.
/
/
ml/min
.
/
/
mg/dL
.
 ULN
Collection date:
U/L
.
U/L
.
ULN
/
/
Liver metastases?
Yes
No
Bone metastases?
Yes
No
.
/
/
/ mcL
,
/
/
/
/
/ mcL
,
ml/min
.
/
/
If UPC > 0.5, please indicate 24-hour urine protein level:
mg/24-hours
ADDITIONAL PRESTUDY DATA:
Albumin:
.
g/dL
LDH:
U/L
U/L
IULN
Date collected:
/
/
Estimated Weight Loss in Last Six Months:
< 5%
5 - < 10%
10 - 20%
> 20%
Height:
cm
Weight:
.
kg
BSA:
.
m2
SWOG Patient ID
11652


SOUTHWEST ONCOLOGY GROUP
S0635 PRESTUDY FORM
Page 3 of 3
Patient Initials
(L, F M)
3/1/2009
SWOG Study No. S 0 6 3 5
Registration Step 1
PRIOR TREATMENT RELATED TO THIS CANCER:
Comments:
If Yes, most recent date received any prior systemic therapy:
/
/
Prior systemic therapy:
Yes
No
If Yes, date prior radiation therapy completed:
/
/
Was prior radiation palliative?
Yes
No
If Yes, date of last prior surgery:
/
/
Prior radiotherapy:
Yes
No
Prior surgery:
Yes
No
SWOG Patient ID
11652


Comments:
Registration Step
SOUTHWEST ONCOLOGY GROUP
BASELINE TUMOR ASSESSMENT FORM
SWOG Study No. S
Page 1 of 1
9/1/2003
Institution / Affiliate
Physician
Patient Initials
(L, F M)
/
/
SWOG Patient ID
Instructions: Record the requested information for all target lesions and all sites of other disease.  Please refer to section 10.0 of
the protocol for definitions.  Choose all measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total to
follow as target lesions.  Record any remaining measurable lesions and all non-measurable disease as non-target disease.
All dates are MONTH, DAY, YEAR.  Circle AMENDED items in red.
The same test procedures used for baseline disease assessment must be used for all required subsequent disease assessments.
Longest
Diameter (cm)
Assessment
Type*
Assessment Date
Assessment
Type*
Assessment Date
Extent
/
/
.
L2
/
/
.
L3
/
/
.
L4
/
/
.
L5
/
/
.
L6
/
/
.
L7
/
/
.
L8
/
/
.
L9
/
/
.
L10
/
/
S1
/
/
S2
/
/
S3
/
/
S4
/
/
S5
/
/
.
L1
List all negative diagnostic tests/studies used to evaluate patient for malignancy.
Assessment Date
Tests/studies
/
/
/
/
/
/
/
/
Tests/studies
Assessment Date
NON-TARGET DISEASE
TARGET LESIONS
18-Cystoscopy
20-Histologic confirmation
21-Cytologic confirmation
12-CT scan
13-MRI scan
14-Radioisotope scan
15-Ultrasound
16-PET scan
17-Spiral CT scan
* Assessment Types:
01-Palpation
02-Visualization
03-Colposcopy
05-Endoscopy
10-Plain film/X-ray without contrast
11-Plain film/X-ray with contrast
Participating Group:  Group Name/Study No./Patient ID
99-Other (specify in Comments and
indicate lesion number)
848


 SOUTHWEST ONCOLOGY GROUP
S0635 TREATMENT FORM
SWOG Patient ID
10/1/2007
(TX0635)
SWOG Study No. S 0 6 3 5
Registration Step 1
Institution/Affiliate
(L, F M)
Patient Initials
Comments:
Date of Last Contact or Death:
/
/
Cycle start date:
/
/
Date of last treatment for this cycle:
/
/
Has the patient progressed per the definition in Section 10.0 of the protocol?
No
Yes
(If Yes, submit Follow-Up Tumor Assessment Form, Off Treatment Notice, and Lung Carcinoma First Site(s) of Progression/Relapse)
Current Cycle Number
Physician
Page 1 of 1
No
Yes, planned (per protocol guidelines), specify in comments
Yes, unplanned (not per protocol guidelines), specify in comments
Were there any dose modifications or additions/omissions to protocol treatment?
STATUS
TREATMENT FOR THIS CYCLE
Vital Status:
Alive
Dead
(submit Notice of Death)
Weight (first day this cycle):
.
kg
Number of days receiving OSI-774 during this cycle:
Was G-CSF given this cycle?
Yes
No
Was Erythropoietin given this cycle?
Yes
No
(If Yes, specify dose in comments)
(If Yes, specify dose in comments)
Instructions:  Please complete this form after each cycle (1 cycle = 21 days).  All dates are MONTH, DAY, YEAR.  Explain any blank
dates or fields in the Comments section.  Place an   X   in appropriate boxes.  Circle AMENDED items in red and write AMENDED
across top of form.
Total dose OSI-774 given this cycle:
mg
Total dose Bevacizumab given this cycle:
mg
37277


 SOUTHWEST ONCOLOGY GROUP
S0635 ADVERSE EVENT FORM
(L, F M)
7/15/2007
Page 1 of 2
 SOUTHWEST ONCOLOGY GROUP
S0635 ADVERSE EVENT FORM
SWOG Patient ID
SWOG Study No. S 0 6 3 5
Registration Step 1
Current Cycle Number
Patient Initials
Institution/Affiliate
Physician
(L, F M)
IM00
Allergic reaction/
hypersensitivity
HE20
Hemoglobin
HE00
Leukocytes (total WBC)
HE30
Neutrophils/granulocytes
(ANC/AGC)
CA01
Cardiac-ischemia/
infarction
CA50
Hypertension
FL40
Fatigue (asthenia,
lethargy, malaise)
FL01
Fever ^
FL10
Rigors/chills
FL51
Weight loss
SK80
Dry skin
SK90
Hair loss/alopecia
SK00
Injection site reaction/
extravasation changes
SK16
Pruritus/itching
SK11
Rash/desquamation
SK12
Urticaria
GI01
Anorexia
GI30
Constipation
GI23
Dehydration
GI20
Diarrhea
GI66
Dysphagia
GI61
Esophagitis
GI51
Gastritis
GI02
Heartburn/dyspepsia
Mucositis/stomatitis (functional/symptomatic)
GIM44
Oral cavity
GIM52
Pharynx
GI00
Nausea
GI43
Taste alteration
GI10
Vomiting
HM10
Hemorrhage, CNS
CTC Adverse Event Term
CTC Adverse Event Term
* Attribution codes:    1-unrelated           2-unlikely           3-possible           4-probable         5-definite
7/15/2007
(see instructions)
Reporting period start date:
/
/
Reporting period end date:
/
/
(Day 1 of this Cycle)
(Day one of next cycle.  If final cycle,
date of first visit or contact after
resolution of acute adverse events.)
ADVERSE EVENTS
Page 1 of 2
No
Yes, but no reportable adverse events occurred
Yes, and reportable adverse events occurred (report below)
Were adverse events assessed during this time period?
continued on next page
^ (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 x 10    /L)
9
Instructions:  Please complete this form after each cycle (1 cycle = 21 days).  Report adverse events occurring up until the next
cycle of treatment begins.  Document the worst Grade seen during the reporting period.  Do not code a condition existing prior to
registration as an adverse event unless it worsens.  Category lists may not include all adverse events from that category.  Record
any observed adverse events not listed on the blank lines at the end.  All dates are MONTH, DAY, YEAR.  Explain any blank dates
or fields in the Comments section.  Place an   X  in appropriate boxes.  Circle AMENDED items in red and write AMENDED across
top of form.
CTCAE (3.0)
Grade
(1 - 5)
CTC Adverse
Event
Attribution
Code*
CTC Adverse
Event
Attribution
Code*
CTCAE (3.0)
Grade
(1 - 5)
SWOG Patient ID
Current Cycle Number
Patient Initials
34254


 SOUTHWEST ONCOLOGY GROUP
S0635 ADVERSE EVENT FORM
(L, F M)
7/15/2007
Page 2 of 2
SWOG Study No. S 0 6 3 5
EY10
Dry eye syndrome
EY02
Keratitis
EY11
Ocular surface disease
Pain
PAL04
Chest/thorax NOS
PAN37
Head/headache
PAM11
Joint
LU60
Cough
LU00
Dyspnea
LU90
Voice changes/dysarthria
SY40
Cytokine release syndrome/
acute infusion reaction
VA53
Thrombosis/embolism
VA52
Thrombosis/thrombus/
embolism
Hemorrhage, pulmonary/upper respiratory
HML05
Lung
HML08
Nose
Infection (documented clinically or microbiologically) with
Grade 3 or 4 neutrophils
ICL02
Bronchus
ICL05
Lung
Infection with normal ANC or Grade 1 or 2 neutrophils
INL02
Bronchus
INL05
Lung (pneumonia)
Infection with unknown ANC
IUL02
Bronchus
IUL05
Lung (pneumonia
ME03
ALT, SGPT (serum glutamic
pyruvic transaminase)
ME04
AST, SGOT (serum glutamic
oxaloacetic transaminase)
ME02
Alkaline phosphatase
ME05
Bilirubin 
(hyperbilirubinemia)
ME06
Creatinine
ME12
Proteinuria
NR25
CNS cerebrovascular 
ischemia
* Attribution codes:    1-unrelated           2-unlikely           3-possible           4-probable         5-definite
ADVERSE EVENTS, continued
Comments: (Please explain any "other" adverse events reported above, e.g. Pain-other)
Registration Step 1
CTC Adverse Event Term, Other
(specify using CTCAE 3.0 terminology)
CTC Adverse Event Term
CTC Adverse Event Term
CTC Adverse
Event
Attribution
Code*
CTCAE (3.0)
Grade
(1 - 5)
CTC Adverse
Event
Attribution
Code*
CTCAE (3.0)
Grade
(1 - 5)
SWOG Patient ID
Current Cycle Number
Patient Initials
34254


SOUTHWEST ONCOLOGY GROUP
FOLLOW-UP TUMOR ASSESSMENT FORM
Page 1 of 2
9/1/2003
Complete disappearance
Present
Clear increase (describe in Comments on page 2)
Not assessed
Complete disappearance
Present
Clear increase (describe in Comments on page 2)
Not assessed
Registration Step
SOUTHWEST ONCOLOGY GROUP
FOLLOW-UP TUMOR ASSESSMENT FORM
SWOG Study No. S
Instructions: Record the requested information for all target lesions and all sites of other disease.  Lesion and site numbers
(L1, S1, etc.) should correspond to the same lesions and sites of disease as indicated on the baseline tumor assessment form.
If a target lesion was assessed but measurements were not obtainable, complete assessment type and assessment date, and
state lesion number and reason measurement was not obtained in Comments section on page 2.  Record site of any new lesions
(since baseline) in the New Lesions section.  Place an  X  in appropriate boxes.  All dates are MONTH, DAY, YEAR.
Circle AMENDED items in red.
The same test procedures used for baseline disease assessment must be used for all required subsequent disease assessments.
SWOG Patient ID
Page 1 of 2
9/1/2003
Date form completed:
/
/
TARGET LESIONS
Longest
Diameter (cm)
Assessment
Type*
Assessment Date
/
/
.
L2
/
/
.
L3
/
/
.
L4
/
/
.
L5
/
/
.
L6
/
/
.
L7
/
/
.
L8
/
/
.
L9
/
/
.
L10
/
/
.
L1
Assessment
Type*
Assessment Date
Extent
NON-TARGET DISEASE
Institution/Affiliate
Physician
Participating Group:  Group Name/Study No./Patient ID
/
/
(L, F M)
Patient Initials
/
/
S1
/
/
S2
18-Cystoscopy
20-Histologic confirmation
21-Cytologic confirmation
99-Other (specify in Comments on
     page 2 and indicate lesion number)
12-CT scan
13-MRI scan
14-Radioisotope scan
15-Ultrasound
16-PET scan
17-Spiral CT scan
* Assessment Types:
01-Palpation
02-Visualization
03-Colposcopy
05-Endoscopy
10-Plain film/X-ray without contrast
11-Plain film/X-ray with contrast
Registration Step
SWOG Study No. S
SWOG Patient ID
Date form completed:
/
/
38305


SOUTHWEST ONCOLOGY GROUP
FOLLOW-UP TUMOR ASSESSMENT FORM
Page 2 of 2
9/1/2003
Comments:
Assessment
Type*
Assessment Date
Extent
NON-TARGET DISEASE, continued
(L, F M)
Patient Initials
/
/
S3
Complete disappearance
Present
Clear increase (describe in Comments)
Not assessed
/
/
S4
Complete disappearance
Present
Clear increase (describe in Comments)
Not assessed
/
/
S5
Complete disappearance
Present
Clear increase (describe in Comments)
Not assessed
S1
S2
Assessment
Type*
/
/
/
/
Assessment Date
NEW LESIONS (Specify Site)
Symptomatic deterioration:
No
Yes, describe in Comments
/
/
Assessment Date
18-Cystoscopy
20-Histologic confirmation
21-Cytologic confirmation
99-Other (specify in Comments
and indicate lesion number)
12-CT scan
13-MRI scan
14-Radioisotope scan
15-Ultrasound
16-PET scan
17-Spiral CT scan
* Assessment Types:
01-Palpation
02-Visualization
03-Colposcopy
05-Endoscopy
10-Plain film/X-ray without contrast
11-Plain film/X-ray with contrast
Registration Step
SWOG Study No. S
SWOG Patient ID
Date form completed:
/
/
38305


6/15/2006
Comments:
SOUTHWEST ONCOLOGY GROUP
OFF TREATMENT NOTICE
SWOG Patient ID
SWOG Study No. S
Registration Step
Physician
Institution / Affiliate
(If more room is needed, please continue on a separate page)
(L, F M)
Patient Initials
Page 1 of 1
Participating Group:  Group Name/Study No./Patient ID
Off Treatment Date
Date of completion, progression, death or decision to discontinue therapy:
/
/
Will patient receive further treatment?
No
Yes, specify:
Unknown
Date of Last Contact or Death:
/
/
Vital Status:
Alive
Dead (submit Notice of Death form)
/
/
Systemic Therapy:
List regimens, start and end dates.  For multidrug regimens, do not list individual drugs separately;
end date would be the date all drugs in the regimen were discontinued.
Surgery:
List type of surgery, and in the "end date" column, the date of surgery.
Radiation:
List sites, start and end dates (inclusive of boosts and implants).
Instructions:
For each registration step, submit this form within 2 weeks after completion (or discontinuation) of treatment.
List protocol-directed treatments that the patient received.
All dates are MONTH, DAY, YEAR.  Explain any blank fields or blank dates in the Comments section.
Place an   X   in appropriate boxes.  Circle AMENDED items in red and write AMENDED at the top of the form.
Treatment Start Date
Treatment End Date
Regimen or Procedure or Site(s)
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
For any patient refusal, was reason due to adverse event/side effects/complications?
Yes, specify:
No, specify other reason for refusal:
Off Treatment Reason
Treatment completed per protocol criteria
Adverse event/side effects/complications, specify:
Patient withdrawal/refusal after beginning protocol therapy, specify:
Patient withdrawal/refusal prior to beginning protocol therapy, specify:
Disease progression, relapse during active treatment; Sites:
Death on study (submit Notice of Death form)
Other, specify:
(select one):
For any adverse event, was treatment termination medically required?
No
Yes, specify:
28829


SOUTHWEST ONCOLOGY GROUP
CAIA RADIOLOGY SUBMISSION FORM
Page 1 of 1
7/15/2007
Comments:
SWOG Study No. S
SWOG Patient ID
Registration Step
Patient Initials
(L, F M)
Institution / Affiliate
Physician
Participating Group:  Group Name/Study No./Patient ID
/
/
Derick H.M. Lau, M.D. Ph.D.
Div. of Hematology/Oncology
Dept. of Internal Medicine
U.C. Davis Cancer Center
4501 X Street, Room 3019
Sacramento, CA  95817-2229
No. of images:
Assessment time (select all that apply):
Prestudy
Instructions: Explain any blank fields or blank dates in the Comments section of the form.  Place an   X   in
appropriate boxes.  Circle AMENDED items in red and write AMENDED across the top of the form.
Submit a copy of this form to the SWOG Data Operations Center.  Mail required materials and this form to the
following oncologist:
7 weeks
13 weeks
End of treatment
Enclosed
Original chest CT scan
Radiology report
Required materials:
(if not enclosed, explain below in Comments)
Yes
No
Yes
No
58117


Instructions:  All dates are MONTH, DAY, YEAR.  Place an  X  in appropriate boxes.  Circle AMENDED items in red.
SOUTHWEST ONCOLOGY GROUP LUNG CARCINOMA
FIRST SITE(S) OF PROGRESSION OR RELAPSE FORM
3/15/2001
Notes:
Page 1 of 1
(PROGLUNG)
Site(s) of Progression or Relapse at the time progression/relapse was detected (select all that apply):
Date of progression or relapse:
/
/
Registration Step 1
SWOG Study No. S
SWOG Patient ID
A. Local (Primary Tumor)
Lung parenchyma adjacent to primary tumor
Bronchial stump
B. Regional/Nodal
Ipsilateral hilar mediastinum (nodal)
Contralateral hilar mediastinum (nodal)
Contralateral pleural effusion
Ipsilateral pleural effusion
Ipsilateral supraclavicular lymph nodes
Contralateral supraclavicular lymph nodes
C. Distant
Opposite lung
Separate lobe of the ipsilateral lung
Brain
Leptomeninges
Liver
Bone
Adrenal glands
Kidney
Skin or subcutaneous
Other site, specify:
Pericardial effusion
Patient Initials
(L, F M)
Groups Other than SWOG:  Group Name/Study No./Pt. ID
Physician
Institution / Affiliate
/
/
Status
Alive
Dead
Date of last contact or death:
/
/
For Local Progression or Relapse:
Yes
No
Not Applicable (No previous RT)
For Regional Progression or Relapse:
Yes
No
Not Applicable (No previous RT)
Progression/Relapse site within previous RT field?
(select one):
Progression/Relapse site within previous RT field?
(select one):
9469


Instructions:  Please submit at each follow up after completion of treatment until recurrence, at time of recurrence, and at
protocol specified intervals after recurrence.  All dates are MONTH, DAY, YEAR.  Answer all questions and explain any blank
fields or blank dates in the Comments section.  Place an   X   in appropriate boxes.  Circle AMENDED items in red.
SOUTHWEST ONCOLOGY GROUP
LUNG CARCINOMA FOLLOW UP FORM
Page 1 of 1
9/1/2002
Comments:
SWOG Patient ID
SWOG Study No. S
Registration Step
Physician
Institution/Affiliate
Groups other than SWOG: Group Name/Study No./Pt. ID
/
/
(L, F M)
Patient Initials
No
Yes
Has the patient received further (non-protocol) treatment for this cancer?
If Yes, Date of first non-protocol therapy:
/
/
Did the patient respond to this treatment?
No
Yes
FURTHER TREATMENT
New Primary Site:
NOTICE OF NEW PRIMARY
No
Yes
If Yes, Date of Diagnosis:
/
/
Has a new primary cancer or myelodysplastic syndrome (MDS) been diagnosed that has not been previously reported?
Has the patient received prophylactic cranial irradiation (PCI)?
No
Yes
PCI Start Date:
/
/
(Note: If multiple regimens were received, please specify only the first regimen received
after going off protocol treatment.)
Specify Regimen:
Has the patient had a documented clinical assessment for this cancer since submission of the previous follow-up form?
No
Yes
Date of Last Clinical Assessment:
/
/
DISEASE FOLLOW UP STATUS
NOTICE OF FIRST RELAPSE OR PROGRESSION
Has the patient developed a first progression (or relapse) that has not been previously reported?
No
Yes
Date of Relapse or Progression:
/
/
(If Yes, please submit the Lung Carcinoma First Site(s) of Progression or Relapse Form.)
Date of last contact or death:
/
/
Vital Status:
Alive
Dead
(If vital status is Dead, complete and submit Notice of Death form.)
VITAL STATUS
≥
LONG TERM TOXICITY
Toxicities and Grades:
Has the patient experienced (prior to treatment for progression or relapse or a second primary, and prior to
non-protocol treatment) any severe (grade    3) long term toxicity that has not been previously reported?
No
Yes
32426


9/1/2003
Comments:
SOUTHWEST ONCOLOGY GROUP
NOTICE OF DEATH
Autopsy?
No
Yes
Unknown
If cancer was the primary cause or if cancer possibly or definitely contributed to death, and the patient
had had multiple tumor types, specify those which were causes of death:
No
Primary Cause
Contributory
Possible
Unknown
Any cancer (select one):
CAUSES OF DEATH
(month / day / year)
Date of Death:
/
/
SWOG Patient ID
Most Recent SWOG Study No. S
Physician
Institution / Affiliate
(L, F M)
Patient Initials
Cancer of most recent SWOG study, specify cancer:
Cancer of other SWOG study, specify cancer:
Other cancer, specify:
If Primary Cause, Contributory or Possible, specify treatment and toxicity:
No
Primary Cause
Contributory
Possible
Unknown
Toxicity from disease related treatment (select one):
If Primary Cause, Contributory or Possible, specify:
No
Primary Cause
Contributory
Possible
Unknown
Non-cancer and non-treatment related causes (select one):
Source(s) of death information:
Autopsy report
Medical record / Death certificate
Physician
Relative or friend
Other, specify:
Instructions:  Answer all questions and explain any blank fields or blank dates in the Comments section.
Place an   X   in appropriate boxes.  Circle AMENDED items in red.
Participating Group:  Group Name/Study No./Patient ID
/
/
Page 1 of 1
49467


 
S0635 
 
Page 87 
 
 
 
 
19.0 
APPENDIX 
 
19.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
19.2 
Intake Calendar 
 


 
S0635 
 
Page 88 
 
 
 
 
19.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.0. 
 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
 
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
 
• 
Sequential administration: When a study includes an investigational agent(s) and 
a commercial agent(s) on the same study arm, but the commercial agent(s) is 
given for a period of time prior to starting the investigational agent(s), expedited 
reporting of adverse events that occur prior to starting the investigational agent(s) 
would follow the guidelines for commercial agents. Once therapy with the 
investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms. All 
appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2:  Grade the event using the NCI CTCAE version specified. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 


 
S0635 
 
Page 89 
 
 
 
 
Step 4:  Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in  
 
• 
the current NCI Agent-Specific Adverse Event List (for treatments using agents 
provided under an NCI-held IND); 
 
• 
the drug package insert (for treatments with commercial agents only); 
 
• 
Section 3.0 of this protocol. 
 
Step 5:  Review Table 16.1 in the protocol to determine if there are any protocol-specific 
requirements for expedited reporting of specific adverse events that require special 
monitoring.  
 
Step 6:  Determine if the protocol treatment given prior to the adverse event included an 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE:  If the patient received at least one dose of investigational agent, follow the 
guidelines in Table 16.1. 
 
NOTE:  This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed possibly, probably, or definitely to the agent(s) must be reported according to 
the instructions in Table 16.1.  
 


 SOUTHWEST ONCOLOGY GROUP
 INTAKE CALENDAR
SWOG Study No. S
SWOG Patient ID
Registration Step
9/15/2004
Special instructions:
Institution/Affiliate
Physician
Month:
Year:
Sunday
   Monday
Tuesday
Wednesday
   Thursday
Friday
Saturday
Instructions for the Nurse or Research Coordinator:
G
ive th
is 
intake ca
lendar to the part
ic
ipant for her use w
ith contact 
informat
ion f
i
l
led 
in.  Instruct the part
ic
ipant to br
ing her 
intake ca
lendar to each v
is
it.
This form does not need to be returned to the Data Operations Center.
Patient Initials (L, F, M)
Page 1 of 1
If you have any questions contact:
Telephone:
Your next appointment is:
Instructions for the participant:
This is a monthly calendar on which you are to record the number of tablets you take each day. Be sure you have
enough calendars to last until your next appointment.  If you develop any side effects from the tablets, mark this on
the calendar on the day you note the effect.  Bring your calendars with you each time you have an appointment.
Participating Group:  Group Name/Study No./Patient ID
/
/
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