Clinical trial NCT01573702
Conditions: Non Small Cell Lung Cancer
Keywords: Non small cell lung cancer EGFR mutant Phase II erlotinib tarceva cyberknife Lineberger
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2012-12-11; Completion date: 2019-03-15
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
\- Progression free survival after locally ablative therapy and erlotinib in EGFR patients progressed after EGFR-TKI therapy

Detailed description:
Primary Objectives

\- To estimate progression free survival (PFS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-TKI therapy

Secondary Objectives

* To evaluate local control of sites previously progressive on erlotinib following stereotactic radiosurgery (SRS) followed by erlotinib
* To estimate overall survival (OS) after locally ablative therapy and erlotinib in EGFR-mutant NSCLC patients who progressed on prior EGFR-TKI therapy
* To characterize the toxicity of SRS
* To characterize the toxicity of erlotinib when preceded by SRS

Exploratory Objectives

* To explore if VeriStrat results at initial progression are associated with longer PFS or OS after study treatment
* To explore if VeriStrat results following completion of SRS are associated with longer PFS or OS after re-initiation of erlotinib
* To explore whether "poor" VeriStrat signatures ever turn to "good" signatures with the study therapy, and to explore PFS and OS of patients whose signature changes

Arms: arm 1: Stereotactic Radiosurgery or Other Local Ablation Followed by Erlotinib
Interventions: intervention 1: Stereotactic Radiosurgery intervention 2: Erlotinib
Intervention descriptions: intervention 1: 21 Gy daily for 5 days intervention 2: 150mg once daily

Protocol documents:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #5: LCCC1123 
DATED 11/18/2014 
LCCC  1123: Phase II Study Of Stereotactic Radiosurgery or Other Local Ablation 
Followed by Erlotinib for Patients with EGFR Mutation Who Have Previously 
Progressed on an EGFR Tyrosine Kinase Inhibitor (TKI)  
 
AMENDMENT INCORPORATES: 
 
_ _ Editorial, administrative changes 
  X   Therapy changes (IRB approval) 
__  
AMENDMENT RATIONALE AND SUMMARY: 
Section 4.3 (Erlotinib Treatment Dosage and Administration) required erlotinib be held 
for 3 days prior to SRS in patients who enroll already receiving this agent.  Not all 
participating sites follow this practice, and data are not clear that one approach is best.  
Therefore, this requirement has been revised to a recommendation. This change is also 
reflected in sections 6.1 (Time and Events table, specifically the footnotes), section 6.3.2 
(Study Assessments) and section 6.7 (Correlative Studies). 
 
In addition, the UNCCN Study Coordinator has been has changed to UNCCN Project 
Manager throughout the protocol.  
 
Section 6.9 (Assessment of Efficacy): clarified that local ablative therapy refers to SRS or 
other local ablative therapy such as surgery 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 11/18/2014 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
LCCC  1123: Phase II Study Of Stereotactic Radiosurgery or Other Local Ablation 
Followed by Erlotinib for Patients with EGFR Mutation Who Have Previously 
Progressed on an EGFR Tyrosine Kinase Inhibitor (TKI)  
 
AMENDMENT INCORPORATES: 
 
_X_ Editorial, administrative changes 
  X   Therapy changes (IRB approval) 
__  
AMENDMENT RATIONALE AND SUMMARY: 
The driver for this amendment was clarification of conflicting guidance on the dose and 
schedule of Stereotactic Radiosurgery (section 4.2) per organ.  Guidance now matches 
the corresponding dosing table for each organ. Specifically: 
• Section 4.2.1d (Brain) specified 3 and up to 5 fractions per day; now indicates 
that treatment to be delivered per institutional preference (i.e. on consecutive days 
versus several per week; one fraction per day) 
• Section 4.2.2  (Chest and Lung) specified in sections 4.2.2b and 4.2.2f  that 
patients could have 3-5 and 3-10 treatments/fractions; the reference to 3-5 has 
been removed 
• Section 4.2.3 (abdomen) was incomplete.  This has been removed as these lesions 
are rare 
• Section 4.2.4 (liver) section 4.2.4f; clarified that 3 to 5 treatments/fractions will be 
given on consecutive weekdays or every other day 
• Section 4.2.5 (spine/soft tissue): deleted reference to dosing schedule in section 
4.2.5b as it conflicted with section 4.2.5f; revised dosing schedule in 4.2.5 to 
indicate dose to be delivered per institutional preference ((i.e. on consecutive days 
versus several per week; one fraction per day, 1 to 5 fractions) 
 
In addition, the following minor clarifications were made: 
• Removed David Morris as Co-Investigator as he is no longer at UNC 
• Inclusion criteria Section 3.1.5; clarified that progressive disease is assessed via 
RECIST1.1 
• Section 4.3; clarified that 3 day washout means 3 full days without erlotinib 
• Section 6.1 Time and events table: added footnotes to clarify tumor evaluations at 
progression and follow-up; added note that post SRS visit can occur on last day of 
SRS; clarified windows allowed around study visits 
• Section 6.9 (assessment of efficacy); refined definition of patients evaluable for 
analysis of efficacy 
 
THE ATTACHED VERSION DATED 6/19/2014 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #3:  LCCC 1123  
DATED 08/15/2012 
 
 
AMENDMENT INCORPORATES: 
 
_X_ Editorial, administrative changes 
_X   Scientific changes (IRB approval) 
__ _ Therapy changes (IRB approval) 
__    Eligibility Changes (IRB approval) 
 
This protocol has been amended to allow multicenter sites participating on this trial to 
utilize their institutional brand of radiosurgery machine. 
 
 
Throughout protocol, and particularly in section 4.2: 
Section 4.2:  We have edited the study to define standard of care (SOC) parameters for 
stereotactic radiosurgery that are not specific to the CyberKnife® brand.   
 
Rationale: The SOC radiosurgery incorporated in this multicenter protocol was referred 
to and specific for CyberKnife®.  However, the intent of this protocol is not to dictate 
which SOC radiosurgery is used, as there are many brands of stereotactic radiosurgery.   
No core content has been modified.  The new parameters will not affect in any way how 
stereotactic radiosurgery is done for UNC patients—it remains SOC.  Similarly, it defines 
the SOC in such a way that parallel procedures will take part at our partner institutions so 
that their patients will also be treated per SOC. 
 
Minor typographical errors have been corrected throughout protocol 
 
Added Co-Investigators as follows:   Julian Rosenman, MD; Timothy Zagar, MD  
 
 
 
 
ATTACH TO THE FRONT OF EVERY PROTOCOL 
 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #2:  LCCC 1123 
 
 
LCCC 1123:   
AMENDMENT INCORPORATES: 
 
_X_ Editorial, administrative changes 
_ X  Scientific changes (IRB approval) 
__ _ Therapy changes (IRB approval) 
__   Eligibility Changes (IRB approval) 
 
Section 1.5: Correlative Studies: Details on VeriStrat® assay revised to: 
• Reflect updated references further confirming the validation of this assay  
• Removed table 5 with analysis from NCIC BR.21 registrational trial 
indicating predictive ability of VeriStrat when data adjusted for EGFR 
mutation status 
• Removed reference to full NMR peaks from the MALDI-TOF as VeriStrat 
does not use NMR (this reference to NMR was also removed from 
Exploratory Objectives 
 
Section 6.7 
• This section has been revised to accommodate blinding.  Since there are 4 
time points for which samples will be taken, the analysis team from 
Biodesix, Inc. requested these blood samples be blinded.   
 
Section 7.3.3 
• Removed Fax # and mailing address to FDA 
 
Section 9.4 
• Revised to reflect recent changes in LCCC protocol template 
 
 
 
 
LCCC 1123 – May 15, 2012 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #1:  LCCC 1123 
 
 
LCCC 1123:   
 
AMENDMENT INCORPORATES: 
 
__x_ Editorial, administrative changes 
_ _   Scientific changes (IRB approval) 
__ _ Therapy changes (IRB approval) 
__   Eligibility Changes (IRB approval) 
___ Other 
 
 
 
Throughout study: Typos corrected  
 
Sections 4.3 and 5.1.2 : Manufacturer of erlotinib (Astellas Pharma) has agreed 
to provide drug free of charge to patients.  Sections 4.3 and 5.1.2 were changed to 
reflect this. 
 
Sections 7.3 and 7.4: These were slightly revised to reflect updated safety 
reporting language for trials conducted under an IND. 
 
 
 
 
 
 
 
 
 
 
 
LCCC 1123 – February 20, 2012 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
LCCC  1123: Phase II Study Of Stereotactic Radiosurgery or Other Local Ablation 
Followed by Erlotinib for Patients with EGFR Mutation Who Have Previously 
Progressed on an EGFR Tyrosine Kinase Inhibitor (TKI)  
 
Principal Investigator 
Jared Weiss, MD 
170 Manning Drive, Room 3115 
Campus Box 7305 
Chapel Hill, NC 27599 
jared_weiss@med.unc.edu 
Office: 919-966-3856; Admin: 919-843-7718Fax: 919-966-6735 
 
Co-Investigator(s) 
Timothy M. Zagar, MD 
Larry Marks, MD 
Julian Rosenman, MD 
Thomas Stinchcombe, MD 
Carrie Lee, MD, MPH 
Juneko Grilley-Olson, MD 
 
Biostatistician  
Allison Deal, MS 
UNC Lineberger Comprehensive Cancer Center, Room 20-024 
Chapel Hill, NC 27599 
Phone: 919-966-1387; Fax: 919-966-4244 
 
Clinical Protocol Office 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 2795 
Chapel Hill, NC 27599-7295 
 
North Carolina Cancer Network (NCCN) Project Manager: 
Phone: 919-966-7359 
Fax: 919-966-4300 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source: Astellas Pharma US 
 
Version Date: August 5th, 2011 
Revised: February 20, 2012  
Revised: May 15, 2012 
Revised: August 15, 2012; June 19, 2014, November 18, 2014 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
LCCC  1123: Phase II Study Of Stereotactic Radiosurgery or Other Local Ablation 
Followed by Erlotinib for Patients with EGFR Mutation Who Have Previously 
Progressed on an EGFR Tyrosine Kinase Inhibitor (TKI) 
 
 
Principal Investigator 
Jared Weiss, MD 
170 Manning Drive, Room 3115 
Campus Box 7305 
Chapel Hill, NC 27599 
jared_weiss@med.unc.edu 
Office: 919-966-3856 
Admin: 919-843-7718 
Fax: 919-966-6735 
 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Principal Investigator (PI) Name: _______________________ 
 
PI Signature: ___________________ 
 
Date: ____________________ 
 
Version Date: November 18, 2014 
 
 
 
 


LCCC1123 
 
CONFIDENTIAL 
PI:Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
EGFR-mutated NSCLC.........................................................................................1 
1.3 
Erlotinib .................................................................................................................1 
1.4 
Rationale for Incorporation of Local Ablative Therapy........................................2 
1.5 
Correlative Studies ................................................................................................5 
2.0 
STUDY OBJECTIVES ...........................................................................................8 
2.1 
Primary Objective .................................................................................................8 
2.2 
Secondary Objectives ............................................................................................8 
2.3 
Exploratory Objectives ..........................................................................................8 
2.4 
Endpoints ...............................................................................................................9 
3.0 
PATIENT ELIGIBILITY ......................................................................................9 
3.1 
Inclusion Criteria ...................................................................................................9 
3.2 
Exclusion Criteria ................................................................................................10 
4.0 
TREATMENT PLAN ...........................................................................................11 
4.1 
Schema ................................................................................................................11 
4.2 
Steroeotactic Radiosurgery .................................................................................11 
4.3 
Erlotinib Treatment Dosage and Administration ................................................21 
4.4 
Toxicities and Dosing Delays/Dose Modifications .............................................21 
4.5 
Concomitant Medications/Treatments ................................................................21 
4.6 
Duration of Therapy ............................................................................................22 
4.7 
Duration of Follow Up ........................................................................................22 
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5.0 
DRUG INFORMATION ......................................................................................22 
5.1 
Erlotinib (Tarceva®) ...........................................................................................22 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................25 
6.1 
Time and Events Table ........................................................................................25 
6.2 
Pre-Study Assessments .......................................................................................27 
6.3 
Treatment Assessments .......................................................................................27 
6.4 
Evaluation at Progression ....................................................................................28 
6.5 
Long-Term Follow-Up ........................................................................................28 
6.6 
Early Termination Visit .......................................................................................28 
6.7 
Correlative Studies Procedures: Veristrat® ........................................................29 
6.8 
Assessment of Safety ..........................................................................................30 
6.9 
Assessment of Efficacy .......................................................................................30 
7.0 
ADVERSE EVENTS ............................................................................................34 
7.1 
Definitions ...........................................................................................................34 
7.2 
Documentation of  non-serious AEs or SARs .....................................................36 
7.3 
SAEs or Serious SARs ........................................................................................36 
7.4 
Data and Safety Monitoring Plan ........................................................................38 
8.0 
STATISTICAL CONSIDERATIONS ................................................................38 
8.1 
Study Design/Study Endpoints ...........................................................................38 
8.2 
Sample Size and Accrual.....................................................................................38 
8.3 
Data Analyses Plans ............................................................................................40 
9.0 
STUDY MANAGEMENT ....................................................................................40 
9.1 
Institutional Review Board (IRB) Approval and Consent ..................................40 
9.2 
Required Documentation.....................................................................................41 
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9.3 
Registration Procedures.......................................................................................41 
9.4 
Data Management and Monitoring/Auditing ......................................................41 
9.5 
Adherence to the Protocol ...................................................................................42 
9.6 
Amendments to the Protocol ...............................................................................44 
9.7 
Record Retention .................................................................................................44 
9.8 
Obligations of Investigators ................................................................................45 
10.0 REFERENCES ......................................................................................................46 
11.0 APPENDICES .......................................................................................................48 
11.1 
Appendix A ECOG Performance Status .............................................................48 
11.2 
Appendix B Charlson Comorbidity Index Scoring System ................................49 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is a single arm phase II trial of 40 patients evaluating a novel treatment 
strategy for patients with epidermal growth factor receptor (EGFR)-mutant non 
small cell lung cancer (NSCLC).  Eligible patients will have just progressed on a 
EGFR-tyrosine kinase inhibitor (TKI).  In the current trial, all sites of progressive 
disease will be treated with local ablation (primarily stereotactic radiosurgery) 
followed by the EGFR-TKI erlotinib until disease progression.  We hypothesize 
that this treatment strategy will lead to a progression free survival of at least 3 
months. 
 
1.2 
EGFR-mutated NSCLC 
75% of NSCLC patients present with metastatic disease, with an expected median 
overall survival (OS) of 10-12 months.  Lung cancer progression is multifactorial.  
Among the influences are cell surface receptors that control intracellular signal 
transduction pathways.  A subset of NSCLC patients harbors an EGFR mutation 
that particularly drives their cancer, rendering them susceptible to the effects of 
small molecular EGFR-TKIs such as gefitinib and erlotinib.  Almost all patients 
with the mutation have adenocarcinoma histology.  Presence of this mutation is 
inversely correlated with history of smoking.  It is present in 6% of patients with 
adenocarcinoma who are current smokers, 15% in former smokers, and 52% of 
never smokers1.  Treatment of mutated disease with these EGFR-TKIs results in a 
median PFS (13 months) that exceeds the median OS for non-mutated patients2.  
Beyond the increased survival, toxicity on EGFR-TKIs is very mild compared to 
cytotoxic chemotherapy, with an acneiform rash and diarrhea being the most 
common side effects associated with their use. 
1.3 
Erlotinib 
The only FDA approved EGFR-TKI in the United States is erlotinib (Tarceva®).  
This agent is approved for maintenance treatment of locally advanced or 
metastatic NSCLC that has not progressed after 4 cycles of platinum-based first-
line chemotherapy.  It is also approved for treatment of locally advanced or 
metastatic NSCLC after failure of at least one prior chemotherapy regimen. 
 
Several studies have compared chemotherapy to EGFR-TKIs in a variety of 
contexts within NSCLC.  Most relevant to the population to be studied here, the 
OPTIMAL3 study compared carboplatin plus gemcitabine to erlotinib for first line 
therapy of metastatic EGFR-mutant NSCLC.  PFS was 13.1 months after erlotinib 
therapy, as compared to 4.6 months after carboplatin plus gemcitabine (hazard 
ratio (HR)=0.16, 95% confidence interval (CI) 0.10 to 0.26; p<0.0001) .  
 
While these impressive results clearly represent an advance in the treatment of 
NSCLC, all patients inevitably develop resistance and experience disease 
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progression within 8-14 months of initiating therapy 4-7 and thereafter require 
second line therapy. 
 
The standard therapy for patients with EGFR mutation who progress on erlotinib 
is cytotoxic chemotherapy.  While cytototoxic chemotherapy is active against 
EGFR mutated NSCLC, it is less active than erlotinib.  For example, patients 
randomized to the chemotherapy arm of OPTIMAL experienced a 4.6 month PFS 
in their first line of treatment.  In addition to being less active, chemotherapy is 
more toxic than erlotinib, requires intravenous infusion, and ultimately also lasts 
only a finite duration. 
1.4 
Rationale for Incorporation of Local Ablative Therapy 
Progression of cancer while on erlotinib may reflect the emergence of a mutant 
clone.  Whether through positive-selection of a resistant clone that was present 
before starting therapy or from the evolution of such a clone during therapy, it is 
clear that some of the cancer cells will remain sensitive to erlotinib while others 
are resistant.  This molecular heterogeneity explains the frequently clinically 
observed mixed response at the time of progression in patients with EGFR 
mutation on erlotinib.  In this situation, many sites of disease remain well 
controlled with erlotinib while one or a small number of sites progress.  If such 
sites could be eliminated, systemic sensitivity to erlotinib could theoretically be 
restored.  Erlotinib could then be used for systemic control of remaining sites of 
disease. 
 
Any modality of local control, such as surgery, radiation, or radiofrequency 
ablation could theoretically be used to eliminate resistant clones.  The following 
section explains the rationale for preferential use of radiation.  However, the 
anatomy of certain sites will be particularly amenable to alternative modalities of 
local control and the study will allow this.  
1.4.1 Radiation for patients with EGFR mutation 
EGFR mutant cells are 500-1,000 fold more sensitive to radiation than wild-type 
cells, a phenomenon that extends to T790M mutant cells (see Figure 1).8,9  In 
EGFR wild-type cells exposed to radiation, EGFR rapidly translocates to the 
nucleus where it binds DNA-PK, a key component of non-homologous end-
joining repair.  In L858R or ΔE746-E750 cells, this mechanism of radioresistance 
is defective.  EGFR mutant cells do not halt DNA synthesis or progression to 
mitosis in response to radiation.  
 
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                                  Figure 1 
 
 
These in-vitro findings are supported by human clinical data.  Investigators at the 
Dana Farber Cancer Institute reviewed their outcomes after thoracic radiation 
between EGFR mutant and wild-type tumors in a retrospective cohort of patients 
with locally advanced NSCLC10.  The two-year locoregional relapse rate was 
45.5% in EGFR wild-type patients and 19.1% in patients with EGFR mutation.  
These findings suggest that radiation may be a particularly effective modality for 
the treatment of EGFR mutant cancers (see Figure 2). 
 
 
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Freedom from Locoregional Recurrence
0
12
24
36
48
60
72
84
96
108
Time (months)
 
   Figure 2 (Grey curve EGFR mutant, Black curve EGFR Wild-Type) 
 
1.4.2 Stereotactic Radiosurgery (SRS) 
A number of studies have investigated stereotactic radiosurgery (SRS) for the 
treatment of cancer.  SRS is a method for delivering focused high dose 
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radiotherapy to a tumor while attempting to spare surrounding normal tissues.  It 
is extremely effective at treating small lesions and with appropriate patient 
selection, has low toxicity.  It can be administered via several different modalities, 
including linear accelerator based (e.g. Varian’s Novalis, Accuray’s CyberKnife) 
which can treat both central nervous system and extracranial disease, as well as 
the GammaKnife which treats intracranial disease exclusively.  Much of the focus 
of research of SRS in lung cancer has been on cure of small lesions in patients 
who are not candidates for surgery.  However, multiple studies have investigated 
its use in metastatic disease. 
 
Investigators at the University of Rochester Medical Center treated 49 patients 
with a total of 125 metastatic lesions and achieved a crude local control rate of 
94%11.  Of note, 8 of these patients had lung cancer; there was a tail to the 
survival curves for both breast cancer and lung cancer (see Figure 3). 
 
 
 
                                                        Figure 3 
 
Another study evaluated only patients with metastatic NSCLC, with only 1 or 2 
sites of oligometastatic disease12.  The long term survival rate of 22% in this study 
was comparable to older studies utilizing primary surgical resection plus 
metastectomy of isolated adrenal or brain metastases from NSCLC (see Figure 4). 
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                                                        Figure 4 
 
 
 
A larger series treated 121 patients with < 5 detectable metastases13.  As shown in 
the Figure 5 below, 2 year overall and progression-free survival was 50% and 
26% and at four years they were 28% and 20%. 
 
 
 
                                                    Figure 5 
 
Sufficient data exists on the appropriate use of SRS in body-specific sites that the 
American Association of Physicists in Medicine (AAPM) has issued guidelines 
for its use14. 
1.5 
Correlative Studies 
VeriStrat® is a commercially available serum proteomic test that identifies 
second and third line NSCLC patients who are likely to have a good or poor 
outcome (as measured by OS) following erlotinib therapy.  Serum is analyzed 
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using Matrix Assisted Laser-Desportion Ionization Time of flight Mass 
Spectrometry (MALDI-TOF).  Eight peaks are analyzed to create a result of 
“good” or “poor.” 
 
 
 
VeriStrat® was initially developed on a training set of 139 patients who were 
treated with gefitinib and validated on two additional cohorts of patients receiving 
EGFR TKIs15.  While the test was able to predict outcomes in patients treated 
with an EGFR-TKI, it did not distinguish results from patients treated with 
chemotherapy.  
 
The plot below shows the overall survival by VeriStrat group of one of the 
original VeriStrat validation cohorts, patients treated in second-line with gefitinib. 
These data (on file at Biodesix), updated from those published originally15, yield a 
hazard ratio between VeriStrat groups of 0.45 (95% confidence interval: 0.25-
0.80), log-rank p=0.006. 
 
 
Interestingly, sera were available from 29 patients who progressed on gefitinib in 
this series.  22 of these patients were VeriStrat®  good at the initiation of the 
study and 11 (50%) of these converted to VeriStrat®  poor at the time of 
withdrawal from study therapy16. 
 
Similar results were found in an analysis of ECOG 3503, a single-arm phase II 
study of erlotinib for first line therapy of NSCLC17.  Of 137 enrolled patients, 
analyzable samples were available on 102.  VeriStrat® identified 73% of these as 
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having a good signature and 27% as having a poor signature.  As shown below, 
both OS and PFS were different for patients with good and poor signatures. 
 
  
 
 
A retrospective analysis of the 441 available pretreatment plasma samples from 
the NCIC BR.21 registrational study of erlotinib versus placebo in second- and 
third-line advanced NSCLC patients confirmed that patients classified as 
VeriStrat Good have significantly better outcomes than those classified as 
VeriStrat Poor. Multivariate analysis showed that VeriStrat remains a significant 
predictor of OS when adjusted for other patient characteristics, including EGFR 
mutation status. In addition to showing in the placebo arm that VeriStrat has a 
clear prognostic component, this study demonstrated that VeriStrat was predictive 
of response to erlotinib, with all but one of the 19 responders being classified as 
VeriStrat Good18.  
 
A study has been undertaken to investigate changes in patient VeriStrat 
classification during the course of gefitinib therapy.16  It was found that, although 
VeriStrat classifications remained generally stable during the course of treatment, 
in approximately 30% of the patients classified as VeriStrat Good at baseline, the 
classification changed to VeriStrat Poor near progression. Progression in these 
patients was found to be associated with the development of new lesions. Changes 
of VeriStrat classification from VeriStrat Poor to VeriStrat Good during the 
course of treatment were observed, but were rare.16 
 
There are several advantages to the use of this assay for biocorrelative studies.  
First, the test is non-invasive so there would be minimal risk or discomfort to the 
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patient and no harm to study accrual secondary to reluctance to undergo a biopsy.  
Second, the test is commercially available and standardized. 
 
Serum will be collected for testing with the VeriStrat® MALDI-TOF assay.  
Several exploratory objectives will be evaluated.  We will evaluate if VeriStrat®  
at the time of initial progression on TKI predicts for longer PFS or OS.  We will 
evaluate if VeriStrat®  following completion of SRS predicts for longer PFS or 
OS with re-initiation of erlotinib.  We will evaluate whether “poor” VeriStrat® 
signatures ever turn to “good” signatures following SRS.  We will evaluate PFS 
and OS of patients whose signature changes from “poor” to “good.”  . We will 
explore response rates and PFS on subsequent treatments (see section 6.5).  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To estimate PFS after locally ablative therapy and erlotinib in EGFR-mutant 
NSCLC patients who progressed on prior EGFR-TKI therapy 
2.2 
Secondary Objectives  
2.2.1 To evaluate local control of sites previously progressive on erlotinib following 
SRS followed by erlotinib 
2.2.2 To estimate OS after locally ablative therapy and erlotinib in EGFR-mutant 
NSCLC patients who progressed on prior EGFR-TKI therapy 
2.2.3 To characterize the toxicity of SRS 
2.2.4 To characterize the toxicity of erlotinib when preceded by SRS 
2.3 
Exploratory Objectives 
 
2.3.1 To explore if VeriStrat® results at the time of initial progression on EGFR-TKI  
are associated with longer PFS or OS with the study therapy of SRS followed by  
erlotinib 
2.3.2 To explore if VeriStrat® results following completion of SRS are associated with 
longer PFS or OS after re-initiation of erlotinib 
2.3.3 To explore whether “poor” VeriStrat® signatures ever turn to “good” signatures 
with the study therapy, and to explore PFS and OS of patients whose signature 
changes  
 
8 


LCCC1123 
 
CONFIDENTIAL 
PI:Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
2.4 
Endpoints 
2.4.1 Primary 
PFS will be measured from the time of initiation of SRS until disease progression 
or death from any cause  
2.4.2 Secondary 
• OS will be measured from the time of initiation of SRS until death from 
any cause   
• Local control rate of sites ablated by SRS will be measured both overall 
and by lesion  
• Toxicity of SRS will be measured by NCI CTCAE version 4 following 
completion of SRS, but prior to erlotinib re-initiation. 
• Toxicity of erlotinib will be graded using NCI CTCAE version 4. 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subject must meet all of the inclusion criteria listed below to participate:   
3.1.1 Written informed consent has been obtained. 
3.1.2 ≥18 years of age 
3.1.3 Histologically or cytologically confirmed stage IV EGFR-mutant NSCLC or, in 
the absence of availability of EGFR testing (for example, inadequate tissue), 
clinical response overwhelmingly consistent with EGFR mutation (PR plus at 
least 6 months free of progressive disease as a consequence of EGFR-TKI 
therapy). 
3.1.4 History of previous response to EGFR-TKI, defined as either a PR by RECIST1.1 
criteria, or at least six months without progressive disease as a result of EGFR-
TKI therapy 
3.1.5 Progressive disease as measured via RECIST1.1 following EGFR-TKI therapy 
(with ≤5 sites of disease amenable to SRS or other locally-ablative treatment) 
3.1.6 Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
3.1.7 Adequate organ and marrow function as defined below: 
• Absolute neutrophil count [ANC] ≥ 1,500 cells/µL  
• Hemoglobin ≥ 10 g/dL 
• Platelets ≥ 100,000/µL  
• Serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 60 mL/min 
• Total bilirubin ≤ 3.0 x upper limit of normal [ULN] 
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November 18, 2014 
 
 
• Alanine aminotransferase [ALT] ≤ 2.5 x ULN 
• Aspartate aminotransferase [AST] ≤ 2.5 x ULN 
3.1.8 Female patients must have a negative urine or serum pregnancy test at screening 
(pregnancy test not required for patients with bilateral oophorectomy and/or 
hysterectomy or for those patients who are > 1 year postmenopausal). 
3.1.9 All patients of reproductive potential must agree to use adequate contraception 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria listed below at baseline will be 
excluded from study participation: 
3.2.1 Any unresolved chronic toxicities > grade 2, measured by CTCAE v4. 
3.2.2 Treatment with any FDA approved or experimental cancer treatment following 
progression on EGFR-TKI (e.g., radiation or chemotherapy; supportive regimens 
such as denosumab or zoledronic acid will not result in exclusion) 
3.2.3 Any history of previous ≥ grade 3 toxicity attributable to erlotinib (except 
dermatological toxicity) 
3.2.4 Pregnant or lactating female 
3.2.5 Any previous radiation to sites of planned SRS.   A patient may be deemed 
eligible in this case if a non-radiation mode of local ablation such as surgical 
resection is deemed safe and feasible by the PI. 
3.2.6 History of another malignancy; exception: Subjects who have been disease-free 
for 3 years, or subjects with a history of completely resected non-melanoma skin 
cancer or successfully treated in situ carcinoma are eligible. 
3.2.7 Concomitant anticancer therapy, immunotherapy, or radiation therapy (no 
radiation within prior 4 weeks) 
3.2.8 Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, or cardiac disease)  
3.2.9 Known hypersensitivity reaction or idiosyncrasy to erlotinib 
3.2.10 Psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol  
3.2.11 Any other concurrent condition that in the investigator's opinion would jeopardize 
compliance with the protocol 
 
 
 
10 


LCCC1123 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
4.0 
TREATMENT PLAN 
4.1 
Schema 
 
The study will be a single arm non-randomized phase II study of forty patients.  
We anticipate completing accrual over a 2 year period. 
4.2 
Steroeotactic Radiosurgery  
All sites of progressive disease will be treated with SRS, unless an alternative 
locally ablative option is chosen.  A maximum of five sites will be treated.  If less 
than five sites have progressed on erlotinib, additional sites up to a total of 5 sites 
may be treated, at the discretion of the treating radiation oncologist.  Guidelines 
for SRS will be defined by body site, consistent with standard of care radiation, as 
reviewed below. 
4.2.1 Radiosurgery Therapy: Brain 
4.2.1a Equipment 
 
Modality: Gamma knife or X-rays with nominal energy of 4 megavoltage (MV) 
or greater for accelerator-based treatments, including isocentric conical 
collimators, mini-multi-leaf (5 mm or less) technology or linear accelerators 
mounted on robotic arms.   
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LCCC1123 
 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
4.2.1b Treatment technique 
An immobilization/patient localization system is mandatory for this study. 
Multiple isocenter and non-isocentric techniques are permitted. 
4.2.1c Treatment volumes 
The goal of treatment planning is to deliver a conformal dose of radiation to the 
contrast enhancing target volume based on MR or CT images. Treatment volumes 
will be determined based on correlation of diagnostic imaging with a treatment 
planning CT scan performed at 1.00 to 1.25mm slice thickness. Minimal margins 
are allowed of up to 3 mm will be used. Typically, no margin is used except in the 
setting of issues of indistinct borders. The relevant target volumes and critical 
structures for treatment planning will be contoured by the participating radiation 
oncologist and/or neurosurgeon. Both radiation oncologist and neurosurgeon need 
to review the target volumes. When a patient is able to undergo a MRI, MRI will 
be used with formal image registration. The preferred image is a T1 image post-
gadolinium at a minimum of 3 mm between image slices. The MRI does not need 
to be performed in the treatment planning position. 
 
The GTV is defined as the gadolinium-enhanced T1 image abnormality. In the 
setting of treating post-surgically, the tumor bed (resection cavity) as defined on 
the T1 gadolinium enhanced image will be treated. This can be termed GTV or 
CTV.  No PTV will be defined unless there is evidenced of registration error. The 
use of a PTV will be at the discretion of the treating physicians but should not be 
greater than a 3 mm 3D expansion. 
 
4.2.1d Treatment schedule / time and dose considerations 
  
Radiosurgery treatments will be delivered per institutional preference (on 
consecutive weekdays versus several per week;one fraction per day).  
 
  
Time and dose considerations: 
 
• 
Prescription isodose: The dose will be calculated to the 50-100% isodose 
curve as normalized to the maximum dose. Dose is specified in Gray (Gy) 
to muscle. 
• 
Coverage: The target lesion should be covered at least 95% by the 
prescription isodose curve; small volume lesions (those treated with a 
single 5 mm collimator and have a high conformity (>1.8) index) may be 
covered with less than a 95% but not less than 90% 
• 
Conformity of dose: Conformity indices PIV*TIV/TV²  should be within 
1.00 – 1.80; small volume lesions (those treated with a single 5  
mm collimator and have a high conformity (>1.8) index) may be treated 
with a conformity index < 2.0 
• 
Total dose: The total dose is to the prescription isodose 
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November 18, 2014 
 
 
• 
Normal tissue dose limitations: The dose to the optic chiasm and nerves 
will be < 8 Gy if a single fraction, < 15 Gy in 3 fractions, < 25 Gy in 5 
fractions; if there has been prior radiation acceptable tolerance limits are < 
6 Gy single fraction, < 12 Gy in 3 fractions, < 20 Gy in 5 fractions. 
Brainstem will be < 15 Gy per fraction or total cumulative dose of < 20 
Gy unless tumor is intrinsic to the brainstem. Volume of brain receiving 
>12Gy should be limited to <10cc in a single fraction treatment. Volume 
of brain for fractionated treatment will not have a limit 
• 
Dose schedule: Patients will receive one treatment daily, delivered per  
institutional preference (on consecutive days versus several per week; one 
fraction per day) 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
RTOG SRS QA Guidelines will be followed and AAPM Report 54 Guidelines 
will be followed 
 
 
Please note: based on anatomic location, edema/mass effect, and patient’s 
extracranial disease status doses can be reduced by 10% or converted to 
fractionated treatment. Normal tissue tolerance limits that are specified should be 
respected unless there are special circumstances. 
 
Anatomic locations where dose reduction or fractionation can be considered are 
posterior fossa, deep and central (thalamic, insular, brainstem) or motor strip (or 
adjacent to motor strip). Dose reductions are allowed but not required. This will 
require clinical judgment. 
 
Although we rarely treat more than 4 intracranial lesions, when doing so dose is 
16 Gy to the lesions. 
 
 
Max diameter of single 
tumor or volume 
 
Fraction # 
 
 
Total Dose (isodose prescription, 
NOT max dose) 
 
<1 cm (<0.5cc) 
1 
20 Gy 
1-2 cm (0.5 cc-4.2cc) 
1 
18-20 Gy 
2-3 cm (4.2cc-14.1cc) 
1 
3 
18 Gy 
18-21 Gy 
3-4.5 cm(14.1 cc-47.7 cc) 
1 
3 
15 Gy 
18-21 Gy 
>4.5 cm (>47.7cc)* 
5 
25 Gy 
*In general tumors greater than 6 cm or 133 cc should not be treated with stereotactic radiosurgery 
13 


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November 18, 2014 
 
 
4.2.2  Radiosurgery Therapy: Chest and Lung 
4.2.2a  Equipment 
Only photon (x-ray) beams produced by linear accelerators with photon energies 
of 4-10 MV will be allowed. Cobalt-60 and charged particle beams (including 
electrons, protons, and heavier ions) are not allowed. Photon beam energies > 10 
MV but not > 15 MV will be allowed only for a limited number (≤ 2) beams that 
must travel more than a cumulative distance of 10 cm through soft tissue (not 
lung) to reach the isocenter. 
4.2.2b Treatment technique 
Inverse treatment planning will be employed using isocentric and/or non-
isocentric beam arrangements..   
4.2.2c Treatment volumes 
The goal of treatment planning is to deliver a conformal dose of radiation to the 
contrast enhancing target volume based CT images. Treatment volumes will be 
determined based on correlation of diagnostic imaging with a treatment planning 
CT scan performed at 1.00 to 1.50 mm slice thickness. Minimal margins of up to 
3-10 mm will be used. The relevant target volumes and critical structures for 
treatment planning will be contoured by the participating radiation oncologist 
and/or thoracic surgeon. The preferred image for target contouring is a CT image 
post-contrast at a minimum of 1.5 mm between image slices with the image 
obtained at the normal end expiratory cycle. When a patient is unable to maintain 
a breath hold for the entire scan (which is an expected common occurrence) the 
breath hold at end expiration should be performed through the region where the 
tumor is located or the therapists can determine the optimal breath hold technique 
for compliance with the planning scan. If a breath hold technique cannot be 
performed a 4D-CT scan should be obtained. 
 
Note: FOV on the “big bore” CT should be limited to 60 cm to avoid intentional 
artifact that may impact dose algorithm. 
4.2.2d Treatment simulation 
• 
The simulation procedure will involve obtaining the CT dataset in the 
treatment position and at normal end-expiratory breath hold throughout 
the region of interest. If this cannot be accomplished the optimal breath 
hold technique can be determined by the therapist. 
• 
All patients will be simulated in the supine position, head at the superior 
portion of the treatment/simulation table. 
• 
In general, the patient’s head will be in the neutral position or in a position 
that maintains a comfortable airway 
• 
The CT dataset for treatment planning will be obtained at 1.00 mm to 1.5 
mm slice thickness and will be a non-contrast study 
• 
The patient’s head and body should remain in the PDP safety zone. 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
• 
A contrasted CT scan will be obtained in the treatment position after the 
non-contrast study has been obtained in a similar fashion as the non-
contrasted study. 
4.2.2e Treatment immobilization 
Patients will be positioned in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment. Positions 
uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments. A variety of immobilization systems may be used, 
including stereotactic frames that surround the patient on three sides and large 
rigid pillows (conforming to patients’ external contours) with reference to the 
stereotactic coordinate system . Patient immobilization must be reliable enough to 
insure that the gross tumor volume (GTV) does not deviate beyond the confines 
of the planning treatment volume (PTV) with any significant probability (i.e., < 
5%). 
4.2.2f Treatment schedule / time and dose considerations 
Time and dose considerations: 
 
• 
Prescription isodose: The dose will be calculated to the 60-100% isodose 
curve as normalized to the maximum dose. In general, the 60-85% isodose 
curve is strived for target coverage 
• 
   Coverage: The target lesion should be covered at least 95% by the 
prescription isodose curve and 99% should be covered by 90% of the 
prescription isodose curve 
• 
Conformity of dose: Conformity indices PIV*TIV/TV² should be within 
1.00 – 1.80 at 2 cm from the PTV, the dose should be no greater than 30 
Gy. The ratio of 50% isodose volume to the prescription Isodose volume 
should be no greater than 3.9 
• 
Total dose: The total dose to the prescription isodose 
• 
Normal tissue dose limitation: The dose to the whole lung (bilateral) will 
be a V20 of < 15% the dose to the spinal cord < 18 Gy with no fraction 
greater than 6 Gy (to < 0.1 cc) esophagus < 27 with no fraction greater 
than 9 Gy heart/ proximal bronchus/trachea/ great vessels < 30 Gy with no 
fraction greater than 10 Gy (to < 3 cc) brachial plexus < 24 Gy with no 
fraction greater than 8 Gy (to < 3 cc) 
• 
Dose schedule: Radiosurgery will be delivered using three to ten 
treatments delivered using an every other day to twice weekly regimen for 
fraction schemes less than or equal to 5 treatments and a daily treatment 
regimen (exception for weekends) for fractionation schemes greater than 5 
treatments .  
 
 
15 


LCCC1123 
 
CONFIDENTIAL 
PI:Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QA Guidelines will be followed and AAPM Task Force Group 101 (AAPM 
Report 101). Guidelines will be followed and the ASTRO/ACR Practice 
Guidelines in regard to treatment (not personnel) will be followed 
 
NB: In all circumstances, normal tissue tolerances need to be respected and dose 
reductions will be acceptable to meet those criteria 
 
In general margin for PTV will be determined by the ability to track the tumors as 
orientation of the tumors and the directions in which they move can vary.  The 
minimum margin will be 3 mm isotropically.  In most circumstances, the margin 
will be 5 mm isotropically when tracking of 3 fiducials is feasible; the placement 
of fiducials is preferable, but not mandatory.  In circumstances in which fiducial 
marker tracking is not able to compensate for rotation (i.e., less than 3 fiducials), 
margins may be increased up to 10 mm in all dimensions or anisotropically at the 
disretion of the radiation oncologist. Evaluation under fluoroscopy to try to assess 
movement would be reasonable to assist in determining margins. 
 
If fiducials cannot be placed, internal target volume (ITV) can be used with daily 
image guidance 
 
 
4.2.4 Radiosurgery Therapy: Liver 
4.2.4a Equipment 
Only photon (x-ray) beams produced by linear accelerators with photon energies 
of 4-10 MV will be allowed. Cobalt-60 and charged particle beams (including 
electrons, protons, and heavier ions) are not allowed. Photon beam energies > 10 
MV but not > 15 MV will be allowed only for a limited number (≤ 2) beams that 
Max diameter of 
single tumor 
 
Fraction # 
 
 
Total Dose 
 
<4 cm 
 3 
4 
54-60 Gy 
48 Gy (preferred) 
4-6.5 cm 
4 
48 Gy 
Tumors located 
within 2 cm of the 
mainstem bronchi, 
adjacent to chest 
wall, or prior 
radiation 
4 
10 
3 
 
4 
48 Gy 
50 Gy 
24-30 Gy (prior RT in 
central location) 
48 Gy (can be considered 
for near chest wall, no 
limit on chest wall except 
not higher than 
prescription dose) 
Multiple Lesions 
4 
10 
48 Gy 
50 Gy 
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CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
must travel more than a cumulative distance of 10 cm through soft tissue (not 
lung) to reach the isocenter. 
4.2.4b Treatment technique 
Inverse treatment planning will be employed using isocentric and/or non-
isocentric beam arrangements.  
4.2.4c Treatment volumes 
The goal of treatment planning is to deliver a conformal dose of radiation to the 
contrast enhancing target volume based on MR or CT images. Treatment volumes 
will be determined based on correlation of diagnostic imaging with a treatment 
planning CT scan performed at 1.00 to 1.50 mm slice thickness. Minimal margins 
of up to 3 mm beyond the GTV will be used for microscopic tumor spread (CTV) 
respecting normal anatomic boundaries. The preferred margin is 3-5 mm in all 
dimensions.  PTV should include an additional margin of 1.5-5 mm depending on 
location of the fiducial markers, image registration quality, tumor deformation, 
and the patient’s respiratory pattern.  The relevant target volumes and critical 
structures for treatment planning will be contoured by the participating radiation 
oncologist and/or surgeon. Both radiation oncologist and surgeon need to review 
the target volumes. The preferred image for target contouring is a CT image post-
contrast at a minimum of 1.5 mm between image slices with the image obtained at 
the normal breathing cycle.   
4.2.4d Treatment simulation 
• 
The simulation procedure will involve obtaining the CT dataset in the 
treatment position and during the normal breathing treatment through the 
region of interest. 
• 
 All patients will be simulated in the supine position, head at the superior 
portion of the treatment/simulation table. 
• 
In general, the patient’s head will be in the neutral position or in a position 
that maintains a comfortable airway 
• 
The CT dataset for treatment planning will be obtained at 1.00 mm to 1.5 
mm slice thickness and will be a non-contrast study 
• 
The patient’s head and body should remain in the PDP safety zone. 
• 
A contrasted CT scan will be obtained in the treatment position after the 
non-contrast study has been obtained in a similar fashion as the non-
contrasted study. 
• 
CT simulation will be obtained with end expiratory breath hold through 
the lesion and fiducial markers (if placed). 
4.2.4e Treatment immobilization 
Patients will be positioned in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment. Positions 
uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments. A variety of immobilization systems may be used, 
including stereotactic frames that surround the patient on three sides and large 
17 


LCCC1123 
 
CONFIDENTIAL 
PI:Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
rigid pillows (conforming to patients’ external contours) with reference to the 
stereotactic coordinate system . Patient immobilization must be reliable enough to 
insure that the gross tumor volume (GTV) does not deviate beyond the confines 
of the planning treatment volume (PTV) with any significant probability (i.e., < 
5%). 
4.2.4f Treatment schedule / time and dose considerations 
 
Time and dose considerations: 
 
• 
Prescription isodose: The dose will be calculated to the 60-100% isodose 
curve as normalized to the maximum dose. In general, the 60-80% isodose 
curve is strived for target coverage 
• 
Coverage: The target lesion should be covered at least 95% by the 
prescription isodose curve and 99% should be covered by 90% of the 
prescription isodose curve 
• 
Conformity of dose: Conformity indices PIV*TIV/TV²  should be within 
1.00  - 2.00 
• 
Total dose: the total dose to the prescription isodose 
• 
Normal tissue dose limitations: The dose to the whole lung (bilateral) will 
be a V20 of < 15% esophagus < 30 Gy with no fraction greater than 10 Gy 
(to 3cc or greater) stomach < 30 Gy (to 3 cc or greater) heart < 30 Gy with 
no fraction greater than 10 Gy. The maximum voxel dose to the spinal 
cord should not exceed 12 Gy in a single fraction and should be < 15 Gy 
in total. Kidney (bilateral or ipsilateral) 15 Gy in total with no fraction 
greater than 5 Gy and no more than a 1/2 of one kidney receiving greater 
than 14 Gy. Chest wall 40 Gy in total and no fraction greater than 12.5 Gy. 
Liver- mean liver dose < 1500cGy and per QUANTEC 
• 
Dose schedule: Patients will receive 3-5 treatments on consecutive 
weekdays or every other day 
  
 
Status of Liver Lesion 
Fraction # 
Total Dose 
Max of single liver lesion 
3 
30-60 Gy 
Multiple liver lesions 
 
3 
5 
30-37.5 Gy 
25-30 Gy 
Previously irradiated, 
cirrhotic or significant 
hepatic impairment 
5 
25 Gy 
 
 
Guidelines will be followed and the ASTRO/ACR Practice Guidelines in regard 
to treatment (not personnel) will be followed 
 
 
 
NB: In all circumstances, normal tissue tolerances need to be respected and dose 
reductions will be acceptable to meet those criteria. Significant hepatic 
impairment is determined by the radiation oncologist, surgeon and their 
consultants. Childs-Pugh Class C can be used as a justification for no treatment 
18 


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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
but patients with Childs-Pugh Class C can be treated if considered medically 
appropriate. 
 
4.2.5 Radiosurgery: Spine/Soft tissue 
Please note soft tissue lesions are expected to be rare except when they are located 
in the paraspinal region.  If there is a soft tissue metastases is in another location 
these cases will need to be reviewed by two credentialed radiation oncologists for 
radiosurgery.  
4.2.5a Equipment 
Photon (x-ray) beams produced by linear accelerators with energies 4-18 MV will 
be allowed, preferably using photon beams with energy of 6 MV or less. IMRT or 
other dose painting techniques are allowed. Proton beams, and other charged 
particle beams (including electrons, heavy ions) are not allowed. Gamma Knife® 
or PerfexionTM treatment is not allowed.  
4.2.5b Treatment technique 
Inverse treatment planning will be employed using isocentric and/or non-
isocentric beam arrangements.  
4.2.5c Treatment volumes 
The goal of treatment planning is to deliver a conformal dose of radiation to the 
contrast enhancing target volume based on MR or CT images. Treatment volumes 
will be determined based on correlation of diagnostic imaging with a treatment 
planning CT scan performed at 1.00 to 1.50 mm slice thickness. Minimal margins 
of up to 3 mm will be used. The relevant target volumes and critical structures for 
treatment planning will be contoured by the participating radiation oncologist 
and/or thoracic surgeon. Both radiation oncologist and thoracic surgeon need to 
review the target volumes. The preferred image for target contouring is a CT 
image post-contrast at a minimum of 1.5 mm between image slices with the image 
obtained at the normal breathing cycle.  A CT myelogram can be performed to 
better delineate the neural structures 
4.2.5d Treatment simulation 
• 
The simulation procedure will involve obtaining the CT dataset in the 
treatment position and during the normal breathing cycle through the 
region of interest. 
• 
 All patients will be simulated in the supine position, head at the superior 
portion of the treatment/simulation table. 
• 
 For cervical and upper thoracic (T5 and higher), immobilization of the 
head with the neck in mildly extended position is expected 
• 
For other regions of the spine, the patient’s head will be in the neutral 
position or in a position that maintains a comfortable airway 
• 
The CT dataset for treatment planning will be obtained at 1.00 mm to 1.5 
mm slice thickness and will be a non-contrast study 
• 
The patient’s head and body should remain in the PDP safety zone. 
19 


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UNIVERSITY OF NORTH CAROLINA 
November 18, 2014 
 
 
• 
A contrasted CT scan will be obtained in the treatment position after the 
non-contrast study has been obtained in a similar fashion as the non-
contrasted study if indicated clinically. 
4.2.5e Treatment immobilization 
Patients must be positioned in a stable supine position capable for reproducibility 
of positioning and immobilization from simulation to treatment, allowing the 
patient to feel as comfortable as possible. Positions uncomfortable for the patient 
should be avoided to prevent unnecessary movement. A prone position is not 
allowed. A variety of immobilization systems may be utilized including vacuum 
bag, alpha cradle, or stereotactic frames that surround the patient on three sides 
and large rigid pillows (conforming to patients external contours) with reference 
to the treatment delivery coordinate system. In addition, for cervical spine or 
cervicothoracic junctional areas, a rigid head and neck immobilization device 
should be used. Patient immobilization must be reliable enough to achieve the 
accuracy requirement of image-guidance. 
4.2.5f Treatment schedule / time and dose considerations 
 
Time and dose considerations: 
 
• 
Prescription isodose: The dose will be calculated to the 60-100% isodose 
curve as normalized to the maximum dose. In general, the 60-80% isodose 
curve is strived for target coverage 
• 
Coverage: The target lesion should be covered at least 95% by the 
prescription isodose curve and 99% should be covered by 90% of the 
prescription isodose curve 
• 
Conformity of dose: Conformity indices PIV*TIV/TV²  should be within 
1.00 – 2.00 
• 
Total dose: The total dose to the prescription isodose 
• 
Normal tissue dose  limitations: 
o 
For single fraction treatment: The maximum voxel dose to the 
spinal cord should not exceed 15 Gy in a single fraction. 10% of 
the volume (as defined as 6mm above and below the PTV) should 
be less than 10 Gy in a single fraction. No voxel to the kidney 
greater than 15Gy with a limit of 6 Gy to 50% of the kidney 
o 
For patients who have received prior radiation or are receiving 
treatment to multiple levels, treatment typically will be 
fractionated: The maximum voxel dose to the spinal canal should 
not exceed 5 Gy in a single fraction and 10% of the volume should 
not exceed 3 Gy in each individual fraction. Total cumulative dose 
to the spinal cord should not exceed 15 Gy to 10% of the volume if 
fractionated treatment is utilized. Attempts to limit dose  to the 
kidney  to < 2 Gy per fraction with absolute limit of 50% of the 
kidney receiving less than 15Gy the dose to the whole lung 
(bilateral) will be a V20 of < 15%. Esophagus < 27 with no 
fraction greater than 9 Gy. Heart/ proximal bronchus/trachea/ great 
20 


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November 18, 2014 
 
 
vessels < 30 Gy with no fraction greater than 10 Gy. Brachial 
plexus < 24 Gy with no fraction greater than 8 Gy 
• 
Dose schedule: Radiosurgery treatments will be delivered on consecutive 
weekdays for one to five fractions (one fraction per day) and delivered per 
institutional preference (on consecutive days versus several per week) 
 
 
 
 
   
 
 
 
 
 
 
 
 
NB: In all circumstances, normal tissue tolerances need to be respected and dose reductions will be ac
4.3 
Erlotinib Treatment Dosage and Administration 
Erlotinib (Tarceva®) will be administered per standard of care.  Of note, patients 
with EGFR mutation often require substantially less than the standard dose to 
achieve efficacy.  Thus, while the study recommends a standard starting dose, 
patients with known intolerance at this dose, but known tolerance with efficacy at 
a lower dose will be allowed to initiate at that dose.  Erlotinib will be taken once 
per day on an empty stomach (one hour before, or two hours after food). 
 
At the time of enrollment into the study, patients may already be on erlotinib 
therapy.  For these patients, it is recommended (but not required) that erlotinib be 
discontinued 3 days prior to the initiation of SRS (i.e., if last dose of erlotinib is 
on a Sunday, SRS can be administered on Thursday).  The study recommends that 
erlotinib be restarted 3 days after the completion of SRS.  At the investigator’s 
discretion, erlotinib may be started sooner (or never discontinued) but not later. .   
4.4 
Toxicities and Dosing Delays/Dose Modifications 
Erlotinib is FDA approved for the population being studied and treating clinicians 
have extensive experience in toxicity management, dosing delays, and dose 
modifications.  As erlotinib is the only FDA approved TKI targeted against EGFR 
in the United States and no international sites are planned, it is anticipated that 
most or all patients will have received erlotinib specifically prior to study entry.  
The study therefore does not demand a specific strategy for toxicity management.  
Rather, the study refers clinicians to the PI and published guidelines. 
4.5 
Concomitant Medications/Treatments 
Erlotinib does not commonly causes significant interactions with concomitant 
medications.  In theory, CYP3A4 inhibitors may increase erlotinib plasma 
Status of 
Vertebral Body 
Fraction # 
Total Dose 
Max of single 
Vertebral Body  
 
1 
 
12-20 Gy 
Multiple Vertebral  
Bodies/NT limits 
3 
5 
21-30 Gy 
25-30 Gy 
Previously 
Irradiated 
3 
5 
21 Gy 
25-30 Gy 
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concentrations and inducers may decrease erlotinib plasma concentrations.  
CYP1A2 inducers may decrease erlotinib plasma concentrations.  Cigarette 
smoking is known to decrease erlotinib serum concentrations.  While standard 
practice does sometimes require an increase in erlotinib dosing, this study is open 
only to patients with the EGFR mutation, who typically are nonsmokers. 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue 
until: 
• Disease progression 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from the study, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator”. 
4.7 
Duration of Follow Up 
Patients will be followed until death.   See section 6.5 for details. 
5.0 
DRUG INFORMATION 
5.1 
Erlotinib (Tarceva®) 
5.1.1 Mechanism of Action 
The mechanism of clinical antitumor action of erlotinib is not fully characterized.  
Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated 
with the epidermal growth factor receptor (EGFR). Specificity of inhibition with 
regard to other tyrosine kinase receptors has not been fully characterized. EGFR 
is expressed on the cell surface of normal cells and cancer cells. 
5.1.2 How supplied 
Erlotinib is a tyrosine kinase inhibitor indicated for the treatment of patients with 
locally advanced or metastatic non-small cell lung cancer (NSCLC) whose 
disease has not progressed after four cycles of platinum-based first-line 
chemotherapy, and for the treatment of locally advanced or metastatic non-small 
cell lung cancer after failure of at least one prior chemotherapy regimen. For the 
present study, it will be supplied by Astellas Pharma at no charge to study 
subjects.   
5.1.3 Dosing and administration 
The standard recommended dose of erlotinib for NSCLC is 150mg.  However, the 
inclusion criteria of this study demand presence of an EGFR mutation.  Previous 
studies have demonstrated that patients with this mutation can achieve efficacy 
with substantially lower dosages with subsequent better tolerance of therapy. 
Thus, while the recommended dose will remain the FDA approved dose of 
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150mg, lower doses, down to the previously effective dose, will be permitted.  
Erlotinib should be taken on an empty stomach, either one hour before or two 
hours after food.  No premedication, hydration, or special storage is required.  
5.1.4 Adverse Events Associated with Erlotinib 
Standard adverse events associated with erlotinib are described from the PI and 
are consistent with those observed in clinical care.  However, it is notable that 
patients with previous intolerance to erlotinib are excluded from the study.   
Therefore, tolerance in this study will likely be higher than that described in the 
literature. 
 
The most common side effects of erlotinib are rash and diarrhea.  Two major 
trials, the SATURN maintenance trial and the BR.21 2nd line trial allow 
comparison of patients treated with erlotinib to those treated with placebo.  These 
data are summarized in the prescribing information for erlotinib (see 
www.tarceva.com), and below.  
 
Table 1 summarizes the SATURN trial, and Table 2 the BR.21 2nd line trial.  Both 
tables summarize AEs occurring more frequently (≥3%) in the single agent 
erlotinib group then in the placebo group, and in ≥3% or ≥10% of patients in the 
erlotinib group (SATURN and BR.21, respectively). 
 
 
 
 
 
 
 
TABLE 1 
 
Erlotinib (n=433) 
Placebo (n=445) 
Grade 
Any 
3 
4 
Any 
3 
4 
 
% 
% 
% 
% 
% 
% 
Rash 
49.2 
6.0 
0 
5.8 
0 
0 
Diarrhea 
20.3 
1.8 
0 
4.5 
0 
0 
Fatigue 
9.0 
1.8 
0 
5.8 
1.1 
0 
Anorexia 
9.2 
<1 
0 
4.9 
<1 
0 
Pruritus 
7.4 
<1 
0 
2.7 
0 
0 
Acne 
6.2 
<1 
0 
0 
0 
0 
Dermatitis 
Acneiform 
4.6 
<1 
0 
1.1 
0 
0 
Dry skin 
4.4 
0 
0 
<1 
0 
0 
Weight decreased 
3.9 
<1 
0 
<1 
0 
0 
Paronychia 
3.9 
<1 
0 
0 
0 
0 
 
 
 
 
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TABLE 2 
 
Erlotinib (n=485) 
Placebo (n=242) 
Grade 
Any 
3 
4 
Any 
3 
4 
 
% 
% 
% 
% 
% 
% 
Rash 
75 
8 
<1 
17 
0 
0 
Diarrhea 
54 
6 
<1 
18 
<1 
0 
Anorexia 
52 
8 
1 
38 
5 
<1 
Fatigue 
52 
14 
4 
45 
16 
4 
Dyspnea 
41 
17 
11 
35 
15 
11 
Cough 
33 
4 
0 
29 
2 
0 
Nausea 
33 
3 
0 
24 
2 
0 
Infection 
24 
4 
0 
15 
2 
0 
Vomiting 
23 
2 
<1 
19 
2 
0 
Stomatitis 
17 
<1 
0 
3 
0 
0 
Pruritis 
13 
<1 
0 
5 
0 
0 
Dry skin 
12 
0 
0 
4 
0 
0 
Conjunctivitis 
12 
<1 
0 
2 
<1 
0 
Keratoconjunctivitis 
12 
0 
0 
3 
0 
0 
Abdominal pain 
11 
2 
<1 
7 
1 
<1 
 
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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
 
Assessment 
Pre-
study1 
Post 
SRS2 
Q 8 
Weeks 
X 33 
Q 6-12 
Weeks4 
Early 
Termination5 
At 
Progression6 
Follow 
-up 
Informed Consent 
X 
 
 
 
 
 
 
History and PE7 
X 
X 
X 
X 
X 
 
X 
ECOG Performance 
Status (Appendix A) 
X 
X 
X 
 
X 
 
 
Pregnancy Test 
X8 
 
 
 
 
 
 
CBC with diff/platelets 
X 
X 
X 
X 
 
 
 
Serum chemistries9 
X 
X 
X 
X 
 
 
 
Liver function tests9 
X 
X 
X 
X 
 
 
 
Tumor evaluation 
X10 
 
X10 
X10 
X10 
X10 
X12 
Concomitant Meds 
X 
 
X 
 
X 
 
 
Toxicity Assessment 
Continuous during the study 
Blood sample for 
Veristrat® Assay11 
X 
X11 
X11 
 
 
X11 
 
Subsequent therapy 
 
 
 
X4 
 
X12 
X12 
Charlson comorbidity 
index (Appendix B) 
X 
 
 
 
 
 
 
 
See Key to Footnotes on next page. 
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Key to Time and Events Table   
1 Unless otherwise noted, perform within 2 weeks prior to initiation of SRS or local ablative 
therapy.  CT or PET within 4 weeks prior to the start of therapy 
2Post SRS or local ablative therapy, pre-erlotinib unless patient enrolled in trial on erlotinib and 
continuing it through SRS, see section 4.3 (NOTE: this visit can occur on the last day of 
radiation) 
3The initial 3 visits post erlotinib initiation will be performed at the enrolling site, and can take 
place every 8 weeks +/- 1 week; however, the tumor measurements at these visits should take 
place within 1 week (7 days) prior to the study visit.  If patient progresses prior to the end of 6 
months, then they will enter long-term follow-up (see section 6.5).  
4 For patients living a distance prohibitive for further travel to the enrolling site, visits after the 
initial 6 months on erlotinib (or after progression) for clinical care may be performed remotely 
by the patient’s primary oncologist.  In this case, records will be requested, specifically 
including doctors’ notes, imaging reports, and CDs of imaging. 
5This visit will be scheduled when a subject is withdrawn from study therapy prior to 
progression  
6 At the time of progression, choice of regimen for next treatment will be requested.  If 
patient is not being treated at an enrolling site, these records may be obtained remotely. 
Imaging reports and images will be requested to ascertain the nature of and duration of 
response to the next line of therapy, when possible. 
7Complete medical history at baseline, thereafter, symptom directed history 
8Serum or urine pregnancy test for women of child bearing potential 
9Serum chemistries include sodium, potassium, chloride, bicarbonate, magnesium, BUN, 
serum creatinine, glucose, calcium, total protein and albumin; liver function tests include total 
bilirubin, alkaline phosphatase, AST, and ALT) 
10CT or PET scan-use consistent imaging throughout study; NOTE: the X10 at progression is 
there to indicate that progression was diagnosed via a tumor evaluation 
11 Draw 3.5 mL of blood into SST (gold -top) Vacutainer tube Blood for Verstrat® assay 
at study entry (prior to SRS or local ablative therapy), post SRS or local ablative therapy 
(and prior to erlotinib, either that day’s dose, or prior to initiating erlotinib), at the first 
visit following SRS, and at the time of progression (if feasible).  See section 6.7 for 
additional information. 
12 See sections 6.5 and 6.9.7. 
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6.2 
Pre-Study Assessments 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy.  CT or PET scan must be done within 4 weeks prior to the start of 
therapy.  Pre-study assessments include: 
 
• Complete medical history and physical examination (including height and 
weight) 
• ECOG Performance Status (see appendix A) 
• Charlson Comorbidity Index (see appendix B) 
• Laboratory evaluations: CBC with differential; serum chemistries (sodium, 
potassium, chloride, bicarbonate, magnesium, BUN, serum creatinine, 
glucose, calcium, liver function tests (LFTs; total bilirubin, alkaline 
phosphatase, AST, ALT), total protein, albumin, urine or serum pregnancy 
test in women of childbearing potential  
• Record all concomitant medication(s) 
• Tumor evaluation: CT or PET Scan 
• Confirmation of EGFR mutation or clinical response to EGFR TKI (see 
inclusion criteria 3.1.3) 
• Toxicity evaluation (for notation of any baseline toxicity) via NCI CTCAE v4. 
• Blood sample for Veristrat® assay: Draw 3.5 mL SST (gold -top) Vacutainer 
tube.  See section 6.7 for additional details. 
6.3 
Treatment Assessments 
6.3.1 Post SRS or other Local Ablation 
• Symptom directed medical history and physical examination  
• ECOG Performance Status (see appendix A) 
• Laboratory evaluations: CBC with differential; serum chemistries (sodium, 
potassium, chloride, bicarbonate, magnesium, BUN, serum creatinine, 
glucose, calcium, liver function tests (LFTs; total bilirubin, alkaline 
phosphatase, AST, ALT), total protein, and albumin 
• Toxicity evaluation (for notation of any baseline toxicity) via NCI CTCAE v4. 
• Blood sample for Veristrat® assay: Draw 3.5 mL SST (gold -top) Vacutainer 
tube.  See section 6.7 for additional details. 
6.3.2 Every 8 weeks x 3 for a total of 6 months (or until progression, whichever 
occurs earliest) 
• Symptom directed medical history and physical examination  
• ECOG Performance Status (see appendix A) 
• Laboratory evaluations: CBC with differential; serum chemistries (sodium, 
potassium, chloride, bicarbonate, magnesium, BUN, serum creatinine, 
glucose, calcium, liver function tests (LFTs; total bilirubin, alkaline 
phosphatase, AST, ALT), total protein, and albumin 
• Record all concomitant medication(s) added or changed. 
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• Tumor evaluation: CT or PET Scan 
• Toxicity evaluation (for notation of any baseline toxicity) via NCI CTCAE v4 
• Blood sample for Veristrat® assay (at first visit post SRS/local ablative 
therapy only): Draw 3.5 mL SST (gold -top) Vacutainer tube.  See section 6.7 
for additional details. 
6.3.3 Subsequent Every 6-12 Weeks until Progression 
For patients who do not progress within the first 6 months on study, following the 
formal 6 month follow-up post erlotinib initiation at the site, patients will be 
assessed per standard clinical practice.  Typically, this involves serial physical 
examination, laboratory and imaging evaluations every 6-12 weeks, but this will 
be done at the discretion of the treating physician.  If the patient does not receive 
his/her clinical care at a participating institution, doctor’s notes, imaging reports, 
and CDs of images will be requested to confirm time of progression, time of 
death, and toxicity. 
6.4 
Evaluation at Progression 
At the time of progression on erlotinib, the time of documented progression will 
be recorded.  If feasible, obtain blood sample for Veristrat® assay: Draw 3.5 mL 
SST (gold -top) Vacutainer tube.  See section 6.7 for additional details. At the 
time of progression, choice of regimen for next treatment will be requested.  If 
patient is not being treated at an enrolling site, these records may be obtained 
remotely. Imaging reports and images will be requested to ascertain the nature of 
and duration of response to the next line of therapy, when possible. 
6.5 
Long-Term Follow-Up 
After progression, follow-up of patients will be limited to collecting response rate 
and PFS to subsequent therapy when possible, and survival status.  If the patient 
does not receive his/her clinical care at a participating institution, doctor’s notes, 
imaging reports, and CDs of images will be requested to confirm response, time 
of subsequent progression, and time of death. Theses data will be collected every 
6 months until death, will be recorded on the electronic case report form (eCRF), 
and may be requested/collected via telephone.   
6.6 
Early Termination Visit 
The following assessments will be performed, if possible, when a subject is 
withdrawn from study therapy prior to progression: 
• Symptom directed medical history and physical examination  
• ECOG Performance Status (see appendix A)  
• Record all concomitant medications(s) added and/or changed 
• Tumor evaluation — CT or MRI Scan and physical examination. 
• Toxicity assessment: record any non-serious and serious AEs and assign 
appropriate toxicity grade (NCI CTCAE, Version 4).  Patients who have on 
ongoing Grade 4 or SAE at the time of discontinuation from treatment will 
continue to be followed until the event is resolved or deemed irreversible by 
the investigator. 
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6.7 
Correlative Studies Procedures: Veristrat® 
Blood will be obtained and samples blinded at the following intervals: 
• At study entry (prior to SRS) 
• Subsequent to completion of SRS/local ablative therapy, but prior to 
rinitiation of erlotinib or that day’s dose of erlotinib 
• At the first visit following SRS/local ablative therapy 
• At the time of progression (if feasible) 
 
The following collection and processing procedures will be followed: 
 
• Biodesix will provide the investigative site with the materials necessary to 
complete this process. 
• Assign a blinded sample number from the Master Worksheet provided by 
Biodesix. Complete 3 study identification labels with the blinded number. 
• Place 1 label on each of the following provided by Biodesix: 
o 3.5 mL SST (gold -top) Vacutainer tube. 
o Serum Collection Card. 
o Study test request form (TRF), upper right corner.  
• Collect venous blood into the 3.5 mL SST Vacutainer. 
• Gently invert the SST 5 times and allow the tube to clot in an upright position for 
30 minutes at room temperature (approximately 70°Farenheit or 21°Celcius (C).  
• Spin the SST in a standard clinical centrifuge at a speed of 1000-1300 gravity (g), 
or equivalent, for 10-15 minutes. Speed should not exceed 1300 g, and time 
should not exceed 15 minutes or hemolysis may occur. 
• Verify that the serum is light yellow in color. Pink or reddish serum indicates 
sample has hemolyzed and must be redrawn. 
• Without disturbing the clot layer, use a transfer pipette to transfer 2 drops (0.1 
mL) of serum to each of the 2 circles on the Serum Collection Card. 
• Dispose of SST. 
• Close cover of Serum Collection Card and follow shipping instructions. Sample 
must be shipped within 24 hours, and may be stored at room temperature until 
shipping. 
The following shipment procedures will be followed: 
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• 
Place the Serum Collection Card into foil bag and seal. 
• 
Place the foil bag and the completed study TRF into the shipping 
envelope. Save the yellow copy of the study TRF for placement in 
the subject’s study records. 
• 
Complete the required FedEx® air bill fields, and if shipping on a 
Friday, check the Saturday delivery box. Remove the sender’s 
copy of the air bill for the subject’s study records, and place the 
remainder of the air bill in the pouch in the shipping envelope.  
• 
Arrange for and confirm FedEx pickup of the package the same 
day as the sample is prepared for shipping.  
Any specimens remaining after protocol-directed studies are complete will be 
destroyed by Biodesix at the completion of the study.   
6.8 
Assessment of Safety  
Any patient who receives treatment on this protocol will be evaluable for toxicity 
via NCI CTCAE version 4.  Further information on this assessment is provided in 
the time and events table.  
6.9 
Assessment of Efficacy 
Patients who complete SRS (or other local ablation), receive at least 14 doses of 
erlotinib, and have their disease re-evaluated at 8 weeks will be evaluable for 
assessment of the primary objective (PFS).  Patients who drop out of the study 
prior to this point will not be evaluable for the primary objective unless they have 
received at least 14 doses of erlotinib, and have either clearly progressed or died. 
  If a patient comes off study at any point after 8 weeks without having progressed 
or died, they will be censored at their last known progression-free date. 
6.9.1 Progression free survival 
Progression free survival will be the primary endpoint of the study.  Progression 
free survival will be measured from the time of initiation of SRS until the time of 
progression or death.  Lesions that progress on initial TKI therapy will be treated 
with SRS or other locally ablative maneuver.  Because of concern for potential 
antagonism between erlotinib and radiation as well as safety concerns, erlotinib 
will be held during SRS.  This could potentially allow growth of non-treated, 
erlotinib-sensitive clones during this period, with later disease control on 
erlotinib.  For this reason, non-treated lesions that progress between the pre-
treatment and pre-erlotinib reinitiation evaluations will not be counted as 
progressive disease unless they also progress on the 1st follow-up imaging while 
on erlotinib.  Further, areas treated with SRS are known to sometimes inflame as a 
consequence of therapy, with no actual disease progression.  In clinical practice, 
radiologist and radiation oncologist assessment of these lesions are predictive of 
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long-term control.  Therefore, clinician judgment will be used for both protocol 
and treatment decisions in evaluating whether a lesion treated with SRS that 
appears larger is actually progressive.  In all cases, the same judgment must be 
used for both evaluation of control on study, and clinical decision making. 
6.9.2 Local control rate of SRS treated lesions 
As noted above, areas treated with SRS are well known to inflame after therapy.  
In these cases, the clinical judgment of the radiologist and radiation oncologist 
will be used to assess the local control of specific lesions.  Of note, observation 
over time may be necessary for definitive assessment of some lesions. 
6.9.3 Overall survival 
Overall survival will be measured from the time of initiation of SRS until the time 
of death. 
6.9.4 Toxicity of SRS 
Toxicity of SRS will be graded by NCI CTCAE version 4. 
6.9.5 Toxicity of erlotinib post SRS/local ablative therapy 
The toxicity of erlotinib has been well defined in multiple phase III studies.  
However, two elements are different in this study.  First, erlotinib is being used 
after SRS.  While this has been done before in clinical practice, the toxicity has 
not been systematically assessed.  Second, if the therapy is efficacious, patients 
may spend a longer time on erlotinib and live a longer time, potentially exposing 
longer-term toxicities that have been masked by previously short PFS and OS. 
6.9.6 Veristrat® in EGFR mutated NSCLC 
Veristrat® has been shown to be prognostic in untreated patients as well as 
predictive of both response and survival in EGFR-TKI treated patients, including 
patients with EGFR mutation.  Although change in Veristrat® result from “good” 
to “poor” has been demonstrated in patients progressing on an EGFR-TKI, the 
assay has never been evaluated in the context of a therapy seeking to restore 
systemic sensitivity to a TKI and a “poor” to “good” transition has never been 
documented.  Exploratory analyses of both the good vs. poor signature and 
individual peaks will be explored at serial time points. 
6.9.7 Responses to subsequent therapies 
It is possible that the study treatment modulates treatment outcomes to subsequent 
therapies.  For example, ablation of clones resistant to erlotinib may also ablate 
cells that bear resistance to the chemotherapy later chosen.  Therefore, to the 
extent possible, response rate and PFS to subsequent therapy will be recorded on 
the electronic case report form (eCRF). 
6.9.8 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
Response rate will be assessed for SRS. 
 
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Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
• >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 20 mm by chest x-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.   
 
All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions, will be considered non-measurable.  Lesions considered truly 
non-measurable include: leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the beginning 
of the treatment.  The same method of assessment and the same technique should 
be used to characterize each identified and reported lesion at baseline and during 
follow-up.  Imaging based evaluation should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
6.9.9 Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline.   
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, only the short axis is 
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added into the sum.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as “present” 
or “absent”, or in rare cases “unequivocal progression”.   
6.9.10 Evaluation of Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all target lesions.  Any pathological 
lymph node (LN) (whether target or non-target)  must have decreased in short 
axis to <10mm. 
 
Partial response (PR)−At least a 30% decrease in the sum of the LD of the target 
lesions taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline if that is the smallest on study.  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
6.9.11 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target lesions and 
normalization of tumor marker levels.  All LN must be non-pathological in size 
(<10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and maintenance of tumor marker level above the 
normal limits. 
 
Progressive disease (PD)−Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
6.9.12 Evaluation of Best Overall Response using RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment provided the confirmation criteria are met.  To 
be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed > 4 weeks after the criteria 
for response are first met. If a CR/PR cannot be confirmed the original "response" 
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should be considered stable disease.  The best overall response will be defined 
according to the following table: 
 
Overall 
Response First 
Time Point 
Overall Response 
Subsequent Time 
Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
NE 
NE2 
NE2 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Best 
response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point.  Under these circumstances, the original CR should be changed to PR and the best response is PR.  
2  NE=inevaluable  
 
7.0 
ADVERSE EVENTS 
7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
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7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
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• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
7.2 
Documentation of  non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue until the AE or SAR is resolved or returns to <grade 1 or 
baseline. 
 
Collected information should be recorded in the Electronic Case Report Forms 
(eCRF) for that patient.  Please include a description of the event, its severity or 
toxicity grade, onset and resolved dates (if applicable), and the relationship to the 
study drug.    Documentation should occur at least monthly.  
7.3 
SAEs or Serious SARs 
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout, or no treatment run-
in).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued. 
 
 
For any other experience or condition that meets the definition of a serious 
adverse event (SAE) or SAR, recording of the event must begin from day 1 of 
study treatment and continue through the 30 day follow-up period after treatment 
is discontinued.   
7.3.2 Documentation and Notification 
These events (SAEs or serious SARs) must be recorded in the eCRF for that 
patient within 24 hours of learning of its occurrence.  For Affiliate sites, an email 
must also be sent to the NCCN Project Manager indicating that an SAE or Serious 
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SAR has been entered into Oncore (email contact will be provided at study start-
up).  
7.3.3 Reporting  
FDA Expedited Reporting requirements for studies conducted under an IND: 
If an investigator deems that an event is both a serious SAR AND unexpected, it 
must also (in addition to Oncore) be recorded on the MedWatch Form 3500A as per 
21 CFR 312.32.  If the event occurs at an Affiliate site, the MedWatch form should 
be faxed to the UNCCN Project Manager at 919-966-4300 along with supporting 
documentation defining the event and causality.  The MedWatch 3500a form can be 
accessed at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
(Please be sure and access form 3500a, and not form 3500). UNC, as the Sponsor of 
the study, will make the final determination regarding FDA submission.   
 
UNC study personnel are responsible for informing the Principal Investigator of the 
SAE, and, if it is also a serious SAR AND unexpected, for forwarding all 
MedWatch 3500A forms to the FDA in accordance with 21 CFR 312.32 (for drugs 
under an IND) and 21 CFR 314.80 (for marketed drugs).    
 
The UNCCN Project Manager will also be responsible for informing each Affiliate 
site of all serious and unexpected SARs via fax as soon as possible.   
 
IRB Reporting Requirements: 
Affiliate sites:   
• For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
• For affiliate sites relying on the UNC-IRB, an aggregated list of all SAEs 
will be submitted to the UNC IRB annually at the time of study renewal 
according to the UNC IRB policies and procedures.  In addition, any 
SAEs that qualify as an Unanticipated Problem will be entered into 
Oncore and reported to the UNC IRB by the UNCCN Project Manager 
using the IRB’s web-based reporting system (see section 9.5.3) within 7 
days of the Investigator becoming aware of the problem.   
 
UNC: 
• UNC will submit an aggregated list of all SAEs to the UNC IRB annually 
at the time of study renewal according to the UNC IRB policies and 
procedures. 
• The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
.   
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7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight of the Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety and Monitoring Committee (DSMC) will 
review the study on a regular (quarterly to annually) basis, with the frequency of 
review based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
This is a single arm phase II trial of 40 patients evaluating a novel treatment 
strategy for EGFR-mutant NSCLC patients who have just progressed on an 
EGFR-TKI.  The primary endpoint of the study will be progression free survival.  
Secondary endpoints include overall survival, local control rate of sites ablated by 
SRS, toxicity of SRS, toxicity of erlotinib after SRS, and proteomics based 
biocorrelates (Veristrat®). 
8.2 
Sample Size and Accrual 
No data exist at this time to define median progression-free survival on 
chemotherapy, following first-line erlotinib.  However, the FDA has approved 
docetaxel, pemetrexed and erlotinib for second line therapy based on a median 
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PFS of 1.8-2.9 months, establishing a standard for minimally effective second line 
therapy. 
 
 
 
 
 
Study 
Regimen 
PFS/TTP 
Hanna19 
Docetaxel 
Pemetrexed 
2.9 
2.9 (PFS) 
BR.2120 
Erlotinib 
Placebo 
2.2 
1.8 (PFS) 
Shepherd21 
Docetaxel 
Placebo 
10.6w 
6.7w (TTP) 
TAX 32022  
Doctaxel 
Vin or ifos 
8.5w 
7.9w (TTP) 
 
 
While a PFS that matched the best previously demonstrated second line results 
would be sufficient to meet the threshold for further study, several factors are 
worthy of note in considering how such results could be interpreted and utilized.  
First, both SRS and erlotinib are substantially less toxic than cytotoxic 
chemotherapy.  Second, this therapy would represent an additional option for 
EGFR mutant patients—after second progression on erlotinib, patients would still 
be eligible for treatment with standard chemotherapy.  Thus, we hypothesize that 
the proposed treatment strategy will lead to a median progression free survival of 
at least 3 months. 
 
A median PFS of 3 months implies that at 3 months, 50% of the population will 
still be progression free (PF).  With 40 patients, the following table shows the 
precision of the 95% confidence interval that will be constructed for the 
percentage of patients who are PF at 3 months.  If the percentage of patients PF at 
3 months is 65% the 95% CI will be (48%-79%). 
 
 
 
Number of Pts 
Progression Free at     
3 months 
3 month PFS 
(95% CI) 
16/40 
40% (25%, 57%) 
18/40 
45% (29%, 62%) 
20/40 
50% (34%, 66%) 
22/40 
55% (38%, 71%) 
24/40 
60% (43%, 75%) 
26/40 
65% (48%, 79%) 
28/40 
70% (53%, 83%) 
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We expect the percentage of patients who are PF at 3 months to be more than 
50%, so with 40 patients, if 65% or 70% of patients are PF at 3 months, the exact 
95% binomial confidence interval will be sufficiently narrow and suggest that the 
median PFS is longer than 3 months.  An exact binomial test with a nominal 0.05 
one-sided significance level will have 80% power to detect the difference between 
the null hypothesis of 50% PF at 3 months and the alternative hypothesis of 70% 
PF at 3 months when the sample size is 40.  
8.3 
Data Analyses Plans 
Kaplan-Meier curves with appropriate confidence bands will be used to estimate 
the primary endpoint of median progression free survival.  An exact 95% 
binomial confidence interval for the percentage of patients progression free at 3 
months will be also be constructed, and a one-sided test will be done to see if it 
significantly higher than 50%.  While the primary objective is to estimate median 
PFS, with 40 patients, we may be able to detect a significant improvement over a 
null hypothesis of only 50% of patients being progression free at 3 months.      
 
Appropriate descriptive statistics including means, standard deviations, medians, 
and ranges will be provided for continuous data (ex. proteomics), and proportions 
will be used to summarize categorical data (ex. control and toxicity rates).  
Standard Kaplan-Meier curves and Cox proportional hazard models will be used 
to analyze time to event endpoints (including secondary endpoint of OS).  
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
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Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  
Otherwise, the Investigator’s signature documenting understanding of 
the protocol and providing commitment that this trial will be 
conducted according to all stipulations of the protocol is sufficient to 
ensure compliance) 
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  For UNC patients, prior to registration, eligibility 
criteria must be confirmed with the UNC Study Coordinator. To register a patient, 
call the Oncology Protocol Office at 919-966-4432 Monday through Friday, 
9:00AM-5:00PM.  
 
For Affiliate patients, to register and confirm patient eligibility, please fax 
registration forms, informed consent,  and source documents to 919-966-4300..  
 
9.4 
Data Management and Monitoring/Auditing 
The CPO of the UNC LCCC will serve as the coordinating center for this trial. 
Data will be collected through a web based clinical research platform, OnCore®.  
Other study institutions will be given a password to directly enter their own data 
onto the web site via electronic case report forms (eCRFs).  UNCCN personnel 
will coordinate and manage data for quality control assurance and integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions.  The 
investigators at each site will allow monitors to review all source documents 
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supporting data entered into OnCore®.   The UNCCN Data Coordinator can be 
reached at 919-843-2742 or 1-877-668-0683. 
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six to twelve  months depending on 
Affiliate site participation.  
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.   
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
• To UNC Principal Investigator for agreement  
• The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the 
UNCCN Regulatory Associate). 
9.5.2 Single Patient/Subject Exceptions 
For Institutions Relying on UNC’s IRB:  
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB.  
 
For Institutions Relying on Their Own IRB: 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the 
participating institution’s IRB, per its policy.  Please forward the IRB response to 
the UNCCN Regulatory Associate by facsimile or via email within 10 business days 
after the original submission.   
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9.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNCCN Project Manager within 
5 days. UNC-CH will determine if the violation affects the safety of the patient 
and integrity of the data.  Once your institution’s IRB response is received, please 
forward to the UNCCN Regulatory Associate. 
 
 
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Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNCCN Project Manager.   The 
UNCCN Project Manager will report the event to the UNC IRB using the IRB’s 
web-based reporting system.  Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 
 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNCCN Regulatory Associate 
prior to submission to their IRB.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
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on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
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10.0 REFERENCES 
     
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Zhou C, Wu YL, Chen G, et al: Erlotinib versus chemotherapy as 
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J. Wang CZ, Y. Wu, S. Lu, L. Zhang, Y. Zhang, M. Ye, J. Ma, J. 
Huang, Q. Xiu: OPTIMAL: Phase III Study of First-line Erlotinib Versus 
Gemcitabine Plus Carboplatin (GC) in Chinese Patients (pts) With Activating 
EGFR Mutation-Positive Advanced Non-small Cell Lung Cancer (NSCLC). On 
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Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or 
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Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin 
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Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-
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Paz-Ares L, Soulieres D, Melezinek I, et al: Clinical outcomes in 
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Das AK, Chen BP, Story MD, et al: Somatic mutations in the 
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R. H. Mak ED, A. Muzikansky, J. Kang, N. C. Choi, H. Willers, D. 
M. Jackman, L. V. Sequist: Thoracic radiation therapy in locally advanced 
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Okunieff P, Petersen AL, Philip A, et al: Stereotactic Body 
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Khan AJ, Mehta PS, Zusag TW, et al: Long term disease-free 
survival resulting from combined modality management of patients presenting 
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Oncology 81:163-167, 2006 
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13. 
Milano MT, Katz AW, Muhs AG, et al: A prospective pilot study 
of curative-intent stereotactic body radiation therapy in patients with 5 or fewer 
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Benedict SH, Yenice KM, Followill D, et al: Stereotactic body 
radiation therapy: the report of AAPM Task Group 101. Med Phys 37:4078-101, 
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Taguchi F, Solomon B, Gregorc V, et al: Mass spectrometry to 
classify non-small-cell lung cancer patients for clinical outcome after treatment 
with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort 
cross-institutional study. J Natl Cancer Inst 99:838-46, 2007 
 
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Lazzari C, Spreafico A, Bachi A, et al: Changes in plasma mass-
spectral profile in course of treatment of non-small cell lung cancer patients with 
epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol 7:40-
8, 2012 
 
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Amann JM, Lee JW, Roder H, et al: Genetic and proteomic 
features associated with survival after treatment with erlotinib in first-line therapy 
of non-small cell lung cancer in Eastern Cooperative Oncology Group 3503. J 
Thorac Oncol 5:169-78, 2010 
 
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Carbone DP SL, Ding K et al.: Serum proteomic prediction of 
outcomes in advanced NSCLC patients treated with erlotinib/placebo in the NCIC 
clinical trials group BR.21 trial. J Thoracic Oncol 5:S80; abstract 2030, 2010 
 
19. 
Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III 
trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer 
previously treated with chemotherapy. J Clin Oncol 22:1589-97, 2004 
 
20. 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in 
previously treated non-small-cell lung cancer. N Engl J Med 353:123-32, 2005 
 
21. 
Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized 
trial of docetaxel versus best supportive care in patients with non-small-cell lung 
cancer previously treated with platinum-based chemotherapy. J Clin Oncol 
18:2095-103, 2000 
 
22. 
Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial 
of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-
small-cell lung cancer previously treated with platinum-containing chemotherapy 
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18:2354-62, 2000 
 
 
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November 18, 2014 
 
 
 
11.0  APPENDICES 
11.1 
Appendix A ECOG Performance Status 
 
Grade 
Definition  
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 house 
work, office work  
2 
Ambulatory and capable of all selfcare but unable to carry out any 
work activities; up and about more than 50% of waking hours  
3 
Capable of only limited selfcare, confined to bed or chair for more 
than 50% of waking hours  
4 
Completely disabled. Cannot carry on any selfcare. Totally confined 
to bed or chair  
5 
Dead  
 
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November 18, 2014 
 
 
11.2 
Appendix B Charlson Comorbidity Index Scoring System 
 
 
 
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