Development of a Tumor Molecular Analyses Program and Its Use to Support Treatment Decisions
Phase: NA
Conditions: Neoplasm
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 9 
 
 
LCCC 1108: Development of a Tumor Molecular Analysis Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes (IRB Approval) 
X    Scientific changes (IRB approval) 
       Therapy changes (IRB approval) 
       Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY 
 
In this amendment, some objectives have been appropriately reclassified as exploratory, and the 
plans for analysis have been amended to reflect the developing understanding of the study. 
 
This amendment includes the following changes: 
 
Editorial and Administrative Changes 
• The study statistician has changed from Anastasia Ivanova to Dominic T. Moore. 
• Per current practice, names of co-investigators are no longer listed. 
 
Scientific Changes 
• Section 2:  Secondary objectives have been re-categorized as exploratory objectives 
due to this set of objectives being less informative than originally anticipated. 
Wording has also been clarified in Section 2.2.1.  
• Section 6.1 and 6.2:  Edits were made to reflect the planned analyses.  These changes 
include deleting obsolete language from the Sample Size and Accrual language in 
Section 6.1, and modifying the Data Analysis language in Section 6.2 to state the 
Kaplan-Meier method will be used. 
 
The attached version dated July 25, 2019 incorporates the above revisions 
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CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 8 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
X    Editorial, administrative changes 
X    Scientific changes (IRB approval) 
       Therapy changes (IRB approval) 
X    Eligibility Changes (IRB approval) 
Other 
AMENDMENT RATIONALE AND SUMMARY 
The amendment includes the following changes: 
1. This protocol now serves as a stand-alone study in all clinics even where the Health 
Registry is established.  
a) The protocol still includes references to the health registry but involvement in the 
Health Registry is no longer required as was previously noted in the eligibility 
criteria. The schema in Section 4 was revised to reflect this change 
2. The protocol now indicates that researchers may or may not collect normal tissue 
samples and they may analyze only tumor samples. 
3. The protocol allows for the possible conduct of systematic germline DNA studies 
although this type of analysis is not required. 
4. The language referring to “incidental germline discoveries” is no longer present 
because these discoveries are no longer incidental.  
5. The protocol indicates that researchers are sequencing other genetic material besides 
DNA due to advancements in next generation sequencing technology (ie, RNA, ChIP, 
methylation sequencing, etc.). 
6. Dr. Jung Wu is no longer on the list of clinical committee members and Dr. David 
Eberhard is no longer on the list of co-investigators. 
7. Minor editorial changes are included in the text and an additional paragraph added to 
the background section that briefly describes NextGen Sequencing Methods.  
8. Revised the description of the responsibilities of the Molecular Tumor Board in 
section 1.4. 
9. Revised the protocol to reflect that the CCRG is no longer named the Committee for 
the Communication of Genetic Research Results (CCGR) but rather is now named the 
Clinical Committee for Genomic Research (section 1.4.1) 
10. Added wording to clarify the CCGR will also use commercial or open-source 
products designed to evaluate the literature to the protocol (p. 36) 
 
The attached version dated May 25, 2016 incorporates the above revisions 
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 7 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
X Editorial, administrative changes 
    Scientific changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY 
The protocol is amended to include the following changes: 
Personnel changes:  D. Neil Hayes, MD was removed as a co-investigator and added as 
a Co-Principal Investigator to the study.  Additionally, the study statistician was changed 
from Anna Snavely to Anastasia Ivanova. 
 
 
. 
 
 
The attached version dated December 5, 2014 incorporates the above revisions 
 
 
  
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UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 6 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
X Editorial, administrative changes 
X Scientific changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY 
The driver for this amendment was to incorporate a statistical analysis plan (and revise the 
primary objectives accordingly) to allow researchers to estimate the proportion of patients who 
have a reportable genetic variant identified, and to compare clinical outcome between a subgroup 
of patients with and without a reportable genetic variant.  In those with a genetic variant, 
researchers will (as a secondary objective) compare clinical outcome between those treated based 
on the genetic variant, and those not treated based on the variant. These major changes are 
reflected in section 2.0 (Study Objectives) and section 6.0 (Statistical Considerations), as well as 
throughout the protocol in sections 1.1 (Study Synopsis), section 1.4 (Study Overview), section 
4.0 (Schema), and section 4.4 (Medical Records Abstraction).  
 
The protocol is also amended to include the following changes: 
Personnel changes: Removed Keith Amos MD from study as Co-Investigator; replaced 
biostatistician Pei-Fen Kuan PhD with Anna Snavely PhD; updated list of CCGR and 
Pathology Committee members in Appendix A.  
 
Inserted a new section (now section 1.3) describing a prior study of use of targeted 
therapy based on genetic variants. 
 
Section 1.4.1 and Appendix A describe the possibility of an additional category for gene 
variants. 
 
Minor editorial changes throughout (e.g., UNCseq # of genes increased from >100 to 
>200); rearranged flow of background to enhance clarity 
 
. 
 
 
The attached version dated May 25, 2014 incorporates the above revisions 
 
 
  
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CLINICAL ONCOLOGY RESEARCH PROGRAM 
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PROTOCOL AMENDMENT # 5 
 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
x    Editorial, administrative changes 
___Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
x    Eligibility Changes (IRB approval) 
x   Other 
 
AMENDMENT RATIONALE AND SUMMARY 
 
Protocol Cover page is updated to include Stergios Moschos, MD and Young Whang, MD, PhD as co-
investigators on the study. 
 
Section 1.2.5: Clarified that study is open to patients <18 years of age provided tissue is already stored or 
can be collected as part of clinically required procedure.  
 
Section 3.1: Inclusion criteria 3.1.5 added to indicate parental consent required for any participant <18 
years old, and separate consents required for minor children and adolescents.   
 
Section 9.1: UNC Committee for the Communication of Genetic Research Results (CCGR): Updated to 
include Ian Davis, MD, PhD as member on CCGR for pediatric oncology. 
 
 
 
 
 
 
The attached version dated March 27, 2013 incorporates the above revisions 
 
 
 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT # 4 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
X    Editorial, administrative changes 
    _ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
X_ Eligibility Changes (IRB approval) 
X   Other 
 
AMENDMENT RATIONALE AND SUMMARY 
The following is the summary of changes in protocol amendment 4: 
i. 
Throughout protocol, Minor typos corrected  
ii. 
Throughout protocol, clarified that sequencing may occur in UNC’s High Throughput Sequencing Facility 
or other UNC research facility 
iii. 
Section 1.2.5 Study Overview: Clarified that when results between UNCseq and analytically validated 
confirmatory testing in CLIA lab are discordant (whether the CLIA results confirm or refute UNCseq) - 
results from the analytically valid test only will be released to the treating physician.   We also revised this 
section to reflect that results from confirmatory testing will be released to the treating physician regardless of 
the current clinical situation, provided the results can potentially inform the care of the patient.   
iv. 
Section 1.2.5 Study Overview and section 4.1.2 Patient Communication: The LCCC1108 research team 
has implemented one additional level of oversight before results may be released to the treating physician, the 
Molecular Tumor Board.  This is described in sections 1.2.5 and 4.1.2.  We also clarified in section 4.1.2 that 
negative reports (that is no alteration found) will also be reported. 
v. 
Section 3.2.4: Exclusion criteria: LCC1108 patients may not undergo a biopsy for research purposes only if 
this biopsy requires general anesthesia.  This has always been the case, but is now explicitly stated in section 
3.2.4., and again in section 4.3 (Expected Risks). 
vi. 
Section 4.1.1 Requested Studies: Some molecular variants may be better detected via similar technologies to 
NextGen sequencing, including RNA sequencing.  Therefore, the following statement was added to section 
4.1.1: “Based on these results, additional molecular studies may be performed, if appropriate” 
vii. 
Sections 4.1.3.2 and 4.1.3.3 were revised to indicate that normal specimens from patients with hematologic 
malignancies may be obtained via skin punch biopsies under LCCC0824 as buccal swabs may be 
contaminated with malignant blood cells or represent an insufficient sample of DNA. 
viii. 
Sections 4.1.3.3 and 4.1.4: Snap-freezing of tissue is performed by research personnel both from TPF, as 
well as from other clinics, so the limitation to TPF was removed. 
ix. 
Section 4.2: Clarified that biopsy risks are described in the LCCC1108 informed consent 
x. 
Section 9.1: Appendix A: Charter: Revised to match the corresponding changes described above for the 
protocol.  Appendix B was removed as this is now outdated (e.g., see changed described in section 12.5 (iii) 
above) 
 
 
The attached version dated November 28 2012 incorporates the above revisions 
 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT # 3 
 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
 x    Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
 x    Eligibility Changes (IRB approval) 
___ Other 
 
AMENDMENT RATIONALE AND SUMMARY 
The following is the summary of changes in protocol amendment 3: 
i). Section 1.1 Study Synopsis: Editorial and clarification changes. 
ii). Section 1.2: Background and Study Overview: Different subsections have been revised for clarity and 
consistency.   
iii). Section 3.1.2, 3.1.3 and 3.1.4: Inclusion Criteria: These sections are revised for clarity. Section 3.1.4 includes 
another bullet point to clarify that subjects undergoing tissue collection per standard of care are willing to have 
additional specimen taken for the study. 
iv). Section 3.2: Exclusion Criteria: Revised for clarity. Sub-Section 3.2.1 includes a bullet point to clarify that any 
condition that would make the participation in the protocol unreasonably hazardous for the subject in the opinion of the 
treating physician. 
 
iv). Section 4.1: Study Methods and Procedures: Sub-Sections 4.1., 4.1.2, 4.1.3, 4.1.3.1-3 and 4.1.4 are revised for 
clarity and consistency. 
v). Section 4.2: Post-collection/Follow-up Assessments: This section is revised for clarity and consistency. 
vi). Sections 4.3 and 4.4: These sections are revised for clarity. 
vi). Section 7.0; Sub-Sections 7.1 and 7.4: Data Management and Monitoring/Auditing: These sections are revised 
for clarity and consistency. 
 
vii). Section 9.1: Appendix A: Charter: Revised for the clarity and consistency. 
 
 
 
 
The attached version dated May 17, 2012 incorporates the above revisions 
 
 
 
 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
PROTOCOL AMENDMENT # 2 
 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
 x    Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
___ Other 
 
 
AMENDMENT RATIONALE AND SUMMARY 
The following is the summary of changes in protocol amendment 2: 
i). Cover Page: David Eberhard,, MD, PhD is added to the study as a co-investigator. Also, Study Coordinator 
information is updated. 
 
ii). Section 1.2: Study Overview: This section is updated and clarified to include information about the acquisitions of 
tumor samples from Health Registry/Cancer Survivorship Cohort (CSC; LCCC0906/IRB#09-0605). For the tumor 
samples already collected under CSC, if available, the subjects will be contacted via phone to obtain their consent for 
LCCC 1108. 
List of reportable test is clarified to include Clinical Laboratory Improvement Amendments, CLIA-certified laboratory 
rather than CLIA approved equivalent. 
 
iii). Section 3.1.2 and 3.1.3: Inclusion Criteria: These two sections are revised in order to access the tissue samples 
from the subjects who are deemed eligible for LCCC 1108, but their samples are either available via CSC or at another 
institution. Also clarified that for the tumor samples already collected under CSC or another study that include tissue 
banking, if available, the subjects will be contacted via phone to obtain their consent for LCCC 1108. 
 
iv). Section 4.1.1.: Added a section on Quality Control (QC) that will be assessed by David Eberhard, MD, PhD or his 
qualified designee. 
v). Section 4.1.4: Subsection Tissue banked at UNC: This section is revised to include facilities at UNC Chapel Hill, 
NC. 
vi). Section 7.4: data management and Monitoring/Auditing: This section is revised for clarity on the sample 
tracking databases. 
 
vii). Section 9.1: Appendix A: Charter: Revised for the clarity of test lists as applicable validation status. Also, Leigh 
Thorne MD and William K. Funkhouser MD, PhD are added to the Pathology Committee for LCCC 1108. 
 
 
 
 
The attached version dated February 6, 2012 incorporates the above revisions 
 
 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
 
 
 
 
PROTOCOL AMENDMENT # 1 
 
 
 
LCCC 1108: Development of a Tumor Molecular Analyses Program and Its Use to 
Support Treatment Decisions 
 
AMENDMENT INCORPORATES: 
 
x     Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
___ Other 
 
 
AMENDMENT RATIONALE AND SUMMARY 
 
The protocol is amended to include the following changes: 
i). Cover Page: Robert Dixon, MD is added to the study as a co-investigator. 
 
ii). Section 1.3: This section is updated to include information about National Institutes of Health (NIH) 
repository for Genome-Wide Association Studies (GWAS) for the submission of genotype and phenotype 
data in order to provide greater public benefit if the information is shared with a large number of 
researchers through the NIH repository.  
 
iii). Appendix A: Appendix A, Clinical Committee, is revised to include David Ollila, MD to the 
committee as surgical oncologist. Pathology Committee is revised to include Ryan Miller, MD, PhD; 
George Fedoriw, MD, both from the Department of Pathology and Laboratory Medicine, UNC Chapel Hill, 
and Nancy Thomas, MD, PhD from the Department of Dermatology, UNC Chapel Hill. David Allan 
Eberhard, MD, PhD is the chair of the Pathology Committee. 
 
 
 
 
 
 
 
 
The attached version dated September 2, 2011 incorporates the above revisions 
 
 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC  1108: Development of a Tumor Molecular Analysis Program and Its Use to 
Support Treatment Decisions 
 
Principal Investigator 
H. Shelton Earp, MD 
 
Principal Co-Investigator 
Juneko E. Grilley-Olson, MDD. Neil Hayes, MD 
 
 
Study Coordinator 
Michele Hayward 
michele_hayward@med.unc.edu 
919-966-9259 
 
Biostatistician: 
Dominic Moore, MPH 
UNC Lineberger Comprehensive Cancer Center 
Chapel Hill, NC 27599 
Phone: 919-966-8647 
dmoore@bios.unc.edu 
 
Sponsor: Lineberger Comprehensive Cancer Center 
Funding Source: University Cancer Research Fund, NCI Funded Grants 
Version Date: July 28, 2011 
Amendment 1: September 2, 2011 
Amendment 2: February 6, 2012 
Amendment 3: May 17, 2012 
Amendment 4:November 28, 2012 
Amendment 5: March 27, 2013 
Amendment 6:  May 23, 2014 
Amendment 7:  December 5, 2014 
Amendment 8: May 25, 2016 
Amendment 9:  July 25, 2019

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
Signature Page 
LCCC  1108: Development of a Tumor Molecular Analysis Program and Its Use to 
Support Treatment Decisions 
 
Principal Investigator 
H. Shelton Earp, MD 
 
 
 
 
 
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:____________________ 
 
Amendment 9 
Version Date: July 25, 2019 
 
 

LCCC 1108 
 
CONFIDENTIAL 
PI: Earp 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 9, Version 1 
 
July 25, 2019 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Tumor Genotyping ................................................................................................2 
1.3 
Using Genotyping to Treat: a Prospective Pilot Study .........................................7 
1.4 
LCCC1108: Study Overview ................................................................................8 
1.5 
Rationale..............................................................................................................12 
2.0 
STUDY OBJECTIVES .........................................................................................12 
2.1 
Primary Objectives ..............................................................................................12 
2.2 
Exploratory Objectives ........................................................................................12 
2.3 
Primary Endpoints ...............................................................................................13 
2.4 
Exploratory Endpoints.........................................................................................13 
3.0 
PATIENT ELIGIBILITY ....................................................................................13 
3.1 
Inclusion Criteria .................................................................................................13 
3.2 
Exclusion Criteria ................................................................................................14 
4.0 
Schema ...................................................................................................................15 
4.1 
Study Methods and Procedures: Screening and Informed Consent ....................16 
4.2 
Post-collection/Follow-up Assessments ..............................................................19 
4.3 
Expected Risks ....................................................................................................20 
4.4 
Medical Records Abstraction ..............................................................................24 
5.0 
ADVERSE EVENTS ............................................................................................24 
5.1 
Definitions ...........................................................................................................24 
5.2 
Reporting .............................................................................................................25 

LCCC 1108 
 
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UNIVERSITY OF NORTH CAROLINA 
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ii 
6.0 
STATISTICAL CONSIDERATIONS ................................................................26 
6.1 
Sample Size and Accrual.....................................................................................26 
6.2 
Data Analysis Plans .............................................................................................27 
7.0 
STUDY MANAGEMENT ....................................................................................27 
7.1 
Institutional Review Board (IRB) Approval and Consent ..................................27 
7.2 
Required Documentation.....................................................................................28 
7.3 
Registration Procedures.......................................................................................28 
7.4 
Data Management and Monitoring/Auditing ......................................................28 
7.5 
Adherence to the Protocol ...................................................................................29 
7.6 
Amendments to the Protocol ...............................................................................30 
7.7 
Record Retention .................................................................................................30 
7.8 
Obligations of Investigators ................................................................................30 
8.0 
REFERENCES ......................................................................................................31 
9.0 
APPENDICES .......................................................................................................33 
9.1 
APPENDIX A .....................................................................................................33 
 

LCCC 1108 
 
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PI: Earp 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 9, Version 1 
 
July 25, 2019 
 
1 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
Cancer is a disease caused by alteration of a cell’s DNA sequence resulting in 
dysregulation of gene expression and aberrant growth.  Researchers are just 
beginning to study the extent of DNA alterations and their consequences for 
patient therapy and outcomes.  New technology (e.g., Next Generation (NextGen) 
sequencing), allows study of the spectrum of tumor genome alteration with 
unprecedented scope and cost-effectiveness. To be fully exploited to improve 
cancer care, however, it is imperative to be able to link genetic analysis to patient 
characteristics, treatment response and outcome.   
 
This protocol creates options to meet these objectives either in conjunction with 
the UNC IRB approved Health Registry/Cancer Survivorship Cohort (CSC; 
LCCC0906/IRB#09-0605) or as a stand-alone study in clinics where the CSC is 
or is not established (and/or if patient is not eligible for or refuses enrollment in 
the CSC).  Lineberger Comprehensive Cancer Center (LCCC) established the 
CSC in 2009 to create a patient registry and biospecimen repository of adult 
patients residing in North Carolina who receive care at the North Carolina Cancer 
Hospital.   This important endeavor includes collection and storage of biological 
specimens as well as medical history and questionnaire data from all subjects 
enrolled.  These specimens and data provide a rich resource for research studies 
that have IRB approval to access these data.   LCCC1108 was designed in part to 
leverage these data, and as a complementary or stand alone study to the CSC. 
 
The primary objectives of this study are to estimate the proportion of patients 
enrolled in LCCC1108 who undergo successful sequencing and have a reportable 
genetic variant, and to compare clinical outcomes between subgroups of cancer 
patients with active disease based on presence or absence of reportable variants 
identified by Next Generation Sequencing methods (NGS)  
 
It is important to clarify that sequencing methodology continues to develop at a 
very rapid pace since the inception and implementation of this protocol and that 
NGS uses a wide variety of methods, allowing researchers to ask virtually any 
question related to the genome, transcriptome, or epigenome of a patient’s tumor. 
Sequencing methods differ primarily by how the DNA or RNA samples are 
obtained (e.g., tissue type, normal vs. affected, experimental conditions) and by 
the data analysis options used. However, after the sequencing libraries are 
prepared, the actual sequencing stage remains the same regardless of the method.  
For example, there are a number of standard library preparation kits that offer 
protocols for whole-genome sequencing, mRNA-Seq, targeted sequencing (i.e., 
exome or 16S sequencing), sequencing of custom-selected regions, protein-
binding regions, etc. 
 

LCCC 1108 
 
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PI: Earp 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 9, Version 1 
 
July 25, 2019 
 
2 
This protocol allows current or prospective cancer patients to be consented for 
evaluation of tumor tissue and blood samples by UNC-CH’s High Throughput 
Sequencing Facility or other UNC research facility via NextGen sequencing 
(UNCseq™).  The source of specimens and the methods used for molecular 
analysis will vary depending on the clinical situation: archival tissue (either 
collected under the CSC, independently of the CSC, or through another protocol). 
The source of specimens include research samples collected from patients already 
scheduled to undergo biopsy for routine clinical purposes; and research samples 
collected from patients willing to undergo biopsy for the purpose of research only.  
Investigators mayalso collect (or access, if already collected under another 
approved tissue banking protocol) normal germline DNA, DNA modifications, 
and RNA in the form of blood samples, cheek swabs, or normal tissue adjacent to 
tumor tissue, etc. These normal specimens may be used for molecular analysis 
depending on the research aim; however, analysis of tumor specimens alone may 
be performed and if significant reported back to the physician. 
 
Specimens will be analyzed for genetic variants in selected genes of research 
interest, but only those variants of potential clinical interest will be released to the 
treating physician to disclose to the patient.  Germline changes that are discovered 
and deemed of clinical interest will be reported in the context of formal genetic 
counseling.    
1.2 
Tumor Genotyping 
1.2.1 Clinical Application-Current Examples 
Advances in molecular genetics and genomics have enabled clinicians to 
minimize general treatment decisions and apply patient-specific information to 
treatment choice in certain situations.  These advances, though currently limited 
in number, have had a profound impact in certain clinical settings, highlighting 
the fact that cancers originating from the same tissue of origin likely represent 
different diseases on a molecular level.[1] 
 
The human epidermal growth factor receptor 2 protein, HER2, became one of the 
first biomarkers with an established role in clinical oncology, and a more patient-
specific approach for treatment in cancer began with trastuzumab (Herceptin®), 
the 
humanized 
monoclonal 
antibody 
(MAB) 
targeted 
against 
HER2.  
Approximately 30% of breast cancers exhibit amplification of the HER2 gene, 
and treatments with targeted drugs that block this receptor have improved 
outcomes in patients with HER2 overexpressing cancers.   
 
Agents targeted against tyrosine kinases associated with the epidermal growth 
factor receptor (EGFR) have an established role in the treatment of non-small cell 
lung cancer (NSCLC), and include erlotinib (Tarceva®) and gefitinib (Iressa®). 
Patients with NSCLC whose tumors exhibit mutations in EGFR, the most 
common of which are deletions in exon 19 and a mutation in exon 21 (occurring 
in approximately 10% of Caucasians and up to 50% of Asians with NSCLC) [2], 

LCCC 1108 
 
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PI: Earp 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 9, Version 1 
 
July 25, 2019 
 
3 
experience significantly increased sensitivity to drugs like erlotinib and gefitinib 
as compared to patients without these mutations.   
 
Biomarkers are also critical in the management of metastatic colorectal cancer 
(mCRC), particularly related to therapy with monoclonal antibodies directed 
against EGFR.  The RAS/RAF/MAPK pathway is downstream of EGFR, and 
approximately 40% of CRCs are characterized by mutations in the KRAS gene.  
These mutations predict for lack of response to the anti-EGFR MABs cetuximab 
and panitumumab.  The relationship between these mutations and response is 
included in the FDA-approved labels for cetuximab and panitumumab, and use of 
these products is not recommended (nor are they used)  in patients who carry 
these mutations.[3] [4]   
 
Molecular profiling of disease may facilitate more rapid drug development and 
time to commercialization than current models of development.   A recent 
example of this involves the EML4-ALK fusion oncogene (fusion between 
echinoderm microtubule-associated protein-like 4 [EML4] and anaplastic 
lymphoma kinase [ALK]).  ALK gene rearrangements in NSCLC are always non-
overlapping with mutations in EGFR, and are estimated to occur in 2-7% of non-
selected NSCLC patients, and ~30% of patients when selected for 
adenocarcinoma, never or former light smoking history, and without EGFR 
mutation.[5]     
 
Two years after the initial report of this ALK translocation, based on results of a 
phase I dose escalation trial, investigators reported evidence of clinical activity in 
NSCLC patients with this mutation treated with crizotinib, an inhibitor of ALK 
and MET tyrosine kinases under development by Pfizer,.[6]  This finding 
prompted investigators to screen ~1500 tumor samples to identify 82 patients 
eligible for enrollment into an expanded cohort of this phase I trial, based on 
testing positive for ALK rearrangements.[7]  Investigators reported a disease 
control rate of ~90% (57% response rate) in this subset, and a phase 3 
registrational trial is now ongoing in ALK-positive patients, just 3 years after 
initiation of the phase 1 trial.[7]    The dramatic results reported in early phase 
clinical testing of targeted therapy, such as those reported with crizotinib, 
prompted a recent editorial in the New England Journal of Medicine calling for 
accelerated approval (post-phase I testing) by the FDA of such drugs in cancer.[8] 
1.2.2 Recent Developments in Tumor Genotyping 
The unprecedented throughput of sequencing technologies creates opportunities to 
study cancer genetics on a new scale.[9]  Increases in sequencing capacity over 
the past 6 years have been exponential and will continue to gain through the next 
decade.  Developments in DNA technology currently permit capture of specific 
loci of interest from genomic DNA not only for focused re-sequencing to identify 
point mutations, but also for the identification of other types of lesions such as 
translocations, insertions, and deletions without a priori knowledge of the 

LCCC 1108 
 
CONFIDENTIAL 
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genomic lesion.  These technological breakthroughs set the stage for the next 
generation of clinical genetic studies of somatic mutations in cancer.  
 
Researchers at UNC believe this new sequencing technology could allow 
expansion of the paradigm by analyzing all mutations and alterations in a 
common gene in cohorts of patients with diverse diseases.  These new 
technologies will allow for the simultaneous, low cost analysis of >200 cancer 
associated genes which can then be matched with clinical data to examine the 
effects of these alterations on disease outcome.  The sequencing methods we plan 
to employ will also allow for the addition of new targets for sequencing as further 
cancer genetic studies become available, or as sequencing capacity increases.   
 
In addition to identifying activating mutations of oncogenes (e.g., K-RAS codon 
12 mutation), new sequencing techniques can identify tumor suppressor mutations 
or deletions, which are more difficult to identify but of equal biologic importance.  
Inactivation of tumor suppressor genes is not generally assessed for clinical use at 
present because of technical limitations in the ability to determine these 
inactivating events.  For the first time, this technology will allow the evaluation of 
how tumor suppressor mutations in cancer alter a patient’s clinical course and 
predict response to therapy.   
1.2.3 Reporting Genetic Results to Support Treatment Decisions 
The reporting of results from research studies of genetic tests to treating 
physicians (and potentially patients) in a clinically relevant time frame varies 
among investigators, who are under increased pressure to report findings quickly 
that may have clinical significance.[10]   In response to this pressure, the National 
Heart, Lung and Blood Institute (NHLBI) convened a working group in 2004 to 
develop recommendations on reporting genetic information to study subjects.[10]   
The panel recommended that institutions establish a standardized approach for 
reporting genetic results which includes a regularly updated list of tests 
potentially reportable to treating physicians and/or patients.  According to the 
panel, this list should be developed and reviewed by “a group with sufficient 
expertise to judge the evolving scientific foundation for reporting these 
results.”[10]   
 
Tests with Accepted Clinical Utility 
Most genetic tests begin under research protocols and move to the clinical setting 
once their use is validated for diagnosis, prognosis, or treatment.[10]   In general, 
a biomarker is considered validated, and becomes established within routine 
clinical practice, if  “it has proven value as a clinical test in standard practice to 
guide patient management”[1].   The further along a genetic test is in achieving 
the benchmark of validation, the more likely results of such tests will be 
communicated from the researcher conducting the test to the treating physician 
and ultimately to the patient.   With canonical mutations, i.e. those validated 
mutations considered foundational in the development of a particular cancer or 
cancers, the implications for treatment and/or prognosis are well established.  It is 

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common and appropriate to share with patients the results of tests measuring these 
mutations, such as those described in section 1.2.1, provided the patient desires 
this information.   
 
For example, clinical practice guidelines incorporate screening for BRCA1 
mutations as well as other high-penetrance germ-line mutations in individuals at 
risk as part of routine standard of care. [11] [12]  Testing for these mutations 
includes patient counseling and education prior to testing and at the time results 
are delivered to the patient.   Incorporating these tests into guidelines is justified 
as results inform clinical decision making, e.g., helping to determine the surgical 
approach in women with newly discovered BRCA1 related breast cancer, or 
offering more frequent endoscopy to individuals who carry the MSH2 mutation to 
address their significantly increased risk of colon cancer.[11]   Although the 
purpose of LCCC1108 is not to provide comprehensive screening for germline 
mutations, it is likely that some participants will be discovered  to have an 
inherited cancer predisposition, in which case such information would be highly 
significant for the participant and for their family members. 
 
Genetic Tests of Uncertain Significance 
The role of other variants, especially shortly after discovery of their association 
with a particular tumor, may be of uncertain significance for cancer susceptibility, 
prognosis, or responsiveness to certain therapies.[11]   
 
Until recently, it has been common practice in research studies to avoid 
communicating genetic test results to research subjects or their treating physicians 
to prevent over-interpretation of research results of uncertain clinical 
significance.[10]  This practice has been changing recently, however,  the poor 
prognosis and limited options available to many cancer patients are recognized, 
including those without an effective standard of care from the time of diagnosis 
(e.g., adenoid cystic carcinoma) as well as those with recurrent and progressive 
cancers who have exhausted all effective treatment options (i.e., candidates for 
many phase I trials). Thus, researchers have begun exploring ways to share 
critical test results when a potential clinical application exists.   
 
A recent advance in acute myeloid leukemia (AML) illustrates the discovery of a 
genetic test early on in its development that could be applied clinically in the near 
future.  Scientists at the Washington University School of Medicine in St. Louis 
were the first to sequence the entire genome of normal cells and tumor cells from 
the same patient with AML.  This pivotal work lead to the discovery of somatic 
mutations in a particular gene (DNMT3A), and prompted investigators to conduct 
targeted DNA sequencing on close to 300 additional AML patient samples to 
confirm the correlation of somatic variants within this gene with treatment failure 
after standard dose chemotherapy.[13]  While recognizing their work needed 
further confirmation, investigators concluded that AML patients found to have 
somatic variants in DNMT3A might need more aggressive treatment.  Once these 
data are reproduced and clinical trials are designed to evaluate frontline dose-

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intensive chemotherapy in this group, the ability to provide information to 
clinicians about variants in such a gene in their patients becomes critical.    
1.2.4 Models of Programs that Include Sharing Genetic Results with Patients 
The Massachusetts General Hospital Cancer Center (MGHCC) has recently begun 
promoting their efforts to share genetic results with treating physicians for rapid 
application into the clinic. MGHCC was the group that first reported that NSCLC 
patients positive for ALK rearrangements responded to the ALK inhibitor 
crizotinib, leading the multi-institutional collaboration that tested the drug in the 
expanded cohort.[7]  Their Translational Research Lab (TRL) currently screens 
patient tumors for 120-130 specific mutations in ~15 genes. Precise robotic 
technology allows the TRL to process up to 100 specimens in a day, allowing for 
rapid genetic profiling and communication of results within a month of 
testing.[14]  Post-testing, the treating physician informs the patient about any 
genetic variants identified that can be treated with targeted therapy, or that may 
render them eligible for enrollment into a clinical trial evaluating therapy targeted 
against their variant.  Samples are stored so they can be re-tested if new variants 
(and trials designed to evaluate drugs to treat them) are discovered in the 
future.[14]  While this system has been informative, the MGH approach employs 
an outdated sequencing approach based on primer extension technology.  The 
UNC effort will identify a much larger class of variants (e.g., deletions, 
amplifications) in a much larger number of genes (>200) using Next Generation 
sequencing techniques. 
 
Another interesting model for rapid genetic profiling specifically geared towards 
clinical 
application 
can 
be 
found 
at 
the 
Clearity 
Foundation 
(www.clearityfoundation.org).  The mission of this foundation is to improve 
treatment outcomes in recurrent and progressive ovarian cancer by providing 
molecular analysis of tumor specimens upon request from physicians.  Through 
partnership with CLIA-certified labs, the foundation offers access to molecular 
tests provided formalin-fixed paraffin-embedded (FFPE) tumor blocks, unstained 
slides, or fresh frozen tissue specimens are available.  The panel of tests they run 
includes biomarkers targeted by commercially available and investigational drugs, 
as well as biomarkers indicating sensitivity or resistance to certain chemotherapy.   
Test results are provided as soon as 7 days after receipt of the sample, with full 
reports provided in 4 weeks.   They have been providing this service for almost 
three years.  The Foundation also offers profiling of newly diagnosed patients not 
for immediate application, but in the event the patient recurs in the future.    
 
Patients have brought results of their genetic tests from outside laboratories to 
UNC clinicians, including tests conducted in the Clearity Foundation partner labs, 
but concerns exist surrounding the application of these results to guide clinical 
care.  While the Scientific Advisory Board of this foundation includes high-level 
representatives from respected institutions in the field of oncology (e.g. Memorial 
Sloan Kettering, Dana Farber Cancer Institute, etc.), relying on this type of testing 
with uncertain validation could be problematic.  From a review of the tests offered 

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via Clearity Foundation’s website, the investigators at UNC-CH would not 
consider many of these tests to be of accepted clinical utility.  
 
While very little data exist regarding communication of individual genetic results 
to cancer patients participating in trials, results to date are encouraging.   A recent 
pilot study evaluated the impact of sharing results of the germline CDKN2A 
mutation in a subset of melanoma survivors who had participated in a Genetics, 
Environment and Melanoma (GEM) study at the University of Michigan hospital.  
This mutation confers a risk of 30-65% through age 80 for development of 
melanoma, and a 5% risk for another melanoma among melanoma survivors.[15] 
 
The majority (70%) of people enrolled in the pilot trial (n=19 of 27 contacted) 
opted to be told whether they carried a CDKN2A mutation, and investigators 
reported the knowledge did not cause the participants emotional distress 
(measured 1 week and 3 months after disclosure) or change their health 
behavior.[15]   Of note, subjects received educational materials about risk factors 
for melanoma and reviewed these materials with a genetic counselor prior to 
disclosure of their mutational status by the genetic counselor.[7]  In addition, most 
participants indicated an increased willingness to participate in genetic research in 
the future because of disclosure. Of note, LCCC1108  focuses on communication 
of genetic results from somatic profiling of tumor tissue, and does  not focus on 
germline genetic profiling.  Germline changes  discovered and deemed clinically 
relevant, however, will be reported to patients in the context of formal genetic 
counseling.   
1.3 
Using Genotyping to Treat: a Prospective Pilot Study 
Treating patients based on genetic variants, a so-called “genome-forward 
approach”, has been applied across tumor types, with clinical benefit reported in a 
prospective pilot study. Von Hoff and colleagues published a multicenter, single 
arm pilot study of patients with a wide variety of refractory cancers that utilized 
molecular profiling to select “targeted” treatment.[16]  Molecular targets were 
detected via oligonucleotide microarray (MA) gene expression assays on fresh 
(frozen) biopsy tissue, and via immunohistochemistry (IHC) and fluorescent in 
situ hybridization (FISH) on formalin-fixed tissue. A list of possible therapies 
based on targets was generated based on an extensive review of the literature and 
using data from a prior retrospective feasibility study.  These agents included 
those that are traditionally considered targeted against a particular molecule (e.g., 
trastuzumab for HER2/Neu) as well as those not traditionally considered targeted 
drugs (e.g., irinotecan for carboxylesterase (CES-2)).  In this pilot study of 86 
patients, 66 were treated according to molecular results.[16] 
 
In terms of efficacy, patients served as their own control; progression-free 
survival (PFS) post “molecularly-targeted” treatment (PFS-MT) was compared 
within individual patients to PFS after their most recent regimen (PFS-RT).  Of 
the 66 patients treated according to molecular results, 27% had a PFS ratio of ≥ 
1.3 (PFS-MT/PFS-RT).   

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Researchers also documented the choice of therapy the treating physician would 
have chosen without molecular results available, and none of them matched the 
targeted therapy.[16]   
1.4 
LCCC1108: Study Overview 
Patients with a diagnosis or potential diagnosis of cancer will be consented for 
enrollment into this study.  In clinics in which the IRB-approved Cancer 
Survivorship Cohort (CSC, LCCC0906) is operating, eligible patients for 
LCCC1108 may be offered enrollment into the CSC via the CSC global consent if 
they are eligible for LCCC0906.  In clinics in which the CSC is or is not yet 
operational and/or the patient is not eligible (or has declined LCCC0906 
participation), LCCC1108 will function as a stand-alone protocol. Patients 
deemed eligible for LCCC 1108 who may have been offered the opportunity to 
enroll into CSC prior to LCCC1108 initiation) and who have stored tumor tissue 
samples in the Tissue Procurement Facility (TPF) may be contacted via telephone 
for enrollment into LCCC1108 and to obtain consent for research access to their 
stored tumor tissue.  
 
Specimens collected under LCCC1108 consent will be stored in the TPF along 
with any specimens previously collected as part of routine clinical care and stored 
under the general TPF banking protocol (LCCC9001), under the CSC global 
consent, under this protocol, or under another approved tissue banking protocol 
for consented participants.  Genomic DNA or RNA will be obtained either as part 
of the CSC (and handled and stored by the Biospecimens Core), or under 
LCCC1108.   Appropriate tissue and possibly germline DNA and RNA will be 
released for molecular analysis to UNC’s High Throughput Sequencing Facility 
or other UNC research facility. Medical records will be abstracted to facilitate 
correlation of clinical data with genetic testing in studies using the mechanisms 
approved for the CSC.   
 
It is expected that most LCCC1108 participants will provide samples through 
procedures that are part of their standard clinical care, and thus, the additional risk 
of providing tissue to be used in this research will be minimal.   Many participants 
will already have tissue and/or blood specimens banked in TPF under the general 
TPF protocol (LCCC9001) or under another approved tissue banking protocol.  
Others, who are consented to LCCC1108 pre-operatively, will allow any surplus 
tissue and/or blood (after the standard diagnostic procedures have been 
completed) to be accessed, stored, and processed for the research described 
herein. Parental consent is required for all patients <18 years old.  Separate 
consent documents are also required for minor children (7-14 years old) and 
adolescents (15-17 years old).  Any participant <18 years of age must have tissue 
already banked, or be undergoing a procedure as part of their standard clinical 
care. 
 

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A subset of patients ≥18 years of age will be asked to submit tissue and blood 
specimens obtained from procedures without a specific identified clinical or 
diagnostic need, based on current clinical standards of care.  Biopsies of vital 
organs (e.g., lung, liver etc.) will be restricted to those participants ≥18 years of 
age whose treatment offers no expectation of cure, such as patients with refractory 
solid tumors who relapse with metastatic disease, e.g.  Other biopsies performed 
outside of clinical standard of care will be limited to those tumors that can be 
accessed without subjecting the participant to unreasonable risk, as determined by 
the physician performing the procedure. 
 
Specimens will be analyzed for alterations in a panel of specific genes of cancer 
relevance, but only genetic variants of potential clinical interest will be released to 
the treating physician to disclose to the patient.  Germline changes that are 
discovered by systematic analysis and deemed  clinically relevant will be reported 
in the context of formal genetic counseling.   Results of genetic tests from the 
“gene list” will be analytically validated in a CLIA-certified laboratory prior to 
distribution to the treating physician (see possible exception to this requirement 
noted below).   Note: when results between NextGen sequencing and CLIA are 
discordant, results from the CLIA-certified laboratory only will be distributed to 
the treating physician.   
 
LCCC1108 Molecular Tumor Board (MTB) reviews the sequencing information 
and identifies the genes of relevance based on CCGR recommendations to move 
forward for clinical confirmation.  This tumor board provides additional 
oversight, ensuring compliance with the protocol, technical quality assurance, and 
appropriate application of results to individual patients.  This board is comprised 
of representatives of the CCGR, the Pathology committee, key laboratory 
scientists involved in technical and bioinformatic aspects of UNCseq™, and 
clinical/molecular pathologists.  
 
The sequencing data and outcomes from the CLIA confirmation assays are 
reviewed in aggregate to ensure quality assurance measures are being met.  Our 
confirmation rate historically is greater than 95%. 
1.4.1 UNC  Clinical Committee for Genomic Research (CCRG) 
The UNC CCGR has been established per the NHLBI recommendations cited 
earlier.[10]  This group will meet quarterly to review and update the list of 
reportable tests, and in what setting each test would be clinically relevant based 
on its potential for clinical application.  See Appendix A for the CCGR Charter.  
In brief, the Committee will categorize reportable tests into 3 lists:  
• List #1: Genetic alterations of accepted clinical utility (and validated 
(whether confirmed or refuted) in a CLIA certified laboratory) used in 
standard of care (SOC) management of patients (e.g., KRAS in mCRC) 

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• List #2: Genetic alterations of potential clinical significance (and 
validated (whether confirmed or refuted) in a CLIA certified laboratory for 
use in non-SOC settings (e.g., EGFR in breast cancer) 
• List #3: Genetic alterations of potential clinical significance (without the 
possibility of validation in a CLIA certified laboratory for use in non-SOC 
settings (e.g., LKB1) 
As of the writing of Amendment #6, a List #4 is under consideration by the 
CCGR.  This list would include genetic variants that predict sensitivity to non-
targeted treatment (e.g. radiation, cytotoxics). 
In developing the lists, the Committee will receive input from the LCCC 
Oncology Disease Groups (e.g., Breast Cancer, Lung Cancer) and the LCCC1108 
Pathology Committee (see Appendix A).  For List #3, when validation in a CLIA 
certified laboratory is not available or possible, results of NextGen sequencing 
will be provided to the patient through the treating physician on a “compassionate 
use” basis, but only if the following criteria are met (which we anticipate will be 
rare): 
• The UNC Committee deems the information would be of clinical interest 
• The patient has advanced cancer for which there is no standard of care  
• Results are reproduced in the research laboratory using NextGen 
sequencing  
• The results include a statement that “This is a research result from a non-
validated test environment” 
• A waiver for the CLIA-certification requirement is obtained from the 
UNC IRB on a case-by-case basis.  
Similar to the program established at MGHCC, we will not share tests performed 
at UNC with treating physicians unless they can potentially inform the care of a 
particular patient disease population.   
1.4.2 Treatment Decisions 
Ideally, reportable findings in patients with refractory disease (after confirmation 
by validation in a CLIA certified laboratory) will be used to influence the choice 
of a clinical trial when standard of care options are exhausted (e.g., identification 
of a PI3K mutation may lead the treating physician to choose a trial that includes 
a PI3K inhibitor if the patient meets eligibility criteria).  Clinical trials may not be 
available in all such patients, however.  Therefore, in patients for whom there is 
no available trial, the finding of an unexpected, but targetable variant could lead 
to the off-label use of an approved therapy.  For example, a small percentage of 
patients with ovarian cancer will be found to harbor activating KIT mutations, and 
such patients could be treated with anti-KIT agents (e.g. dasatinib) based on 
results of NextGen analysis (with re-testing in a CLIA certified laboratory) even 
though dasatinib is not presently approved for use in ovarian cancer.     
 

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Use of results of the UNCseq™ intervention from the “Gene List” as the basis for 
treatment or to refer a patient to a clinical trial, will be up to the discretion of the 
treating physician,.    Treatment decisions will be documented via use of the 
UNCseq™ Physician survey (an IRB-approved survey provided separate from 
this protocol) and review of medical records. If treatment is based on molecular 
testing, the specific treatment (including referral to a clinical trial, or choice of 
commercial agent(s), dose and duration) will be documented when this 
information is available.   
 
It is expected that any therapy chosen based on this list by the treating physician 
will be carried out using the most current prescribing information for that therapy 
available from the FDA, and/or based on a review of the scientific literature for 
that particular tumor type.  Outside of a clinical trial, we anticipate that most 
physicians will evaluate tumor response every 6-8 weeks (or other as per standard 
of care for the particular tumor type) as they would when starting any patient on a 
new anti-cancer therapy.  These data will be recorded, as will the date of 
progression (if available) and patient survival.     
1.4.3 Characterization of Population and Treatment Outcomes 
While several attempts have been made to document the proportion of specific 
genetic alterations in selected Phase I populations, the intervention in LCCC1108 
will provide the opportunity to characterize the proportion of most of the known 
clinically relevant genetic alterations across a wide variety of tumors. [17-19]  
Specifically, as a primary objective, we will estimate the proportion of enrolled 
patients who have undergone successful sequencing and who have a reportable 
genetic variant identified via UNCseq™. The study intervention, includes the use 
of highly and ever evolving sequencing methods and genomic technologies that 
may be applied to both somatic and germline tissues, and correlated with 
extensive clinical annotation and outcome data. These technologies may associate 
known molecular alterations in a variety of tumors with prognosis and/or clinical 
outcomes.  A primary objective of this study is to compare PFS ratios between 
cancer patients with active disease with a reportable genetic variant and those 
without a reportable genetic variant. We chose the PFS ratio as it is the approach 
already used and published by Von Hoff, and it allows the patient to serve as his 
or her own control. Whether disease is defined as active or not takes place at the 
time of the MTB meeting. In this context, a patient is considered to have active 
disease provided they have not been declared to have NED (no evidence of 
disease) and they are not in hospice.  The PFS ratio is defined as the PFS after the 
first treatment post UNCseq™ results divided by the PFS post the most recent 
therapy prior to UNCseq™on which the patient has just experienced progression. 
See section 4.4 for additional details on this endpoint.   
 
Using clinical data from patients enrolled in this protocol, either through 
LCCC0906 (the CSC) or LCCC1108, we plan to facilitate explorations of any 
correlation between these genetic alterations and response to molecularly based 
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objective, we will compare PFS ratios between patients with active disease and a 
reportable genetic variant who were treated based on this variant versus those  not 
treated based on this variant (see section 4.4). 
1.5 
Rationale 
By sequencing targeted regions of a subject’s tumor genome, and returning 
relevant and individual results to the treating physician, we hope to provide a 
mechanism for rapid, patient-specific treatment decisions.  These data will 
become part of the patient’s information in the CSC database if they have 
consented to be part of that study. 
 
The number and type of situations appropriate for patient-specific approaches to 
cancer treatment are expected to grow as scientists, including those at UNC, 
discover new molecular alterations across a broader range of tumor types.   These 
discoveries are essential, as traditional approaches to treatment have made limited 
progress over the past several decades, and virtually none against advanced solid 
tumors.[20]   
 
Patient samples and/or data from this repository may also be submitted to the 
National Institutes of Health (NIH), National Cancer Institute (NCI) repository for 
the purposes of Genome-Wide Association Studies (GWAS).  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To estimate the proportion of patients enrolled in LCCC1108 who have 
undergone successful sequencing (see section 6.0) and have a reportable genetic 
variant identified via UNCseq™ 
2.1.2 To  estimate 2 year PFS in cancer patients with active disease (defined in section 
1.4.3) with a reportable genetic variant and those without a reportable genetic 
variant  
 
2.2 
Exploratory Objectives  
2.2.1 To  estimate differences in PFS  between cancer patients with active disease with 
a reportable genetic variant who were treated based on variant, versus those who 
were not treated based on a variant. 
2.2.2 To collect and describe clinical data (e.g., medical history, demographics) 
including treatment outcomes after availability of UNCseq™ results in patients  
2.2.3 To link tumor samples and other biospecimens for future IRB approved clinical 
trials that have a tissue specimen component 

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2.3 
Primary Endpoints 
2.3.1 The proportion of those patients with successful sequencing (see section 6.2) who 
have any non-standard of care variant discovered via UNCseq™ and confirmed 
after UNCseq™ in a CLIA certified laboratory (or provided by a waiver by the 
IRB).    
2.3.2 PFS is defined as the time from day 1 of treatment until disease progression or 
death as a result of any cause.   
2.4 
Exploratory Endpoints 
Other efficacy outcomes that may be evaluated include objective response (OR), 
stable disease (SD) and overall survival (OS), and will be defined as per 
RECIST1.1 or per the appropriate hematologic disease guidelines [21-26]. 
Treatment decisions using UNCseq™ are based on the treating physician’s 
responses to the UNCseq™ Physician survey (an IRB-approved survey provided 
separate from this protocol). 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Patients must fulfill all criteria to be eligible for this study: 
3.1.1 Current or prospective cancer patients; current cancer patients must have 
histologically or cytologically confirmed diagnosis of cancer 
3.1.2 Patients who are considering enrollment in LCCC1108, who are eligible for the 
CSC, and who are seen in a clinic at UNC in which the UNC Health 
Registry/CSC is operational may be offered enrollment into the CSC via the CSC 
global consent; however participation in the CSC is optional and patients can 
enroll in LCCC1108 alone. Patients deemed eligible for LCCC 1108 who have 
enrolled into CSC or another study that included banking of tumor tissue prior to 
LCCC1108 initiation (and who have tumor tissue already stored) may be 
contacted via telephone for enrollment into LCCC1108 for access to their stored 
tumor tissue.  Telephone consenting will be documented properly per IRB 
guidelines. 
3.1.3 Participant must have tumor tissue available and suitable for molecular analysis 
from at least one of the following sources: 
• Tissue previously stored at UNC, Chapel Hill, NC (e.g., tissue collected 
under the CSC (IRB # 09-0605), IRB # 01-1283, IRB #90-0573, IRB#09-
0768, or IRB #05-2015) 

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• Tissue previously stored at an outside institution (other than UNC-CH), 
provided investigators can determine that the tumors were sampled and 
stored under appropriate conditions for inclusion in LCCC 1108 study 
• Patient is undergoing tissue collection as per clinical standard of care and 
is willing to allow specimens from surplus tissue to be diverted for 
research purposes 
• Patient is undergoing tissue collection as per clinical standard of care and 
is willing to have additional specimens taken for research purposes 
• Patient is willing to undergo biopsy to procure tissue samples for research 
purposes only without a previously identified clinical or diagnostic need 
3.1.4 For those ≥ 18years old capable of providing informed consent and willing to sign 
the IRB-approved written informed consent agreements for the present protocol 
3.1.5 For minor children 7-14 years of age, and adolescents 15 to 17 years of age, 
capable and willing to provide informed consent; parental consent also required. 
 
 
The following additional inclusion criteria apply only to patients undergoing biopsy 
for research purposes only under this protocol (i.e., without a previously identified 
clinical or diagnostic need): 
3.1.6 ≥18 years of age 
3.1.7 Treatment options offer no expectation of cure (e.g., advanced solid tumor 
patients with metastatic disease) NOTE: This restriction applies to biopsy of vital 
organs only (e.g., lung, liver) 
3.1.8 Appropriate candidate for research biopsy based on institutional standards for 
target biopsy site 
3.2 
Exclusion Criteria 
Patients who fulfill any of the following criteria will be excluded: 
3.2.1 Any condition that would make participation in the protocol unreasonably 
hazardous for the patient in the opinion of the treating physician  
3.2.2 Affected by dementia, altered mental status, or any psychiatric or co-morbid 
condition that would prohibit the understanding or rendering of informed consent 
 
The following additional exclusion criteria apply only to enrolled patients 
undergoing biopsy for research purposes only: 
3.2.3 History of serious or life-threatening allergic reaction to local anesthetics (i.e. 
lidocaine, xylocaine) or any medications used for conscious sedation (if 
applicable) 

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3.2.4 Requires general anesthesia for collection of biopsy 
3.2.5 Currently pregnant or lactating 
3.2.6 Active cardiac disease, defined as: 
a.  History of uncontrolled or symptomatic angina. 
b.  History of uncontrolled arrhythmias  
c.  Myocardial infarction < 3 months from study entry 
d.  Uncontrolled or symptomatic congestive heart failure 
e.  Any other cardiac condition, which in the opinion of the treating physician 
would make this protocol unreasonably hazardous for the patient 
3.2.7 Patients receiving bevacizumab less than 6 weeks prior to enrollment into this 
study should not undergo research core biopsies because of the concern for 
potential increased bleeding risk and delayed healing. (NOTE: Patients receiving 
bevacizumab who are undergoing a research biopsy of accessible organs (e.g. 
breast, lymph node, skin etc.) must be two weeks from the last dose of the 
angiogenesis inhibitor).    
4.0 
Schema 
 
 
 
 
 
1. Patients may be offered enrollment in UNC Health Registry/Cancer Survivorship Cohort (CSC) if 
eligible and CSC is operational in their clinic or offered enrollment in LCCC1108 alone. 
2. Normal specimen may be collected adjacent to tumor, blood sample, buccal swab etc. but this is 
not required. 
3. See section 6.0 for definition of successful sequencing. The PFS will be documented in cancer 
patients with active disease (see section 1.4) 

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4.1 
Study Methods and Procedures: Screening and Informed Consent  
During the informed consent process, patients will be informed that results of 
some (but not all) of the genetic testing on their tumor specimens may be 
communicated directly to them through their treating physician.  Along with the 
results that are communicated, the participant’s treating physician will explain the 
implications of their testing results, including whether their genetic profile renders 
them eligible for a specific therapy or clinical trial, and/or if their genetic profile 
carries any prognostic significance for their disease.  Participants will be informed 
that any specimens remaining after genetic profiling of their tumor to support 
their clinical care is complete, will be stored indefinitely and may be used for 
future unspecified research related to cancer.  This may include development of 
cell lines or commercial products from their specimens.    
 
We will inform patients that researchers may contact them in the future to request 
their participation in new research or in the event new discoveries or therapies 
become available that may be applicable to their specific genetic profile. We 
recognize that some patients may transfer their care to an outside institution.  In 
the event a participant moves or transfers his or her care to an outside institution, 
he or she will be asked to contact the Study Coordinator to provide information 
about his or her disease status.   
 
As is standard with all trials that may incorporate germ-line studies, we will 
inform patients of the potential implications for family members and the risks 
associated with such studies, including those related to insurability and 
employment and the limitations of laws designed to protect against such risks.   
However, it will be made clear to patients that although a blood sample is being 
obtained that may be used for comparison to their germline genome sequence, this 
study is not aimed at discovering germline mutations.  We will emphasize that our 
analyses should not be construed as genetic testing for genetic mutations 
associated with hereditary cancer susceptibility.  Nevertheless, because of the 
methods used, it is possible that we will discover a germline mutation that 
predisposes to cancer, in which case this information will be conveyed to the 
participants and their families through standard genetic counseling.  
4.1.1 Requested Studies 
Researchers at UNC’s High Throughput Sequencing Facility (or other UNC 
research facility) will perform molecular studies on genes of relevance to cancer.  
DNA and/or RNA isolation will be performed under the direction of Dr. Xiaoying 
Yin. Genomic data analysis will be conducted under the direction of Dr. D. Neil 
Hayes. Based on these results, additional molecular studies may be performed, if 
appropriate. Only variants of clinical interest, as determined by the UNC CCGR, 
will be conveyed to the treating physician (see Appendix A).  If possible, results 
of reportable genetic tests will be validated (whether confirmed or refuted) 
analytically in a CLIA-certified Laboratory prior to distribution to the treating 
physician.  NOTE: See Section 1.2.5 for possible exceptions to the CLIA 
requirement.   

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Quality Control (QC) of Tissue Samples 
Prior to molecular analysis of samples accessed under this protocol, it is essential 
that QC be performed by qualified personnel to ensure that the case diagnosis and 
tissue histopathology are adequately represented to permit successful DNA and 
RNA sequencing.  A qualified person will perform this QC prior to molecular 
analysis.    
4.1.2 Patient Communication 
Results will be placed in the patient’s medical record if confirmed by a CLIA-
certified laboratory and signed off by the MTB. Notification of results of 
reportable genetic profiling will be provided to the patient’s treating physician 
who will be responsible for sharing results with their patient. Negative reports 
(i.e. no alteration found) will also be reported. If a germline mutation is 
discovered that has clinical implications with respect to hereditary cancer 
predisposition, for example, this information will be conveyed through formal 
genetic counseling.   Along with the results, the participant’s physician will 
explain the implications of the testing, including whether their genetic profile 
renders them eligible for a specific therapy or clinical trial, and/or if their genetic 
profile carries any prognostic significance for their disease.  Participants will be 
informed that researchers may contact them in the future, to request their 
participation in new research or in the event new discoveries or therapies become 
available that may be applicable to their specific genetic profile. 
4.1.3 Normal Specimen Samples 
NOTE: If the patient is co-enrolled in LCCC0906 (the CSC), LCCC0824 
(IRB#09-0768), LCCC0121 (IRB#01-1283), and/or other specimen protocols that 
include collection and storage of normal specimens in the TPF, these samples 
may be accessed if sufficient quantities are available, if samples are of the 
appropriate type, and if distribution is approved by the PI of the study.  The 
following sections apply to patients who are not co-enrolled into one of these 
protocols. 
4.1.3.1 Blood Samples 
During screening, potential study subjects should be queried about any 
medications they are taking (see Eligibility Criteria).  If applicable, a pregnancy 
test (blood or urine) should be done. For patients undergoing biopsy, the 
physician performing the procedure will ensure the patient meets all institutional 
standards for the procedure, and may collect ~8mLs in a single yellow top ACD 
tube (i.e., collection of normal tissue is not required). Alternatively, the 
participant can have a blood sample obtained during pre-operative care or in the 
outpatient phlebotomy clinic as appropriate.  Inpatient participants may have 
blood samples taken as part of their regular phlebotomy draw.  
 
For eligible patients who are not undergoing biopsy, a single yellow top ACD 
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possible), unless the investigator deems another source of normal DNA (or RNA) 
is more appropriate (see below).   
 
For storage, serum will be processed by and stored in TPF, with each aliquot 
assigned a unique identification code, as per standard TPF procedures.  Genomic 
DNA (or RNA) may be obtained and appropriate germline DNA (or RNA) may 
be released to the High Throughput Sequencing Facility or other UNC research 
facility for molecular analysis. 
4.1.3.2 Buccal (Cheek) Swab Collection 
For patients in which blood sample collection is not obtained, we may obtain two 
buccal swabs from the inner cheek to obtain germline DNA. DNA will be isolated 
from the swabs, frozen, stored in the TPF, and given a unique identification code, 
as per standard TPF procedures.  Genomic DNA may be obtained and germline 
DNA may be released to the High Throughput Sequencing Facility or other UNC 
research facility for molecular analysis.  
4.1.3.3 Other  
The collection of normal tissue is not required. However, normal specimens may 
also be obtained from other sources, such as normal tissue adjacent to tumor 
during the biopsy procedure, or via a skin punch biopsy in patients with 
hematological malignancies (note: skin punch biopsies for hematological patients 
will be collected under LCCC0824).   Normal specimens adjacent to tumor tissue 
collected during a biopsy procedure and skin punch biopsies will be immediately 
snap-frozen by research personnel using standard procedures, stored in the TPF 
facility in a -70°C freezer, and given a unique identification code.  Genomic DNA 
(or RNA) from the tumor and the germline sample maybe released to the High 
Throughput Sequencing Facility or other UNC research facility for molecular 
analysis. 
4.1.4 Tumor Biopsy Collection 
Research Biopsies 
In order to minimize the risk of a tissue procurement procedure (biopsy, 
thoracentesis, or paracentesis, e.g.), only qualified personnel will perform these 
procedures.  Prior to the procedure, the physician performing the procedure will 
ensure the patient meets institutional standards for the procedure, discuss the risks 
with each study participant, answer any questions, and obtain separate procedure 
consent.   
 
For biopsies of lesions that are not superficial and clearly palpable, imaging 
studies such as CT or ultrasound will be used to guide the biopsy in order to 
minimize the risk of damage to adjacent structures.  Under sedation, biopsies will 
be made with an 11g -18g core needle depending on site and judgment of the 
physician performing the biopsy, with a maximum of 4-6 passes through tumor 
made if this is felt to be safe by the physician performing the biopsy procedure. 
Alternatively, surgical excision of superficial sites of disease is also appropriate if 

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preferable to the patient over needle biopsy.  After lymph node biopsies, patients 
will be observed for approximately 2 hours (range 2-4 hours) after the procedure, 
or per institutional standard guidelines.  After liver biopsies, patients will be 
observed for approximately 4 hours (range 4-6 hours) after the procedure, or per 
institutional standard guidelines.   
 
Biopsies will be immediately snap-frozen by research personnel using standard 
procedures, stored in the TPF facility in a -70°C freezer, and given a unique 
identification code.  Genomic DNA or RNA will be obtained and appropriate 
tissue DNA or RNA released to the High Throughput Sequencing Facility or other 
UNC research facility for molecular analysis. 
 
Biopsy/Surgery as Part of Routine Clinical Care 
Tumor biopsy samples and surgical specimens will also be eligible for genotyping 
in patients scheduled to undergo biopsy and/or surgery as part of routine clinical 
care.  In this situation, patients will be consented to have additional specimens 
taken for research purposes only, and/or to have any excess tissue remaining after 
clinical purposes are satisfied analyzed for molecular alterations (via LCCC0906, 
if possible). Researchers will ensure that the tumors were appropriately sampled 
and stored for inclusion in this study. If a blood, buccal sample, or other normal 
specimen is not collected during the procedure, patients may be asked to provide 
one as soon as practicable (see 4.1.3). 
 
 
Tissue Banked at UNC 
If a patient consenting for enrollment into this protocol has had tissue and blood 
stored in the TPF or other UNC-CH facility from a prior procedure, we will 
request their consent for access to their stored specimen(s). If a blood or buccal 
sample or other normal specimen was not collected, patients may be asked to 
provide one as soon as practicable (see 4.1.3). 
4.2 
Post-collection/Follow-up Assessments 
Post-procedure observation will be per the standard of care for the particular 
anatomic site to be biopsied.  For example, patients undergoing liver biopsy will 
either be observed for approximately 4-6 hours in the interventional radiology 
suite (PRU-Procedural Recovery Unit, 2nd floor Main Hospital) or held for 
overnight observation at the discretion of the physician performing the biopsy, or 
per institutional standard guidelines (also in the PRU).  
 
For biopsies performed for research purposes only, patients will be seen by one of 
the study investigators one to two weeks after the biopsy to rule out any late 
complication thereof.  Complications will be recorded as adverse events using 
NCI CTCAE version 4.0 and Serious Adverse Events will be reported as 
described below. For clinically indicated biopsies, follow-up and recording of 
adverse events will be completed as per standard of care by the treating physician 
for the particular anatomic site to be biopsied.   

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4.3 
Expected Risks 
Pain or discomfort related to the procedure is minimized with the use of sedation.  
Patients who require general anesthesia to undergo a separate biopsy procedure 
for research purposes only are not eligible for LCCC1108. 
 
Biopsy Risks 
Potential adverse effects of biopsy include bleeding (which can necessitate a 
blood transfusion and/or hospitalization, and can be life-threatening) and 
infection, both with very low frequencies. Bleeding at the time of biopsy will be 
controlled by standard clinical procedures.  Damage to local structures will be 
minimized by knowledge of local anatomy and standard pre-biopsy imaging 
studies. Other risks related to biopsies are dependent on the site of the biopsy.  
These are described in the LCCC1108 informed consent.  
Local Anesthesia 
With regard to anesthesia, all biopsy procedures require local anesthesia using 
lidocaine, xylocaine, or related compounds.  There is a small risk of an allergic 
reaction associated with these drugs.  In order to minimize the risk of local 
anesthesia, only qualified personnel will perform the biopsy procedure.  Patients 
will be queried if they have had previous allergic reactions to local anesthetics.   
 
Intravenous Conscious Sedation 
Certain biopsy procedures, such as lymph node or liver biopsies, may require 
intravenous conscious sedation (IVCS).  IVCS is a minimally depressed level of 
consciousness that retains the patient’s ability to maintain continuously a patent 
airway independently and respond appropriately to physical stimulation and 
verbal commands.  
 
The medications used to induce conscious sedation include the benzodiazepine 
midazolam and the opioid agonist fentanyl, or as per standard of care.  IVCS is 
performed once over a 30-60 minute period, and may require administration of 
multiple doses of each agent over this time frame.  Rarely, IVCS will last longer 
than 60 minutes.   
 
Midazolam: 
See 
http://www.drugs.com/pro/midazolam-injection.html 
for 
complete 
prescribing information on midazolam, including complete information on risks 
associated with its use.   
 
The risks of midazolam include respiratory depression and respiratory arrest, 
especially when used for sedation in non-critical settings.  Respiratory arrest 
could require intubation.  In some cases, when not recognized promptly and 
treated effectively, death or hypoxic encephalopathy has resulted.  Other serious 
cardiorespiratory adverse events have occurred after administration of midazolam, 
including airway obstruction, oxygen desaturation, apnea, and cardiac arrest, 
sometimes resulting in death or permanent neurologic injury.  There have also 
been rare reports of hypotensive episodes requiring treatment, particularly in 

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patients with hemodynamic instability.  Agitation, involuntary movements, 
hyperactivity and combativeness have been reported in adult patients treated with 
midazolam.   
 
Concomitant use of midazolam with other respiratory depressants like fentanyl 
may increase the risk of hypoventilation, airway obstruction, desaturation, or 
apnea, and may contribute to profound and/or prolonged drug effect.    Prolonged 
sedation may also be seen when midazolam is administered concomitantly with 
drugs known to inhibit the P450 3A4 enzyme system such as cimetidine, 
erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole.   
 
Adverse effects reported after intravenous administration of a single dose when 
used as a sedative include the following (Note: percentages given represent the 
fraction of all reported adverse events in adults): hiccoughs (3.9%), nausea 
(2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache 
(1.5%), and drowsiness (1.2%).  In addition, the following local effects at the site 
of the injection have been reported: tenderness (5.6%), pain during injection 
(5.0%), redness (2.6%), induration (1.7%), and phlebitis (0.4%).   Additional rare 
(<1.0%) adverse events occurring when midazolam is used as a sedative include: 
 
Respiratory (laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, 
shallow respirations, airway obstruction, tachypnea); 
 
Cardiovascular (bigeminy, premature ventricular contractions, vasovagal episode, 
bradycardia, tachycardia, nodal rhythm); 
 
Gastrointestinal (acid taste, excessive salivation, retching); 
 
CNS/Neuromuscular (retrograde amnesia, euphoria, hallucination, confusion, 
argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence 
delirium or agitation, prolonged emergence from anesthesia, dreaming during 
emergence, sleep disturbance, insomnia, nightmares, athetoid movements, 
seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, 
paresthesia); 
 
Special Senses (blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic 
movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, 
loss of balance, light-headedness); 
 
Integumentary (hive-like elevation at injection site, swelling or feeling of burning, 
warmth or coldness at injection site); 
 
Hypersensitivity (allergic reactions including anaphylactoid reactions, hives, rash, 
pruritus); 
 

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Miscellaneous (yawning, lethargy, chills, weakness, toothache, faint feeling, 
hematoma). 
 
Fentanyl  
See http://www.drugs.com/pro/fentanyl-injection.html for complete prescribing 
information on fentanyl (Duragesic®), including complete information on risks 
associated with its use.   
 
Fentanyl may cause muscle rigidity, particularly involving the muscles of 
respiration.  Skeletal muscle movements in the extremities, neck and external eye 
have also been reported with fentanyl; rarely, these have been strong enough to 
pose patient management problems.   Fentanyl may also produce euphoria, 
miosis, bradycardia and bronchoconstriction, as seen with other narcotic 
analgesics.    The most common serious adverse reactions reported with fentanyl 
include respiratory depression, apnea, rigidity, and bradycardia.  If these remain 
untreated, respiratory arrest, circulatory depression, or cardiac arrest could occur.  
Other adverse reactions that have been reported are hypertension, hypotension, 
dizziness, blurred vision, nausea, emesis, laryngospasm, and diaphoresis.   
 
The risks of IVCS also include allergic reactions to the sedative or analgesic 
medications and inhibition of the gag reflex and concomitant risk of aspiration.  
The chance of serious risks from IVCS are small but real; for example, a recent 
retrospective evaluation of 324,737 patients sedated using opioids and 
benzodiazepines for endoscopic procedures reported in the Clinical Outcomes 
Research Initiative of the American Society for Gastrointestinal Endoscopy 
reported 39 deaths (11 per 100,000), including 28 cardiopulmonary deaths (8 per 
100,000) (Sharma et al, Gastrointest Endosc 2007;66:27-34).  
   
In order to minimize the risk of IVCS, only qualified, licensed personnel (M.D. 
and R.N.) will be responsible for conscious sedation.  A minimum of two 
individuals will be involved in the care of patients undergoing conscious 
sedation—the physician performing the biopsy procedure, and the individual 
(R.N.) who monitors the patients and his/her response to both the sedation and the 
procedure, and who is capable of assisting with any necessary supportive or 
resuscitative measures.  The room where the procedure utilizing IVCS takes place 
(in the interventional radiology suite, e.g.) will have adequate equipment to 
provide supplemental oxygen, monitor vital signs, and maintain an airway, should 
this be necessary.  An emergency cart will also be immediately accessible, and 
emergency support services will be available.  Patients will be screened and 
evaluated for their fitness to undergo conscious sedation by a trained physician.  
Patients with active cardiac disease are excluded from this study. Following the 
procedure, patients will be observed closely in the recovery room according to 
standard institutional guidelines. 
 
 
 

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Risks of Blood Draws and I.V. Insertion 
Blood draws may be associated with slight discomfort from the needle-stick, 
localized erythema, bleeding/bruising, or soreness around the area where the 
needle is inserted.  Insertion of an intravenous catheter (I.V.) has similar risks, in 
addition to a small risk of infection at the site where the needle is inserted.   
In order to minimize the risk of blood draws and I.V. insertion, only trained 
personnel will perform these procedures, according to standard institutional 
guidelines. 
Risks of Imaging Studies 
Some biopsy procedures require imaging studies, either to plan or guide the 
procedure.  Imaging studies that may be used in obtaining tissue samples include 
CT scans, endoscopy, and ultrasound. CT scans will expose study participants to 
controlled amounts of limited radiation.  The total dose of radiation from these 
tests is not anticipated to cause any adverse effects and is recorded for future 
review.  The estimated radiation dose from a CT biopsy procedure is 258 mrem. 
For comparison, the average person in the United States receives a radiation 
exposure of 300 mrem per year from natural background source.   There is also a 
risk of an allergic reaction to the intravenous contrast dye used during CT 
imaging, as well as a risk of experiencing feelings of anxiety or claustrophobia 
while undergoing a CT scan.  Upper or lower endoscopy carries small risks of 
bleeding, infection, or perforation of the GI tract. There are no anticipated risks 
with the use of ultrasound. 
 
In order to minimize these risks, participants will be queried, as per standard 
institutional practice, regarding their history of reactions to intravenous contrast 
dye.  If a participant has had such a reaction, s/he will be pre-medicated, or dye 
will not be used, as per standard institutional practice.  If a patient has previously 
experienced anxiety or claustrophobia while undergoing a CT scan, s/he will be 
encouraged to discuss this with the primary oncologist. For endoscopy, adequate 
preparation will be confirmed (e.g. fasting for 24 hours  for upper endoscopy and 
removal of dentures; bowel prep for colonoscopy). Anxiolytics may be prescribed 
by the patient’s primary oncologist as indicated. 
 
Patient Privacy 
TPF personnel will provide coded tissue and blood samples collected under 
LCCC1108 to researchers conducting genetic analysis.   
 
All medical information abstracted from patient medical records under 
LCCC1108 will be recorded and stored in a secure password protected database. 
Medical records collected under the CSC will be downloaded into the LCCC Data 
Warehouse (LDW) managed by the LCCC Bioinformatics and Genomics Core.  
 
As is standard with all trials that incorporate germ-line studies, we will inform 
patients of any implications for family members, and the risks associated with 
such studies, including those related to insurability and employment, and the 
limitations of laws designed to protect against such risks.  Specific information 

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about heritable conditions will be communicated to participants by a trained 
genetic counselor.    
4.4 
Medical Records Abstraction 
Medical records will be abstracted via the CSC, or by the LCCC1108 Study 
Coordinator for details on the following: cancer diagnosis, cancer stage, surgical 
and medical management,  any treatment decisions made in response to the results 
communicated to the physician, PFS after the most recent therapy prior to 
UNCseq™ results on which the patient has just experienced progression, PFS 
after the first treatment post UNCseq™ results,  PFS after any targeted treatment 
prescribed based on  UNCseq™ results, and survival.  Responses post treatment 
may also be documented.  For eligible patients who are previously untreated at the 
time of 1108 enrollment and for whom no clear standard of care exists (e.g., 
metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands), 
PFS prior to UNCseq™ results will be estimated from published data on the most 
commonly used regimens for the specific tumor.  For patients whose prior 
treatment was therapy specifically targeted against their tumor (e.g., trastuzumab 
for HER2+ metastatic breast cancer), PFS prior to UNCseq™ results will be PFS 
post first-line chemotherapy in target refractory disease.  In such cases, historical 
comparator rates will be determined a priori by members of the CCGR.   
 
  
5.0 
ADVERSE EVENTS 
5.1 
Definitions 
5.1.1 Adverse Event 
An adverse event or adverse experience (AE) is any untoward or unfavorable 
medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or 
not considered related to the subject’s participation in the research.    
 
In this study, toxicity will be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 (if appropriate), 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
5.1.2 Unexpected Adverse Event 
An unexpected adverse event is  an adverse event  that is unexpected (in terms of 
nature, severity, or frequency) given (a) the research procedures that are described 
in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject 
population being studied; 

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5.1.3 Serious Adverse Event (SAE) 
An SAE is any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• 
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 disability/incapacity; 
• 
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 that must be reported as an important medical 
event. 
 
*Hospitalization for anticipated or standard of care specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor or recurrent disease, or elective surgery, will 
not be considered serious adverse events. 
5.1.4 Unanticipated Problems 
As defined by UNC’s IRB, unanticipated problems involving risks to study 
subjects refers to any incident, experience, or outcome that: 
• Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• Is related or possibly related to a subject’s participation in the research; 
and  
• Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or recognized.    
5.2 
Reporting 
Any unanticipated problem that occurs during the conduct of this study and that 
meets at least the first two criteria listed in 5.1.4 must be reported to the UNC 
IRB using the IRB’s web-based reporting system.   If any SAE occurs in a patient 
undergoing a biopsy for research purposes only, the information should be 
recorded in the eCRF for that patient.  Please include a full description of the 
event, its severity or toxicity grade, the relationship to the procedure, and the 
treatment, outcome and sequelae of the event. 

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6.0 
STATISTICAL CONSIDERATIONS 
6.1 
Sample Size and Accrual 
One primary objective of this study is to estimate the proportion of patients 
enrolled in LCCC1108 who have undergone successful sequencing and have a 
reportable genetic variant identified via UNCseq™.  There is not a fixed sample 
size for this study. The number of specimens collected under this protocol will be 
reviewed on an annual basis and assessed in the context of ongoing and planned 
research.  Based on this, a decision will be made, after discussion each year at the 
continuing review of the protocol, as to whether to continue this study.  Based on 
enrollment into IRB # 01-1283 (LCCC0121: Molecular Analysis of Aerodigestive 
Cancers), we anticipate enrolling up to 5000 subjects into this study. The table 
below provides precision estimates for the proportion of patients with a reportable 
genetic variant for various sample sizes.  As an example, with a sample size of 
1000 patients, the maximum width of an exact 95% confidence interval (CI) will 
be 0.063.  In other words, we will be able to estimate the proportion of patients 
with a reportable genetic variant within 3.1% if there are 1000 patients available 
who have undergone successful sequencing. 
 
 
 
 
Total Successfully 
Sequenced Sample Size 
Maximum Width of 
Exact 95% CI 
Maximum Half Width 
of Exact 95% CI 
500 
0.089 
0.045 
750 
0.073 
0.036 
1000 
0.063 
0.031 
1250 
0.056 
0.028 
1500 
0.051 
0.026 
1750 
0.047 
0.024 
2000 
0.044 
0.022 
2250 
0.042 
0.021 
2500 
0.040 
0.020 
2750 
0.038 
0.019 
3000 
0.036 
0.018 
3250 
0.035 
0.017 
3500 
0.033 
0.017 
3750 
0.032 
0.016 
4000 
0.031 
0.016 
 
An additional primary objective of this study is to estimate  PFS   in cancer 
patients with active disease with a reportable genetic variant and those without a 
reportable genetic variant.  
 

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6.2 
Data Analysis Plans 
Patients will be evaluable for the primary objective of estimating the proportion of 
patients with a reportable genetic variant if they undergo successful sequencing 
via UNCseq™.  A patient will be considered to have had successful sequencing as 
long as they fall into one of the following 4 groups:   
 
1. Patients who had variants reported 
2. Patients who had no variants reported  
3. Patients who died before study results could be confirmed and so 
confirmation was halted 
4. Patients whose only variants reported were confirmed by a standard of 
care assay that had been run in the clinical setting.  
 
Patients included in group 1  (non-standard of care variant discovered via 
UNCseq™ and confirmed after UNCseq™ in a CLIA certified laboratory (or 
provided by a waiver from the IRB)) will be considered reportable for the 
purposes of this primary objective.  The proportion of patients with a reported 
genetic variant will be estimated and reported along with an exact 95% 
confidence interval.     
 
Only active cancer patients who have undergone successful sequencing will be 
evaluable for the other primary objective of estimatingPFS  -in patients who have 
a reportable genetic variant and those who do not. Active patient status is 
determined at the time of MTB, as described in section 1.4.3. The Kaplan-Meier 
method will be used to estimate PFS and the 2 year PFS will be reported with its 
95% confidence intervals using the log-log method. 
 
 
 
7.0 
STUDY MANAGEMENT 
7.1 
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 participant 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 

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essential information has been provided to the participant and the investigator is 
assured that h/she understands the implications of participating in the study, the 
participant will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a subject’s participation in the trial, s/he should sign and date the written 
informed consent agreement, preferably in the presence of the person who 
conducted the informed consent discussion, who will also sign and date the 
document. 
7.2 
Required Documentation 
Before LCCC1108 can be initiated, the following documentation must be 
provided to LCCC1108 Study Coordinator. 
 
• 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 
• Investigator’s signature documenting understanding of the protocol and 
providing commitment that this trial will be conducted according to all 
stipulations of the protocol 
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
7.3 
Registration Procedures 
All patients must be registered with the LCCC 1108 Study Coordinator  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 919-966-9259.  
7.4 
Data Management and Monitoring/Auditing 
For tracking of specimens collected or accessed under LCCC1108, researchers 
will use password protected databases stored under secure conditions.  TPF staff 
will track the number of vials procured (one specimen may be distributed into 
multiple freezing vials), the location of the vials in the freezer, and the utilization 
and distribution of any vial.  
 
Abstracted clinical data will be collected into a secure, password protected 
database by Research Personnel from UNC LCCC.     
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six months.  

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7.5 
Adherence to the Protocol 
Except for an emergency 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.   
7.5.1 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 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.   
7.5.2 Single Patient/Subject Exceptions 
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.  
7.5.3 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, the guidelines below must be followed: 
 
Protocol Deviations: UNC personnel will record the deviation in in a log, 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. 

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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.   
7.6 
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.   
 
The written protocol amendment, and the amended consent form, if required, 
must be sent to UNC’s IRB for approval prior to implementation.   
7.7 
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.  For this protocol, study documents will be kept in accordance 
with institutional IRB guidelines.  
7.8 
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 will be responsible for ensuring that all the required 
data are 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 whose final 
signature will attest to the accuracy of the data. 
 

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8.0 
REFERENCES 
 
1. 
Peppercorn, J., et al., Ethics of mandatory research biopsy for correlative end 
points within clinical trials in oncology. J Clin Oncol, 2010. 28(15): p. 2635-40. 
2. 
Hirsch, F.R. and P.A. Bunn, Jr., EGFR testing in lung cancer is ready for prime 
time. Lancet Oncol, 2009. 10(5): p. 432-3. 
3. 
Cetuximab (Erbitux®) Package Insert. 2010, Imclone Systems Incorporated: 
Branchburg, NJ. 
4. 
Panitumumab 
(Vectibix®) 
Package 
Insert. 
2010; 
Available 
from: 
http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf. 
5. 
Shaw, A.T., et al., Clinical features and outcome of patients with non-small-cell 
lung cancer who harbor EML4-ALK. J Clin Oncol, 2009. 27(26): p. 4247-53. 
6. 
Kwak EL, C.D., CLark J, et al., Clinical activity observed in a phase I dose 
escalation trial of an oral c-MET and ALK inhibitor, PF-02341066. J Clin Oncol, 
2009. 27(Suppl): p. 148s. 
7. 
Kwak, E.L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung 
cancer. N Engl J Med, 2010. 363(18): p. 1693-703. 
8. 
Chabner, B.A., Early accelerated approval for highly targeted cancer drugs. N 
Engl J Med, 2011. 364(12): p. 1087-9. 
9. 
Bentley, D.R., Whole-genome re-sequencing. Curr Opin Genet Dev, 2006. 16(6): 
p. 545-52. 
10. 
Bookman, E.B., et al., Reporting genetic results in research studies: summary and 
recommendations of an NHLBI working group. Am J Med Genet A, 2006. 
140(10): p. 1033-40. 
11. 
Robson, M.E., et al., American Society of Clinical Oncology policy statement 
update: genetic and genomic testing for cancer susceptibility. J Clin Oncol, 2010. 
28(5): p. 893-901. 
12. 
National Comprehensive Cancer Network Guidelines: Genetic/Familial High-
Risk Assessment: Breast and Ovarian 2010  [cited 2011 March 8, 2011]; 
V1.2010:[ 
13. 
Ley, T.J., et al., DNMT3A mutations in acute myeloid leukemia. N Engl J Med, 
2010. 363(25): p. 2424-33. 
14. 
Massachusetts General Hospital Cancer Center News. 2011  [cited 2011 March 
5]; 
Available 
from: 
http://www.massgeneral.org/cancer/about/newsarticle.aspx?id=1590. 
15. 
Christensen, K.D., et al., Disclosing individual CDKN2A research results to 
melanoma survivors: Interest, impact, and demands on researchers. Cancer 
Epidemiol Biomarkers Prev, 2011. 
16. 
Von Hoff, D.D., et al., Pilot study using molecular profiling of patients' tumors to 
find potential targets and select treatments for their refractory cancers. J Clin 
Oncol, 2010. 28(33): p. 4877-83. 
17. 
Janku, F., et al., PIK3CA mutations frequently coexist with RAS and BRAF 
mutations in patients with advanced cancers. PLoS One, 2011. 6(7): p. e22769. 
18. 
Janku, F., et al., PIK3CA mutations in patients with advanced cancers treated 
with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther, 2011. 10(3): p. 558-65. 

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19. 
Janku, F., et al., PI3K/AKT/mTOR inhibitors in patients with breast and 
gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol, 2012. 
30(8): p. 777-82. 
20. 
Hamilton, E.P., G.H. Lyman, and J. Peppercorn, Availability of experimental 
therapy outside oncology randomized clinical trials in the United States. J Clin 
Oncol, 2010. 28(34): p. 5067-73. 
21. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
22. 
Cheson, B.D., et al., Revised recommendations of the International Working 
Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, 
and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J 
Clin Oncol, 2003. 21(24): p. 4642-9. 
23. 
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin 
Oncol, 2007. 25(5): p. 579-86. 
24. 
Cheson, B.D., The International Harmonization Project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin North Am, 2007. 21(5): p. 841-54. 
25. 
Cheson, B.D., et al., Report of an international workshop to standardize response 
criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working 
Group. J Clin Oncol, 1999. 17(4): p. 1244. 
26. 
Durie, B.G., et al., International uniform response criteria for multiple myeloma. 
Leukemia, 2006. 20(9): p. 1467-73. 
 
 

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9.0 
 APPENDICES 
9.1 
APPENDIX A 
CHARTER 
UNC COMMITTEE FOR THE COMMUNICATION OF GENETIC 
RESEARCH RESULTS 
 
Objective of Committee 
The UNC Committee for the Communication of Genetic Research Results (CCGR) has 
been established to create and periodically update the list of genetic tests that are 
appropriate for researchers to share with treating physicians and their patients within the 
context of LCCC1108.   As an operating principle, researchers will not share genetic test 
results with treating physicians unless they can inform the care of a particular patient 
disease population.   
Meetings: 
The first meeting of CCGR will be scheduled to occur in Quarter 4 2011.   The focus of 
the initial meetings will be to create the lists of reportable genetic tests (the “Master Gene 
Lists” as per LCCC1108).   Follow-up meetings will occur quarterly for CCGR to review 
and update each list.  
Master Lists 
Disease Groups 
To begin the process of generating the Master Gene Lists, the PI of LCCC1108 (Dr. H. 
Shelton Earp) will request that each cancer Disease Group (e.g., breast, head and neck, 
lung, etc.) provide the Chair of the CCGR (see list of members on page 4) a written 
summary of the standard of care (SOC) treatment/management by stage for diseases 
covered within their group.  In generating these summaries, disease groups need to 
include the role of genetic alterations in this SOC management (e.g., to determine KRAS 
at diagnosis of mCRC, or to determine the status of HER2 at the time of breast cancer 
diagnosis, regardless of stage).   This list of SOC genes will be compiled by tumor as List 
#1.   
Through this process, disease groups will also identify when patients within their purview 
have run out of SOC treatment options, and would potentially be appropriate candidates 
for non-SOC treatment and/or for enrollment into clinical trials.    They will also draft 
List #2, the list of non-SOC genetic alterations of potential clinical significance for 
review by the Pathology Committee. 

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Pathology Committee 
The Pathology Committee (see list of members on page 4) will be responsible for 
reviewing the drafts of List 1 and List 2 prepared by the CCGR.   As part of their review, 
the Pathology Committee must describe the validation status of the assay used to measure 
each genetic alteration.   If a genetic alteration from the CCGR list #2 can be validated 
(either confirmed or refuted) in a CLIA environment, e.g., KRAS for use in the non-SOC 
setting, or verification of NextGen sequencing results by single nucleotide polymorphism 
(SNP) chip (or similar technology) in a CLIA environment, then the test will remain on 
List #2.  If the genetic alteration from the CCGR list #2 cannot be validated in a CLIA 
research laboratory (e.g., IDH1), then it will be placed on List #3.   
CCGR 
CCGR will use  reports, literature reviews, commercial or open-source products to 
evaluate the literature, and lists drafted by the Disease Groups and Pathology Committee 
to review and routinely update Master Gene Lists 1-2.    List #1 will be categorized by 
tumor.  For example, for any stage breast cancer, it is SOC to determine expression of 
HER2, PR or ER, while KRAS is SOC in CRC. 
Treating physicians may consider using positive results from Lists 2-3 for participants 
who have run out of SOC options outside the context of a clinical trial.  The point at 
which this occurs will vary for each participant according to tumor type/stage/clinical 
situation, as outlined earlier.  As of the writing of Amendment #6, a List #4 is under 
consideration by the CCGR.  This list would include genetic variants that predict 
sensitivity to non-targeted treatment (e.g. radiation, cytotoxics). 
Individual Patient Reports 
Researchers will prepare an Individual Participant Report from the genetic studies 
performed on a particular patient’s tumor.    
• If NextGen sequencing identifies a mutation in a SOC (list 1) test (e.g., the 
HER2/neu gene in a breast cancer patient), and the SOC test has not already been 
ordered by the treating physician, the Principal Co-Investigator of LCCC1108 
will recommend that the treating physician order this test.   In this case (which we 
anticipate will be rare), HER2 testing would be standard of care, and the 
participant and/or their insurance company would be charged for the SOC test 
(there will be no charge for the NextGen sequencing provided via the subject’s 
participation in the study).      
• For results from List 2-3 the following will apply: 
o Prior to release to the treating physician, any positive genetic tests from 
List #2 will be analytically validated (whether confirmed or refuted) in a 
CLIA-certified laboratory.  The participant (and/or their insurance 

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company) will not be charged for this test in a CLIA-certified laboratory 
as this will not be considered standard of care. 
o After confirmation, results will not be released to the treating physician 
until the LCCC1108 molecular tumor board reviews and signs off.  This 
tumor board provides additional oversight, ensuring compliance with the 
protocol, and appropriate application of results to individual patients.  This 
board is comprised of representatives of the CCGR, the Pathology 
committee, key laboratory scientists involved in technical and 
bioinformatic aspects of UNCseq™, and clinical/molecular pathologists. 
o Any positive results from List #3 must be reproduced via NextGen 
sequencing.  These results may not be reported to the treating 
physician/participant until a waiver for the CLIA requirement is obtained 
from the UNC IRB.  Therefore, results from List #3 (once they have been 
reproduced) must first be released to the LCCC1108 Study Coordinator.   
The Study Coordinator and the Principal Co-Investigator, Dr. Juneko 
Grilley-Olson, will work with the LCCC1108 Regulatory Associate to 
obtain a waiver from the IRB for the CLIA requirement.  Once obtained, 
and the molecular tumor board has reviewed and signed off, results may 
be released to the treating physician/ participant with the following 
statement included “This is a research result from a non-validated test 
environment.” 
In the case of List 3 results, any validation testing performed would not be 
charged to the participant and/or their insurance company.   
 
Minutes 
Minutes from each of the CCGR meetings will be recorded, and kept on a password-
protected computer by the Committee Chair.  A paper copy of all minutes will be 
maintained in the Regulatory files for this study.   

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Clinical Committee Members: 
CHAIR: William Y. Kim, MD 
Clinical Genetics:  James P. Evans MD, PhD, Jonathan Berg MD, PhD 
Developmental Therapeutics (Phase I): Claire Dees, MD 
Breast Cancer: Lisa Carey, MD 
Lung Cancer: Carrie Lee, MD 
Melanoma: Carrie Lee, MD 
Hematology: Kristy Richards, MD, PhD 
Sarcoma: Hong Jin Kim, MD 
GI Tumors: Autumn McRee, MD 
GU Tumors: William Y. Kim, MD 
Gynecologic Oncology: Victoria Bae-Jump, MD 
Pediatric Oncology: Ian Davis, MD, PhD 
Surgery: Hong Jin Kim, MD, David Ollila, MD 
Radiation Oncology: Andrew Wang, MD 
Ex-officio members of the Committee: H. Shelton Earp MD, Juneko Grilley-Olson MD 
 
Pathology Committee Members: 
CHAIR: David Allan Eberhard MD, PhD 
Molecular Pathology/Genetics: Karen Weck-Taylor, MD 
Pathology and Laboratory Medicine: Ryan Miller, MD, PhD; George Fedoriw, MD, 
Leigh Thorne MD, WilliamK. Funkhouser MD, PhD 
Dermatology: Nancy Thomas, MD, PhD 
Ex-officio members of the Committee: Norman E. Sharpless, MD