Detecting Cancers Earlier Through Elective Plasma-based CancerSEEK Testing - Ascertaining Serial Cancer Patients to Enable New Diagnostic
Conditions: Early Cancer Detection
Sponsor: Exact Sciences Corporation

 
 
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Study Number: HEOR 24 
 
Protocol Date: 9 November 2020  
 
 
 
 
 
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HEOR 24 
Detecting cancers Earlier Through Elective plasma-based CancerSEEK 
Testing - Ascertaining Serial Cancer patients to Enable New Diagnostic 
(DETECT-ASCEND) 
 
 
NCT04213326 
 
 
November 9th, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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HEOR 24 
Detecting cancers Earlier Through Elective plasma-based CancerSEEK 
Testing - Ascertaining Serial Cancer patients to Enable New Diagnostic 
(DETECT-ASCEND) 
INNOVATIONS STUDY NUMBER: 
HEOR 24 
SPONSOR: 
 
Thrive Earlier Detection Corp.  
 
 
PRINICPAL INVESTIGATOR: 
Dax Kurbegov, MD  
 
DATE FINAL: 
18 October 2019 
AMENDMENT 1  
25 October 2019 
AMENDMENT 2 
27 January 2020 
AMENDMENT 3 
5 March 2020 
AMENDMENT 4 
13 March 2020 
AMENDMENT 5 
13 July 2020 
AMENDMENT 6 
9 November 2020 
 
This document is confidential and is property of Sarah Cannon. No part of this document may be 
transmitted, reproduced, published, or used by other persons without prior written authorization from 
Sarah Cannon. 
 
 
 
 

 
 
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Clinical Study Statement of Compliance 
HEOR 24 
Detecting cancers Earlier Through Elective plasma-based CancerSEEK 
Testing - Ascertaining Serial Cancer patients to Enable New Diagnostic 
(DETECT-ASCEND)  
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
• 
International Council for Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki 
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards (IRBs) 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance with the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the 
protocol, and shall be formally documented as such. 

 
 
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Clinical Study Principal Investigator Signature Form 
Detecting cancers Earlier Through Elective plasma-based CancerSEEK 
Testing - Ascertaining Serial Cancer patients to Enable New Diagnostic 
(DETECT-ASCEND) 
INNOVATIONS STUDY NUMBER: 
HEOR 24 
DATE FINAL: 
18 October 2019 
AMENDMENT 1 
25 October 2019 
AMENDMENT 2 
27 January 2020 
AMENDMENT 3 
5 March 2020 
AMENDMENT 4 
13 March 2020 
AMENDMENT 5 
13 July 2020 
AMENDMENT 6 
9 November 2020 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
___________________________            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
Sarah Cannon Development Innovations, LLC 
 
 
 
 
 
 

 
 
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HEOR 24 Summary of Changes 
AMENDMENT NUMBER: 
6 
AMENDMENT DATE:       9 November 2020 
Additions are noted by bolding. Deletions are noted by cross outs.  
Throughout the protocol, enrollment of healthy subjects was changed from 3,300 to 4,300 and the 
total number of subjects enrolled changed from 4,300 to 5,300. 
Synopsis  
A total of 5,3004,300 patients are planned to be enrolled on this study, 1,000 subjects with 
known or suspected cancer confirmed through pathology reports and/or clinical/radiographic 
data and 4,3003,300 subjects with no known cancer. 
Synopsis and Section 2.1 Primary Objective 
• 
Up to the first 700 subjects with known or suspected cancer and the firstapproximately 
1,400 subjects with no known cancer collected will be used as training cases to develop a model 
to discriminate cancer from non-cancer cases. 
Synopsis and Section 3.1 Inclusion Criteria 
• 
Age ≥50 years (both cancer and non-cancer cohorts) or age 18-30 years (non-cancer 
cohort only). 
Synopsis and Section 9 Determination of sample size 
The overall study aims to consent 5,3004,300 subjects (1,000 confirmed cancer subjects, 
4,3003,300 non-cancer).  The cancer cohort will limit breast and endometrial cancer to 
approximately 200 subjects and 50 subjects, respectively. 
Section 2 Study Objectives and Endpoints 
Thrive Earlier Detection is seeking to conduct a development and validation study for a new 
version of the CancerSEEK assay, in a cohort of 1,000 subjects diagnosed with cancer and a cohort 
of 4,3003,300 non-cancer volunteers with no known diagnosis of cancer. The overall study aims 
to consent 5,3004,300 subjects meeting eligibility criteria (1,000 confirmed cancer subjects and 
4,3003,300 non-cancer subjects).  
Section 5.1 Overview 
To ensure inclusion of that a heterogeneous group of cancer types and that breast and 
endometrial cancer patients are not overrepresented in the sample of cancer patients (NTotal = 
1,000), we will limit enrollment of those tumor sites as shown in Table 1. Each cancer type 
should include a distribution of Stage I-IV. to approximately 20% of the overall sample 
(NBreast = 200, Nendometrial = 50).  Initial data analysis will be conducted after collecting 70% of our 
cancer cohort (NInitial = 700).  Breast and endometrial cancer patients will be capped at 
approximately 20% and 5% of the initial sample as well (NBreast = 140, NEndometrial = 35) (See  
Table 1 below). 

 
 
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Table 1 Proposed Cancer Cohort Enrollment 
 
Testing Analysis 
First 700 Cancer 
Blood Samples 
Validation Analysis 
Final 300 Cancer 
Blood Samples 
Total Requirement 
Breast Cancer 
193 
82 
275 
Lung Cancer 
280 
120 
400 
Colorectal Cancer 
105 
45 
150 
Other Cancers 
122 
53 
175 
Endometrial 
(35) 
(15) 
(50) 
Breast Cancer Limit 
140 
60 
200 
Endometrial Cancer 
Limit 
35 
15 
50 
 
 
 
 

 
 
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HEOR 24 PROTOCOL SYNOPSIS 
Title of Study: 
Detecting cancers Earlier Through Elective plasma-based CancerSEEK Testing - 
Ascertaining Serial Cancer patients to Enable New Diagnostic (DETECT-ASCEND) 
Study Number: 
HEOR 24 
Sponsor: 
Thrive Earlier Detection Corporation– Cambridge, MA 02139 
Number of 
Patients: 
A total of 5,300 patients are planned to be enrolled on this study, 1,000 subjects with 
known or suspected cancer confirmed through pathology reports and/or 
clinical/radiographic data and 4,300 subjects with no known cancer. 
Objectives: 
The primary objective of the study is to develop and validate the classification algorithm 
used by the CancerSEEK cancer screening test by collecting clinically annotated 
peripheral blood specimens from subjects with cancer and no known cancer. 
• 
Up to 700 subjects with known or suspected cancer and approximately 1,400 
subjects with no known cancer collected will be used as training cases to develop 
a model to discriminate cancer from non-cancer cases. 
• 
The subsequent cases collected will be used as test cases to validate a model that 
discriminates cancer from non- cancer cases. 
In addition to planned analyses for the primary objective, future exploratory investigation 
may study histology, pathology, medical records, tissue, and other biospecimens collected 
as part of standard of care. 
Study Design: 
This is a prospective, observational study of 1,000 subjects with known or suspected 
cancer and 4,300 subjects with no known cancer. 
Potential participants will be asked questions to confirm their eligibility by a nurse 
navigator, study staff member, physician or via the patient web portal. 
Informed consent will be carried out for eligible subjects in accordance with applicable 
federal regulations and International Council for Harmonisation (ICH)/Good Clinical 
Practice (GCP) guidelines. 
Subjects will then complete a survey, and either study staff will draw 60 mL of blood and 
measure the height and weight of the subject, or a home health visit will be scheduled to 
complete the blood draw and collect height and weight. 
Where available, data from the medical records of the cancer subjects will reviewed and 
collected. In addition, non-cancer subjects will be requested to allow access to their 
medical records as an optional portion of their informed consent. 
Inclusion Criteria: 
All Patients 
• 
Age ≥50 years (both cancer and non-cancer cohorts) or age 18-30 years (non-
cancer cohort only). 
• 
Ability to understand the nature of this study and give written informed  consent. 
Cancer cohort 
Either of the following: 
• 
Histologic diagnosis of cancer with no prior systemic or definitive therapy (any 
stage, inclusive of in-situ carcinoma) 
Or 

 
 
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• 
Subject with high suspicion of cancer through radiological and/or clinical 
assessment who are scheduled for resection or biopsy within 6 weeks of study blood 
collection and have not received prior systemic or definitive therapy. 
Non-cancer cohort 
• 
No prior history of cancer with the exception of localized, non-melanoma skin 
cancer. 
Exclusion Criteria: 
All Patients 
• 
Evidence of active febrile infection prior to blood draw. 
• 
Women who are pregnant or breast-feeding. 
• 
History of an allogeneic bone marrow, stem cell transplant, or solid organ 
transplant. 
• 
Judgment by the Investigator or study staff of any other reason that would 
prohibit the inclusion of the subject in the study.  
Cancer cohort 
• 
Subjects newly diagnosed with a hematologic malignancy, primary central 
nervous system tumor, prostate cancer, or skin cancer (including melanoma). 
• 
History of, or currently receiving, systemic or definitive cancer treatment 
including curative surgical resection (with the exception of localized, non-melanoma skin 
cancer), chemotherapy, radiation therapy, immunotherapy, and hormone therapy. 
Non-cancer cohort 
• 
None 
Statistical 
Methodology: 
The statistical analysis will be descriptive and consist of subject listings, graphs, and 
summary statistics comprising geometric mean, arithmetic mean, standard deviation (SD), 
median, minimum (min) and maximum (max) values as appropriate. 
The overall study aims to consent 5,300 subjects (1,000 confirmed cancer subjects, 4,300 
non-cancer).  

 
 
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HEOR 24 CONTACT INFORMATION 
Outcomes Contact Address and Phone#: 
Sarah Cannon Health Economics and 
Outcomes Research 
 
 
Study Chair: 
Dax Kurbegov, MD  
 
 
Sarah Cannon Health Economics and 
Outcomes Research Enrollment email: 
 
 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
CFR 
Code of Federal Regulations 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
HCA 
Hospital Corporation of America 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identifier 
Innovations 
Sarah Cannon Development Innovations 
IRB 
Institutional Review Board 
Outcomes 
Sarah Cannon Health Economics and Outcomes Research 
PPV 
Positive predictive value 
SAE 
Serious adverse event 

 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 10 
1. 
INTRODUCTION ................................................................................................. 13 
 
Background and Study Rationale .......................................................................... 13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 13 
 
Primary Objective .................................................................................................. 13 
 
Exploratory Objective ........................................................................................... 14 
 
Endpoints ............................................................................................................... 14 
3. 
STUDY POPULATION........................................................................................ 14 
 
Inclusion Criteria ................................................................................................... 14 
 
Cancer cohort ........................................................................................................ 14 
 
Non-cancer cohort ................................................................................................. 14 
 
Exclusion criteria ................................................................................................... 15 
 
Cancer cohort ........................................................................................................ 15 
 
Non-cancer cohort ................................................................................................. 15 
 
WITHDRAWAL FROM STUDY PARTICIPATION ......................................... 15 
4. 
STUDY REGISTRATION.................................................................................... 15 
5. 
STUDY DESIGN .................................................................................................. 17 
 
Overview ............................................................................................................... 17 
6. 
BLOOD SAMPLE COLLECTION ...................................................................... 19 
7. 
DATA COLLECTION .......................................................................................... 19 
 
Benefit/risk and ethical assessment ....................................................................... 20 
 
Study timetable and end of study .......................................................................... 20 
8. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 20 
 
Institutional Review Board Approval.................................................................... 20 
 
Amendments to the Protocol ................................................................................. 20 
 
Study Documentation and Storage ........................................................................ 21 
 
Data Management.................................................................................................. 21 
 
Confidentiality ....................................................................................................... 22 
 
Disclosure and Publication Policy ......................................................................... 23 
9. 
STATISTICAL ANALYSIS ................................................................................. 23 
 
Determination of sample size ................................................................................ 23 
 
Subject characteristics ........................................................................................... 23 

 
 
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10. 
SAFETY REPORTING AND ANALYSES ......................................................... 24 
 
Definitions ............................................................................................................. 24 
 
Serious Adverse Events ......................................................................................... 24 
 
Relatedness ............................................................................................................ 24 
 
Definitions of serious adverse event ..................................................................... 24 
 
Recording of serious adverse events ..................................................................... 25 
 
Reporting of serious adverse events ...................................................................... 25 
 
Recording of Serious Adverse Events ................................................................... 25 
 
Diagnosis versus Signs and Symptoms ................................................................. 25 
 
Persistent or Recurrent Adverse Events ................................................................ 25 
11. 
REFERENCES ...................................................................................................... 27 
 
Tables 
Table 1 
Proposed Cancer Cohort Enrollment ....................................................... 18 
 
Appendices 
Appendix A 
 Screening & Survey Questions ............................................................... 28 
 
 
 

 
 
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1. 
INTRODUCTION 
 
Background and Study Rationale 
Recommended screening is known to reduce the mortality and morbidity of breast, colorectal, 
cervix, prostate, and lung cancer.  At present, a screening assessment, the prostate-specific antigen 
(PSA) test, can be performed with a blood sample.  Cervical cancer screening involves a Pap smear 
test, and in countries where the test is the standard-of-care cervical cancer has nearly disappeared.  
Breast and colorectal cancer screenings are conducted with mammography and colonoscopy, 
respectively, and may detect precancerous lesions that can be removed (Kalinich et al 2018).  
Screening heavy smokers with low-dose chest computed tomography (CT) scans can detect lung 
cancer and improve cancer-specific survival (Siegel et al 2019).   
Timely, less invasive, and effective screening for cancer provides the best opportunity to reduce 
cancer mortality and morbidity for patients.  The CancerSEEK assay constitutes an important step 
towards early cancer detection (Cohen et al 2018).  The CancerSEEK assay was characterized in 
a retrospective study of over 1800 subjects (1,005 previously diagnosed with cancer and 812 non-
cancer subjects).  A cross-validation technique was used to train and evaluate the performance of 
classified algorithms.  Eight cancer types (ovary, liver, stomach, pancreas, esophagus, colorectal, 
lung, and breast) were used to demonstrate the performance of the assay.  Altogether, the algorithm 
for detection demonstrated sensitivity of 62% and specificity of 99.14%.  In cases where the 
CancerSEEK result was positive for presence of cancer (N=626) the algorithm for localization 
further predicted the 2 most likely anatomical sites (out of 8) for each assayed tumor.  During 
cross-validation this prediction contained the actual site of origin of the tumor in a median of 83% 
of subjects (Cohen et al 2018).   
In this study a new analytic feature of the CancerSEEK test not available in previous CancerSEEK 
studies will be validated.  The new CancerSEEK test will measure genome-wide aneuploidy and 
as a result, a new version of the algorithm will be developed. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
Thrive Earlier Detection is seeking to conduct a development and validation study for a new 
version of the CancerSEEK assay, in a cohort of 1,000 subjects diagnosed with cancer and a cohort 
of 4,300 non-cancer volunteers with no known diagnosis of cancer. The overall study aims to 
consent 5,300 subjects meeting eligibility criteria (1,000 confirmed cancer subjects and 4,300 non-
cancer subjects). Enrolled subjects will complete a brief survey and supply a sample of blood to 
be sent to a central laboratory where the CancerSEEK blood test is in development. 
 
Primary Objective 
The primary objective of the study is to develop and validate the classification algorithm used by 
the CancerSEEK cancer screening test by collecting clinically annotated peripheral blood 
specimens from subjects with cancer and no known cancer. 
• 
Up to 700 subjects with known or suspected cancer and approximately 1,400 subjects with 
no known cancer collected will be used as training cases to develop a model to discriminate 
cancer from non-cancer cases. 

 
 
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• 
The subsequent cases collected will be used as test cases to validate a model that 
discriminates cancer from non-cancer cases. 
 
Exploratory Objective 
 
 
 
 
Endpoints 
The primary endpoint is the ability of the CancerSEEK assay to effectively discriminate cancer 
from non-cancer as measured by sensitivity, specificity, and positive predictive value (PPV). 
Additional indicators of accuracy will be provided in a full confusion matrix, which is a table that 
shows the full performance of a classification model against true values.  
 
 
 
 
 
 
 
3. 
STUDY POPULATION  
 
Inclusion Criteria  
• 
Age ≥50 years (both cancer and non-cancer cohorts) or age 18-30 years (non-cancer cohort 
only). 
• 
Ability to understand the nature of this study and give written informed consent. 
 Cancer cohort 
Either of the following: 
• 
Histologic diagnosis of cancer with no prior systemic or definitive therapy (any stage, 
inclusive of in-situ carcinoma) 
Or 
• 
Subject with high suspicion of cancer through radiological and/or clinical assessment who 
are scheduled for resection or biopsy within 6 weeks of study blood collection and have not 
received prior systemic or definitive therapy. 
 Non-cancer cohort 
• 
No prior history of cancer with the exception of localized, non-melanoma skin cancer. 

 
 
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Exclusion criteria 
• 
Evidence of active febrile infection prior to blood draw. 
• 
Women who are pregnant or breast-feeding. 
• 
History of an allogeneic bone marrow, stem cell transplant, or solid organ transplant. 
• 
Judgment by the Investigator or study staff of any other reason that would prohibit the 
inclusion of the subject in the study.  
 
Cancer cohort 
• 
Subjects newly diagnosed with a hematologic malignancy, primary central nervous system 
tumor, prostate cancer, or skin cancer (including melanoma). 
• 
History of, or currently receiving, systemic or definitive cancer treatment including curative 
surgical resection (with the exception of localized, non-melanoma skin cancer), 
chemotherapy, radiation therapy, immunotherapy, and hormone therapy. 
 
Non-cancer cohort 
• 
None. 
 
WITHDRAWAL FROM STUDY PARTICIPATION 
Participation in this study is voluntary.  Subjects are not required to participate and may decide to 
withdraw their information from the study at any time, without penalty and without affecting their 
medical care.   
• 
If a subject elects to discontinue participation in the study and withdraws consent and 
authorization, Outcomes will make all reasonable efforts to take the following actions:  
• 
Future use of the subject’s biological sample and future access to the subject’s medical 
information will not take place.  
• 
Any information already obtained through study of the subject’s biological sample will 
continue to be used as described in this protocol.   
• 
Any information already collected from the subject’s medical record or through study 
surveys will continue to be used as described in this protocol. 
• 
Any remaining portion of the subject’s biological sample will be destroyed. 
Note:  It may not be possible to retrieve and/or destroy biological sample and other information 
previously released; in addition, the biological sample may have already been depleted at the time 
of the request.  
4. 
STUDY REGISTRATION 
The subject must willingly consent after being informed of the procedures, the experimental nature 

 
 
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of the study, potential benefits, alternatives, side-effects, risks, and discomforts.  Human protection 
committee approval of this protocol and associated consent form(s) is required.   
Study subjects will be identified for one of the two cohorts (Cancer Cohort or Non-Cancer Cohort 
[healthy volunteer]) (please refer to Table 1).   
In the confirmed Cancer Cohort, subjects for the study will be identified by physicians, study 
staff and nurse navigators.  For some participants, a Natural Language Processing (NLP) 
machine learning algorithm will be applied to pathology reports to predict a positive cancer 
diagnosis and the most likely primary tumor site.   
Cancer subjects will then be populated into an application where they will be assigned a nurse 
navigator or study coordinator who may identify them as eligible for the study.  
All subjects participating in the cancer cohort will receive compensation after signing informed 
consent and completing the study survey (see Appendix A).  Completion of the study survey is 
defined as an attempt at survey, and compensation will be sent regardless of any skipped or 
“prefer not to answer” responses present. 
Navigated gateway 
For sites using the navigated gateway, a nurse navigator will recruit potential participants.  
Because nurse navigators will only be recruiting potential participants for the study and not 
consenting them, their activities are limited to screening activities, entering subject 
demographics, tablet activation and distribution of Institutional Review Board (IRB)-approved 
materials.  They will be trained to direct participants to the study phone line if they have 
questions related to the informed consent form.  Patients will be supplied with the consent by the 
nurse navigator, but will call the study phone line if they have any questions.   
Study site gateway 
For sites using a study coordinator, the study coordinator will conduct the consent survey and 
blood draw.   
In the Non-Cancer Cohort, subjects will be recruited and enrolled from several sources.  Firstly, 
from the Hospital Corporation of America (HCA) employee base, referrals to non-HCA-
employed individuals (e.g., friends, family, neighbors) and others in waves until enrollment 
targets are met. This approach will include messaging to create awareness of the opportunity 
within targeted departments/subsidiaries of HCA Healthcare. While employee email addresses 
may be used to inform individuals of the study opportunity, no data regarding individual 
employee participation will be shared with the employer, and participation will have no impact on 
employees’ standing with their employer. A financial incentive will not be offered to HCA 
employees or HCA-employee referrals.  Secondly, subjects will be recruited and enrolled via a 
study web portal.  Informed consent and survey data collection will be performed via the web 
portal, and the blood draw performed using home health visits.  A financial incentive will be 
offered to this non-cancer cohort for additional time and effort in participating. 
Study site gateway 
For sites using a study coordinator, the study coordinator will conduct the consent survey and 
blood draw.   

 
 
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5. 
STUDY DESIGN 
 
Overview 
This is a prospective, observational study of 1,000 subjects with known or suspected cancer 
confirmed through pathology reports (Table 1) and/or clinical/radiographic data and 3,300 
subjects with no known cancer.  De-identified blood samples and clinical data will be collected 
from subjects to validate a classification algorithm for a new version of the CancerSEEK assay.  
All subjects in the cancer cohort signing informed consent and completing the study survey will 
receive compensation for participating.  
Potential participants will be asked questions to confirm their eligibility by a nurse navigator, 
study staff member, physician (see Appendix A), or via the patient web portal, to document 
screening including date of upcoming therapy or surgery for cancer patients if one has been 
scheduled, before providing informed consent to participate in the study.  Study procedures 
outside of the pre-screening for eligibility will not be performed prior to the subject providing 
consent.  Informed consent will be carried out in accordance with applicable federal regulations 
and International Council for Harmonisation (ICH)/Good Clinical Practice (GCP) guidelines. 
Prior to signing the informed consent form (ICF), potential participants will confirm that they 
understand the study and that they have no questions about the study. 
The ICF may be offered by paper, electronically, or via a secure web site, with the option to also 
review a paper copy provided by the nurse navigator or study coordinator either face-to-face on a 
tablet, via printing, or via email.  Potential participants will be given a phone number to call with 
any study specific questions.  Copies of all signed consent forms will be stored centrally in a 
secure environment, and signed consent forms will thereby be available for verification by 
Thrive or its designee at any time. 
Once the subject completes the survey, study staff will complete the blood draw and collect 
height and weight data. For some participants, their contact information and unique study 
identifier (ID) will be sent securely to a third-party vendor who will contact the subject within 24 
hours to schedule the blood draw and height and weight measurements at a location convenient 
to the subject.  
For all subjects, study staff and/or the third-party vendor performing the blood collection will 
verify the following before performing the blood draw and height and weight measurements: 
participant identity and age against a form of identification, that consent to participate has been 
given, that the participants in the cancer arm are still treatment naïve, and that they do not have a 
fever that could be caused by an infection.  The blood collection vendor or study staff will ensure 
all required data are captured and included with the blood sample, that the sample is collected 
and packaged according to laboratory manual specifications, and that the sample is shipped to 
the indicated processing lab with the required expediency.  Following all study visits, study staff 
and third party vendor or study staff will complete a visit checklist confirming all of the study 
activities that occurred.  
Subjects in the Cancer cohort will be identified via nurse navigation, study staff or oncology 
physicians in local offices.  The nurse navigator or study staff will verify eligibility through chart 

 
 
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review and pre-screen, approach the subject about the study opportunity, and present the 
informed consent form. For participants enrolling electronically, participants will be presented 
with a secured tablet device on which the subject will watch a brief video about the study, read 
the informed consent and provide electronic consent.  Some participants may also have the 
option of having the video, informed consent and survey emailed to them. Upon consent and 
enrollment, subjects will be assigned a unique subject study ID, which will be used to track the 
subject, their data and their biospecimen throughout study operations.  Consented subjects will 
then be directed to complete a survey via the tablet device, email or paper. Participants will be 
allowed to skip questions in the survey or select the answer option “prefer not to answer.”  
Subject data will be tracked in real-time by central study staff to ensure desired tumor type 
diversification and communicate enrollment strategy changes to the nurse navigators and study 
staff.  
To ensure inclusion of a heterogeneous group of cancer types and that breast and endometrial 
cancer patients are not overrepresented in the sample of cancer patients (NTotal = 1,000), we will 
limit enrollment of those tumor sites as shown in Table 1. Each cancer type should include a 
distribution of Stage I-IV.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6. 
BLOOD SAMPLE COLLECTION 
Subjects will have 6 (10 mL) biological samples (blood) collected in Streck circulating free DNA 
(cfDNA) tubes with a needle no larger than 21G.  Tubes will be filled completely and then 
immediately mixed by gentle inversion 8-10 times.  A temperature monitor is required to ensure 
the blood samples do not become too hot or cold as samples must be shipped at ambient 
temperature (43-99ºF, 6-37ºC).  Sample shipping instructions are detailed in the study operations 
manual.  
7. 
DATA COLLECTION  
Data from the non-cancer subjects (healthy volunteers) and cancer subjects will be self-reported 
for this study.  Where available, data from the medical records of the cancer subjects will reviewed 
and collected.  In addition, non-cancer subjects will be requested to allow access to their medical 
records.  These subjects will be asked to check and sign the optional section of the consent allowing 
access to their long-term outcomes data.   
The following demographic data will be collected from each subject (cancer and non-cancer):  
• 
Date of birth 
• 
Gender 
• 
Race 
• 
Ethnicity 
• 
Education 
• 
Family history of cancer 
• 
Family member(s) with cancer diagnosis 
• 
Current medications 
• 
Known comorbidities 
• 
Recent or current flare-up of inflammatory disease 
• 
Smoking status 
This set of data demographic data may expand based on emergent data. 
Additional data points will be collected from the cancer subjects.  These data points will include 
but are not limited to the following: 
• 
Cancer diagnosis at enrolment 
• 
Procedure used for cancer diagnosis 

 
 
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• 
Date of any cancer diagnosis 
• 
Cancer histology 
• 
Clinical staging 
• 
Pathological staging, where available 
 
Benefit/risk and ethical assessment 
There are no benefits for the subjects participating in the study. 
No test results will be provided to the Investigator or subject. 
Inclusion and exclusion criteria as well as study restrictions are chosen to ensure the selected 
subjects are exposed to minimal risk in this study. 
 
Study timetable and end of study 
The study is expected to start in 4th quarter of 2019. 
The end of the study is defined as the last visit of the last subject undergoing the study. 
8. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
This research study will be conducted according to the standards of GCP outlined in the ICH E6 
Tripartite Guideline and Code of Federal Regulations (CFR) Title 21 part 312, applicable 
government regulations, institutional research policies and procedures, and any other local 
applicable regulatory requirement(s). 
 
Institutional Review Board Approval 
The clinical study protocol and ICF will be submitted to the IRB for review and approval prior to 
study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to ensure 
appropriate, initial, and on-going IRB study review.  The Principal Investigator/Sponsor must 
submit and, where necessary, obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent document. Informed consent will be obtained 
using the method outlined above in Section 5.1. 
 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented by 
Sarah Cannon Health Economics and Outcomes Research (Outcomes).  All amendments require 
review and approval of the Principal Investigator/Sponsor supporting the study.  The written 
amendment must be reviewed and approved by Outcomes and submitted to the IRB at the 
Investigator’s facility for the board’s approval. 

 
 
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Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he has 
delegated study duties and should ensure that all persons assisting in the conduct of the study are 
informed of their obligations.  All persons authorized to make entries and/or corrections on the 
electronic case report forms (eCRFs) are to be included on this document.  All entries in the 
subjects’ eCRFs are to be supported by source documentation where appropriate.   
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the subjects’ eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, 
electrocardiogram (ECG) traces, copies or transcriptions certified after verification as being 
accurate and complete, photographic negatives, microfilm or magnetic media, x-rays, and 
correspondence. 
The Principal Investigator and study staff members are responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or Investigator study file 
[ISF]) of all essential study-related documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain at a minimum all relevant documents 
and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, including key 
documents such as the Investigator’s Brochure (IB) and any amendments, the protocol and any 
amendments, copies of completed eCRFs, IRB approval documents, subject identification lists, 
and enrollment logs.   
 
Data Management 
The Data Science team will work with the Sponsor and Investigator to provide operational 
definitions for each variable and the Data Manager will work with the appropriate subject matter 
experts (SME) to map these required variables to the appropriate data fields, ensuring their 
existence and completeness, and will design requirements for their collection.  Variables to be 
abstracted will be outlined and collected via study staff manually entering the data into the study 
electronic data capture EDC system or through automated direct transfer of electronic health record 
(EHR) data elements to the EDC system.  Requirements for the EDC eCRF will be identified, 
documented and developed under the oversight of Sarah Cannon Data Management. 
Innovations will monitor enrolled subjects – receiving both their EMR subject ID and unique study 
ID – and will ensure that other required study variables are abstracted from the subject records into 
the EDC.  A percentage of these cases will be reviewed in entirety for quality assurance, and 
monitoring of all collected data will be performed according to the agreed-upon Monitoring Plan. 
Quality-assured abstracted subject data will be merged with quality-assured subject survey data 
via unique subject ID to produce a final dataset.  

 
 
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Electronic Case Report Form 
The study eCRF is the primary data collection instrument for the study.  Case report forms will be 
completed using the English language and should be kept current to enable Outcomes to review 
the subjects’ status throughout the course of the study.   
In order to maintain confidentiality, only study number, subject number, and year of birth will 
identify the subject in the eCRF.  If the subject’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to Outcomes 
and be replaced instead with the subject number and other identifier (i.e., subject initials) as 
allowed per institutional policy.  The Investigator will maintain a personal subject identification 
list (subject numbers with corresponding subject identifiers) to enable records to be identified and 
verified as authentic.  Subject data/information will be kept confidential, and will be managed 
according to applicable local, state, and federal regulations. 
All data requested in the eCRF system must be supported by and be consistent with the subject’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the test was “Not Done” or the result was “Unknown.”  For 
any entry errors made, the error(s) must be corrected, and a note explaining the reason for change 
should be provided. 
The Investigator will electronically sign and date the subject eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the 
Principal Investigator, once all data for that subject is final. 
 
Confidentiality 
Confidentiality of subjects’ personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, in order to 
participate in the study, a subject must sign an authorization form for the study that he or she has 
been informed of the following: 
• What protected health information will be collected from subjects in the study; 
• Who will have access to that information and why; 
• Who will use or disclose that information; 
• The health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed, the information may no longer be protected by federal 
or state privacy laws; 
• Whether the authorization contains an expiration date; 
• The rights of a research subject to revoke his or her authorization. 
In the event that a Subject revokes authorization to collect or use his or her personal health 
information (PHI), the Investigator retains the ability to use all information collected prior to the 
revocation of authorization.    

 
 
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The Investigator and institution must permit authorized representatives of Outcomes, Innovations, 
applicable regulatory authorities and the IRB to review the subject’s original medical records for 
verification of trial-related procedures and data.  
 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right to 
release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the study design, the analysis or interpretation of data, or the drafting 
and/or critically revising of any manuscript(s) derived from the study.   
9. 
STATISTICAL ANALYSIS 
The primary objective of the study is to collect clinically annotated peripheral blood specimens 
from subjects with confirmed cancer and subjects with no known cancer (healthy volunteers) to 
develop and validate the classification algorithm used by the CancerSEEK cancer screening test. 
The primary endpoint is the assay’s ability to effectively discriminate cancer from non-cancer as 
measured by the full confusion matrix, including sensitivity, specificity, and PPV. 
 
 
 
 
 
Determination of sample size 
Given the exploratory nature, no formal statistical analysis will be performed in this study.  The 
statistical analysis will be descriptive and consist of subject listings, graphs, and summary statistics 
comprising geometric mean, arithmetic mean, standard deviation (SD), median, minimum (min) 
and maximum (max) values as appropriate. 
The overall study aims to consent 5,300 subjects (1,000 confirmed cancer subjects, 4,300 non-
cancer). 
 
Subject characteristics 
Demographic and baseline characteristic data will be recorded.  Demographic data will include 
date of birth, age, sex, race and ethnicity.  Subject characteristics, cancer history, family history, 
and baseline data will include smoking details (quantity and duration of smoking history).  

 
 
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10. 
SAFETY REPORTING AND ANALYSES 
The Principal Investigator is responsible for recognizing and reporting serious adverse events 
(SAEs) to the Innovations Safety Department.  It is the Sponsor’s responsibility to report relevant 
SAEs to the applicable national regulatory bodies.  In addition, the Principal Investigator must 
report SAEs and follow-up information to the responsible IRB according to the policies of that 
IRB.  
The Principal Investigator is also responsible for ensuring that every staff member involved in the 
study is familiar with the content of this section. 
 
Definitions   
 
Serious Adverse Events 
Each SAE must be assessed for severity and intensity using the following classification guidelines: 
Mild: Awareness of a sign or symptom that does not interfere with the subject’s usual activity or 
is transient, resolved without treatment and with no sequelae. 
Moderate: Interferes with the subject’s usual activity and/or requires symptomatic treatment. 
Severe: Symptom(s) causing severe discomfort and significant impact on the subject’s usual 
activity and requiring treatment. 
 
Relatedness 
An SAE should be considered definitely related if, in the opinion of the Investigator, the study 
procedure caused or contributed to the SAE.  The initial assessment may be revised as new 
information becomes available. 
Related: there is a reasonable relationship to study application 
Unrelated: there is not a reasonable relationship to the study application 
Unknown: there is no clear or compelling evidence that the event is or is not due to the study 
application   
 
Definitions of serious adverse event 
An SAE is an adverse event occurring during any study phase that fulfills one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening (e.g. subject cannot breathe) 
• Requires in-subject hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.  Examples of these would include: 
angioedema not severe enough to require intubation but requiring IV hydrocortisone 

 
 
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treatment, intensive treatment in an emergency room or at home for allergic bronchospasm, 
or convulsions that do not result in hospitalization. 
 
Recording of serious adverse events 
All SAEs whether volunteered by the subject, discovered by study personnel during questioning, 
or detected through other means will be reported appropriately.    
 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the study procedure(s).  
All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel must 
inform appropriate Innovations Safety Department representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it. 
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to Innovations Safety Department via fax or e-mail using the 
following contact information (during both business and non-business hours): 
 
Sarah Cannon Innovations Safety Department 
Safety Dept. Fax #:      
 
Safety Dept. Email:     
 
Transmission of the SAE report should be confirmed by the site personnel submitting the report, 
and a copy of the confirmation should be retained with the subject’s records. 
The Principal Investigator must report SAEs and follow-up information to the responsible IRB 
according to the policies of the responsible IRB. 
 
Recording of Serious Adverse Events 
 
Diagnosis versus Signs and Symptoms 
All SAEs should be recorded individually in the subject’s own words (verbatim) unless, in the 
opinion of the Principal Investigator, the SAEs constitute components of a recognized condition, 
disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be named 
rather than each individual sign or symptom.  If a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an SAE as appropriate on the SAE Report Form.  If a 
diagnosis is subsequently established, it should be reported as follow-up information is available.  
If a diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
 
Persistent or Recurrent Adverse Events 
A persistent SAE is one that extends continuously, without resolution, between subject evaluation 
time points.  Such events should only be recorded once on the SAE Report Form.  If a persistent 

 
 
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SAE becomes more severe or lessens in severity, it should be recorded on a separate SAE Report 
Form. 
A recurrent SAE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs.  All recurrent SAEs should be recorded on an SAE Report Form. 

 
 
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11. 
REFERENCES 
 
Cohen et al 2018 
Cohen et al 2018. Detection and localization of surgically resectable cancers with a multi-analyte 
blood test.  Science. 2018;359:926-30.  
 
Diaz and Bardelli et al 2014 
Diaz LA and Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 
2014;32:579-86. 
 
Kalinich et al 2018 
Kalinich M and Haber D. Cancer detection: seeking signals in blood. Science. 2018;359:866-867. 
 
Siegel et al 2019 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019.  CA Cancer J Clin. 2019;69:7-34. 
 
 
 
 

 
 
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Appendix A 
Screening & Survey Questions 
SURVEY QUESTIONS  
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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___ Uterine cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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