COMET - Communication and Education in Tumor Profiling: A Randomized Study of Pre-Disclosure Genetic Education v. Usual Care in Tumor Profiling for Advanced Cancer and a Pilot Study of Remote Genetic Counseling for Participants With Potential Germline Mutations Identified on Tumor Profiling
Phase: NA
Conditions: Advanced Malignant Neoplasm, Locally Advanced Malignant Neoplasm
Sponsor: ECOG-ACRIN Cancer Research Group

 
EAQ152 
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COMET - Communication and Education in Tumor Profiling: 
A Randomized Study of Pre-disclosure Genetic Education v. 
Usual Care in Tumor Profiling for Advanced Cancer and a Pilot 
Study of Remote Genetic Counseling for Participants with 
Potential Germline Mutations Identified on Tumor Profiling 
STUDY CHAIR: Angela R. Bradbury, MD 
STUDY STATISTICIANS: Ju-Whei Lee, PhD 
Shuli Li, PhD 
STUDY CO-CHAIR: Lynne Wagner, PhD 
MATCH STUDY CHAIR: Keith Flaherty, MD 
STUDY EPIDEMIOLOGIST: Ilana F. Gareen, PhD 
CANCER CARE DELIVERY RESEARCH (CCDR) 
COMMITTEE CHAIR: 
 
Ruth C. Carlos, MD 
CANCER CONTROL AND SURVIVORSHIP 
COMMITTEE CHAIR: 
 
Lynne Wagner, PhD 
Version Date:  May 14, 2019 
STUDY PARTICIPANTS 
ACTIVATION DATE 
Step 1: Primary Intervention Study - RCT of Web-based 
Pre-disclosure Genetic Education v. Usual Care 
September 26, 2016 
PRE-ACTIVATION DATE 
 
August 15, 2016 
US Sites Only 
Addendum #1 – Prior to Activation 
SWOG / SWOG 
Addendum #2 – 2/17 
NRG / NRG Oncology 
Addendum #3 – 7/17 
ALLIANCE / Alliance for Clinical Trials in Oncology 
Addendum #4 – 12/17 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
Addendum #5 
COG / Children's Oncology Group 
Addendum #6 
 
Addendum #7 
Select Non-MATCH Expansion Sites: Please see Section 
4.1.4.5 for more information. 
 
 
 
Step 2: Secondary Genetic Counseling Substudy - 
 
Genetic Counseling for Incidental Germline Findings 
 
 
 
US Sites Only 
 
Select Participating Institutions: Please see Section 
4.2.3.2 for detailed instructions and requirements. 
 
NOTE: As of 11/17, all protocol changes will be noted 
by addendum number. Please reference the 
activation memo for the addendum activation 
date. 
 
 
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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 8 
1.1 
Study Overview ......................................................................................... 8 
1.2 
Hypotheses ................................................................................................ 8 
1.3 
Background ............................................................................................... 8 
1.4 
Summary and Rationale for the Study .................................................... 11 
1.5 
Current Supporting Data ......................................................................... 13 
2. Objectives ......................................................................................................... 16 
2.1 
Primary Objectives .................................................................................. 16 
2.2 
Secondary Objectives .............................................................................. 16 
2.3 
Exploratory Objectives ............................................................................ 16 
3. Selection of Patients ......................................................................................... 18 
3.1 
Eligibility Criteria (Step 1) - Primary Intervention Study (RCT): .............. 18 
3.2 
Eligibility Criteria (Step 2) - Secondary Genetic Counseling Substudy: ... 19 
4. Registration Procedures .................................................................................... 21 
4.1 
Step 1 - Primary Intervention Study (RCT) Registration .......................... 23 
4.2 
Step 2 - Secondary Genetic Counseling Substudy Registration .............. 29 
4.3 
Instructions for Patients who Do Not Complete Baseline Survey and/or 
Do Not Start Assigned Study Intervention .............................................. 31 
5. Methodology ..................................................................................................... 32 
5.1 
Randomization ........................................................................................ 32 
5.2 
Interventions ........................................................................................... 32 
5.3 
Patient Recruitment ................................................................................ 35 
5.4 
PRO/QOL Data Collection Process .......................................................... 35 
5.5 
Study Instruments ................................................................................... 36 
5.6 
Survey Assessment Schedule: ................................................................. 39 
5.7 
Duration of Participation: ....................................................................... 39 
5.8 
Duration of Follow-up ............................................................................. 39 
6. Study Parameters .............................................................................................. 40 
6.1 
Step 1 - Primary Study Intervention: RCT – Arms A & B ......................... 40 
6.2 
Step 2 – Secondary Genetic Counseling Substudy – Arm D and Arm E .. 42 
7. Statistical Considerations .................................................................................. 43 
7.1 
Primary Study: Randomized Study of Web-based Pre-disclosure Genetic 
Education versus Usual Care (Step 1 – Arms A & B) ............................... 43 
7.2 
Secondary Germline Genetic Testing & Counseling Substudy (Step 2 – 
Arm D and Arm E) ................................................................................... 48 
7.3 
Gender and Ethnicity .............................................................................. 49 

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8. Electronic Data Capture .................................................................................... 51 
9. Patient Consent and Peer Judgment ................................................................ 51 
10. References ........................................................................................................ 51 
Appendix I  Patient Thank You Letter ...................................................................... 56 
 

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STUDY CHAIR 
ECOG-ACRIN STUDY CO-CHAIR 
Angela R. Bradbury, MD 
Department of Medicine, 
Hematology/Oncology 
Department of Medical Ethics and Health Policy  
Perelman School of Medicine  
at the University of Pennsylvania  
3 West Perelman Center 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Phone: 215-615-3341 
Fax: 215-615-3349 
E-mail: angela.bradbury@uphs.upenn.edu 
 
Lynne I. Wagner, Ph.D. 
Department of Social Sciences and Health Policy 
Division of Public Health Sciences 
Wake Forest University School of Medicine 
Medical Center Boulevard 
Winston Salem, NC 27151 
Phone: (336) 713-1478 
Fax: (336) 716-7554 
E-mail: lywagner@wakehealth.edu 
 
MATCH STUDY CHAIR 
STUDY EPIDEMIOLOGIST 
Keith Flaherty, MD 
Massachusetts General Hospital 
55 Fruit Street, Yawkey 9E 
Boston, MA 02114 
Phone: 617-726-4800 
Fax: 617-724-6898 
E-mail: kflaherty@partners.org 
 
Ilana F. Gareen, Ph.D. 
Center for Statistical Sciences 
Brown University, Box G-S121-7 
Providence, RI 02912 
Phone: (401) 863-1758 
Fax: (401) 863-9182 
E-mail: igareen@stat.brown.edu 
 
STUDY CHAIR LIAISON (SCL) 
COMET TEAM ALIAS 
Jill Bennett Gaieski, PhD, JD 
Department of Medicine 
Hematology/Oncology 
Perelman School of Medicine  
at the University of Pennsylvania 
3260 Hamilton Walk, Anatomy Chemistry B23 
Philadelphia, PA 19104 
Phone: 215-573-9660 
E-mail: jill.bennettgaieski@uphs.upenn.edu 
 
COMETstudy@uphs.upenn.edu 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
through Medidata Rave 
and the ECOG-ACRIN 
Systems for Easy Entry 
of Patient Reported 
Outcomes (EASEE-
PRO) system. Please 
see the data submission 
section of the protocol 
for further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
Step 1, Arm A:
Pre-disclosure on-line 
genetic education;
Post-education survey 
(T1): 1-2 weeks after 
completion of T0
1. Select expansion sites only: See Section 4.1.4.5 for more information. 
2. Stratification Factors:
a. Gender: Male vs. Female
b. Race: White vs. Others
c. Age: < 65 vs. > 65 years
d. Education level: No College vs. College vs. Professional/Graduate
3. If patient is eligible for COMET Step 2 (secondary genetic counseling substudy) based on their testing results and the eligibility criteria, they can also continue on to participate in Step 2 in parallel with Step 1. 
The 3 month survey (T3) for Step 1 will still be requested, even if Step 2 is pursued.
S
T
E
P
1
R
E
G
I
S
T
R
A
T
I
O
N
Patient consented to 
COMET RCT.
Patient enrolled in 
MATCH screening (Step 
0), and proceeded with 
biopsy and molecular 
profiling 
OR 
Patient will be receiving 
molecular profiling 
outside of MATCH at 
select expansion sites1
Screening participant 
(patient) receives 
treatment assignment 
results and/or tumor 
molecular profile results 
from their research/clinical 
team/treating physician
Post-disclosure 
survey (T2):
Within 3 days 
from receipt of 
results
Accrual Goal (Primary On-line Genetic Education Study): 670
B
L
I
N
D
E
D
R
A
N
D
O
M
I
Z
A
T
I
O
N2
Step 1, Arm B:
Usual care;
Post-education survey 
(T1): 1-2 weeks after 
completion of T0
Complete 
Baseline Survey 
(T0)
3 month survey (T3)3:
3 months after receipt of 
results
Usual care (Arm B) 
participants provided 
access to on-line genetic 
education
Step 1 - Primary On-line Genetic Education Study (RCT)
Additional participation 
in the secondary 
genetic counseling 
substudy3
See Step 2 schema 
(ii) on the following 
page
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Step 2 Registration:
Arm D:
Step 1 Arm A or Arm 
B participants
Arm E:
Step 1 Arm C 
Participants
4. Select Participating Institutions Only: See Section 4.2.3.2 for instructions and requirements. 
5. Please note, per Section 3.2.1.1, patients entering the study via an expansion site (see footnote #1 in the Step 1 schema) are only eligible for Step 2 if they participated in Step 1. They are 
not eligible for Step 2 via this path, without any prior participation in the study.
6. GC = genetic counseling
7. SS = substudy
Patient participating in 
COMET RCT (Step 1: 
on-line genetic 
education) is interested 
in pursuing Step 2 after 
receiving their tumor 
testing results.
Remote GC Visit 
1; Post V1 survey 
(T1SS):
Within 3 days of 
GC Visit 1
Accrual Goal (Secondary Genetic Counseling Study): 100
Step 1, Dummy
 Registration (Arm C)
For patients who did 
not participate in the 
primary on-line 
genetic education 
study (Arms A & B)
Screening participant 
(patient) receives 
tumor molecular profile 
results (report of any 
actionable mutations) 
from their treating 
physician.
Step 2 - Secondary Genetic Counseling Substudy4
ii
Patient meets criteria for 
potential actionable germline 
mutation based on their 
testing results, and other 
eligibility requirements.
Patient consents to GC6 
Substudy
Patient declined to 
participate in COMET 
RCT (Step 1: on-line 
genetic education 
study).5
Patient consented and 
enrolled to Step 0 of 
MATCH, and proceeded 
with biopsy and 
molecular profiling
Patient meets 
criteria for 
potential 
actionable 
germline 
mutation based 
on their testing 
results, and other 
eligibility 
requirements.
Patient consents 
to GC Substudy
Baseline survey (T0SS7):
For Arm D participants - 
Limited items (T0SS pre-
populated with T2 
information)
For Arm E participants - 
Baseline survey
3 month survey 
(T3SS):
3 months after GC 
Visit 2
If patient agrees to 
confirmatory 
testing:
GC Visit 2;
Post V2 survey 
(T2SS):
Within 3 days of 
GC Visit 2
 

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1. 
Introduction 
1.1 
Study Overview 
The Communication and Education in Tumor Profiling (COMET) study consists of 
two major components, divided into two steps, each occurring by itself or 
sequentially. Only a subset of participants and select sites will participate in the 
Secondary Genetic Counseling Substudy. 
1. Primary Intervention Study – Randomized Clinical Trial (RCT) of Web-based 
Pre-disclosure Genetic Education v. Usual Care (Step 1) 
A randomized substudy of pre-disclosure genetic education v. usual care in 
tumor profiling for advanced cancer  
2. Secondary Genetic Counseling Substudy - Genetic Counseling for Incidental 
Germline Findings (Step 2) 
A pilot substudy of remote genetic counseling for participants with potential 
germline mutations identified on tumor profiling 
1.2 
Hypotheses 
1. The provision of web-based genetic education prior to receipt of tumor 
profiling results will be associated with greater increases in genetic 
knowledge and less increase in distress (Primary Intervention Study : RCT) 
2. Participant factors, suggested by the Self-Regulation Theory of Health 
Behavior (SRTHB; e.g. test result, sociodemographic factors, health literacy, 
baseline knowledge or distress) will identify subgroups of patients who benefit 
more or less from the intervention (web-based pre-disclosure genetic 
education). (Primary Intervention Study: RCT) 
3. The majority of participants with potential incidental germline mutations 
identified through tumor profiling will be willing to participate in: a) remote 
genetic counseling and b) genetic testing for potential germline mutations. 
(Secondary Genetic Counseling Substudy) 
4. The uptake of remote counseling and testing among advanced cancer 
patients with potential germline incidental findings will be associated with 
patient factors (e.g. distress, uncertainty, family history, etc.) predicted by the 
Self-Regulation Theory of Health Behavior (SRTHB).  Additionally, we 
hypothesize that remote pre- and post-test counseling with a genetic 
counselor will be associated with increases in knowledge, decreases in 
uncertainty and distress and increases in communication to at-risk relatives. 
(Secondary Genetic Counseling Substudy) 
1.3 
Background 
1.3.1 
Primary Intervention Study (RCT): 
How and when to best communicate limitations of tumor profiling and 
the potential for incidental findings is unknown.  Cancer has long been 
recognized as a genetic disease, driven and sustained by the 
accumulation of alterations in genes that code key signaling 
pathways41-43. With the advent of next-generation sequencing (NGS), 
in which multiple genes, even the entire genome, can be sequenced 
rapidly and at relatively accessible costs, we have entered an era of 
precision cancer care3,43,44. We can now readily identify numerous 
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acquired genetic aberrations in tumors, which can be used to identify 
targeted therapies with the hopes of improving patient outcomes44. 
The implementation of NGS in cancer care has raised a range of 
practical, ethical, and legal challenges for patients, providers, and the 
health care system as a whole1,2.  As we move from “discrete” tests 
(e.g., single-gene or single-marker tests) to “bundled” (targeted 
sequencing of a panel of cancer genes) or “broad” tests (e.g., whole-
exome or whole-genome sequencing), there is an increasing 
possibility of increasing confusion, distress or disappointment given 
the limitations of our current knowledge13,46. Equally important, tumor 
profiling has the potential to identify incidental germline findings2,3,4. In 
small qualitative studies, patients have reported confusion between 
somatic and germline testing and 71% reported potential psychosocial 
risks including unwanted information, germline implications for 
relatives and the potential for loss of hope with no actionable or 
targeted mutations based on testing13.  Additionally, many patients 
have high expectations of benefit with tumor profiling and some 
experience disappointment if there are no actionable mutations are 
identified14. Additionally, while many patients report interest in 
incidental germline findings, some patients identify this as an 
additional burden, given a diagnosis of advanced cancer14. These 
studies highlight the potential risks and limitations associated with 
clinical implementation of tumor profiling in advanced cancer patients 
and the need to further understand patient outcomes and delivery 
models to enhance the benefits and minimize the risks of tumor 
profiling in cancer care4. 
Pre-disclosure (i.e. prior to the disclosure of test results to patients) 
genetic education has the potential to improve understanding, 
minimize negative responses to receipt of tumor molecular profile 
results and identification of incidental germline findings.  How to best 
address these clinical challenges to benefit patients and their families 
remains unknown. The traditional approach to informed consent for 
germline genetic testing has been to share the risks, benefits and 
limitations of testing with patients prior to testing and to honor their 
preferences for receipt genetic information*. Recent guidelines from 
the Presidential Commission for the Study of Bioethical Issues and 
the American College of Medical Genetics suggest that the potential 
to identify incidental findings with tumor profiling be shared with 
patients in advance of testing so that they can consider and share 
their preferences for receipt of incidental germline information1,7. Yet, 
how to achieve this remains unknown, and there is pressing need for 
empiric studies to evaluate communication and delivery strategies1,4. 
Traditional provider-mediated genetic counseling is not feasible for 
every patient undergoing tumor profiling for therapeutic intent. Thus, if 
pre-disclosure education is required, alternative scalable models for 
provision of education and assessment of preferences will be needed 
as tumor profiling is widely adopted for the care of cancer patients. 
In some settings the frequency of incidental findings may be relatively 
low4. For example, in the setting of tumor only sequencing (i.e. rather 
than paired tumor and germline platforms) a potential germline finding 

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may be identified but secondary germline confirmation would be 
necessary.  This provides a second opportunity to assess patient 
preferences for germline findings. In this proposal, we hypothesize 
that pre-disclosure genetic education in this setting will improve 
understanding of germline implications and other risks, benefits and 
limitations of tumor profiling and reduce distress and uncertainty. 
Nonetheless, it remains possible that providing extensive genetic 
education and counseling at pre-disclosure may be overwhelming or 
lack salience for patients, and could even be associated with greater 
confusion and potential distress. Thus, we propose a randomized 
study to evaluate the relative advantages of on-line pre-disclosure 
education compared to usual care in order to address the pressing 
need for empirical studies to evaluate how to best communicate and 
deliver cancer genetic education and counseling in the setting of 
tumor profiling. 
1.3.2 
Secondary Genetic Counseling Substudy: 
How to best address incidental germline findings in the setting of 
clinical tumor profiling remains unknown.  The implementation of NGS 
in cancer care has raised a range of practical, ethical, and legal 
challenges for patients, providers, and the health care system as a 
whole1,2.  One of the most pressing challenges in the field is how to 
address incidental or secondary germline findings identified in 
advanced cancer patients undergoing tumor profiling for therapeutic 
intent2-4. Studies have shown that patients undergoing sequencing for 
therapeutic intent differ in their preferences for secondary germline 
information5,6. Obligations to intentionally interrogate germline data to 
return incidental findings in potential clinically important germline 
mutations (e.g. germline mutations with established clinical utility) 
remain uncertain. In recent clinical guidelines, the ACMG argued that 
laboratories intentionally seek and report clinically important germline 
findings in a list of detected gene mutation results7. Such an obligation 
to seek clinically important germline findings in the setting of tumor 
profiling has been debated, but there is a growing consensus that 
patients (in research and clinical settings) should be informed about 
the potential for incidental or secondary germline findings and that 
their preferences for these should be honored1,8-10. Yet, how to 
accomplish this in clinical patient care, and particularly in the setting of 
advanced cancer patients undergoing tumor profiling to inform 
therapeutic decisions remains unknown. Many have highlighted that 
additional research to evaluate outcomes and delivery models 
designed to honor preferences is crucial to this ongoing debate and 
the implementation of tumor profiling1,8,11. 
While the potential for germline findings has been greatly debated, 
many practicing clinicians are utilizing tumor profiling but report 
variable confidence in their genetic knowledge12. Additionally, there is 
variability in how clinicians describe tumor profiling and how frequently 
they discuss potential germline implications is unknown4,12. In small 
qualitative studies, patients have reported confusion between somatic 
and germline testing and 71% reported potential psychosocial risks 
including unwanted information, germline implications for relatives and 
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the potential for loss of hope with negative tumor profiling13.  
Additionally, while many patients report interest in incidental germline 
findings, some patients identify this as an additional burden, given a 
diagnosis of advanced cancer14. These studies highlight the need to 
both develop clinical care models which assist practicing physicians to 
facilitate identification of patients who may be candidates for further 
germline testing and to further evaluate how to best honor patient 
preferences for incidental or secondary germline information and the 
outcomes of identifying incidental germline findings among patients 
undergoing tumor for sequencing for therapeutic intent. 
In light of the clear gap in knowledge concerning the risks for returning 
potential germline findings, any effort to provide this kind of 
information to patients should only be undertaken by an experienced 
team of genetic providers. Our team has experience with remote 
cancer genetic counseling with community sites in a NCI funded 
feasibility study (R21 CA164121: Bradbury, Bradbury et al. Utilizing 
remote real-time videoconferencing to expand access to cancer 
genetic services in community practices, JMIR, in press, 2015), and 
additional community sites in an ongoing randomized study of remote 
counseling v. usual care for cancer genetic testing (funded through 
the Basser Center for BRCA1/2 Research). These studies include 
both patients without cancer and patients with advanced cancer, 
specifically patients with metastatic breast cancer. Thus, the PENN 
telegenetic counselors have clinical experience counseling patients 
with advanced cancer at community sites and are sensitive to the 
unique issues facing patients with advanced cancer undergoing tumor 
profiling. Further, counseling patients with potential germline findings 
is within the scope of cancer genetic counseling practice.  
Additionally, the cancer genetics team at PENN has experience with 
cancer genetic counseling for patients with potential germline findings 
in tumor profiling both through COMET pilot work in metastatic breast 
cancer patients and other clinical tumor profiling, The PENN cancer 
genetics team and weekly case conference will be an additional 
resource for the genetic counselors participating in the COMET 
remote counseling substudy. 
1.4 
Summary and Rationale for the Study 
The study has been designed to address the need for empirical studies to 
evaluate how to best communicate and deliver cancer genetic education and 
counseling in the setting of tumor profiling.  
1.4.1 
Primary Intervention Study - RCT of Web-based Pre-disclosure 
Genetic Education v. Usual Care for Patients Undergoing Tumor 
Profiling for Cancer Treatment (Step 1): 
The proposed randomized study will evaluate the utility of a scalable 
web-based pre-disclosure genetic education compared to the current 
usual care communication prior to receipt of tumor profile results. If 
this pre-disclosure education model successfully improves cognitive 
and affective responses to tumor profiling, it has the potential to be 
widely implemented in clinical care to benefit advanced cancer 
patients and their families. Given that COMET will recruit cancer 
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patients with a wide spectrum of tumor types and in both academic 
and non-academic centers, the web-based intervention and findings 
are expected to be broadly applicable to the advanced cancer 
population. 
Additionally, secondary analyses evaluating groups that benefit more 
and less from the intervention will provide crucial data to enhance the 
intervention for future use in clinical practice. Even if the study finds 
no difference between intervention groups, these secondary analyses 
are likely to identify subgroups of patients who may benefit more from 
the intervention, or alternative modifications or interventions to 
maximize the benefits and minimize the risks associated with 
widespread clinical adoption of tumor profiling in cancer care. Thus, 
we expect this work to be highly relevant to clinical practice. 
1.4.2 
Secondary Genetic Counseling Substudy - Genetic Counseling for 
Incidental Germline Findings (Step 2): 
The proposed genetic counseling substudy will evaluate the feasibility 
and preliminary outcomes of remote genetic provider mediated 
counseling for the subset of patients with potential germline mutations 
incidentally identified through molecular tumor profiling.  If successful, 
this substudy will provide key preliminary data to support further 
research evaluating delivery models for potential incidental germline 
findings. While this may include remote counseling to provide access 
to genetic counselors for the subset of patients with incidental 
germline findings where additional germline testing is indicated, given 
a limited genetic counselor workforce and the anticipated broad 
application and use of tumor profiling in cancer care, alternative 
scalable models will need to be evaluated. These could include web-
based delivery that could be combined with provider mediated 
counseling in select cases.  
The proposed substudy seeks to evaluate patient preferences for, and 
outcomes of genetic counseling and testing in the setting of the 
identification of potential incidental germline findings, which are key 
first steps to developing scalable delivery models for the future. In 
related work and the proposed COMET randomized study of pre-
disclosure genetic education, we have experience adapting provider 
mediated counseling and education to on-line patient-mediated 
delivery, providing expertise for the proposed subsequent research. 
As an example, in the ongoing RESPECT study (R01-
CA190871:Bradbury/Patrick-Miller), we have adapted provider-
mediated tiered-binned pre-disclosure counseling for return of 
individual research results to an on-line genetic education followed by 
remote counseling with a genetic counselor at the time of result 
disclosure to address patient burdens associated with in-person visits. 
The ongoing multi-site RESPECT study will evaluate the outcomes of 
receipt of individual germline research results with this alternative 
delivery model. Thus, this genetic counseling substudy and the 
anticipated subsequent work are expected to contribute significantly to 
the ongoing debate over how to best communicate and deliver genetic 

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information with the delivery of tumor profiling in cancer care and how 
to honor patient preferences for incidental germline information. 
1.5 
Current Supporting Data 
1.5.1 
Primary Intervention Study - RCT of Web-based Pre-disclosure 
Genetic Education v. Usual Care (Step 1): 
To address the need for empirical studies to evaluate how to best 
communicate and deliver cancer genetic education and counseling in 
the setting of tumor profiling, we have been conducting a pilot study of 
pre-disclosure genetic education delivered by a health educator 
among breast cancer patients undergoing tumor profiling on a related 
clinical trial (COMET Pilot Study). This genetic education is designed 
to educate patients regarding the benefits, risks and limitations of 
tumor profiling for cancer treatment, including the potential for 
incidental germline findings, which would need to be confirmed 
through additional germline genetic testing. In related studies 
evaluating germline multiplex testing for cancer susceptibility (R01 
CA160847:Bradbury; R01-CA190871:Bradbury/Patrick-Miller), we 
have developed a novel tiered binned approach to genetic counseling 
and informed consent to address the increasing complexity of genetic 
testing in the era of multiplex and whole genome sequencing15,44,46. 
We have adapted the tiered binned approach for genetic education in 
the setting of tumor profiling for advanced breast cancer given the 
complexity of information and the need for efficient education in the 
setting of patients undergoing active treatment and testing for 
treatment decisions. 
The goals of the COMET pilot study are:  
1. To obtain patient feedback and conduct audiotape review of 
session to inform modifications to our  tiered binned genetic 
education for tumor profiling and  
2. To obtain preliminary outcome data to inform future studies 
evaluating outcomes of genetic education and counseling delivery 
models in the setting of tumor profiling. 
While the original education was delivered via a health educator, this 
approach was chosen to maximize patient feedback regarding key 
elements and content. We had originally envisioned that it could be 
adapted for delivery by alternative modalities (e.g. print, web), if 
acceptable to patients. As an example, in the ongoing RESPECT 
study (R01-CA190871:Bradbury/Patrick-Miller), we have adapted 
provider-mediated tiered-binned pre-disclosure counseling for return 
of individual research results to an on-line genetic education followed 
by remote counseling with a genetic counselor at the time of result 
disclosure to address patient burdens associated with in-person visits. 
The ongoing multi-site RESPECT study will evaluate the outcomes of 
receipt of individual germline research results with this alternative 
delivery model. 
To date, 25 breast cancer patients have enrolled in the COMET pilot 
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surveys. 14 have received results and have completed post-
disclosure surveys. 
Key preliminary findings relevant to this proposal include: 
1. Many patients reported a limited understanding of the difference 
between germline and somatic genetics and the limitations of 
tumor profiling (e.g. the potential for no druggable targets). 
2. Participants reported greater interest in web-based administration 
as an alternative to provider-mediated counseling than print 
materials. Patients reported advantages to web-based education 
included convenience, the ability to revisit information, faster 
access and the individual ability to select information to view. 
Many reported no disadvantages to a web-based alternative, while 
some identified losing the personal interaction, getting confused or 
not knowing what to view on a website. 
3. Preliminary data suggests pre-disclosure genetic education may 
be associated with increases in knowledge and decreases in 
depression and general and state anxiety from baseline to post-
disclosure. 
In this pilot, there was no comparison arm, so changes in these 
outcomes need to be evaluated in a randomized study. 
1.5.2 
Secondary Genetic Counseling Substudy - Genetic Counseling for 
Incidental Germline Findings (Step 2): 
In four NIH and foundation funded studies, we have been evaluating 
telephone and real-time videoconferencing counseling as alternative 
delivery models to increase the efficiency and improve access to 
genetic providers (R01 CA160847:Bradbury; R21-CA-
164121:Bradbury) and for return of individual genetic research results 
(R01-CA190871:Bradbury/Patrick-Miller Conquer Cancer Foundation 
Advanced Clinical Research Award: Bradbury). These studies have 
established that remote counseling is a feasible alternative for further 
evaluation15-17. Benefits include expanded patient access to services 
and centralized provider expertise, particularly in the setting of a 
limited genetic counselor workforce. Communication protocols utilized 
in these ongoing studies will be adapted for use in the proposed 
genetic counseling substudy. 
As described above, in our related studies utilizing telephone and 
videoconferencing to provide more efficient and accessible genetic 
services, particularly in populations where genetic providers are not 
available, we have found remote counseling to be feasible, acceptable 
to patient and providers and associated with increases in genetic 
knowledge and comparable affective outcomes to in-person 
counseling.  Two recent randomized studies evaluating germline 
testing for BRCA1/2 have reported similar findings39,40. Given related 
ongoing research and clinical activities in telegenetics, our genetic 
counselors are already licensed in several states with plan for 
licensure across over 20 states (Alzheimer’s Prevention Initiative 
APOE4 Trial. 1UF1AG046150-01: Reiman. A randomized substudy of 
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Thus, genetic provider licensure is not anticipated to be a barrier to 
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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
Primary Intervention Study: RCT (Step 1) 
To evaluate the efficacy of web-based pre-disclosure genetic 
education (i.e. before receipt of tumor profile results) to:  
a) Increase knowledge (genetic knowledge and knowledge of test 
benefits and limitations) 
b) Decrease distress (anxiety, depression and cancer specific worry) 
compared to usual care services in patients undergoing tumor 
profiling for advanced cancer 
2.1.2 
Secondary Genetic Counseling Substudy (Step 2) 
To evaluate the uptake of: 
a) Remote genetic counseling  
b) Germline testing among advanced cancer patients with a 
potential clinically significant incidental germline mutation 
identified through tumor profiling 
2.2 
Secondary Objectives 
2.2.1 
Primary Intervention Study: RCT (Step 1) 
To evaluate potential moderators suggested by the SRTHB (e.g test 
result, sociodemographic factors, health literacy, baseline knowledge 
or distress) to changes in:  
a) Knowledge of genetic disease and test benefits and limitations 
b) Distress in patients undergoing tumor profiling for advanced 
cancer 
2.2.2 
Secondary Genetic Counseling Substudy (Step 2) 
To evaluate: 
a) Factors associated with uptake of genetic counseling and 
germline testing 
b) Cognitive and affective responses to confirmatory germline testing 
in advanced cancer patients with potential clinically significant 
incidental germline mutation identified in tumor profiling. 
2.3 
Exploratory Objectives 
2.3.1 
Primary Intervention Study: RCT (Step 1) 
To explore: 
a) Satisfaction and regret/disappointment related to tumor genetic 
test results 
b) How to better deliver tumor genetic test results and germline 
information in the future 
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2.3.2 
Secondary Genetic Counseling Substudy (Step 2) 
To explore: 
a) Behavioral responses (communication to others) to confirmatory 
germline testing in advanced cancer patients with potential 
clinically significant incidental germline mutation identified in tumor 
profiling 
b) Satisfaction and regret/disappointment related to genetic 
counseling service or germline genetic test results 
 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria (Step 1) - Primary Intervention Study (RCT): 
3.1.1 
Patients must be registered to the first screening step (Step 0) for the 
NCI-MATCH trial (EAY131) OR must be having tumor profiling for 
advanced cancer performed at or ordered by one of the select 
expansion sites described in Section 4.1.4.5. 
3.1.2 
Patients must speak English. 
NOTE: 
The restriction to English-speaking participants is based on 
the challenges encountered in creating and/or translating 
web content for the Primary Intervention Study. 
3.1.3 
Patients must have web and e-mail access. 
NOTE: 
The restriction to those with web and e-mail access is 
based on funding constraints for the costs associated with 
paper-based surveys. 
3.1.4 
Patients in the MATCH trial must have not received his/her MATCH 
tumor genetic test results to be eligible to participate in COMET’s 
RCT. Non-MATCH expansion site patients must have not received 
his/her results from tumor profile genetic testing to be eligible to 
participate in the COMET’s RCT. 
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3.2 
Eligibility Criteria (Step 2) - Secondary Genetic Counseling Substudy: 
NOTE: 
Only available to patients from select participating sites (see Section 
4.2.3.2 for instructions and requirements). 
3.2.1 
Patients must meet the eligibility requirements in Section 3.1 (except 
for Section 3.1.3 and 3.1.4) and have had the results from their tumor 
genetic testing study shared with them. 
3.2.1.1 
Non-MATCH expansion site patients must have 
participated in COMET Step 1, the primary intervention 
study (RCT), in order to be eligible for Step 2. 
3.2.2 
Patients must have a potential germline mutation, as determined by 
the NCI-MATCH tumor profiling assay or other clinical lab, and must 
meet one of the following criteria: 
• 
Patient’s tumor contains one of the following genetic variants: 
BRCA1, BRCA2, MLH1, MSH2, TSC1, TSC2, VHL, CDH1, 
CDKN2A 
• 
Patient has an APC mutation and NOT colon cancer 
• 
Patient has an APC mutation, colon cancer and a history of 
polyposis 
• 
Patient has a PTEN mutation and NOT uterine cancer 
• 
Patient has a TP53 mutation AND either a personal history of 
breast cancer diagnosed at age 65 or younger, OR a personal 
history of any other cancer diagnosed at age 40 or younger.  
• 
Patient has a RB1 mutation with personal and/or family history of 
retinoblastoma or other associated RB tumor (e.g. soft tissue 
sarcoma, melanoma, PNET). 
• 
Patient has a RET mutation with personal history of medullary 
thyroid cancer and/or family history of thyroid cancer. 
3.2.2.1 
Genes listed below require additional internal vetting by 
genetic counseling team. 
TSC1/TSC2 
1. All kidney cancers 
2. Any cancer type with: 
a. Personal history of seizures or developmental 
delay, OR 
b. Personal history of renal tumors, OR 
c. Personal history of cardiac rhabdomyomas, OR 
d. Personal history of TSC-associated skin findings 
(shagreen patches), OR 
e. Personal history of TSC-associated brain tumors 
(SEGA) 
CDKN2A 
1. Personal and/or family history of melanoma < 60 years 
of age, OR 
2. Personal and/or family history of pancreatic cancer, OR 
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3. Any cancer type with personal history >30 dysplastic 
nevi 
STK11 
1. NOT lung adenocarcinoma OR lung adenocarcinoma 
with history of small bowel or colon polyps 
(histopathology is hamartoma but confirmation is not 
requirement for eligibility) 
VHL 
1. Patient has Von Hippel-Lindau syndrome. 
3.2.3 
Patients must be able to speak English and hear by phone. 
NOTE: 
The restriction to English-speaking participants is based on 
the availability of translators for the Secondary Genetic 
Counseling Substudy. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov . 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
NOTE: Sites must utilize the CIRB as their IRB of record to participate in EAQ152. 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review. However, sites must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB (via IRB 
Manager) to indicate their intention to open the study locally. The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office for compliance in the RSS. 
The Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in a given study so that the study 
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approval can be applied to those institutions. Other site registration requirements (i.e., 
laboratory certifications, protocol-specific training certifications, or modality credentialing) 
must be submitted to the CTSU Regulatory Office or compliance communicated per 
protocol instructions. 
For sites under the CIRB initiative, IRB data will automatically load to RSS. 
Downloading Site Registration Documents:  
Site registration forms may be downloaded from the EAQ152 protocol page located on 
the CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EAQ152 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements For EAQ152 Site Registration:  
• 
Sites must be willing to provide patient contact information to the Outcomes and 
Economics Assessment Unit (OEAU) located at Brown University. 
• 
The Genetic Counseling Substudy is only available to patients from select 
participating sites (see Section 4.2.3.2 for instructions and requirements). 
Checking Your Site’s Registration Status: 
Please refer to Section 4.1.4.4 for details on the EASEE-PRO system. 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website. 
NOTE: 
Sites will not receive formal notification of regulatory approval from the 
CTSU Regulatory Office. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
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Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam ) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
• 
The patient’s highest education level has been obtained. 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Step 1 - Primary Intervention Study (RCT) Registration 
4.1.1 
Patient Registration Information 
The following information will be captured at time of registration. 
4.1.1.1 
Protocol Number 
EAQ152  
4.1.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
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• 
Country of residence 
4.1.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.3 
Classification and Stratification Factors 
4.1.3.1 
Classification Factors: 
• 
Primary Study (RCT) Participation: Yes vs. No. 
4.1.3.2 
Stratification Factors: 
• 
Gender: Male vs. Female 
• 
Race: White vs. Others 
• 
Age: ≤ 65 vs. > 65 years 
• 
Education level: No college vs. College vs. 
Professional/Graduate 
4.1.4 
Additional Requirements  
4.1.4.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.1.4.2 
If the participant is coming from a clinical trial, the Protocol 
ID and case number of that trial must be indicated (e.g. for 
example, if the participant is registered to MATCH Step 0, 
then the Protocol ID would be EAY131 and the case 
number would be the MATCH assigned subject ID). If the 
participant is not coming from an associated clinical trial, 
the Protocol ID and case number should be left blank. 
4.1.4.3 
Data collection for this study will be done through the 
Medidata Rave clinical data management system and the 
ECOG-ACRIN Systems for Easy Entry of Patient Reported 
Outcomes (EASEE-PRO) system. Access to the trial in 
Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory 
Support System (RSS). To access Rave via iMedidata, the 
site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave 
role (Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization 
roster at the enrolling site. To the hold Rave CRA role or 
CRA Lab Admin role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR. 
Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
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Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com. 
4.1.4.4 
ECOG-ACRIN Systems for Easy Entry of Patient Reported 
Outcomes (EASEE-PRO) System: 
Access to the study in EASEE-PRO is granted to all 
participants registered to the study through the OPEN 
registration system with a valid participant email address.  
Upon registration, an account verification email will be sent 
to the user with a link to activate their account.  The user 
will be required to enter some verification information (e.g. 
DOB) in order to activate their EASEE-PRO account. 
Additionally, site persons with the appropriate roles in RSS 
will be granted access after IRB approval is obtained.  In 
some studies, this access may allow CRAs to assist the 
participant accessing baseline surveys, educational 
materials, or other EASEE-PRO materials. 
EASEE-PRO Participant Access: 
To access EASEE-PRO, the participant must have an 
active EASEE-PRO user account.  Upon registration to the 
study in OPEN, an account activation email will be sent to 
the address entered for the participant in OPEN eligibility 
checklist.  This email address must be a valid email 
address for the participant. All participants in the COMET 
Study are required to have access to the internet and a 
valid email address to participate. (If the patient email 
address were entered incorrectly in OPEN, the CRA must 
contact the OEAU [COMET-help@stat.brown.edu] to 
manually correct the error.)   To activate their account, 
users must click the link in the email and verify their 
account before they can login and complete surveys or 
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view web education materials. Once the account is 
activated, participants may login to the EASEE-PRO 
system through the OEAU-PRIDE web portal 
(https://pride.stat.brown.edu/Participant-Login).  Upon 
login, users will be presented with a list of available 
surveys and materials they can view. 
EASEE-PRO CRA Access: 
To access EASEE-PRO, the site user must have an active 
CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam). In 
addition, site users that are a member of ECOG-ACRIN 
must have the mapped ECOG-ACRIN roles or explicit 
Rave roles (Rave CRA) in RSS at the enrolling site. Site 
users that are not members of ECOG-ACRIN must have 
the Rave roles on the CTSU roster at the enrolling sites. 
The Site Administrator or Data Administrator at the 
enrolling site may assign the appropriate roles from the 
Site Roles tab on the CTSU website. To login, CRAs will 
use their CTSU(IAM) credentials on the OEAU-PRIDE web 
portal (https://pride.stat.brown.edu/CRA-Login) using the 
familiar IAM interface.  No e-learnings are required for use 
of this site. 
The ECOG-ACRIN Outcomes and Economics Assessment 
Unit can be contacted for Patient Reported Outcome 
Questions via email at comet-help@stat.brown.edu. An 
EASEE-PRO instructional guide for both sites and patients 
can be found on both the E-A and CTSU websites. 
Please see below for additional details on the EASEE-PRO 
system. 
1) A secure environment for control of user records, 
information, and transactions (SECURIT): Provides a 
secure – limited access point for entering data into the 
restricted secure PII Database, for management of 
user data, creating user accounts, and reporting. The 
SECURIT web management interface requires the 
secure hypertext transfer protocol (HTTPS) to ensure 
encryption of transmitted data. 
a) PII database: is a dedicated secure limited access 
database, used to store protected PII. 
i) 
Secure: All communications to the PII database 
through SECURIT are encrypted. The database 
resides behind a firewall and cannot be reach 
from outside the OEAU. 
ii) Limited access: this database is restricted not 
only by username and password but is also 
restricted to specified internal OEAU computers 
by IP address, so that only authorized users 
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computers may access/enter PII.  At no time is 
outside access allowed to this database. 
iii) Protected restricted PII (e.g. SSN) are 
encrypted at the time of data entry and double 
data entered for verification.  All users 
regardless of their security level are blinded to 
this protected data, and it cannot be decrypted 
without the encryption key, housed in a safe, in 
a location separate from the OEAU. This type of 
data is generally collected for long term follow-
up where it may be needed to be decrypted for 
select patients in order to search registries like 
the national death index to determine survival 
status of lost participants. In these instances, 
with appropriate approvals, the Database 
Administrator will decrypt this data in 
accordance with the approved retrieval 
specification. 
b) User records: This functionality allows OEAU 
personnel, using specific computers within the 
OEAU, to create user records, enter user 
information into the PII database, and establish 
user web accounts in the separate user database. 
Allows the management of users and their data, 
including the ability to update a participant’s 
preferred contact method, address, and 
participation status (e.g. no longer wishes to be 
contacted with respect to the PRO component of 
the study). 
c) Information: This functionality allows the OEAU to 
record all participant contact, document any 
changes to the participant, and make any important 
notes related to the participant. 
d) Transactions: SECURIT provides a reporting and 
monitoring interface to the PRO database, which is 
used to store non-PII patient reported survey 
responses. 
i) 
Allows OEAU to monitor per patient form 
completion status using the tracking 
management facility. This facility reports on 
what data is currently expected from 
participants, CRAs, and the OEAU interviewers. 
ii) Aggregate reporting: this series of reports 
allows the OEAU to monitor the distribution of 
patients over data completion methods and 
form completion methods (both overall and by 
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2) Database utility and control environment (PRO-DUCE):  
This utility interfaces with the main clinical database 
containing CRF/trigger data (Medidata RAVE), 
monitors the clinical database for events 
(eg., participant registrations, scheduled procedures, 
and other triggers) and establishes event scheduling.  
The system sets up e-mail reminders to CRAs, 
participants [and SMS text message reminders, when 
applicable to the study], and OEAU personnel to 
ensure timely completion of surveys. 
3) Web entry systems (PROWESs): a Web site where 
participants complete online surveys 
a) PROWESs provides a front facing web portal for 
participants to complete questionnaires and have 
those results stored in the PRO database. 
b) Secure site using HTTPS and requiring a username 
and password login. 
c) On login, user is presented with brief instructions; 
including approx. time for completion, number of 
questions to be completed in this session, any 
important information regarding this survey 
(including help and contact information) 
d) PROWESs is a one-way interface, data cannot be 
returned from the PRO-DB to the user. 
4) Valet Interface and data entry system (PROVIDES). 
a) The PROVIDES system is a web interface that 
allows site CRAs to act as a valet and enter a 
participant’s responses to a survey into the PRO 
database should the survey be completed on 
paper. This allows Site CRAs to enter forms 
completed by the patient on site. 
b) Secure site using HTTPS and requiring a username 
and password login. 
c) Which forms can be entered is restricted by 
username, site affiliation, and role, thus Sites RAs 
can only enter surveys predesignated as on-site 
data collection surveys and only for their own 
patients. 
d) On login, user is presented with brief instructions; is 
requested to select the protocol, case number, 
timepoint and verify the case Id by providing the 
participant birthdate. 
e) PROVIDES is a one-way interface, data cannot be 
returned from the PRO-DB to the user. 
4.1.4.5 
Only those select expansion sites listed in the associated 
study tool found on the ECOG-ACRIN and CTSU websites 
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will be permitted to enroll patients on the COMET study 
without prior involvement in the NCI-MATCH (EAY131) 
study. 
To participate as a select expansion site for the Primary 
Intervention Study (RCT) and enroll patients unrelated to 
MATCH, sites must contact the study team for their review 
and approval. 
• 
The designated CRA must send an e-mail to 
COMETstudy@uphs.upenn.edu with the following 
information: 
First and Last Name(s) of the Designated Contact(s) at 
your Institution 
E-mail address(es) for Designated Contact(s) 
Site Name 
CTEP Site ID 
Street Address 
City, State, Zip 
NOTE: 
The person(s) identified as the Designated 
Contact(s) will be responsible for data entry in 
Rave in the event that the site participates. 
Participation will require appropriate site staffing and 
resources to support the coordination of the non-MATCH 
tumor profiling arrangements and the study’s requirements, 
including: 
• 
Staff to identify, approach and consent potential 
participants. 
• 
Staff to track survey completion and contact 
participants when a survey is late. 
• 
Staff to identify when a participant has received their 
tumor genetic testing results and upload the test report 
into the Rave system. 
4.1.5 
Registration of a patient to the COMET Ancillary Study Protocol does 
not relieve the registering investigator from adhering to correlative 
study requirements specific for the MATCH or other molecular 
profiling protocol and not specified by this ancillary protocol. 
4.1.6 
Patients assigned to the web-based education who do not view the 
website but complete baseline survey will still complete follow-up 
surveys. 
4.2 
Step 2 - Secondary Genetic Counseling Substudy Registration 
Select Participating Institutions: Please see Section 4.2.3.2 for detailed 
information and instructions on how to express interest in participation. 
4.2.1 
Patient Registration Information: 
4.2.1.1 
Protocol Number 
EAQ152 
4.2.1.2 
Investigator Identification 
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• 
Institution and affiliate name 
• 
Investigator’s name 
4.2.1.3 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2. 
4.2.3 
Additional Requirements  
4.2.3.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.2.3.2 
To participate in the Genetic Counseling Substudy, sites 
must contact the study team. 
• 
The designated CRA must send an e-mail to 
EAQ152step2@jimmy.harvard.edu with the following 
information: 
First and Last Name(s) of the Designated Contact(s) at 
your Institution 
E-mail address(es) for Designated Contact(s) 
Site Name 
CTEP Site ID 
Street Address 
City, State, Zip 
NOTE: 
The person(s) identified as the Designated 
Contact(s) will be responsible for data entry in 
Rave in the event that the site participates. 
All interested sites will be considered for participation in the 
substudy. Participation will require licensure assessment 
and licensure of the study team’s genetic counselors (at 
the University of Pennsylvania), per state laws. 
Participation also requires a designated CRA to assist with 
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appointments and ensuring communication with the 
treating provider, patient and medical team. 
4.2.3.3 
For patients consented to the COMET Secondary Genetic 
Counseling Substudy, the responsible/designated CRA 
must fax the MATCH or other molecular profiling screening 
results report to the study team (Fax #: 215-573-1578), 
and discuss the results with the study team, including the 
genetic counselors at the University of Pennsylvania, over 
telephone. 
4.2.3.4 
Data collection for this study will be done through the 
Medidata Rave clinical data management system and the 
EASEE-PRO system. Please refer to Section 4.1.4.3 
above for Rave access information. 
4.2.3.5 
EASEE-PRO System: 
Please refer to Section 4.1.4.4 above with the following 
modification: Participants who do not have internet 
access/e-mail may still participate in the Step 2 Genetic 
Counseling sub-study. For these participants only, site 
CRAs will need to complete a participant contact form and 
fax it to the OEAU so that the participant account can be 
activated manually within EASEE-PRO. 
4.2.3.6 
Registration of a patient to the COMET Ancillary Study 
Protocol does not relieve the registering investigator from 
adhering to correlative study requirements specific for the 
MATCH or other molecular profiling protocol and not 
specified by this ancillary protocol. 
4.3 
Instructions for Patients who Do Not Complete Baseline Survey and/or Do Not 
Start Assigned Study Intervention 
If a patient is randomized in the Primary Intervention Study (Step 1) but the 
baseline survey (T0) is not completed, patient is considered off study and no 
additional data will be requested and patients will not be available to register to 
the Secondary Genetic Counseling Substudy (Step 2). 
Patients registered to Step 1 and further registered to Step 2, but who do not 
proceed with the genetic counseling, are to complete the requirements for Step 
1. Specifically, Step 1 follow-up data will still be collected and must be submitted 
through Medidata Rave and the EASEE-PRO System according to the schedule 
in the EAQ152 Forms Completion Guidelines. 
For Step 2 participants, if the patient does not complete the baseline survey 
(T0SS) for Step 2, patient is considered off the substudy and no additional data 
will be requested for Step 2. 
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5. 
Methodology 
5.1 
Randomization 
5.1.1 
Primary Intervention Study - RCT of Web-based Pre-disclosure 
Genetic Education v. Usual Care (Step 1): 
We will use a permuted block design for the randomization scheme. 
We will have 1:1 randomization between arms. 
5.1.2 
Secondary Genetic Counseling Substudy - Genetic Counseling for 
Incidental Germline Findings (Step 2): 
Single arm pilot study (no randomization) 
5.2 
Interventions 
5.2.1 
Primary Intervention Study (RCT) (Step 1): 
As shown in the study schema, participants will be randomly assigned 
to web-based genetic education or a control group receiving usual 
care. 
• 
Genetic education website (Arm A – intervention group): 
Upon completion of the baseline survey, Arm A participants will 
receive an access code to enter and complete the online 
education module. Adapted for COMET participants from the 
COMET pilot study materials, the module is designed to provide 
information on what can be learned through tumor testing, 
including the differences between genetic tumor changes and 
potential germline findings, and next steps including confirmation 
testing should a germline mutation be suspected. The module, 
which will be content and usability tested with patients of varied 
background and cancer diagnosis, features simple text, graphic, 
and video components. 
Arm A participants will be offered access to the web-based 
genetic education module at the study site following completion of 
the baseline survey, and will be able to revisit the site using any 
computer with web access, including a smart phone. 
• 
Usual care (Arm B - control group): 
Participants in the usual care arm will not initially have access to 
the web-based genetic education. Rather their education will be 
consistent with usual care including conversations with the 
treating physicians, interaction with and information from clinical 
and/or MATCH research staff and any additional information they 
seek out through usual resources. This is intended as a “real 
world” comparison group. All usual care arm participants will be 
provided access to on-line genetic web education three months 
after receiving their tumor genetic testing results. These patients 
will be e-mailed a link to the website and a code to access the 
materials, which are viewable on any web-enabled device. 
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• 
Both Arms (A & B): 
Patients on both Arms A and B will be asked to complete a total of 
four surveys electronically (see Section 0). A baseline survey (T0) 
will be administered immediately following registration to COMET.  
A second survey (T1) will be administered following the 
intervention/usual care. An electronic link to the T1 survey will be 
emailed to all patients at 7 days following completion of the 
baseline survey (T0). A third survey (T2) will be sent to all patients 
within three days following their receipt of their tumor profile 
results. An electronic link to a fourth survey (T3) will be emailed to 
all patients three months following receipt of tumor profile results. 
All patients will receive periodic email reminders to complete 
surveys. 
We will coordinate COMET study activities closely with MATCH or 
other tumor profile procedures to ensure that surveys do not alter 
the treatment schedule. If participants have not completed 
surveys, this will not prevent next steps in their care or other tumor 
profile activities. 
We will test surveys and assess burden and completion rates. If 
there is evidence of burden, we will revisit length and prioritize 
outcomes and constructs of interest. 
5.2.2 
Secondary Genetic Counseling Substudy (Step 2 – Arm D and Arm 
E): 
As shown in the study schema, all participants who meet inclusion 
criteria and criteria for a potential germline mutation identified with 
molecular tumor profiling at a participating substudy site will be 
offered the study (up to accrual of 100 patients). 
• 
Genetic Counseling: 
Patients who meet criteria for the remote counseling substudy will 
complete remote counseling visits and surveys as outlined in the 
study schema. Visit 1 will be standard pre-test counseling; if 
patients agree to confirmatory germline testing, Visit 2 will consist 
of result disclosure and review of implications for relatives, 
consistent with clinical standards in the field. Genetic counselors 
will be licensed to practice (if necessary) in the states where sites 
reside consistent with state laws. Similar to our other remote 
counseling studies, standardized counseling checklists will be 
utilized by genetic counselors to ensure fidelity to the 
communication protocols15,17,18. All sessions will be audiotaped to 
evaluate fidelity and to inform potential future modifications for 
alternative delivery models. Genetic counselors will collaborate 
with the patient’s treating physician as they will be the ordering 
provider. Thus, test results and recommendations will be 
communicated to the patient’s treating physician and genetic 
counselors will collaborate with the treating physician as needed. 
Implications of germline findings for relatives will be 
communicated to patients, including how relatives can obtain 
clinical genetic testing. 
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There will be no genetic counselors providing counseling services 
in the primary randomized study. A large number of genetic 
counselors from the PENN cancer genetics team will be involved 
in development of the web-based genetic education. 
For the sub-study, we will utilize genetic counselors from the 
PENN cancer genetics team, as this pool of counselors has 
cultivated extensive experience in conducting genetic counseling 
with advanced cancer patients in the context of tumor profiling. 
• 
Germline Genetic Testing: 
All confirmatory germline testing will be completed through a 
commercial CLIA-approved lab. The genetic counselor will provide 
recommendations for testing and the treating physician will be the 
ordering provider for clinical germline testing. The genetic 
counselor will disclose the genetic test results to patients during 
Visit 2 and will collaborate with the treating physician to provide 
recommendations for testing relatives.  
• 
In summary, the Step 2 procedures for both Arm D and Arm E 
(per Section 6.2) will include the completion of up to 4 surveys and 
the associated interventions, as listed below: 
• 
All Step 2 participants will complete: 
• 
a baseline survey (T0SS) 
• 
a visit with a genetic counselor for germline mutation 
counseling (GC Visit 1) 
• 
a post GC Visit 1 survey (T1SS) 
• 
Additionally, if a participant agrees to confirmatory testing, this 
individual will also have: 
• 
a second visit (GC Visit 2) with a genetic counselor 
• 
a post GC Visit 2 survey (T2SS) 
• 
and a 3 month survey (T3SS) 
• 
For Arm D patients (i.e., those from Step 1 Arm A or Arm B), 
information taken from T2 (see Sec. 6.1) will be used to pre-
populate T0SS, and only the remaining items in T0SS will 
need to be completed. 
• 
Participants with email access will be directed to complete 
surveys online. Those without email access may complete 
paper surveys instead. 
5.2.3 
Alternative pathway to Substudy (Step 1 - Arm C, then Step 2 – Arm 
E): 
In an effort to reduce the length of time to recruitment and completion 
of the substudy, we have included an alternative pathway for entry 
therein. 
• 
As indicated in the study schema, following enrollment in 
screening for MATCH, a subgroup of patients who receive their 
tumor molecular profile results (report of any actionable mutations) 
from their treating physician, and who meet criteria for potential 
actionable germlne mutation (AIM 2), will be consented to the 
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COMET substudy. These individuals will not be required to 
complete the main study (Step 1 - Arm A or B) to be eligible for 
the substudy (Step 2). 
• 
Patients who are eligible and consent to participate in the 
substudy, and who were not enrolled on either Arm A or Arm B, 
will be registered to Arm C (Step 1; substudy only). These 
individuals will not participate in or complete any primary study 
(Arm A or B) education or surveys. 
• 
Arm C participants will immediately be registered to Arm E (Step 
2) and complete all of the Step 2 procedures (per Section 6.2), 
including the completion of up to 4 surveys and the associated 
interventions (see Section 5.2.2 above). For Arm E patients, the 
entire T0SS will be completed as the baseline survey. 
5.3 
Patient Recruitment 
All eligible patients will be recruited to Step 1 by MATCH site research staff at the 
time that they enroll in the MATCH Master (Screening) Protocol or will be 
undergoing clinical tumor profiling at a select expansion site. 
Potential participants at expansion sites will be approached by site research staff 
after permission of the treating physician. 
At sites participating in the Substudy (Step 2), potential Substudy participants will 
be identified according to the selection criteria (see Section 3.2). MATCH or other 
site research staff will notify potential participants, introduce the study and 
consent interested participants. 
We will collaborate with the ECOG-ACRIN Underserved Populations Recruitment 
and Retention Subcommittee to develop recruitment strategies to facilitate the 
enrollment of a diverse sample of participants. Dr. Edith Mitchell is chair of this 
subcommittee, and she is also involved in an initiative to facilitate minority 
accrual to the MATCH trial (“Impact”) and will contribute her expertise to facilitate 
diverse patient participation for the proposed COMET trial. 
5.4 
PRO/QOL Data Collection Process 
Patient completed outcomes:  
Patients will be recruited at the time of registration into the COMET study. At the 
time of registration at the sites, the patient's contact information should be 
collected on the Patient Contact (PC) form by the site CRA for all participants 
who do not have email/internet access (Note: all RCT Step 1 participants are 
required to have email/internet and thus no PC should be collected for these 
individuals). The completed PC should then be fax it to the OEAU and stored in a 
secure locking file storage location.  Participants with email/internet access will 
be asked to enter this information themselves directly into the OEAU servers 
when they activate their EASEE-PRO account. The contact information is stored 
in a Biostatistics Center (BC) database and IS NOT linked to the master ECOG-
ACRIN database. The OEAU RA will not have access to the main ECOG-ACRIN 
database that contains screening results. 
Administration of web-based questionnaires will be coordinated by the OEAU. 
Administration of the questionnaires will be triggered based on completion of 
study milestones. 
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Questionnaire completion 
Patients on Step 1, and those with e-mail access on Step 2, will be prompted to 
complete web-based forms via an e-mail. These e-mails will include a link to the 
web site for questionnaire completion. Each participant will be required to log in 
with their unique user ID and password to complete the requested instruments. 
The web site will reference a study-specific e-mail address and a toll-free phone 
number that patients can use to reach the OEAU staff should they have 
questions or need assistance. All participant data will be stored on a secure 
server. 
Because the timings of survey completion in relation to events lie in very narrow 
windows, patients who do not complete the web questionnaires within 3 working 
days of the initial request e-mail will receive additional e-mail reminders. These 
reminder e-mails, like the initial e-mail, will provide a link to the current surveys, 
ask the participant to confirm that they have been able to access the web site, 
and provide both the e-mail address and the toll free help number for support. 
If patients still have not responded within 12 days of the original e-mail, the 
OEAU Research Associate may attempt to telephone the patient and administer 
the questionnaire over the telephone. If questionnaires are telephone-
administered, they will be marked as such in the data base. All surveys, while 
desired within 3 days of the event, will remain available for participants until 
either the surveys are completed or they are off-study.  Since the completion 
date is recorded for all surveys, the study team will be able to make relevant 
determinations for inclusion of this data in specific analyses.  However, after 
telephone follow-up, no additional or extraordinary means will be employed to 
collect overdue/missing questionnaires. 
Only participants on Step 2 without email access may complete paper survey. 
The timing of administration will be the same as the web-based surveys. 
Participants unable to enter their survey responses may designate a “scribe” to 
relay their responses. Participants will be able to indicate whether the survey was 
filled in by the participant or the designated scribe. 
5.5 
Study Instruments 
NOTE: 
All participants of the Genetic Counseling substudy will complete 
surveys as shown in the Study Schema. Surveys will evaluate the 
primary and secondary endpoints informed by our theoretical models 
grounded in the Self Regulation Theory of Health Behavior18 and 
Diffusion of Innovation Theory17. 
The study instruments are as follows: 
5.5.1 
Knowledge of Genetic Disease (T0-T3; T0SS-T3SS): 
This will be evaluated using an adapted version of the Cancer 
Genetics Knowledge Scale and clin seq knowledge scale 19-21. 
Adaptations were made for Somatic Testing. This scale is composed 
of items evaluating the differences between somatic and germline 
testing (3 items); the limitations of somatic testing (7 items), the 
limitations of germline testing (3 items) and relationship between 
tumor testing and clinical trials (1 item).  
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5.5.2 
Knowledge of Germline (i.e. inherited) Genetic Disease (T0SS-T3SS): 
This will be evaluated using an 8-item scale adapted from the Cancer 
Genetics Knowledge scale (Cronbach’s α=0.58-0.60)21. This scale 
includes items evaluating mechanism of inheritance (3 item), meaning 
of positive (2 items) and negative results (3 items). 
5.5.3 
Health Literacy (T0 and T0SS): 
Health literacy is assessed using a 3-item scale for identifying patients 
with inadequate or marginal health literacy49. 
5.5.4 
Promis (assessments of emotional distress anxiety/emotional distress 
depression) (T0-T3; T0SS-T3SS): 
Emotional distress anxiety and depression are each assessed with 
the 4-item short Patient Reported Outcomes Measurement 
Information System (PROMIS), a system of highly reliable, precise 
measures of patient–reported health status for physical, mental, and 
social well–being50, 51. 
5.5.5 
State Anxiety (T0-T3; T0SS-T3SS): 
Measured with the 20-item State Inventory of the State-Trait Anxiety 
Inventory (STAI). The state scale is a sensitive indicator of transient or 
situational changes in anxiety (see Project 3, Section B.3.d)24-27. 
5.5.6 
Cancer Specific Distress (T0-T3; T0SS-T3SS): 
Measured using the Impact of Events Scale (IES)28,29. The 14 item 
IES is compromised of the Intrusion subscale (7 items) and the 
Avoidance subscales (7 items), which can be summed for the Total 
scale. Although the IES was developed to assess stress reactions 
following non-cancer-related traumatic events, it has more recently 
been utilized to assess response to cancer-related stressors, such as 
being at hereditary risk for cancer, which have been conceptualized 
as a continuous, rather than event-specific stressor 25,30,31. Thus, the 
IES has been used in the context of learning of one’s genetic status, 
to assess cancer-specific distress over time 25,26,31-34.  The IES has 
been validated in individuals experiencing many different kinds of 
stressors 28,29,35.  On the bases of our preliminary studies, we have 
chosen not to use one item that did not have good face validity in our 
population.  Thus, our modified IES will include 14 items (7 Intrusion; 
7 Avoidant). 
5.5.7 
Uncertainty About Genetic Testing (T0-T3 for tumor; T0SS-T3SS for 
germline): 
Assessed using a 3-item scale adapted from the uncertainty subscale 
of the Multi-dimensional Impact of Cancer Risk Assessment Question 
(MICRA)36. This subscale has had high internal consistency in our 
related research (Cronbach’s α=0.88)18. This instrument has been 
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5.5.8 
Perceived Utility of Genetic Testing (T0-T3 for tumor; T0SS-T3SS for 
germline): 
This novel construct was developed to evaluate patient perceptions of 
the utility of germline and tumor genetic information for various 
aspects of their life and the life of their family members. It is 
comprised of 10-items and has had high internal consistency in our 
related research (Cronbach’s α=0.90)18. 
5.5.9 
Preferences for Germline (i.e. inherited) Risk Information and Delivery 
(T2 only): 
We will assess preferences for learning germline information querying 
patients about interest in germline information if additional testing was 
needed and in the hypothetical situation where germline information 
was available as part of somatic testing. We will also assess 
preferences for delivery of germline information assessing provider 
(e.g. with a genetic counselor, medical oncologist) and mode of 
delivery (e.g. phone, videoconference, web-based genetic 
portal).These will be novel items developed specifically for the 
purpose of this study. 
The genetic counselor will make recommendations for testing and will 
work with the local oncologist to facilitate germline confirmation testing 
through a contract with a commercial lab (likely Ambry Genetics 
based on an existing relationships). The local oncologist will be the 
ordering doctor. 
We will use the standardized remote counseling communication 
protocols utilized in related research (COGENT R01  
CA160847:Bradbury, RESPECT R01 CA190871:Bradbury) and 
adapted for this context. Communication to at risk-relatives will be 
included in the standardized counseling protocols, which will be 
developed and finalized during the development period. 
5.5.10 
Satisfaction with Receipt of Tumor Genetic Test Results (T2 only) 
This is a 9-item satisfaction with communication scale that evaluates 
participants’ perceptions of their tumor profile test experience and of 
their experience receiving their tumor profile test results, including 
cognitive, affective and time/attention items. These scales were 
adapted for somatic testing52, 53, 54. 
5.5.11 
Preferences for Receipt of Tumor Genetic Test Results (T2 only) 
We will assess patient preferences for receipt of tumor profile test 
results, including queries related to the actual modes of sharing and 
receiving results, satisfaction with receiving results using these 
communication modes, and alternatives thereto. These will be novel 
items developed specifically for the purpose of this study. 
5.5.12 
Satisfaction with Genetic Counseling Services (T1SS and T2SS only): 
Assessed with a 9-item satisfaction with communication scale 
items27,36,37 utilized in our prior and related studies and has 
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5.5.13 
Regret and Disappointment Regarding Genetic Test Result (T2 and 
T3 for tumor; T2SS and T3SS for germline): 
Assessed with the 7-item Regret and Disappointment Scale (RDS) 
which has been utilized in the general population to assess regret and 
disappointment in decision making48. This instrument has been 
adapted to address both germline and tumor genetic testing. 
5.5.14 
Communication about Germline (i.e. inherited) Genetic Test Results 
(T2SS, T3SS) 
Psychosocial intention (T2SS) will be assessed using a 4-item 
measure of intent to communicate genetic test results previously 
developed and utilized in our COGENT study to assess intent to share 
genetic test results with health care providers, family members and 
other third parties. 
Performance of psychosocial behaviors (T3SS) will be assessed 
using a 4-item measure of communication of genetic test results as 
described in the psychosocial intention. 
5.6 
Survey Assessment Schedule: 
Please refer to Section 0 for Step 1 - Primary Study Intervention: RCT and 
Section 6.2 for Step 2 – Secondary Genetic Counseling Substudy. 
5.7 
Duration of Participation:  
Patients can withdraw consent at any time. The duration of participation is 
anticipated to be no more than 4-5 months for those patients participating in the 
Primary Intervention Study. For those participating in the Substudy (Step 2), 
participation on this part is expected to be no more than 1 month if participants 
don’t opt to have confirmatory germline genetic testing, or no more than 4 
months if participants do have confirmatory germline genetic testing. For those 
participating in both the Primary Study (Step 1) and the Substudy (Step 2), 
participation is expected to last no more than 5 months. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who do not complete all steps, will 
be followed until the time of their last planned survey. Individual activity on the 
online genetic education web site will be followed through completion of all 
protocol therapy (if enrolled in MATCH). 
In addition, all patients will be followed for survival per the standard ECOG-
ACRIN follow-up schedule: at 3 months and 6 months after study entry. 
 
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6. 
Study Parameters 
NOTE: 
All patients enrolled into Step 1 (including Arms A, B, and C) will be followed 
for survival per the standard ECOG-ACRIN follow-up schedule: at 3 months 
and 6 months after study entry.  
Below is information specifically for patients enrolled into Arms A and B for the primary 
study. 
6.1 
Step 1 - Primary Study Intervention: RCT – Arms A & B 
NOTE: 
Patients on Arm C (see Section 
) will not participate in or 
complete any primary study (Step 1) education or surveys, and will 
immediately be registered to Arm E and complete all of the substudy 
(Step 2) procedures. 
Survey Schedule: 
Surveys 
Baseline 
Post-Genetic 
Education  
(1-2 weeks after 
completion of T0) 
Post-MATCH or Clinical 
Tumor Test Results 
Received A 
(within 3 days) 
3 Months After the 
Receipt of MATCH or 
Clinical Tumor Test 
Results A 
T0 
X 
 
 
 
On-line Genetic Education (T1) 
 
Arm A 
 
 
Usual Care/Standard Genetic 
Education (T1) 
 
Arm B 
 
 
T2 
 
 
X 
 
T3 
 
 
 
X 
A. Refers to the written test report, not the notification of treatment assignment 
Assessment Schedule: 
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Primary Intervention Study (Step 1) 
Assessments A 
T0 
T1 
T2 
T3 
3 
Months 
6 
Months 
Health Literacy 
X 
 
 
 
 
 
Knowledge of Genetic Disease 
X 
X 
X 
X 
 
 
PROMIS Anxiety/Depression 
X 
X 
X 
X 
 
 
State Anxiety 
X 
X 
X 
X 
 
 
Cancer Specific Distress 
X 
X 
X 
X 
 
 
Uncertainty About Tumor Genetic Testing 
X 
X 
X 
X 
 
 
Perceived Utility of Tumor Genetic Testing 
X 
X 
X 
X 
 
 
Satisfaction with Receipt of Tumor Genetic Test 
Results 
 
 
X 
 
 
 
Preferences for Receipt of Tumor Genetic Test 
Results 
 
 
X 
 
 
 
Preferences for Germline (i.e. inherited) Risk 
Information and Delivery 
 
 
X 
 
 
 
Regret and Disappointment Regarding Tumor 
Genetic Test Result 
 
 
X 
X 
 
 
Follow-UpB 
 
 
 
 
X 
X 
A. Descriptions of individual measures (except for Follow-Up) are included in Section 5.5. All instruments 
will be included as a single survey for each timepoint. 
B. All patients will be followed for survival per the standard ECOG-ACRIN follow-up schedule: at 3 months 
and 6 months after study entry. 
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6.2 
Step 2 – Secondary Genetic Counseling Substudy – Arm D and Arm E 
NOTE: 
The designated CRA must fax the MATCH or clinical tumor screening 
results report to the study team and discuss the results with the study 
team over telephone (See Section 4.2.3.3). 
Survey Schedule: 
Survey 
Baseline 
Post-Remote Genetic 
Counseling A 
(within 3 days) 
Post-Germline Testing 
Results Received B 
(within 3 days) 
3 Months After Germline 
Testing Results Received B 
T0SSC 
X 
 
 
 
T1SS 
 
X 
 
 
T2SS 
 
 
X 
 
T3SS 
 
 
 
X 
A. Post-GC (Genetic Counseling) Visit 1, see schema for details 
B. Post-GC (Genetic Counseling) Visit 2; see schema for details 
C. For Arm D patients (i.e., from Step 1 Arm A or B patients), information taken from T2 (see Sec. 6.1) will be used to 
pre-populate T0SS, and only the remaining items in T0SS will need to be completed. The “Uncertainty” and 
“Perceived Utility of Genetic Testing” assessments in T2 are exceptions, and must be completed in T0SS for all 
patients. For Arm E patients (i.e. those from Step 1 Arm C), the entire T0SS will be completed as the baseline 
survey. 
Assessment Schedule: 
Secondary Genetic Counseling Substudy (Step 2) 
Assessment A 
T0SS 
T1SS 
T2SS 
T3SS 
Health Literacy 
X 
 
 
 
Knowledge of Genetic Disease 
X 
X 
X 
X 
Knowledge of Inherited Genetic Disease 
X 
X 
X 
X 
PROMIS Anxiety/Depression 
X 
X 
X 
X 
State Anxiety 
X 
X 
X 
X 
Cancer Specific Distress 
X 
X 
X 
X 
Uncertainty About Germline (i.e. inherited) Genetic Testing 
X 
X 
X 
X 
Perceived Utility of Germline (i.e. inherited) Genetic 
Testing 
X 
X 
X 
X 
Satisfaction with Genetic Counseling Services 
 
X 
X 
 
Regret and Disappointment Regarding Germline (i.e. 
inherited) Genetic Test Result 
 
 
X 
X 
Communication about Germline (i.e. Inherited) Genetic 
Test Results 
 
 
X 
X 
A. Descriptions of individual measures are included in Section 5.5. All instruments will be included as a 
single survey for each timepoint. 
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7. 
Statistical Considerations 
The primary objective of the primary Intervention Study (RCT, Step 1) is to evaluate the 
efficacy of web-based pre-disclosure genetic education (i.e. before receipt of tumor 
profile results) on knowledge (genetic knowledge and knowledge of test benefits and 
limitations) and distress (anxiety, depression and cancer specific worry) compared to 
usual care services in patients undergoing tumor profiling for advanced cancer. The 
primary analysis will, thus, be based on patients who have survey data evaluable at both 
T0 (baseline) and T1 (post-genetic education) (or T2, post-disclosure of test results). 
Given the survey completion rate for both T0 and T1 is approximately 60% (as analyzed 
in May 2018), the accrual goal of the primary intervention study needs to be increased 
from 400 to 670 patients in order to maintain sufficient power for evaluating the effect of 
web-based pre-disclosure genetic education. 
As MATCH has approached its goal of sequencing ~6000 patient tumors, this section 
incorporates changes to expand eligibility criteria (effective since Addendum #3) to allow 
patients from select sites who potentially undergo tumor profiling through non-MATCH 
assays and to increase the accrual goal (effective since Addendum #6). In this section, 
patients who enter COMET through MATCH Step 0 (prior to or after the activation of this 
addendum allowing for eligibility expansion) will be referred as the MATCH cohort, and 
other patients (who enter after the corresponding addendum activates) will be referred 
as the non-MATCH cohort. 
7.1 
Primary Study: Randomized Study of Web-based Pre-disclosure Genetic 
Education versus Usual Care (Step 1 – Arms A & B) 
NOTE: 
Patients on Arm C (see Section 
) will not participate in or 
complete any primary study (Step 1) education or surveys, and will 
immediately be registered to Arm E and complete all of the substudy 
(Step 2) procedures. 
7.1.1 
Primary endpoints will include change in knowledge and distress 
(state anxiety, Promis anxiety, Promis depression and cancer specific 
distress) from baseline to post-education (T0 to T1) and baseline to 
post-disclosure (T0 to T2). 
The following 10 analyses are of primary interest: change scores from 
T0 to T1, and T0 to T2 of each of the following five outcomes: 
knowledge, state anxiety, cancer specific distress, Promis anxiety and 
Promis depression, which correspond to 10 primary analyses. To 
account for the 10 primary analyses, A Bonferroni correction is 
considered here, setting the nominal p-value to declare statistical 
significance of p< 0.005 (5% Typical Type I error rate / 10 
comparisons = 0.5% nominal p-value for declaring statistical 
significance). Preliminary data from the COMET pilot study (State 
Anxiety, IES-Total, Knowledge) is used to calculate power. As there 
was no preliminary data for Promis Depression/Anxiety in a similar 
setting, power calculation for these two measurements are based on 
data reported in Hinds et al. (2012). A sample size of 200 (with 
evaluable paired data) /arm is chosen here, which provides at least 
85% power for all short-term outcomes (e.g. T0-T1) and changes in 
knowledge and cancer specific distress after receipt of tumor profiling 
results (e.g. T0-T2), using t test at two-sided 0.005 significance level. 
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With the completion rate for both T0 and T1 surveys at approximately 
60% (as analyzed in May 2018) and the goal of evaluable sample size 
at 200/arm (at least for the analysis of changes between T0 and T1), 
the accrual goal of the primary intervention study needs to be inflated 
from 400 to 670 patients in order to maintain sufficient power for 
detecting proposed changes from T0 to T1 and changes in knowledge 
and cancer specific from T0 to T2 (as described in the preceding 
paragraph). With the completion rate for both T0 and T2 surveys at 
approximately 45% (as analyzed in May 2018), the projected 
evaluable sample size of 150 patients/arm can give the power of 72% 
for changes in knowledge and 95% for changes in cancer specific 
distress from T0 to T2. These 670 patients will be randomized 1:1 
between the two arms, and the randomization will be stratified by 
gender, race, age (> 65 vs. ≤ 65), and education level. As of this 
analysis time, 320 patients have been enrolled into the primary 
intervention study. The current COMET accrual rate is approximately 
15 patients per month (based on the last 3 months). Assuming 15, 20 
or 25 patients per month (as more expansion sites are added over 
time) can be accrued to COMET from the select sites, it is expected to 
take 23, 17 or 14 additional months, respectively, to complete Step 1 
accrual of 670 patients. 
The original accrual plan posed a limitation on White patients at 80% 
of the accrual goal to ensure diversity of patients. Given that the 
accrual of this study might terminate early if the funding of this study 
ends, the accrual limitation on White patients is being lifted to ensure 
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Power for various sample sizes 
Variable 
Change score 
time period 
Sample 
Size Per 
Arm 
Power for 
p< 0.005, 
2-sided 
Change 
Score 
Group 1 
Change 
Score 
Group 2 
Standard 
Deviation 
Group 1 
Standard 
Deviation 
Group 2 
State Anxiety 
T0 to T1 
100 
98% 
2.71 
-2.78 
8.24 
7.43 
State Anxiety 
T0 to T1 
150 
100% 
2.71 
-2.78 
8.24 
7.43 
State Anxiety 
T0 to T1 
200 
100% 
2.71 
-2.78 
8.24 
7.43 
State Anxiety 
T0 to T1 
300 
100% 
2.71 
-2.78 
8.24 
7.43 
State Anxiety 
T0 to T1 
400 
100% 
2.71 
-2.78 
8.24 
7.43 
State Anxiety 
T0 to T1 
61 
85% 
2.71 
-2.78 
8.24 
7.43 
IES-Total 
T0 to T1 
100 
100% 
0.29 
-1.78 
1.70 
3.19 
IES-Total 
T0 to T1 
150 
100% 
0.29 
-1.78 
1.70 
3.19 
IES-Total 
T0 to T1 
200 
100% 
0.29 
-1.78 
1.70 
3.19 
IES-Total 
T0 to T1 
300 
100% 
0.29 
-1.78 
1.70 
3.19 
IES-Total 
T0 to T1 
400 
100% 
0.29 
-1.78 
1.70 
3.19 
IES-Total 
T0 to T1 
46 
85% 
0.29 
-1.78 
1.70 
3.19 
Knowledge 
T0 to T1 
100 
97% 
1.70 
-1.50 
6.11 
3.02 
Knowledge 
T0 to T1 
150 
100% 
1.70 
-1.50 
6.11 
3.02 
Knowledge 
T0 to T1 
200 
100% 
1.70 
-1.50 
6.11 
3.02 
Knowledge 
T0 to T1 
300 
100% 
1.70 
-1.50 
6.11 
3.02 
Knowledge 
T0 to T1 
400 
100% 
1.70 
-1.50 
6.11 
3.02 
Knowledge 
T0 to T1 
68 
85% 
1.70 
-1.50 
6.11 
3.02 
State Anxiety 
T0 to T2 
100 
13% 
-2.43 
5.00 
4.04 
14.58 
State Anxiety 
T0 to T2 
150 
23% 
-2.43 
5.00 
4.04 
14.58 
State Anxiety 
T0 to T2 
200 
34% 
-2.43 
5.00 
4.04 
14.58 
State Anxiety 
T0 to T2 
300 
55% 
-2.43 
5.00 
4.04 
14.58 
State Anxiety 
T0 to T2 
400 
72% 
-2.43 
5.00 
4.04 
14.58 
State Anxiety 
T0 to T2 
512 
85% 
-2.43 
5.00 
4.04 
14.58 
IES-Total 
T0 to T2 
100 
79% 
-1.00 
-2.17 
1.53 
2.86 
IES-Total 
T0 to T2 
150 
95% 
-1.00 
-2.17 
1.53 
2.86 
IES-Total 
T0 to T2 
200 
99% 
-1.00 
-2.17 
1.53 
2.86 
IES-Total 
T0 to T2 
300 
100% 
-1.00 
-2.17 
1.53 
2.86 
IES-Total 
T0 to T2 
400 
100% 
-1.00 
-2.17 
1.53 
2.86 
IES-Total 
T0 to T2 
114 
85% 
-1.00 
-2.17 
1.53 
2.86 
Knowledge 
T0 to T2 
100 
48% 
5.86 
4.40 
4.30 
3.05 
Knowledge 
T0 to T2 
150 
72% 
5.86 
4.40 
4.30 
3.05 
Knowledge 
T0 to T2 
200 
86% 
5.86 
4.40 
4.30 
3.05 
Knowledge 
T0 to T2 
300 
98% 
5.86 
4.40 
4.30 
3.05 
Knowledge 
T0 to T2 
400 
100% 
5.86 
4.40 
4.30 
3.05 
Knowledge 
T0 to T2 
194 
85% 
5.86 
4.40 
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Power for Promis Depression and Promis Anxiety 
With 200 evaluable patients per arm, there is 91% power to detect an 
effect size of 0.33 (as fraction of standard deviation), using t-test at 
two-sided significance level 0.005. Based on data from 92 
children/adolescents, Hinds et al. (2012) reported standard deviation 
of 10.74 for Promis Depression and 12.5 for Promis Anxiety, 
respectively. Assuming the standard deviations for these two 
measurements in our proposed study are similar, the following table 
gives the absolute difference that can be detected with 91% power, 
under different assumptions for the correlation between the 
measurements across two timepoints, at two-sided significance level 
0.005. 
Variable 
Correlation 
Standard 
deviation of 
change 
Effect size  
(as fraction of 
standard deviation) 
Absolute 
difference 
Power 
Promis Depression 
0.4 
11.8 
0.33 
3.89 
91% 
Promis Depression 
0.6 
9.6 
0.33 
3.17 
91% 
Promis Depression 
0.8 
6.8 
0.33 
2.24 
91% 
Promis Anxiety 
0.4 
13.7 
0.33 
4.5 
91% 
Promis Anxiety 
0.6 
11.2 
0.33 
3.7 
91% 
Promis Anxiety 
0.8 
7.9 
0.33 
2.6 
91% 
7.1.2 
Analysis Plan 
Outcome change scores (primary endpoints) between time points for 
each study participant will be calculated. Two-sample T-tests will be 
conducted first to evaluate whether there is any difference in outcome 
change scores (with respect to the primary endpoints) between 
MATCH patients and non-MATCH patients. If differences are 
observed, the analysis described below will be performed separately 
for each cohort. 
Two-sample T-tests assuming unequal variances will be used for the 
primary analyses of the change scores between arms. An intention-to-
treat approach will be used in which the effect between randomized 
arms is evaluated, regardless of any treatment crossover. In 
secondary analyses of the primary endpoints, demographic 
characteristics between the two arms will be evaluated using T-tests 
and Fisher’s Exact Tests to investigate if the arms were unbalanced 
with respect to potential confounders. If any potential confounders (in 
particular age, race/ethnicity and health literacy) are found to have 
means/proportions that are different between the arms at a p-value of 
less than 0.1, we will examine the treatment effect in multiple linear 
regressions of the outcomes in which the randomized arms will be 
included as a binary (0/1) dummy indicator and all potential 
confounders that have a p-value < 0.1 will be included as covariates. 
These analyses will be repeated using the as-treated approach in 
which we compare differences between the interventions the patient 
actually received (for example, patients were randomized to the on-
line pre-disclosure genetic education but instead received usual care). 
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There is no plan to perform interim outcome monitoring for this study. 
Participating patient will be at minimal risk given the nature of the 
study. The study will be closely monitored for feasibility (Section 
7.1.4), and if feasible, information/data gathered would be useful and 
informative in patient care. 
7.1.3 
Exploratory analysis will be longitudinal changes in cognitive (e.g. 
genetic knowledge), affective (cancer specific distress, state anxiety, 
general anxiety and general depression, perceived utility, uncertainty). 
In these analyses, multiple linear or logistic regressions will be fit to 
investigate temporal changes in the randomization arm effect, using 
the Generalized Estimating Equations (GEE) to account for correlated 
data over time. Unstructured working correlation matrices for GEE will 
first be considered unless there are model convergence problems, in 
which case exchangeable working correlation matrices will be used 
instead. In the regressions, survey wave and the randomized arm will 
be included as dummy indicator (0/1 variables) covariates. As there 
are four survey time points, we include three dummy indicators for T1, 
T2 and T3. In analyzing the change of scores (T1-T0, T2-T0, T3-T0), 
two dummy indicators will be needed. We will also include interactions 
between the survey wave indicators and the arm indicator to see if the 
arm effect changes over time. We will also include potential baseline 
confounding variables that were not balanced between arms at a p-
value < 0.1 (using T-Tests and Fisher’s Exact Tests). These analyses 
will be repeated using the as-treated approach as well. 
To evaluate potential moderators as described in Section 2, we will 
add relevant interaction terms to the GEE-estimated multiple linear 
and logistic regressions described above. Of most interest are 
interactions between the potential moderators (e.g. test result, 
sociodemographic factors, health literacy, baseline knowledge or 
distress) and the arm indicator. 
Other exploratory endpoints include satisfaction and 
regret/disappointment related to tumor genetic test results, and how to 
better deliver tumor genetic test results and germline information in 
the future. Summary statistics will be provided and comparison may 
be explored between arms using T-Tests or Fisher’s Exact Tests at 
two-sided significance level of 0.05. 
7.1.4 
Feasibility 
Monitoring enrollment on the primary study: 
Accrual will be closely monitored after the addendum expanding 
eligibility criteria activates, A formal evaluation will start at 6 months 
after the addendum expanding eligibility criteria activates, allowing 
some time for the select sites to get ready for enrolling patients. If the 
rate of enrollment on Step 1 of EAQ152 is < 5 patients per month, the 
data will be discussed with the study team and the NCI to reevaluate 
the feasibility of the study. 
Monitoring rate of compliance and questionnaire response: 
Primary analysis will be based on randomized arms. Patients who 
have survey data at T0, and at least one of the follow-up timepoints 
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(T1 or T2), will be considered as evaluable. Among the first 100 
patients who are enrolled on Step 1 for the primary study, if proportion 
of evaluable patients is < 60%, the data will be discussed with the 
study team and the NCI to re-assess the feasibility. Proportion of 
patients who cross-over, and proportion of the patients on Arm A who 
complete the web-based education, will also be reported. 
7.2 
Secondary Germline Genetic Testing & Counseling Substudy (Step 2 – Arm D 
and Arm E) 
7.2.1 
The primary endpoints for the substudy will be uptake of remote 
genetic counseling and uptake of clinical germline testing. 
This substudy will be exploratory in nature. We will evaluate, 
separately, the proportion of individuals who complete a) remote 
genetic counseling and b) germline testing, among patients (whose 
hospital sites open accrual to COMET Step 2) with a potential 
clinically significant incidental germline mutation identified through 
MATCH or non-MATCH tumor profiling. The current COMET Step 2 
accrual rate through MATCH is 1-2 patients per month. The substudy 
will stop patient accrual either when the accrual goal of 100 patients is 
met or 4 months after the primary study is closed to accrual (allowing 
the tumor profiling results to be returned back to the sites and so any 
remaining qualifying patients can be enrolled into the substudy), 
whichever is earlier. 
7.2.2 
Analysis Plan 
The proportions of individual uptake of remote genetic counseling and 
uptake of clinical germline testing will be calculated separately, along 
with the 95% confidence intervals. 
Changes in knowledge and distress (state anxiety, general anxiety, 
general depression and cancer specific distress) from baseline to 
post-pre-test genetic counseling (T0SS to T1SS) and baseline to post-
test for those who proceed with confirmatory genetic testing (T0SS to 
T2SS) will be described using descriptive statistics (e.g. means, 
standard deviations, proportions, 95% confidence intervals). Multiple 
linear regressions will be fit to further investigate temporal changes. 
Again, regression parameters will be estimated using GEE to account 
for correlated data over time. Unstructured working correlation 
matrices for GEE will be considered first unless there are model 
convergence problems, in which case exchangeable working 
correlation matrices will be used instead. In the regressions, survey 
wave as dummy indicator (0/1 variables) will be included as 
covariates. As there are three survey time points, we include two 
dummy indicators for T1 and T2 (leaving T0 as the baseline reference 
time period). We will also include potential baseline confounding 
variables in the models (e.g. age, sociodemographic variables). 
Other exploratory endpoints include communication to others, 
satisfaction and regret/disappointment related to genetic counseling 
service or germline genetic test results. Summary statistics will be 
provided. 
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7.3 
Gender and Ethnicity 
7.3.1 
Primary Study: Randomized Study of Web-based Pre-disclosure 
Genetic Education versus Usual Care (Step 1) 
Assuming the number of enrolled patients will be approximately 670, 
based on the past 2 years of accrual to ECOG-ACRIN coordinated 
therapeutic studies by any participating group, excluding leukemia 
and myeloma, the anticipated accrual in subgroups by gender and 
race is as follows: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic/Latino 
Hispanic/Latino 
Female 
Male 
Female 
Male 
American Indian or 
Alaskan Native 
2 
2 
0 
0 
4 
Asian  
15 
7 
0 
0 
22 
Native Hawaiian or other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
28 
25 
0 
0 
53 
White 
275 
291 
15 
10 
591 
Total 
320 
325 
15 
10 
670 
The accrual targets in individual cells are not large enough for 
definitive subgroup analyses. Therefore, overall accrual to the study 
will not be extended to meet individual subgroup accrual targets. 
7.3.2 
Secondary Germline Genetic Testing & Counseling Substudy (Step 2) 
Assuming the number of treated patients will be approximately 100, 
based on the past 2 years of accrual to ECOG-ACRIN coordinated 
therapeutic studies by any participating group, excluding leukemia 
and myeloma, the anticipated accrual in subgroups by gender and 
race is as follows: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic/Latino 
Hispanic/Latino 
Female 
Male 
Female 
Male 
American Indian or 
Alaskan Native 
0 
0 
0 
0 
0 
Asian  
2 
1 
0 
0 
3 
Native Hawaiian or other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
4 
0 
0 
8 
White 
42 
44 
2 
1 
89 
Total 
48 
49 
2 
1 
100 
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The accrual targets in individual cells are not large enough for 
definitive subgroup analyses. Therefore, overall accrual to the study 
will not be extended to meet individual subgroup accrual targets. 

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8. 
Electronic Data Capture 
Please refer to the EAQ152 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed in Medidata Rave (refer to Section 4.1.4.3) 
and the EASEE-PRO (refer to Section 4.1.4.4) system. Please refer to Section 5.4 for 
information on the PRO/QOL data collection process. 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
9. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
10. 
References 
1. 
Presidential Commission for the Study of Bioethical Issues. Anticipate and 
Communicate: Ethical Management of Incidental and Secondary Findings in the 
Clinical, Research and Direct-to-Consumer Contexts 2013, Washington, D.C. 
2. 
Lolkema MP, Gadellaa-van Hooijdonk CG, Bredenoord AL, et al. Ethical, legal, 
and counseling challenges surrounding the return of genetic results in oncology. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. May 20 2013;31(15):1842-1848. 
3. 
Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the 
tumor genome. JAMA : the journal of the American Medical Association. Aug 28 
2013;310(8):795-796. 
4. 
Catenacci DV, Amico AL, Nielsen SM, et al. Tumor genome analysis includes 
germline genome: are we ready for surprises? International journal of cancer. 
Journal international du cancer. Apr 1 2015;136(7):1559-1567. 
5. 
Tabor HK, Berkman BE, Hull SC, Bamshad MJ. Genomics really gets personal: 
how exome and whole genome sequencing challenge the ethical framework of 
human genetics research. American journal of medical genetics. Part A. Dec 
2011;155A(12):2916-2924. 
6. 
Tabor HK, Stock J, Brazg T, et al. Informed consent for whole genome 
sequencing: a qualitative analysis of participant expectations and perceptions of 
risks, benefits, and harms. American journal of medical genetics. Part A. Jun 
2012;158A(6):1310-1319. 
7. 
Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of 
incidental findings in clinical exome and genome sequencing. Genetics in 
medicine : official journal of the American College of Medical Genetics. Jul 
2013;15(7):565-574. 
8. 
Jarvik GP, Amendola LM, Berg JS, et al. Return of genomic results to research 
participants: the floor, the ceiling, and the choices in between. American journal 
of human genetics. Jun 5 2014;94(6):818-826. 
9. 
Burke W, Matheny Antommaria AH, Bennett R, et al. Recommendations for 
returning genomic incidental findings? We need to talk! Genetics in medicine : 
official journal of the American College of Medical Genetics. Aug 1 2013. 

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10. 
Wolf SM, Annas GJ, Elias S. Point-counterpoint. Patient autonomy and incidental 
findings in clinical genomics. Science. May 31 2013;340(6136):1049-1050. 
11. 
Hegde M, Bale S, Bayrak-Toydemir P, et al. Reporting incidental findings in 
genomic scale clinical sequencing--a clinical laboratory perspective: a report of 
the Association for Molecular Pathology. The Journal of molecular diagnostics : 
JMD. Mar 2015;17(2):107-117. 
12. 
Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians' 
attitudes about multiplex tumor genomic testing. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. May 1 
2014;32(13):1317-1323. 
13. 
Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks JC. 
Attitudes of patients with cancer about personalized medicine and somatic 
genetic testing. Journal of oncology practice / American Society of Clinical 
Oncology. Nov 2012;8(6):329-335, 322 p following 335. 
14. 
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COMET - Communication and Education in Tumor Profiling 
Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] __________________________________________________ [DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME]